Nutraceuticals in Brain Health and Beyond [1° ed.] 0128205938, 9780128205938

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Nutraceuticals in Brain Health and Beyond

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Nutraceuticals in Brain Health and Beyond

Edited by Dilip Ghosh Nutriconnect Sydney, NSW, Australia

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2021 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www. elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library ISBN: 978-0-12-820593-8 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

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Contents Contributors

1. Introduction

xi 1

Dilip Ghosh References

2. Role of food or food component in brain health

2

3

Dilip Ghosh Introduction Energy status and brain health Neuroactive in foods Omega-3 and phytochemicals: potential future therapeutic candidates Cognition beyond foods: just diet or lifestyle pattern? Food “liking” versus food “wanting” Diet, aging, and neurodegenerative diseases Diet, cognition, and epigenetics Microbiota-targeted functional foods for brain health Thinking outside the brain Conclusion References

3. Bacopa monnieri for cognitive healthda review of molecular mechanisms of action

3 4 4 6 8 8 8 9 9 11 11 11

15

Divya Purusothaman, Nehru Sai Suresh Chalichem, Bharathi Bethapudi, Sasikumar Murugan and Deepak Mundkinajeddu Cognition Approved drugs as cognition enhancers Nutraceuticals for cognitive performance Bacopa monnieri for cognitive performance Neuronal molecular mechanisms of cognitive benefits of BM in relation to signal transduction Summary References

15 18 18 19

19 24 24

4. Indian medicinal plants as drug leads in neurodegenerative disorders

31

Rohit Sharma, Neha Garg, Deepanshu Verma, Preeti Rathi, Vineet Sharma, Kamil Kuca and Pradeep Kumar Prajapati Abbreviations Introduction Methodology Etiopathology of neurodegenerative disorders Ayurvedic herbs: traditional usages in brain disorders Role of Indian ayurvedic herbs in neurodegenerative brain disorders Conclusion Acknowledgments References

5. Role of nutraceuticals in the management of severe traumatic brain injury

31 31 32 32 32 32 42 44 44

47

Ramesh Teegala Introduction Traumatic brain injury Nutritional management in TBI Herbs and traditional medicines Conclusions References

6. Understanding the relationship between oxidative stress and cognition in the elderly: targets for nutraceutical interventions

47 47 50 52 52 53

57

Naomi Perry, Laura Martin, Frank Rosenfeldt, Ruchong Ou, Renee Rowsell and Con Stough The aging population What is cognitive aging? What are the biological factors influencing cognitive aging? Oxidative stress Oxidative stress and cognition

57 58 58 59 61 v

vi

Contents

Potential nutraceutical targets for improving cognition via reducing oxidative stress Coenzyme Q10 Pycnogenol Vitamins E and C Carotenoids Polyphenols Conclusions References

7. Brain and mental health in Ayurveda

63 63 64 66 67 70 74 74 81

Chandra Kant Katiyar, Satyajyoti Kanjilal and Avinash Narwaria Ayurvedic principles of brain health 81 Brain diseases in Ayurveda - Manas roga 84 Ayurvedic drugs used in management of brain 86 disorders Ayurvedic herbs in brain health- medhya 86 rasayan herbs Acknowledgments 110 References 110

8. 10 Persian herbal medicines used for brain health

113

Zahra Ayati, Seyed Ahmad Emami, Gilles J. Guillemin, Diana Karamacoska and Dennis Chang Introduction 113 Herbal medicines for brain health 113 Polyherbal formulations and synergistic effects 120 Conclusion 120 References 120

9. Beneficial effects of nutraceuticals in healthy brain aging

125

Preeticia Dkhar and Ramesh Sharma Introduction Brain aging and associated neurodegenerative diseases Conclusion Acknowledgments References

10. Investigating the acute effect of pomegranate extract on indicators of cognitive function in human volunteers: a double-blind placebo-controlled crossover trial

125 126 134 134 134

11. Glucosinolates: paradoxically beneficial in fighting both brain cell death and cancer

141

141 141

151 151 151 154

155

Zeenat Ladak, Mostafa Khairy, Edward A. Armstrong and Jerome Y. Yager Introduction Background and significance Signaling apoptosis through the extrinsic pathway Redox signaling Effect on HDAC enzymes ERK pathway Activation of tumor suppressor genes: p53, p21, p27, and p73 Endoplasmic reticulum (ER) stress The effect on cancer stem cells The effect on SMYD3 genes NrF2-ARE signaling pathway AMPK and SFA toxicity and protection Conclusion Acknowledgments References

12. Efficacy of dietary polyphenols for neuroprotective effects and cognitive improvements

155 156 163 163 163 164 164 164 164 164 165 165 165 165 165

169

Divya Chandradhara, Augustine Amalraj and Sreeraj Gopi Introduction Neuroprotective effects of curcumin Neuroprotective effects of resveratrol Neuroprotective effects of EGCG isolated from green tea Application of other polyphenolic compounds in human central nervous system functions Conclusion References

13. The gut microbiotaebrain axis and role of probiotics

Angela V.E. Stockton, Andrea Zangara and Emad A.S. Al-Dujaili List of abbreviations Introduction

Potential mechanisms Conclusions References Further reading

169 170 170 171

171 172 172

175

Ruby Sound Introduction Gut microbiota Gut microbiome and the gut-brain axis Impact of gut microbiota on CNS Gut microbiotaebrain communication

175 176 176 177 178

Contents

How does gut microbiota affect the brain? Microbiota-gut-brain axis and depression Microbiota-gut-brain axis and autism Prebiotics and probiotics Conclusion References

14. The gut microbiome: its role in brain health

180 181 181 184 187 187

193

Christine A. Houghton Introduction The human gut microbiomeda new frontier in medicine The GI tract and its microbiome as an ecosystem Shifting the therapeutic emphasis from the probiotic toward the host How intestinal microbes communicate with the host Other biochemical influences on neural function in the gut-brain axis Nutrition-specific requirements of the host and its microbiota How does nature maintain the gut-microbiome-brain axis? Therapeutic interventions Conclusion References

15. The psychopharmacology of saffron, a plant with putative antidepressant and neuroprotective properties

193

227

Kaustubh S. Chaudhari Introduction Alzheimer’s disease Nutraceuticals in AD Bacopa monnieri Fundamental and clinical research in B. Monnieri in AD Bacopa monnieri clinical practice Conclusions References

227 228 232 233 240 243 245 246

194 196

17. Nutraceuticals in neurodegenerative diseases

197

Sharmistha Banerjee, Sayanta Dutta, Sumit Ghosh and Parames C. Sil

202

Introduction Alzheimer disease Huntington disease Parkinson disease Amyotrophic lateral sclerosis Conclusion References

204 205 206 207 207 208

213

DezsT Csupor, Barbara To´th, Javad Mottaghipisheh, Andrea Zangara and Emad A.S. Al-Dujaili Introduction Traditional and ethnomedicinal uses Chemical constituents Stigma Flowers except stigma Tepal Stamen Mode of action Clinical applications Conclusions References

16. Comprehensive review of Alzheimer’s disease drugs (conventional, newer, and plant-derived) with focus on Bacopa monnieri

vii

213 213 214 214 214 215 215 216 217 222 222

18. Transforming curry extract-spice to liposome-based curcumin: lipocurc to restore and boost brain health in COVID-19 syndrome

249

249 251 254 256 259 261 262

271

Simon S. Chiu, Kristen Terpstra, Michel Woodbury-Farina, Vladimir Badmaev, Josh Varghese, Hana Raheb, Ed Lui, Zack Cernovsky, Yves Bureau, Mariwan Husni, John Copen, Mujeeb Shad, Autumn Carriere, Zahra Khazaeipool, Weam Sieffien, Marina Henein, Brendan Casola and Siddhansh Shrivastava COVID-19 pandemic Curcumin pharmacology and COVID-19 Nanotechnology, epigenetics, and PK studies of liposome-curcumin COVID-19 brain rehabilitation: role of epigenetics diet and exercise Summary References

271 272 274 276 278 278

viii

Contents

19. Cognitive health and nutrition: a millennial correlation

281

Arun Balakrishnan, Muralidhara Padigaru and Abhijeet Morde Molecular signaling of energy metabolism and synaptic plasticity Oxidative damage and cognition Nutrition and neurotransmitters Nutrition and brain well-being Correlation between metabolic diseases and psychiatric conditions Diet and cognitive health Cognitive enhancers Active sports and cognitive performance: role of nutritional supplements Diet and epigenetics Nutraceuticals as key drivers for brain health Future recommendations References

20. Mediterranean diet and its components: potential to optimize cognition across the lifespan

281 282 283 283 285 286 287 287 288 288 288 288

293

Sarah Gauci, Lauren M. Young, Helen Macpherson, David J. White, Sarah Benson, Andrew Pipingas and Andrew Scholey Diet, cognition, and dementia Assessment of Mediterranean diet Mediterranean diet and cognition across the lifespan Mechanisms and food components Olive oil Fish Nuts Fruits and vegetables Practical translation into Western countries References

21. Centella asiatica (Gotu kola) leaves: potential in neuropsychiatric conditions

293 293 294 300 301 301 301 302 302 303

307

Prasad Arvind Thakurdesai Introduction Psychological disorders

307 308

Cognitive disorders Neurological disorders Neurodegenerative and neuroinflammatory disorders Recent advance: nasal delivery of CA extract References

22. Big data for clinical trials

311 314 318 320 320 329

Nikhil Verma Introduction Role of big data in research Technology of big data Life cycle and management of data using technologies Approach of regulatory agencies Big healthcare data: security and privacy Big data ¼ big prospects References

23. The multifactorial contributions of Pycnogenol® ® for cognitive function improvement

329 329 330 331 331 332 332 333

335

Frank Schoenlau Introduction Pycnogenol® ® as a herbal medication Deteriorating cognitive function in the aging brain Mechanism of action of Pycnogenol® Pycnogenol® as a cognitive enhancer References

24. Advancements in delivery of herbal drugs for cognitive disorders

335 336 336 337 337 339

343

Nidhi Prakash Sapkal and Anwar Siraj Daud Introduction Herbal drugs in neurological health Factors limiting brain delivery of herbal products Advancements in the brain delivery technologies Industrial applicability of these novel technologies and commercial viability Regulatory challenges Conclusion References

343 344 344 348 351 351 352 352

Contents

25. Impact of cardiometabolic disease on cognitive function

357

28. Management of Alzheimer’s Disease with nutraceuticals 391

Bradley J. McEwen Introduction Cardiometabolic disease The impact of cardiometabolic disease on brain and cognitive health The effect of nutritional medicine on cardiometabolic disease and cognitive function Conclusion References

26. Vitamin B6, B9, and B-12: can these vitamins improve memory in Alzheimer’s disease?

Jay Kant Yadav

27. Sri Lankan medicinal herbs used for the management of neurodegenerative diseases of the brain

Introduction Alzheimer’s disease: the leading cause of dementia Understanding the origin of AD Social and economic impact Management and care of patients suffering with AD Treatment and care Nutraceuticals: an emerging trend in disease management Dietary components of nutraceuticals Conclusions References

357 358 358

361 364 365

369

29. Nutraceuticals in brain health

Rohit Ghosh Vitamin B6, B12, and folate Cognitive decline, dementia, and the homocysteine hypothesisdwhat is the evidence showing? Alzheimer’s disease and the effect of vitamin B6, folate, and B12 Clinical recommendations and application Conclusions References

Introduction to nutraceuticals Nutraceutical and overall brain health: Traditional versus modern outlook Mechanistic insights into nutraceuticals functioning as protectors of brain health Nutraceuticals from an evolutionary perspective Conclusion References

370 373 374 374 376

30. Ayurveda and Brain health

392 393 396 396 396 397 397 401 401 409

409 413 422 427 430 430 441

Bhushan Patwardhan and Hema Sharma Datta

379

Introduction - The brain and the nervous system Ayurvedic perspective of the nervous systemdMajja dhatu and Majjavaha srotas Brain patterns and Dosha type Brain agingdModern and Ayurvedic perspective Discussion and way forward References

379 379

382

383 387

391

Swati Haldar, Souvik Ghosh, Viney Kumar, Saakshi Saini, Debrupa Lahiri and Partha Roy

369

W.A.L. Chandrasiri Waliwita Introduction Neurodegenerative diseases of the brain Herbal medicines that could be recommended for the Neurodegenerative diseases of the brain Review on medicinal herbs used for the management of neurodegenerative diseases of the brain References

ix

Index

441 442 443 444 451 452

455

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Contributors Emad A.S. Al-Dujaili, Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom Augustine Amalraj, R&D Centre, Aurea Biolabs Pvt Ltd, Cochin, Kerala, India Edward A. Armstrong, University of Alberta, Department of Pediatrics, Division of Pediatric Neuroscience, Edmonton, AB, Canada Zahra Ayati, Department of Traditional Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; NICM Heath Research Institute, Western Sydney University, Westmead, NSW, Australia Vladimir Badmaev, Medical Holdings Inc, New York, NY, United States Arun Balakrishnan, R&D j OmniActive Health Technologies, Mumbai, Maharashtra, India Sharmistha Banerjee, Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India

Dennis Chang, NICM Heath Research Institute, Western Sydney University, Westmead, NSW, Australia Kaustubh S. Chaudhari, Department of Internal Medicine & Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States; Department of Kayachikitsa, Smt. K.G. Mittal Punarvasu Ayurvedic College, Mumbai, Maharashtra, India; Department of Samhita Siddhanta, Smt. K.G. Mittal Punarvasu Ayurvedic College, Mumbai, Maharashtra, India Simon S. Chiu, Lawson Health Research Institute, London, ON, Canada; Geriatric Mental Health Program, London Health Sciences Centre, London, ON, Canada; Department of Psychiatry, University of Western Ontario, London, ON, Canada John Copen, Department of Psychiatry, University of British Columbia, University of Victoria Medical Campus, Victoria, BC, Canada

Sarah Benson, Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC Australia

DezsT Csupor, Department of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary; Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary

Bharathi Bethapudi, Research and Development Center, Natural Remedies Private Limited, Bengaluru, Karnataka, India

Hema Sharma Datta, Interdisciplinary School of Health Sciences (ISHS), Savitribai Phule Pune University (SPPU), Pune, India

Yves Bureau, Department of Psychology, University of Western Ontario London ON, Lawson Health Research Institute, London, ON, Canada

Anwar Siraj Daud, Zim Laboratories Limited, Nagpur, Maharashtra, India

Autumn Carriere, Faculty Applied Sciences, Nipissing University, North Bay, ON, Canada Brendan Casola, University of Guelph, Guelph, ON, Canada

Preeticia Dkhar, Department of Biochemistry, North Eastern Hill University, Shillong, Meghalaya, India Sayanta Dutta, Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India

Zack Cernovsky, Department of Psychiatry, University of Western Ontario, London, ON, Canada

Seyed Ahmad Emami, Department of Traditional Pharmacy, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

Nehru Sai Suresh Chalichem, Research and Development Center, Natural Remedies Private Limited, Bengaluru, Karnataka, India

Neha Garg, Department of Medicinal Chemistry, Faculty of Ayurveda, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India

Divya Chandradhara, BioAgile Therapeutics Pvt Ltd, Bangalore, Karnataka, India

Sarah Gauci, Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC Australia

xi

xii Contributors

Dilip Ghosh, Nutriconnect, Sydney, NSW, Australia Rohit Ghosh, Nutriconnect, Sydney, NSW, Australia Souvik Ghosh, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India Sumit Ghosh, Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India Sreeraj Gopi, R&D Centre, Aurea Biolabs Pvt Ltd, Cochin, Kerala, India Gilles J. Guillemin, Department of Biomedical Sciences, Biomolecular Discovery and Design Research Centre, Macquarie University Centre for Motor Neuron Disease Research, NSW, Sydney, Australia Swati Haldar, Centre of Nanotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India Marina Henein, National University of Ireland Galway, Research Institution in Galway, Galway, Ireland Christine A. Houghton, University of Queensland, St Lucia, QLD, Australia; Cell-Logic, Brisbane, QLD, Australia; 3X4 Genetics, Seattle, A, United States Mariwan Husni, Department of Psychiatry, Northern Ontario Medical School, Thunderbay, ON, Canada Satyajyoti Kanjilal, Emami Limited, Research and Development Centre, Kolkata, West Bengal, India

Ed Lui, Department of Pharmacology, Schulich School of Medicine, University Western Ontario, London, ON, Canada Helen Macpherson, Institute for Physical Activity and Nutrition, Deakin University, Geelong, VIC Australia Laura Martin, Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, Australia Bradley J. McEwen, School of Health and Human Sciences, Southern Cross University, Lismore, NSW, Australia Abhijeet Morde, R&D j OmniActive Health Technologies, Mumbai, Maharashtra, India Javad Mottaghipisheh, Department of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary Deepak Mundkinajeddu, Research and Development Center, Natural Remedies Private Limited, Bengaluru, Karnataka, India Sasikumar Murugan, Research and Development Center, Natural Remedies Private Limited, Bengaluru, Karnataka, India Avinash Narwaria, Emami Limited, Research and Development Centre, Kolkata, West Bengal, India

Diana Karamacoska, NICM Heath Research Institute, Western Sydney University, Westmead, NSW, Australia

Ruchong Ou, Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, Australia

Chandra Kant Katiyar, Emami Limited, Research and Development Centre, Kolkata, West Bengal, India

Muralidhara Padigaru, R&D j OmniActive Health Technologies, Mumbai, Maharashtra, India

Mostafa Khairy, University of Alberta, Department of Pediatrics, Division of Pediatric Neuroscience, Edmonton, AB, Canada

Bhushan Patwardhan, Interdisciplinary School of Health Sciences (ISHS), Savitribai Phule Pune University (SPPU), Pune, India

Zahra Khazaeipool, University of Western Ontario, London, ON, Canada

Naomi Perry, Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, Australia

Kamil Kuca, Department of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové, Czech Republic

Andrew Pipingas, Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC Australia

Viney Kumar, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India

Pradeep Kumar Prajapati, Department of Rasa Shastra and Bhaishajya Kalpana, All India Institute of Ayurveda, Delhi, New Delhi, India

Zeenat Ladak, University of Alberta, Department of Pediatrics, Division of Pediatric Neuroscience, Edmonton, AB, Canada

Divya Purusothaman, Research and Development Center, Natural Remedies Private Limited, Bengaluru, Karnataka, India

Debrupa Lahiri, Centre of Nanotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India; Department of Metallurgical and Materials Engineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India

Hana Raheb, Lawson Health Research Institute, London, ON, Canada Preeti Rathi, School of Basic Sciences, IIT Mandi, Mandi, Himachal Pradesh, India

Contributors

xiii

Frank Rosenfeldt, Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, Australia

Ramesh Teegala, Department of Neurosurgery, Anu Institute of Neuro & Cardiac Sciences, Vijayawada, Andhra Pradesh, India

Renee Rowsell, Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, Australia

Kristen Terpstra, Neurological Unit, St Michel’s Hospital Affliliated with University Toronto, Toronto, ON, Canada

Partha Roy, Centre of Nanotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India; Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India

Prasad Arvind Thakurdesai, Indus Biotech Private Limited, Pune, Maharashtra, India

Saakshi Saini, Department of Biotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India Nidhi Prakash Sapkal, Department of Pharmaceutical Chemistry, Gurunanak College of Pharmacy, Nagpur, Maharashtra, India; Zim Laboratories Limited, Nagpur, Maharashtra, India Frank Schoenlau, Horphag Research (Europe) LTD, Limassol, Cyprus

Barbara Tóth, Department of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary; Institute for Translational Medicine, Medical School, University of Pécs, Pécs, Hungary Josh Varghese, Marian University College of Osteopathic Medicine, Indianapolis, IN, United States Deepanshu Verma, School of Basic Sciences, IIT Mandi, Mandi, Himachal Pradesh, India Nikhil Verma, THINQ Pharma-CRO Ltd., Mumbai, Maharashtra, India

Mujeeb Shad, Department of Psychiatry, Oregon Health Sciences University, Portland, OR, United States

W.A.L. Chandrasiri Waliwita, Department of Cikitsa (Ayurveda Medicine), Gampaha Wickramarachchi Ayurveda Institute, University of Kelaniya, Yakkala, Heath Care Research Foundation and Ayurveda College of Physicians, Yakkala, Western Province, Sri Lanka

Ramesh Sharma, Department of Biochemistry, North Eastern Hill University, Shillong, Meghalaya, India

David J. White, Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC Australia

Rohit Sharma, Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India

Michel Woodbury-Farina, Department of Psychiatry, School of Medicine, University of Puerto Rico, PR, United States

Vineet Sharma, Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India

Jay Kant Yadav, Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Ajmer, Rajasthan, India

Siddhansh Shrivastava, Avalon University School of Medicine, Sta. Rosaweg 122-124 WIllemstad, Curacao, Girard, OH, United States

Jerome Y. Yager, University of Alberta, Department of Pediatrics, Division of Pediatric Neuroscience, Edmonton, AB, Canada

Weam Sieffien, University of Toronto Faculty of Medicine, Toronto, ON, Canada

Lauren M. Young, Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC Australia

Parames C. Sil, Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India

Andrea Zangara, Euromed S.A., Barcelona, Spain; Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC, Australia

Andrew Scholey, Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC Australia

Ruby Sound, Eatwise Nutrition and Wellness Clinic, Mumbai, Maharashtra, India Angela V.E. Stockton, Dietetics, Nutrition and Biological Sciences, Queen Margaret University, Edinburgh, United Kingdom Con Stough, Centre for Human Psychopharmacology, Swinburne University of Technology, Melbourne, Australia

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Chapter 1

Introduction Dilip Ghosh Nutriconnect, Sydney, NSW, Australia

Chapter outline References

2

The brain is a complex organ that neuroscientists are still attempting to understand. This is unique because of its high metabolism and high turnover of nutrients, and this makes it a high-maintenance device in terms of optimal nutrient intake. Moreover, the brain is highly prone to oxidative stress owing to high fatty acid content (especially polyunsaturated fatty acids, which contribute to 10% of total dry brain weight), high oxygen consumption and redox signaling (about 20% basal oxygen for ATP production), low antioxidant content with higher neurotransmitter autooxidation [2]. Due to the multifactorial nature, the role of nutrition and nutritional products in cognitive neuroscience is complex. The concern is not simply with the impact of a single chemical on the brain but with multiple nutrients, metabolites, and interacting factors. In addition, a myriad of nutrient-specific transport systems and physiological mechanisms add more complexities in the nutrient-gutbrain interaction. As people live longer, dysfunction of the brain is becoming a predominant issue for the healthcare system. Cognitive decline, particularly in elderly people, often derives from the interaction between age-related changes and age-related diseases, and covers a wide spectrum of clinical manifestations, from intact cognition through mild cognitive impairment and dementia. Chang et al. [1] classified 92 diseases as age related, meaning that the incidence rate of each disease increased quadratically with age. The disability-adjusted life-years (DALYs) from each disease among adults are used to calculate the age-related disease burden. Burden varied between countries, being lowest in Switzerland (104$9 DALYs per 1000 adults) and Singapore (108$3 DALYs) and highest in Papua New Guinea (506$6 DALYs) and

Nutraceuticals in Brain Health and Beyond. https://doi.org/10.1016/B978-0-12-820593-8.00001-X Copyright © 2021 Elsevier Inc. All rights reserved.

Afghanistan (380$2 DALYs), with low socio-demographic index. The effect is quite pronounced for age groups 60e64 and above. By 2050, the 85-year-old and above population in the United States will triple [3]. Other than cardiovascular diseases and cancer, brain-related disorders such as psychological and cognitive health-associated disorders, dementia-related neurodegenerative diseases, and depression are the leading causes of ill-health in the older population. Older people make up a considerable proportion of Australia’s populationdin 2017, over one in seven people were aged 65 and over. The increase in costs due to the 85þ age group ($2.9 billion) represents some 23% of the total increase in costs ($12.5 billion) but only about 8% of the total projected health costs ($35 billion). Age-related changes in cognitive function vary considerably across individuals and lifecycle stages, with some cognitive functions appearing to be more susceptible than others to the effects of aging. The brain undergoes tremendous age-associated structural and functional changes as we age. Like age-related changes in brain structure and function, age-related changes in cognition are not uniform across all cognitive domains, or across all older individuals. The basic cognitive functions most affected by age are attention and memory. Older adults show significant impairments in attention tasks, particularly on multitasking platforms. General knowledge, vocabulary, and verbal ability do not significantly decline throughout the lifecycle. In this book Nutraceuticals in Brain Health and beyond, the editor brings together contributions from experts in nutraceutical research to provide a contemporary overview of how evidence-based nutraceuticals can

1

2 Nutraceuticals in Brain Health and Beyond

beneficially affect brain function at the molecular and clinical level. When we are talking about brain health, mostly we are focusing on cognition and memory. But there are many complex brain disorders beyond cognition and memory. From the perspective of prehistoric medicine in the ancient world, plants have been used in the treatment of medical conditions throughout human history. Historically, all these terms, apothecary, herbalism, ethnopharmacology, phytotherapy, and alternative medicine, are linked to modern nutraceuticals. Nutraceutical-related research of molecular and clinical actions follows from the concept that traditional medicines or tribal practices offer neuroactive agents that cure brain-related diseases or disorders. The goal then is to elucidate how these neuroactive molecules from these sources might make the brain healthier and, in this book, we have several exciting basic studies that represent the prototype of how this field needs to evolve. The neuroscience in the 21st century has shown tremendous growth, particularly in the identification of targets that provide therapeutic benefit in degenerative conditions, and neurodevelopmental, psychological, and psychiatric disorders through many randomized clinical trials. Since many natural products used in traditional medicine have long been known to exert beneficial actions on diverse brain functions and often the active principles have been identified, the prospect of future success in the field of neuro(nutra)ceuticals continues to capture the imagination of many neuroscientists and is also entering the developmental drug pipeline [4]. This book presents the state-of-the-art scientific evidence, challenges, and potential applications within this exciting field, by providing insight into the treasures of Ayurvedic, Persian, and Western traditional medicines to treat neurodegenerative, neurodevelopmental, psychological,

and psychiatric disorders of brain. Few important and upcoming issues such as brain epigenetics, gut-microbe-brain axis, and intelligent drug delivery mechanism are also discussed by eminent scientists. How “Big Data” is impacting clinical research is also discussed here. Well publicized and controversial role of vitamin B-6, B-9, and B-12 in Alzheimers disease is also discussed. The exciting fields of cardiometabolic impact on cognitive health and role of oxidative stress-antioxidant in elderly are also presented here. I believe our readers in the community, students, researchers, and industry R&D use the information, techniques, and insights of the book to support application of this research and teaching. It is also my belief that this book be used to promote a collaborative understanding of the field between industry and academia. More broadly, however, I hope that this book is accessible to nonspecialist readers, and so can also be utilized by those in the community with keen interest in understanding this research to learn more about (neuro)nutrients and dietary patterns which may provide cognitive protection or benefit, particularly to elderly people.

References [1] Chang AY, Skirbekk VF, Tyrovoras S, Kassebaum NJ, Dielman JL. Measuring population ageing: an analysis of the global burden of disease study. Lancet Public Health 2019;4:e159e67. [2] Cobley JN, Fiorello ML, Bailey DM. 13 reasons why the brain is susceptible to oxidative stress. Redox biol 2018;15:490e503. [3] Jaul E, Barron J. Age-related diseases and clinical and public health implications for the 85 years old and over population. Front Public Health 2017;5:335. https://doi.org/10.3389/fpubh.2017.00335. [4] Williams RJ, Mohanakumar KP, Beart PM. Neuro-nutraceuticals: further insights into their promise for brain health. Neurochem Int 2016;95:1e3.

Chapter 2

Role of food or food component in brain health Dilip Ghosh Nutriconnect, Sydney, NSW, Australia

Chapter outline Introduction Energy status and brain health Neuroactive in foods Omega-3 and phytochemicals: potential future therapeutic candidates Cognition beyond foods: just diet or lifestyle pattern? Food “liking” versus food “wanting”

3 4 4 6 8 8

Introduction With magnificent advancement in medical science over the last century, human life span has also increased significantly. However, with this advancement comes another potential challenge particularly, the people aged 70 years and more are become increasingly susceptible to chronic and extremely debilitating brain diseases, most notably Alzheimer’s and Parkinson’s disease. There is growing concern that many existing drug treatments for neurodegenerative disorders are unable to prevent the underlying degeneration of neurons and consequently there is a strong market pull to develop alternative therapies capable of preventing progressive neurodegeneration. Conventional use of antioxidant therapies to combat neuronal damage is well accepted, but exploration of neuroprotective effects of a group of plant secondary metabolites known as flavonoids and other natural products is increasing. The potential beneficial effects of specific polyunsaturated fatty acids (PUFAs) have also been explored more than before. Increasing aging population and subsequent cognitive disability have now emerged

Nutraceuticals in Brain Health and Beyond. https://doi.org/10.1016/B978-0-12-820593-8.00002-1 Copyright © 2021 Elsevier Inc. All rights reserved.

Diet, aging, and neurodegenerative diseases Diet, cognition, and epigenetics Microbiota-targeted functional foods for brain health Thinking outside the brain Conclusion References

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as one of the greatest health threats globally. There is a common consumer belief that neurological diseases such as dementia, Alzheimer’s and Parkinson’s might be prevented or treated through personalized dietary intervention. However, there is limited evidence that such approaches are effective, and they might even be harmful in some cases. Nutrition plays a central role in hypotheses about human evolution, particularly the emergence of large-brained, anatomically modern Homo sapiens in Africa w200 ka. Encephalization, increase in brain size that characterizes the human species, is supposed to be linked with the availability of food resources rich in energy as well as trace elements and fatty acids collectively referred to as brainselective nutrients [1]. Neurodiversity has become a popular topic not only in medical science but also in business. The overlapping Venn diagram (Fig. 2.1, courtesy Dr. Nancy Doyle based on the work of Mary Colley) pictured shows how different conditions are often related and need to be explored for truly understanding the benefits of cognitive difference between people. We are all aware about the recent controversies of the relationship of vitamin B with dementia [2] and vitamin D

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4 Nutraceuticals in Brain Health and Beyond

Dyscalculia Verbal skills Innovative thinking

DCD/ Dyspraxia

Verbal skills

Creativity

Dyslexia Visual thinking Creativity 3D mechanical skills

Verbal Skills Empathy Intuition Honesty

Authenticity

ASC

ADHD

Autism Spectrum Condition

Concentration Fine detail processing Memory

Neurodiversity

Sensory Awareness

Creativity Hyper-focus Energy and passion Hyperfocus

Mental Health Depth of thinking Expression

Attention Deficit Hyperactivity Disorder

Tourette Syndrome Resilience

Innovative thinking

Observational skills Cognitive control Creativity

Acquired Neurodiversity Adaptability Empathy

FIGURE 2.1 Neurodiversity shows how interrelated conditions need to be explored for understanding the benefits of cognitive difference between people.

insufficiency in patients with Parkinson’s disease (PD) [3]. Indeed, there is convincing evidence that nutrients are essential for human health and physiological functioning. The human body cannot synthesize certain nutrients internally (not at all or not in sufficient amount) and they need to be complemented from food [4]. Particularly the brain with a high metabolism and high turnover of nutrients requires optimal nutrient intake.

Energy status and brain health Brain health has been defined as, “a state of well-being in which the person can realize their potential, cope with normal stresses of life, work productively and fruitfully and contribute to the community.” In addition to cultural, economic, social, and environmental factors, energy status has been identified as holding a critical role in brain health and well-being. The term energy status mentioned here includes energy intake, physical activity, and energy metabolism. Considerable evidence links physical activity and optimal energy intake with improved mood and cognitive function, while both underweight and obesity are associated with impaired cognitive performance. Suboptimal energy status, including undernutrition and overnutrition, is linked with mental and neurological disorders such as depression, schizophrenia, dementia, and Alzheimer’s disease (AD).

Individual differences in genetic variability are related to the incidence of these disorders. Rather than considering an individual as having high or low energy status, the focus is on optimal compared with suboptimal energy status.

Neuroactive in foods A neuroactive substance is defined as a chemical agent synthesized by a neuron, which affects the properties of other neurons and muscle cells. Many neuroactive compounds have significant roles as neurotransmitters, neuromodulators, and neurohormones [5]. These compounds have been not only synthesized by humans but also plants and microorganisms [6]. Therefore, the presence of neuroactive compounds in foods is inevitable. Most common neuroactive compounds in foods are gammaaminobutyric acid (GABA), serotonin, melatonin, kynurenine, kynurenic acid, dopamine, norepinephrine, histamine, tryptamine, tyramine, and b-phenylethylamine. Fermented foods contain some of these compounds, which can affect human health and mood [7,8]. Neuroactive compounds present in certain raw and nonfermented foods are given in Table 2.1. Health effects of neuroactive compounds consumed with foods have no definite mechanism. Potential positive and negative health effects of neuroactive compounds are summarized in Table 2.2.

Role of food or food component in brain health Chapter | 2

TABLE 2.1 Presence of neuroactive compounds in certain nonfermented foods.

TABLE 2.1 Presence of neuroactive compounds in certain nonfermented foods.dcont’d

Compound

Food

Concentration (mg/g)

Compound

Food

Concentration (mg/g)

Serotonin

Tomato

221.9

Histamine

Spinach

27.2

Spinach

34.4

Green coffee

212e793

Banana

11.5

Fish

0.1e41.1

Kiwi

9.5

Salami

8.54

Pecan

13.6

Tomato

147.1

Walnut

155

Strawberry

57.0

Chocolate

6.1

Paprika

6.8

Green coffee

1800e3200

Lettuce

24.5

Orange

1.96

Spinach

6.5

Banana

6.4

Chocolate

2.67

Chocolate

18.6

Fish

0.2e2.4

Banana

6.07

Salami

3.2

Pineapple

0.86

Dopamine

Norepinephrine

Kynurenic acid

Melatonin

GABA

Tryptamine

b-phenylethylamine

Fish

0.1e2.9

Potato

0.13

Cumin seed

0.6

Basil

14.1

Thyme

8.9

Chestnut honey

129e601

Tart cherry

0.0021e0.0135

Pistachio

226e233

Wheat

0.1

Infant formula

0.4e8.2

Cow milk

0.000024

Green coffee

0.00004

Sesame

90.7

Wheat germ

1000

Yellow soybean

120

Black soybean

370

Mung bean

132

Wheat bran

200

Spinach

42.7

White tea

240e2070

Oolong tea

90e970

Chocolate

111e325 Continued

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Adapted and modified from Yılmaz C, Go¨kmen V. Neuroactive compounds in foods: occurrence, mechanism and potential health effects. Food Res Int 2020;128:108744.

It is now established that the composition of diet is significant for gut microbiota profile. There are a number of functional networks in the brain related to different mind states and mood, such as depression and anxiety, sleep, wakefulness, arousal, perception of pain, etc. Neuronal signaling is mediated by the release of neurotransmitters (NTs) at synapses between axons and dendrites. There are many types of NTs and other signaling substances in the brain: amino acids (glutamate, g-aminobutyric acid (GABA), glycine), catecholamines (dopamine, norepinephrine), monoamines (serotonin, acetylcholine ACh), biogenic amines (histamine, tryptamine, tyramine, etc.), a number of peptides, purines such as adenosine as well as nitric oxide (NO) [9,10]. The delicate balance between synthesis, uptake, and regeneration of NTs can easily be disturbed, and this is one of the main targets when treating neuropsychiatric disorders. Many dietary components can affect the amount and effect of NTs [11]. The amino acid tryptophan is the precursor of serotonin, and dietary supply of tryptophan can influence serotonin levels in the brain [12]. The amino acid tyrosine is the precursor of the NTs dopamine and norepinephrine, and its supplementation seems to enhance cognitive performance, particularly in stressful situations [13]. The biogenic amines, histamine and tyramine, present in stored or fermented foods, are considered as active NTs in the brain [14,15]. There are more reports about the effects of carbohydrates, proteins,

6 Nutraceuticals in Brain Health and Beyond

TABLE 2.2 Potential positive and negative health effects of neuroactive compounds. Neuroactive compounds

Health effects

GABA

Reducing psycological and physical fatigue and stress Reducing sleep latency and increasing total nonrapid eye movement sleep time Blood pressure regulation

Melatonin

Protection from oxidative stress Decreasing blood pressure Reducing jet lag and sleep problems Decreasing glucose tolerance and insulin sensitivity

Kynurenic acid

Reducing oxidative stress

Histamine

Managing hypotension, flushing, headache, abdominal cramps, diarrhea, and vomiting

Tryptamine b-phenylethylamine

Managing hypertension, headaches, vomiting, and perspiration

L-Dopa

Increasing dopamine concentrations in treatment of Parkinson’s disease

5-Hydroxytryptophan

Antidepressant effect

Adapted and modified from Yılmaz C, Go¨kmen V. Neuroactive compounds in foods: occurrence, mechanism and potential health effects. Food Res Int 2020;128:108744.

and polyphenols on the composition of the gut microbiota. Synthesis of neuroactive compounds can be affected by diet in three ways: 1. Firstly, since amino acids are precursors of neuroactive compounds, proteins or peptides, in the diet which reach the colon, it can lead to the formation of neuroactive compounds by gut microbiota. 2. Secondly, some metabolites (short-chain fatty acids, etc.) formed because of fermentation of carbohydrates and proteins in the gut can trigger the synthesis of neurotransmitters in the human gut. 3. Thirdly, carbohydrates, proteins, lipids, and polyphenols can alter the composition and count of microorganisms which have the ability to produce neuroactive compounds.

Omega-3 and phytochemicals: potential future therapeutic candidates The brain is one of the most metabolically active organs and, as such, utilizes a large proportion of the dietary intake of carbohydrates to function effectively. The dietary lipids, such as PUFAs, are also thought to play a much important role in supporting optimum brain function by maintaining the optimal function of cholinergic neurons arising from the basal forebrain and terminating in the cortex and hippocampus [16]. This information is leading the way to develop a strategy to prevent the cognitive decline that occurs during normal aging and in AD. The well-

characterized and demonstrated effects of both dietary phytochemicals and lipids on endothelial function and peripheral blood flow may also enter into the list of future candidate molecules for brain health. Phenolic compounds are secondary metabolites of plants and include flavonoids, lignans, stilbenes, coumarins, and tannins [17]. Please refer Table 2.3 for more information on food components that have ability to ameliorate brain function. Despite this list, components derived from Vitis vinifera (grape), Camellia sinensis (tea), Theobroma cacao (cocoa), and Vaccinium spp (blueberry) have demonstrated beneficial effects on human vascular function and on improving memory and learning. The PAQUID Study was one of the first epidemiological studies to suggest that flavonoids play a protective role against cognitive decline and AD [18,19,20]. More recent findings from the SU.VI.MAX studies confirm earlier results, showing an association between polyphenols intake and better performance in language and verbal memory tasks [21]. PUFAs could be involved in the maintenance of cognitive function and have a preventive effect against dementia through their antithrombotic and antiinflammatory properties, in addition to their specific effect on neural functions [22]. Indeed, DHA is a key component of membrane phospholipids in the brain, and adequate n-3 PUFA status may help maintain neuronal integrity and function via a range of potential mechanisms. DHA may modify the expression of genes that regulate a variety of biological functions potentially important for cognitive

Role of food or food component in brain health Chapter | 2

TABLE 2.3 Food components that ameliorate brain function. Components

Efficacy

Source

Omega-3 fatty acid (especially DHA)

Amelioration of cognitive decline in both human and animal models

Fish (salmon), flax seeds, krill, chia, kiwi Fruit, butternuts, walnuts

Bacopasides

Improves memory and cognitive function of all ages people, mostly from human trials

Indian Ayurvedic herb, Bacopa monniera

Curcumin

Amelioration of cognitive decay in neurodegenerative diseases, mostly in animal model

Turmeric (curry spice)

Flavonoids

Cognitive enhancement in both human and animal models

Cocoa, green tea, Ginkgo tree, citrus fruits, wine (higher in red wine), dark chocolate

B-vitamins

Supplementation with vitamin B6, vitamin B12, or folate has positive effects on human memory performance of various ages

Various natural sources. Vitamin B12 is not available from plant products

Vitamin D

Preserving cognition function in the elderly

Fish liver, fatty fish, mushrooms, fortified products, milk, soy milk, cereal grains

Vitamin E

Amelioration of cognitive impairment in brain injured rodents and also reduces cognitive decay in the elderly humans

Asparagus, avocado, nuts, peanuts, olives, redpalm oil, seeds, spinach, vegetable oils, wheat germ

Ginsenosides

Improves mental capacity and concentration

Ginseng herb, Panax ginseng

Ginkgolides, Bilobalide, and Flavonglycosides

Improves memory and concentration

Ginkgo biloba herb

Adapted from Gomez-Pinilla, F., Tyagi, E., Diet and cognition: interplay between cell metabolism and neuronal plasticity. Cur Opin Clin Nutr Metab Care 2013;16:726e733.

health, including neurogenesis and neuronal function [23]. Fatty fish is the primary dietary source of EPA and DHA, the longer-chain n-3 fatty acids. A growing body of evidence suggests that monounsaturated fatty acids (MUFA), and oleic acid may also have antiinflammatory effects [24]. Recent longitudinal studies support the hypothesis that MUFA may play a protective role toward the development of cognitive decline and dementia [25,26]. Table 2.4 demonstrated the associations of fish consumption with dementia risk to populations in low and middle-income countries. Kyriacou et al. [27] study confirmed that marine animals and, especially, intertidal shellfish indigenous to the region contain relatively large amounts of omega-6 and omega-3 PUFAs, as well as iron, copper, and zinc. The collection and consumption of abundant, accessible and reliable marine mollusks would have been beneficial to early modern humans visiting the Atlantic west coast, particularly in the case of pregnant and lactating mothers. The relatively high EPA and DHA content of intertidal mussels and limpets suggests that small

TABLE 2.4 Association between prevalent dementia and dietary fish consumption. Country

Prevalence ratio (95% CI)

Weekly fish intakesomeday (n %)

Cuba

0.81

80

Dominic Republic

0.80

57.9

Peru

0.76

73.3

Venezuela

0.87

45.0

Mexico

0.81

66.5

China

0.58

67.9

Indiaa

1.47

71.3

a Modest increased risk of dementia due to higher meat consumption. Adapted from Albanese E, Dangour AD, Uauy R, Acosta D, Guerra M, Guerra SSG. Dietary fish and meat intake and dementia in Latin America, China, and India: a 10/66 dementia research group populationbased study. Am J Clin Nutr 2009;90(2):392e400.

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8 Nutraceuticals in Brain Health and Beyond

numbers of these marine foods would be needed to fulfill even the highest requirements for these PUFAs. Their inclusion in the diet of early modern humans may have conferred an evolutionary advantage on their consumers by providing sufficient PUFAs for optimal neurological development during gestation and infancy.

Cognition beyond foods: just diet or lifestyle pattern? “Mediterranean diet” is a term always closely association with cognitive health. This concept is supported by many observational studies. But some lifestyle behaviors, beyond diet, have an evidence-based synergistic “associationeffect” with cognitive health, although not well studied by robust clinical setup. In the lines of the concept of “food synergy,” several nutritional experts propose a “lifestyle behavior synergy” to investigate the link between food and cognitive decline. Other factors such as socialization, physical activity, leisure activities, and appropriate rest could be expanded by studying all these in concert, or/and as an independent factor also. This approach may help to develop even more comprehensive dietary intervention strategies on cognitive health. It is well accepted that diet and lifestyle have been shown to play an important role in halting the progression of neurodegenerative diseases and impaired cognitive function through the enhancement of structural and functional plasticity in the hippocampus, increased expression of neurotrophic factors, maintenance of synaptic function, and adult neurogenesis [28]. Dietary interventions have emerged as potential inducers of brain plasticity, e.g., calorie restriction and intermittent fasting [29,30]. There is a long-term positive effect on cerebral blood flow in response to lifestyle interventions with restricted diet, weight loss, and increased physical activity [31]. In order to provide the brain with all components necessary to support the synthesis of new synapses and maintenance of existing neuronal connections, thereby possibly reducing the consequences of AD, specially designed multicomponent (DHA, EPA, UMP, choline, folic acid, vitamins B6, B12, C E, selenium and phospholipids) diets have been proposed, e.g., Souvenaid (Fortasyn Connect) [32,33].

Food “liking” versus food “wanting” We need a better understanding of how humans evaluate foods and make choices about them, particularly if associated with objective brain markers underlying decisionmaking processes. This is of great interest because eatingrelated disorders and especially obesity incidences are still increasing world-wide. In daily life, decisions of food eating are determined by hunger (homeostatic needs), and also by hedonic drives that can even override homeostatic

needs [34]. In human food choice behavior science, a prominent concept dominates a dissociation of processes related to food “liking” as opposed to “wanting,” as well as how liking and wanting impact food choices and intake [35]. Behaviorally, Bielser et al. showed (unsurprisingly) that “strongly liked food items were more frequently chosen than dismissed, and that disliked items were more frequently dismissed than chosen.” In this study, participants rated how much they liked each food item (valuation) and subsequently chose between the two alternative food images. The findings [34] show that the spatiotemporal brain dynamics to food viewing are immediately influenced both by how much foods are liked and by choices taken on them. Because food intake is influenced by neurosensory stimulation and memory cues, personalized food images may be useful in prompting appropriate affective responses to food intake, which may subsequently lead to healthier eating behaviors. Whole brain analyses suggested [36] that the visualization of personal images of diet evoked greater brain activation in memory regions (e.g., superior frontal gyrus). This also generates mediating emotion (e.g., thalamus, putamen, anterior cingulate cortex), imagery, and executive functions (e.g., inferior orbitofrontal gyrus, fusiform, and parietal lobe) compared to a written dietary record.

Diet, aging, and neurodegenerative diseases Aging is commonly associated with a decline in cognitive functioning, which ranges from mild cognitive impairment to dementia. Up to 50% of individuals with mild cognitive impairment will develop dementia within 5 years [37]. AD, the most prevalent cause of dementia, is a progressive neurodegenerative disorder characterized by global cognitive impairment affecting memory, language, and other behavioral functions [38,39]. Although old age is the main risk factor for dementia, other prominent factors have been shown to be diet-related [40]. These include obesity, hypertension, and unbalanced diets [41]. Dietary components have been demonstrated to modulate cerebral structure and connectivity, cognition and emotion, and to induce changes in brain and behavioral functions [42]. Nutritional approaches to manage AD include “healthy” dietary patterns (e.g., Mediterranean diet) with individual components that may produce positive effects on pathophysiological processes of AD [43]. Ketogenic dietary approaches target energetic deficits and reduce glucose utilization in AD [44], and medical foods also meeting specific nutritional needs of individuals with AD [45]. PD is the second-most common neurodegenerative disease after AD and is hallmarked by damage to the dopaminergic neurons of the substantia nigra and by alpha synuclein containing inclusion bodies (Lewy pathology;

Role of food or food component in brain health Chapter | 2

LP) in the surviving neurons, resulting in the characteristic motor impairment. Although PD is generally considered as a movement disorder, it has long been recognized that the symptoms go beyond motor dysfunction, since PD patients very often develop nonmotor symptoms, including cognitive impairment [46], depression [47], and others. Levodopa is the most commonly used drug in the treatment of PD. No current therapeutic strategies have a favorable influence on PD progression and they have shown to develop several side effects [48]. Current treatment does not prevent dopaminergic neuron degeneration and has no effect on nonmotor symptoms [49]. Nutritional interventions including phospholipid membrane precursors and/or microbiota-directed therapy like prebiotics and probiotics might provide opportunities to complement the traditional PD therapies and overcome some of their shortcomings including lack of efficacy for GI symptoms/dysfunction. Dietary interventions might have some positive effect on the gut-brain axis by altering microbiota composition (and therefore altering PD pathogenesis) [50,51]; or by affecting neuronal functioning in both the ENS and the central nervous system. Specific nutrient combination containing neuronal precursors and cofactors may counteract synaptic loss and reduce membrane-related pathology in the CNS and the ENS of PD patients. Uridine (as uridine monophosphate, UMP), the omega-3 fatty acid docosahexaenoic acid (DHA), and choline are phospholipid precursors needed for the formation and maintenance of neuronal membranes [52]. Various studies have reported the beneficial effects of probiotics such as representatives of Lactobacilli, Enterococci, Bifidobacteria, yeasts by enhancing intestinal epithelial integrity, protecting from barrier disruption, stimulating a healthy homeostasis of the mucosal immune system and suppressing pathogenic bacterial growth [53,54]. Ingestion of selected probiotics also exhibited beneficial effects on brain function in humans. The administration of Lactobacillus casei strain Shirota in chronic fatigue syndrome patients significantly decreased anxiety symptoms [55]. The insulin Insert ’-’ in-between ’Insulin’ & ’like’like growth factor 1 (IGF-1) plays an essential role in energy metabolism in the brain. The metabolic capacity of the mitochondria is dependent on the IGF-1 signaling pathway [56]. The degradative product of IGF-1, cyclic glycineproline (cGP), is a key factor in the brain that normalizes IGF-1 signaling, essential for cognitive function [57]. Several clinical trials in which patients suffering from PD received supplementation of blackcurrant anthocyanins extract have demonstrated increased levels of cGP [58].

Diet, cognition, and epigenetics Several recent groundbreaking studies have highlighted the potential possibility of extending the effects of diet on

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cognitive health across generations. The outcomes of these studies have great impact on the development of future strategies for combating several diseases. Overall these studies indicate the importance of dietary components in influencing epigenetic events i.e., nongenetic events, such as DNA methylation, transcriptional activation, translational control, and posttranslational modifications that cause a potentially heritable phenotypic change and, thus, their potential for disease modulation. Although the exact molecular mechanisms for the epigenetics influence of diet are not properly known, it is understood that the brainderived neurotrophic factor system is particularly susceptible to epigenetic modifications that influence cognitive function. For instance, the serotonergic system is influenced by early nutrition and stress, causing epigenetic modifications that affect expression and are linked to bipolar disorders and depression in later stage of life [59]. A number of additional direct connections between nutrition and epigenetics have been identified [60]. As for example, methionine, folic acid, vitamins B6 and B12, choline, and glycine betaine are all important for the one-carbon metabolism which can affect DNA methylation. Genistein from soy and tea catechins affect DNA demethylation and histone modification, whereas resveratrol from red wine, sulforaphane from broccoli, butyrate, diallyl sulfide (garlic), and curcumin (turmeric) all affect histone acetylation, and retinoic acid is affecting miRNA transcription. Oleuropein, tyrosol, and hydroxytyrosol from olive tree (Olea europaea) demonstrate neuroprotective effects, partly via epigenetic modifications [61]. These studies clearly demonstrating the intracellular signaling pathways triggered by lifestyle factors can promote long-lasting changes in DNA function in the brain and in cognitive capacity. For an example, a diet that is high in saturated fat reduces the expression of Silent information regulator 2 (SIRT2) in the rat hippocampus, whereas a diet that is high in omega-3 fatty acids has the opposite effect. This is just an early warning on stable and heritable association of our own bad lifestyle and cognitive decline for generations.

Microbiota-targeted functional foods for brain health The etiology of most neuropsychiatric disorders is likely multifactorial, based on both genetic and environmental factors (Fig. 2.2 [62]), particularly, the environmental factors can directly affect the gut microbiome that, in turn, can affect host physiology. In recent years accumulating body of evidence indicates a bidirectional communication between the gastrointestinal tract and the brain, an interaction termed as the “gut-brain axis” [63]. This interaction relates to the gut microbiota and the physiology and pathology of the mammalian brain. During homeostasis, we have a

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Nutraceuticals in Brain Health and Beyond

FIGURE 2.2 Interaction of gut microbiota with brain development, physiology, and pathology (a) Healthy gut microbiota in normal brain development, fetal neuro proliferation, and adult neurogenesis. (b) Altered gut microbiota (“dysbiosis”) affects neurodegenerative diseases (e.g., AD, amyotrophic lateral sclerosis, and PD). (c) Altered gut microbiota affects host behavior and neuropsychiatric diseases. (d) Altered gut microbiota affects brain pathologies (e.g., stroke, autoimmune diseases) and related-immune response. Adapted and modified from Hajjo H, Geva-Zatorsky N. Gut microbiota e host interactions now also brain-immune axis. Curr Opin Neurobiol 2020;62:53e59.

symbiotic relationship with our gut microbes that ensure a regulated and healthy brain development. However, “dysbiosis” (i.e., an imbalanced population of gut microbes), can lead to pathological states, including brain pathologies. Normal gut microbiota has been shown to lead to proper brain development and behavior. Gut dysbiosis has been shown to be associated with neurological disorders, such as psychiatric disordersddepression and anxiety, as well as autism and neurodegenerative diseases [64,65]. The gut microbiota has been shown to impact CNS neurogenesis. In addition, the gut microbiota was shown to impact neuronal excitability and communicate with the host via neurochemicals. Considering all study outcomes in recent years, modulation of the gut microbiota using dietary intervention, in

particular with prebiotics and probiotics, is a promising strategy in promoting normal brain function and mental health. Prebiotics may exert a beneficial brain effect through improving host immunity, enhancing SCFA production, reducing potentially pathogenic microbes, and improving gut barrier function [66]. Lactobacillus spp. and Bifidobacterium spp. are the most used probiotics and may act via a number of mechanisms to alter the gut microbiota of the host in order to improve brain health. This intervention may help in production of antimicrobial compounds, reduction of the luminal pH through the production of SCFA, competitive exclusion of other microbes from adhering to epithelial cells, production of growth substrates, enhancing barrier function, and modulation of immune responses [67].

Role of food or food component in brain health Chapter | 2

As discussed previously, polyphenols are a large group of compounds naturally occurring in plants and a variety of foods, including citrus fruits, cocoa, red wine, tea, and coffee. Large-scale epidemiological investigations suggest that a diet rich in polyphenols may help maintain normal brain function and mental health [19]. Interventional studies in humans provide some supportive evidence for this epidemiological data (see Table 2.3). Antiinflammatory and antioxidant properties and modulation of enzyme activity have been proposed to be responsible for the positive CNS effects of polyphenols [19], but due to the poor bioavailability of most of the polyphenols [68], approx. 90%e95% of total dietary polyphenols accumulate in the large intestine where they are broken down into less complex metabolites by the gut microbiota [69]. For example, black and green tea (epigallocatechin, epicatechin, catechin) have been shown to affect the growth of Helicobacter pylori, Staphylococcus aureus, Salmonella typhimurium, Listeria monocytogenes, while other polyphenols have been shown to promote the growth of beneficial bacteria, such as Bifidobacterium spp. [70]. It is likely that the beneficial CNS effects of polyphenol compounds are mediated, at least in part, by interactions with the gut microbiota [71]. So it is imperative that when food scientists and technologists are developing polyphenol-based brain function enhancing products, they should consider the large interindividual variation in gut microbiota composition, which may significantly affect polyphenol bioefficacy [69].

Thinking outside the brain The brain is traditionally known to play an essential role in governing and coordinating our systemic homeostasis. In recent years, it is also becoming clear that the conditions of brain health are intimately associated with other physiological systems. Therefore, a much more complex picture has emerged concerning the exact pathophysiological basis of cognitive deficits and many other neuropsychological disorders [72]. Despite much conceptual progress made so far, disappointment exists for the CNS drug discovery mode that solely focuses on the brain but ignores peripheral mediators. To achieve this holistic goal, it will be imperative to look beyond the brain and integrate an interdisciplinary approach to the research pipeline. These emerging findings have shed novel insights into cognitive dysfunctions and also raised a number of interesting questions on future preventive and therapeutic strategies. Major pathways outside brain in cognitive regulation are: l l

Neuroimmune signaling and cognition Endocrinal signaling and cognition

l l

11

Metabolic signaling and cognition The blood-brain barrier

Conclusion Although food has traditionally been perceived as a supplier of energy and building material to the body, its ability to prevent and protect against diseases is starting to be recognized by consumers, industries, and regulators. There is a tendency to think of nutritional supplements “as harmless at worst and beneficial at best.” However, at the same time several recent trials warn about this hypothesis. Due to the encouraging results of clinical and preclinical studies, the topic has attracted substantial global media attention in recent years. The downside of this hype is scientific understanding of perceived benefits and actual cause-benefit relationships of such supplementation. The roles of genomics and epigenomics in modulating the effects of nutrition on the brain and mental health are very important directions and need to be included in our future healthcare strategies. In the long term, personalized nutrition, based on individual genetic variability and environmental susceptibility, should help to optimize brain function, and prevent or alleviate mental disorders. Finally, one important issue to be determined under strict clinical environment is that whether the functional foods (prebiotics, probiotics, omega-3 PUFAs, and polyphenols) can be employed as stand-alone nutritional solutions to promote normal brain function and mental health, or will be most effective as adjunct to current therapeutic approaches. Brain health is one of the rapidly developing fields, new findings are continually emerging which bolster our knowledge of how the gut microbiota influence brain function and behavior. Despite significant gains over the past decade in understanding the mechanisms underlying the development and manifestation of most major psychiatric disorders, few advances have been made in the discovery of novel CNS acting agents. As a result, Psychobiotic’ interventions, which target pathways of microbiota-gut-brain axis, represent a new era in psychotropic therapies and hold great promise in promoting normal brain function and mental health across the lifespan.

References [1] Kuipers E, Onwumere J, Bebbington P. Cognitive model of caregiving in psychosis. Br J Psychiatry 2010;196(4):259e65. [2] Garrard P, Jacoby R. B-vitamin trials meta-analysis: less than meets the eye. Am J Clin Nutr 2015;101(2):414e5. [3] Hiller AM, Murchison CF, Lobb B, O’Connor S. A randomized, controlled pilot study of the effects of vitamin D supplementation on balance in Parkinson’s disease: does age matter? PLoS One 2018;13(9):e0203637.

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[4] Morris MC. Nutritional determinants of cognitive aging and dementia. Proc Nutr Soc 2012;71:1e13. [5] Zieger E, Schubert M. New insights into the roles of retinoic acid signaling in nervous system development and the establishment of neurotransmitter systems. In: Galluzzi L, editor. Int. Rev. Cell Molec. Biol. Academic Press; 2017. p. 1e84. [6] Roshchina VV. Evolutionary considerations of neurotransmitters in microbial, plant, and animal cells. In: Lyte M, Freestone PPE, editors. Microbial endocrinology: interkingdom signaling in infectious disease and health. New York, NY: Springer; 2010. p. 17e52. [7] Yılmaz C, Gökmen V. Formation of tyramine in yoghurt during fermentation eInteraction between yoghurt starter bacteria and Lactobacillus plantarum. Food Res Int 2017;97:288e95. [8] Yılmaz C, Gökmen V. Kinetic evaluation of the formation of tryptophan derivatives in the kynurenine pathway during wort fermentation using Saccharomyces pastorianus and Saccharomyces cerevisiae. Food Chem 2019;297:124975. [9] Calabrese V, Mancuso C, Calvani M, Rizzarelli E, Butterfield DA, Stella AM. Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 2007;8(10):766e75. [10] Lovinger DM. Communication networks in the brain: neurons, receptors, neurotransmitters, and alcohol. Alcohol Res Health 2008;31(3):196e214. [11] Briguglio M, Dell’Osso B, Panzica G, Malgaroli A, Banfi G, Zanaboni Dina C, et al. Dietary neurotransmitters: a narrative review on current knowledge. Nutrients 2018;10(5). https://doi.org/10.3390/ nu10050591. [12] Young SN. How to increase serotonin in the human brain without drugs. J Psychiatry Neurosci 2007;32(6):394e9. [13] Jongkees BJ, Hommel B, Kuhn S, Colzato LS. Effect of tyrosine supplementation on clinical and healthy populations under stress or cognitive demands-a review. J Psychiatr Res 2015;70:50e7. [14] Ladero V, Calles-Enriquez M, Fernandez MA, Alvarez M. Toxicological effects of dietary biogenic amines. Curr Nutr Food Sci 2010;6(2):145e56. [15] Passani MB, Panula P, Lin JS. Histamine in the brain. Front Syst Neurosci 2014;8:64. [16] Caracciolo B, Xu W, Collins S, Fratiglioni L. Cognitive decline, dietary factors and gutebrain interactions. Mech Ageing Dev 2014;136e137:59e69. [17] Ghosh D, Scheepens A. Vascular action of polyphenols. Mol Nutr Food Res 2009;53:322e31. [18] Commenges D, Scotet V, Renaud S, Jacqmin-Gadda H, BarbergerGateau P, Dartigues JF. Intake of flavonoids and risk of dementia. Eur J Epidemiol 2000;16:357e63. [19] Letenneur L, Proust-Lima C, Le Gouge A, Dartigues JF, BarbergerGateau P. Flavonoid intake and cognitive decline over a 10-year period. Am J Epidemiol 2007;165:1364e71. [20] Schaffer S, Asseburg H, Kuntz S, Muller WE, Eckert GP. Effects of polyphenols on brain ageing and Alzheimer’s disease: focus on mitochondria. Mol Neurobiol 2012;46:161e78. [21] Kesse-Guyot E, Fezeu L, Andreeva VA, Touvier M, Scalbert A, Hercberg S, et al. Total and specific polyphenol intakes in midlife are associated with cognitive function measured 13 years later. J Nutr 2012;142:76e83. [22] Gillette-Guyonnet S, Secher M, Vellas B. Nutrition and neurodegeneration: epidemiological evidence and challenges for future research. Br J Clin Pharmacol 2013;75:738e55.

[23] Sydenham E, Dangour AD, Lim WS. Omega 3 fatty acid for the prevention of cognitive decline and dementia. Cochrane Database Syst Rev 2012;6:CD005379. [24] Galland L. Diet and inflammation. Nutr Clin Pract 2010:25. [25] Naqvi AZ, Harty B, Mukamal KJ, Stoddard AM, Vitolins M, Dunn JE. Monounsaturated, trans, and saturated fatty acids and cognitive decline in women. J Am Geriatr Soc 2011;59:837e43. [26] Vercambre MN, Grodstein F, Kang JH. Dietary fat intake in relation to cognitive change in high-risk women with cardiovascular disease or vascular factors. Eur J Clin Nutr 2010;64:1134e40. [27] Kyriacou K, Blackhurst DM, Parkington JE, Marais AD. Marine and terrestrial foods as a source of brain-selective nutrients for early modern humans in the southwestern Cape, South Africa. J Hum Evol 2016;97:86e96. [28] Murphy T, Dias GP, Thuret S. Effects of diet on brain plasticity in animal and human studies: mind the gap. Neural Plasticity 2014;2014:563160. [29] Guo J, Bakshi V, Lin AL. Early shifts of brain metabolism by caloric restriction preserve white matter integrity and long-term memory in aging mice. Front Aging Neurosci 2015;7:213. [30] Martin B, Mattson MP, Maudsley S. Caloric restriction and intermittent fasting: two potential diets for successful brain aging. Ageing Res Rev 2006;5(3):332e53. [31] Espeland MA, Luchsinger JA, Neiberg RH, Carmichael O, Laurienti PJ, Pi-Sunyer X, et al. Long term effect of intensive lifestyle intervention on cerebral blood flow. J Am Geriatr Soc 2018;66(1):120e6. [32] Cummings J, Scheltens P, McKeith I, Blesa R, Harrison JE, Bertolucci P/, et al. Effect size analyses of Souvenaid in patients with Alzheimer’s disease. J Alzheim Dis 2017;55(3):1131e9. [33] Mi W, van Wijk N, Cansev M, Sijben JW, Kamphuis PJ. Nutritional approaches in the risk reduction and management of Alzheimer’s disease. Nutrition 2013;29(9):1080e9. [34] Bielser M, Crézé C, Murray MM, Toepel U. Does my brain want what my eyes like? e how food liking and choice influence spatiotemporal brain dynamics of food viewing. Brain Cognit 2016;110:64e73. [35] Berridge KC. “Liking” and “wanting” food rewards: brain substrates and roles in eating disorders. Physiol Behav 2009;97:537e50. [36] Dodd SL, Long JD, Hou J, Kahathuduwa CN, O’Boyle MW. Brain activation and affective judgements in response to personal dietary images: an fMRI preliminary study. Appetite 2020;148:104561. [37] Gauthier S, Reisberg B, Zaudig M, Petersen RC, Broich RK, Belleville S, et al. Mild cognitive impairment. Lancet 2006;367:1262e70. [38] Lange KW, Sahakian BJ, Quinn NP, Marsden CD, Robbins TW. Comparison of executive and visuospatial memory function in Huntington’s disease and dementia of the Alzheimer-type matched for degrees of dementia. J Neurol Neurosurg Psychiatry 1995;58:598e606. [39] Scheltens P, Blennow K, Breteler MM, Strooper Bde, Frisoni GB, Salloway S, et al. Alzheimer’s disease. Lancet 2016;388:505e17. [40] Moore K, Hughes CF, Ward M, Hoey L, McNulty H. Diet, nutrition and the ageing brain: current evidence and new directions. Proc Nutr Soc 2018;77:152e63. [41] World Health Organization. Towards a dementia plan: a WHO guide. Geneva: World Health Organization; 2018. [42] Gustafson DR, Morris MC, Scarmeas N, Shah RC, Sijben J, Yaffe K, et al. New perspectives on Alzheimer’s disease and nutrition. J. Alzheimers Dis. 2015;46:1111e27.

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[43] Petersson SD, Philippou E. Mediterranean diet, cognitive function, and dementia: a systematic review of the evidence. Adv Nutr 2016;7:889e904. [44] Lange KW, Lange KM, Makulska-Gertruda E, Nakamura Y, Reissmann A, Kanaya S, et al. Ketogenic diets and Alzheimer’s disease. Food Sci Hum Wellness 2017;6:1e9. [45] Shah RC. Medical foods for Alzheimer’s disease. Drugs Aging 2011;28:421e8. [46] Aarsland D, Creese B, Politis M, Chaudhuri KR, Ffytche DH, Weintraub D, et al. Cognitive decline in Parkinson disease. Nat Rev Neurol 2017;13:217e31. [47] Remy P, Doder M, Lees A, Turjanski N, Brooks D. Depression in Parkinson’s disease: loss of dopamine and noradrenaline innervation in the limbic system. Brain J Neurol 2005;128:1314e22. [48] Schrag A, Quinn N. Dyskinesias and motor fluctuations in Parkinson’s disease. A community-based study. Brain J Neurol. 2000;123:2297e305. [49] Lee HM, Koh SB. Many faces of Parkinson’s disease: non-motor symptoms of Parkinson’s disease. J Mov Disord 2015;8:92e7. [50] Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative view. Cell 2012;148:1258e70. [51] Maslowski KM, Mackay CR. Diet, gut microbiota and immune responses. Nat Immunol 2011;12:5e9. [52] Wurtman RJ. A nutrient combination that can affect synapse formation. Nutrients 2014;6:1701e10. [53] Corridoni D, Pastorelli L, Mattioli B, Locovei S, Ishikawa D, Arseneau KO, et al. Probiotic bacteria regulate intestinal epithelial permeability in experimental ileitis by a TNF-dependent mechanism. PLoS One 2012;7:e42067. [54] Patel RM, Myers LS, Kurundkar AR, Maheshwari A, Nusrat A, Lin PW. Probiotic bacteria induce maturation of intestinal claudin 3 expression and barrier function. Am J Pathol 2012;180:626e35. [55] Rao AV, Bested AC, Beaulne TM, Katzman MA, Iorio C, Berardi JM, et al. A randomized, double-blind, placebo-controlled pilot study of a probiotic in emotional symptoms of chronic fatigue syndrome. Gut Pathog 2009;1:6. [56] Yin F, Jiang T, Cadenas E. Metabolic triad in brain aging: mitochondria, insulin/IGF-1 signalling and JNK signalling. Biochem Soc Trans 2013;41(1):101e5. [57] Guan J, Gluckman P, Yang PZ, Krissansen G, Sun X, Zhou Y, et al. Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1. Sci Rep 2014;4:4388. https://doi.org/ 10.1038/srep04388.

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[58] Fan D, Alamri Y, Liu K, MacAskill M, Harris P, Brimble M, et al. Supplementation of blackcurrant anthocyanins increased cyclic glycine-proline in the cerebrospinal fluid of Parkinson patients: potential treatment to improve insulin-like growth factor-1 function. Nutrients 2018;10(6). https://doi.org/10.3390/nu10060714. [59] Dauncey MJ. Genomic and epigenomic insights into nutrition and brain disorders. Nutrients 2013;5(3):887e914. [60] Choi SW, Friso S. Epigenetics: a new bridge between nutrition and health. Advan. Nutr. (Bethesda, Md) 2010;1(1):8e16. [61] St-Laurent-Thibault C, Arseneault M, Longpre F, Ramassamy C. Tyrosol and hydroxytyrosol, two main components of olive oil, protect N2a cells against amyloid-beta-induced toxicity. Involvement of the NF-kappaB signaling. Curr Alzheimer Res 2011;8(5):543e51. [62] Hajjo H, Geva-Zatorsky N. Gut microbiota e host interactions now also brain-immune axis. Curr Opin Neurobiol 2020;62:53e9. [63] Khanna S, Tosh PK. A clinician’s primer on the role of the microbiome in human health and disease. Mayo Clin Proc 2014;89:107e14. [64] Lurie I, Yang YX, Haynes K, Mamtani R, Boursi B. Antibiotic exposure and the risk for depression, anxiety, or psychosis. J Clin Psychiatr 2015;76:1522e8. [65] Rogers GB, Keating DJ, Young RL, Wong ML, Licinio J, Wesselingh S. From gut dysbiosis to altered brain function and mental illness: mechanisms and pathways. Mol Psychiatr 2016;21:738e48. [66] Slavin J. Fiber and prebiotics: mechanisms and health benefits. Nutrients 2013;5:1417e35. [67] Power SE, O’Toole PW, Stanton C, Ross RP, Fitzgerald GF. Intestinal microbiota, diet and health. Br J Nutr 2014;111:387e402. [68] Yılmaz C, Gökmen V. Neuroactive compounds in foods: occurrence, mechanism and potential health effects. Food Res Int 2020;128:23. 108744. [69] Crozier A, Jaganath IB, Clifford MN. Dietary phenolics: chemistry, bioavailability and effects on health. Nat Prod Rep 2009;26:1001e43. [70] Selma MV, Espin JC, Tomas-Barberan FA. Interaction between phenolics and gut microbiota: role in human health. J Agric Food Chem 2009;57:6485e501. [71] Duda-Chodak A, Tarko T, Satora P, Sroka P. Interaction of dietary compounds, especially polyphenols, with the intestinal microbiota: a review. Eur J Nutr 2009;54(3):325e41. [72] Schaffer S, Halliwell B. Do polyphenols enter the brain and does it matter? Some theoretical and practical considerations. Genes Nutr 2012;7:99e109. [74] Zheng X, Zhang X, Kang A, Ran C, Wang G, Hao H. Thinking outside the brain for cognitive improvement: is peripheral immunomodulation on the way? Neuropharmacology 2015;96:94e104.

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Chapter 3

Bacopa monnieri for cognitive healthda review of molecular mechanisms of action Divya Purusothaman, Nehru Sai Suresh Chalichem, Bharathi Bethapudi, Sasikumar Murugan and Deepak Mundkinajeddu Research and Development Center, Natural Remedies Private Limited, Bengaluru, Karnataka, India

Chapter outline Cognition 15 Signal transduction, cognition, and cognitive impairment 16 Factors influencing signal transduction 16 Neurotransmitters 16 Receptors 16 Second messenger system 17 Genes and their expression 17 Structural factors and neuronal connections 18 Cerebral blood flow 18 Approved drugs as cognition enhancers 18 Nutraceuticals for cognitive performance 18 Bacopa monnieri for cognitive performance 19 Neuronal molecular mechanisms of cognitive benefits of BM in relation to signal transduction 19 Effect of BM on neurotransmitters 19 Enzymes/protein regulating neurotransmitters 19 Transporters 19 Effect of BM on receptors 19 Effect of BM on receptor density 19

Effect of BM on second messenger system PKC: PI3K/Akt signaling pathway Effect of BM on regulation of gene expression Regulation of reelin-dependent NMDAR-BDNF expression Regulation of miRNA Gene ontology analysis Effect of BM on structural factors and neuronal connections Synaptic plasticity Neuronal density and dendritic arborization Beta-amyloid and tau proteins Effect of BM on CBF Effect of BM as neuroprotective agent BM as an antioxidant BM as antiapoptotic agent BM as antiinflammatory agent Summary References

Cognition

attention, and social cognition [1]. These processes are attained either naturally or artificially, consciously or unconsciously. Most of the times, they work rapidly even without realization. The most important physiological component of cognition is reputed to be neurons that are connected by synapses. The signal transduction between these neurons helps in detecting, amplifying, and integrating various external signals to generate response as cognition.

Cognition is defined as the mental ability in the process of acquiring knowledge through learning, thinking, and experience. Fundamentally, it is cognition that controls our thoughts and behavior. The six principal domains in cognitive process include executive function, learning and memory, perceptual-motor function, language, complex

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Signal transduction, cognition, and cognitive impairment Cognition takes its physiological foundation in the brain with around 86 billion neurons, each of which is connected with thousands of other neurons through synapses, forming a complex circuit. A brain of an individual probably has more than 100 trillion synapses. Simply, the basis of cognition lies with processing of information and communication between these synapses. The neurons communicate via synapses and process the information constantly and instantly by signal transduction through electrical and chemical carriers. The excitatory and inhibitory signals received by dendritic spines of presynaptic neurons get converged in neuronal stroma. When signal exceeds the threshold, the generated action potential transmitted down the axon triggers the release of neurotransmitters at the synaptic cleft, a small gap between two neurons. Depending on the nature of the neurotransmitters released, the receptors to which it binds, and the cell type of (postsynaptic) neuron receiving the signal, neurons experience either excitatory or inhibitory activity and hence change in the behavior occurs. Cognition development starts right even at the fetal stage and is unending throughout the lifespan. Each behavior, each thought, and each move by an individual decisively depend on the organized flow of electric potentials across the neurons. Any disruption or interference in neuronal communication at any stage of life could affect the cognition. Disruption could be anatomical (e.g., brain injury/damage during accidents), physiological (e.g., lack of cerebral blood flow), or biological (e.g., formation of amyloid b-protein). For example, as a basic physiological process in humans, glutamate, a primary neurotransmitter, induces excitatory potential by influx of Ca2þ ions into membrane via NMDA (N-methyl-D-aspartate), AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid), mGlu (metabotropic glutamate), and kainite receptors, helping in memory and learning. It also plays a role in promoting long-term potentiation (LTP), a form of synaptic plasticity, growth cones, and synaptogenesis during neural development. But disruption of these signals by endogenous or exogenous excitotoxins induces overactivation of glutamate receptors. Consequently, overload of Ca2þ impulse in the cells leads to the activation of many enzymes like proteases, calcium/calmodulin-dependent protein kinases, phospholipases, endonucleases, nitric oxide synthases triggering the release of free radicals and lipid peroxidation, cell membrane degradation, and protein lysis, thereby inducing neuronal damage or death. Ultimately, it is signal transduction that is responsible for information processing (cognition) in every individual. This indicates that neurotransmitters, receptors, action potential/electrical signals, pre- and postsynaptic events, events in synaptic

cleft integrated by signaling transduction pathways contribute to cognition. Changes in cognition are constant and thereby make the signal transduction also to adapt to the newer information. But if a persistent difficulty is experienced in organizing the cognitive processes in dayto-day tasks, then it can be designated to be a neurocognitive impairment, which could be attributed to dysregulation of neuronal signal transduction.

Factors influencing signal transduction Neurotransmitters There are more than 100 neurotransmitters known till date and still many are being discovered by scientists. Neurotransmitters are critical as they carry information (signal) from one neuron to the other. The various neurotransmitters that are known to play an important role in cognitive functions are excitatory and inhibitory amino acids: glutamate, glycine and gamma aminobutyric acid (GABA); monoamines: epinephrine, norepinephrine, dopamine, serotonin, histamine, and acetylcholine; neuromodulatory peptides: calcitonin, hormones like oxytocin, vasopressin, growth hormone releasing hormone, corticotropin releasing hormone, somatostatin, gonadotropin releasing hormone, adrenocorticotropic hormone, neurotensin, neuropeptide-Y (NPY), neuropeptide-K (NPK), neuropeptide YY, endorphins, enkephalin, neurokinin A, neurokinin B, substance P, and glucagon; and atypical neurotransmitters: nerve growth factor, brain-derived neurotrophic factor (BDNF), nitric oxide (NO), ATP, cannabinoids, ghrelin, cytokines, etc. Levels and activation of neurotransmitters are very critical for signal transduction and to maintain normal cognitive function. Imbalance of neurotransmitters leads to neurodegeneration followed by cognitive dysfunction, and even death. Increased or decreased level of these neurotransmitters could be because of at least one of these reasons, viz., amount of neurotransmitters synthesized by neurons, amount released into synaptic cleft (by exocytosis) from synaptic vesicles by activation of synaptic vesicle proteins (e.g., synaptotagmin, Rab3a, proton ATPase and SNARE proteindsynaptobrevin/vesicle-associated membrane protein, syntaxin, and synaptosomal-associated protein), amount metabolized or deactivated by presynaptic enzymes, amount utilized by postsynaptic neurons, or amount reabsorbed by reuptake mechanism [2].

Receptors Signals from neurotransmitters transduce into neurons via any of the four trends: by binding to (1) ligand gated ion channels, (2) G-protein coupled receptor (GPCR), (3) enzyme-linked receptor, and (4) by activation of nuclear transcription factors. Homeostatic regulation of these receptors/channels is essential to maintain cognition as loss in

Bacopa monnieri for cognitive healthda review of molecular mechanisms of action Chapter | 3

control of receptor regulation affect the signal transduction. Two major factors that alter the regulation of receptors are receptor density and the function of receptor itself. Alteration in receptor density is caused because of continuous/ surplus stimulation or deprivation of signals by neurotransmitters and dysfunction of receptor function is by alteration of second messenger system [2e4].

Second messenger system Alteration in second messenger system greatly affects signal transduction generally via three pathwaysdAdenylyl cyclase: cAMP pathway, Guanylyl cyclase: cGMP pathway, and Phospholipase C: IP3-DAG pathway. Psychological changes like stress and depression, and environmental changes like oxygen deficit and lack of blood flow, alter the second messenger system. For example, cerebral ischemia decreases the activation of adenylyl cyclase leading to Y activation of cAMP / Y binding activity of cAMP-dependent protein kinase (PKA) / changes in phosphorylation of DNA-binding transcription factor, cyclic AMP response element binding protein (CREB) which plays a critical role in cognition [2,5,6]. G proteins: G-protein coupled with respective receptor transduces the signal through second messengers via activation of effector proteins (like adenylyl cyclase and guanylyl cyclase) or opening of ion channels (like inwardly rectifying Kþ channels [GIRKs]). G proteins are heterotrimeric (with a, b, g subunits) or monomeric. Some of the monomeric G-proteins or small G-proteins that contribute critical role in signal transduction are Ras, Rab, Rac, cdC42, ADP-ribosylation factor (ARF), EF-2, Ran, Rho, signal recognition particle, etc. The activity of G proteins is regulated by modulatory proteins like guanine nucleotide exchange factor that releases GDP and facilitates binding to GTP, Regulators of G-protein signaling protein that activates GTPase activity of alpha subunit of G-protein and phosducin that binds to bg subunits and makes a subunit to remain active for longer duration [2]. Second messengers: Second messengers help in amplification of signals by activating intracellular pathways. Cyclic nucleotides like cAMP and cGMP, calcium (Ca2þ), nitric oxide (NO), inositol triphosphate (IP3), diacylglycerol (DAG), arachidonic acid are major secondary messengers that serve signal transduction. The levels and the activity of second messengers are regulated by catalyzing effector proteins (adenylyl cyclase, guanylyl cyclase, phospholipase C, etc.), endogenous precursors (ATP, GTP, PIP2, etc.), cofactors (Mg, Ca), and degrading enzymes (phosphodiesterases [PDEs]). Diffusion of messengers from one location to the other also regulates their activity. In case of ions, expression of ion channels; its storage, activation, and release from intercellular storage compartments; and cytoplasmic buffering affect the regulation [2].

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Protein phosphorylation: Second messengers are critical in inducing phosphorylation of many important elements like neurotransmitter synthesizing enzymes, receptors, voltage gated ion channels, synaptic vesicle proteins, cytoskeletal proteins, and nuclear proteins. The effects of second messengers are regulated by protein phosphorylation on serine or threonine residues. Second messengeredependent phosphorylation involves cAMPdependent protein kinase (protein kinase A), cGMPdependent protein kinase (protein kinase G), Ca2þ-dependent protein kinases (CaM-kinase, protein kinase C). These protein kinases in turn are regulated by factors like protein kinase-anchoring proteins (A kinasee anchoring proteins [AKAPs], receptors for activated C kinase [RACKs]), protein kinase inhibitors, protein serinethreonine phosphatases (protein phosphatases 1 [PP1], PP2A). Phosphoproteins generated on phosphorylation could act as third messengers and produce biological responses. Recently, these factors have gained more attention in the therapeutic area of neurodegeneration diseases. Apart from second messengeredependent phosphorylation, the other major phosphorylation cascade involved in signal transduction is neurotrophic factor-dependent phosphorylation via neurotrophin signaling pathways (the Ras-Raf-ERK, IRS-PI3-kinase-Akt, and phospholipase Cg [PLCg] pathway), JAKeSTAT pathway, glial cell linee derived neurotrophic factor (GDNF) signaling pathway, cytoplasmic protein tyrosine kinases, glycogen synthase kinases, casein kinases, and cyclin-dependent kinases. Factors those regulate these pathways include receptor dimerization, phosphorylation, activation of transcription factors, phosphatase inhibitors [2].

Genes and their expression Signals from synapses that reach the nucleus could alter gene expression, which plays a key role in long-term memory, biological rhythm, neuronal and behavioral plasticity, neuronal survival and death, etc. The mechanisms behind alteration of gene expression include structural change in chromatin, transcription (DNA to RNA), splicing (RNA to mRNA), covalent modification of mRNA, translation (mRNA to protein), and modification of protein. Collective factors regulating these processes are protein activators, transcription factors (CREB, activator protein AP-1, signal transducer and activator of transcription STAT, c-Fos, NF-ƙB), dimerization, or multimerization of transcription factors, phosphorylation, availability of adapter protein (binding protein), translocation of transcription factor from cytoplasm into nucleus, chaperone proteins (Hsp90, Hsp56), binding of transcription factors to promoter or enhancer region of gene, histone, modification of histone through acetylation, methylation, phosphorylation, ubiquitylation, etc., by histone acetyltransferases (HAT), histone

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deacetylases (HDAC), and RNA polymerase. Malfunction in these factors interrupts gene expression affecting learning and memory. Apart from influencing neurotransmitter levels directly by acting on transporters and enzymes, recent research is focused on drugs or nutraceuticals targeting transcription factors and related proteins that are involved in gene expression to act as a cognition enhancer and to treat neurological diseases [2].

Structural factors and neuronal connections The so far discussed factors that regulate signal transduction directly or indirectly depend upon brain morphology itself. The phenomenon of neuronal transmission through neuronal connections defines the process of signal transduction. Any damage or modification to the cytoskeleton/organelles of neurons, which regulates the entire function, greatly affects the signal transduction. Dendritic spine density, size, dendritic arborization, preand postsynaptic density, and synaptic plasticity (ability of synapse to increase or decrease its strength of communication) aid in conducting signals from one neuron to the other, glial cells help in maintaining extracellular environment like ion concentration, metabolism of neurotransmitters, microtubules, and the associated proteins like tau play an important role in signal transduction [2,7].

Cerebral blood flow Brain consumes more glucose and oxygen from the circulating blood than any other organ in the body, which is disproportionate to its relative mass of the body (2%). Blood flow in the brain accounts for 15% of cardiac output which supplies approximately 20% of total oxygen required by the body. Human body can lose its complete consciousness on stopping the cerebral blood flow for 10 s. Interruption in blood flow could severely affect the signal transduction, hence the impairment in cognition, stroke, and fatality [2].

Approved drugs as cognition enhancers There are several categories of drugs that are approved in various countries to treat cognitive decline. These drugs are prescribed to improve cognition in mild cognitive impairment, dementia, Alzheimer disease (AD), attention deficit hyperactivity disorder (ADHD), autism, stroke, head injury, etc. There exist multiple approaches of treatment to improve cognition. The currently employed one approach is to improve cognition symptomatically. The mechanism behind this strategy is either by activating cholinergic pathway or by blocking the glutamate-NMDA receptors. The drugs under this approach include choline facilitators (Anti-choline esterases): tacrine, rivastigmine, donepezil,

galantamine; NMDA (glutamate) receptor antagonist: memantine; and miscellaneous group of drugs that include piracetam, pyritinol, citicoline, dihydroergotoxine, piribedil, whose mechanisms are not well delineated. All these drugs are known to work through one of these mechanisms, viz., increases cerebral blood flow (CBF), supports neuronal metabolism, increases neurotransmission, and improves cerebral function. There are few other cholinergic agonists like arecoline, bethanechol, and oxotremorine, which can clinically improve the symptoms of cognitive decline but have side effects [2,3]. The other approach is to alter the disease process/ progress itself, which is responsible for cognitive decline. This strategy has gained extensive attention of researchers to deal with complicated cognition impairment. Approach of neuroprotection by antioxidants and antiinflammatory agents is also employed as adjunct approach to prevent cognitive decline at times of neuronal damage and to prevent further consequent progression of cognitive decline after neuronal damage [2].

Nutraceuticals for cognitive performance In ayurvedic system of medicine, the herbs that enhance cognition are classified as Medhya Rasayana. Some of the important herbs under this category include Acorus calamus, Benincasa hispida, Bacopa monnieri, Celastrus panniculata, Centella asiatica, Convolvulus pluricaulis, Glycyrrhiza glabra, Nardostachys jatamansi, and Tinospora cordifolia [8]. Apart from these herbs, there are other herbal nutraceuticals and phytocomponents that are widely used as cognitive enhancers. Nicotine and caffeine are widely recognized to improve aspects of cognitive function like attention [9,10]. Ginkgo biloba was identified with positive effects on cognitive function in healthy young and elderly volunteers [11e13], mild cognitively impaired elderly patients [14e16], patients with AD and other dementias [17,18]. Combination of Ginkgo biloba and Panax ginseng exhibited improvements in working and episodic memory [19,20]. Some of the other important herbs that have been shown to improve cognition are Panax ginseng [21e23], Melissa officinalis [20,24,25], Rhodiola rosea [26e29], Hypericum perforatum [30], and Salvia lavandulaefolia [31]. Other phytoactives/metabolites that were found to improve cognitive function in the young and elderly include caffeine [10,32,33], acetyl-L-carnitine [34,35], pyroglutamic acid [36], guanfacine [37], huperzine [38,39], Ginseng þ vitamins [40,41], alpha lipoic acid [42], phosphatidylserine [43], pycnogenol [44], docosahexaenoic acid [45], essential oils and aromas [46], S-adenosyl-L-methionine [47], citicoline [48e50], and L-theanine [51].

Bacopa monnieri for cognitive healthda review of molecular mechanisms of action Chapter | 3

Bacopa monnieri for cognitive performance Bacopa monnieri (BM) is traditionally well known for its activity as cognition enhancer. Scientifically BM has been extensively studied both clinically and preclinically to understand its effects on cognition during nonpathological and pathological conditions like epilepsy, diabetes, ischemia, stroke, schizophrenia, and AD. Clinically BM was demonstrated to improve cognitive function in various groups of people. BM increased cognition in elderly people [52e58], healthy adults [59e64], in subjects with mild cognitive impairment (MCI) [65,66], in subjects with AD [67], in school children [68], and in college students [69]. BM was also proved to improve symptoms of learning ability in ADHD children [70] and in children requiring individual education program [71]. The possible neuronal molecular mechanisms of BM behind these clinical outcomes have been studied via different aspects of signal transduction. In this review the reported mechanisms of action pertaining to learning and memory, attention, social cognition, and executive function are described.

Neuronal molecular mechanisms of cognitive benefits of BM in relation to signal transduction Effect of BM on neurotransmitters BM has been shown to modulate the level of neurotransmitters that play critical role in cognitive function. Treatment with BM elevated the level of acetylcholine [72e74] and serotonin [74e76], and modulated the levels of dopamine [74,76e78], GABA [74,79], noradrenaline [76], and glutamate [74]. BM enhanced the level of BDNF [80e82]. BDNF, a well-known neurotrophic factor, plays niche role in amplifying the response of neurotransmitters and enhancing the release of other neurotransmitters and vesicle docking (bringing synaptic vesicles at the active zone of a nerve terminal) [83,84].

Enzymes/protein regulating neurotransmitters Multiple studies have shown that BM regulates the level of neurotransmitters by acting on the enzymes involved in their synthesis or degradation. BM inhibited acetylcholinesterase (AChE) [85] and enhanced choline acetyltransferase toward regulating acetylcholine (Ach) levels [80]. The extracts of BM have been shown to inhibit many other enzymes, viz., tryptophan hydroxylase that regulates serotonin [75], tyrosine hydroxylase that regulates catecholamines [86], glutamic acid decarboxylase that regulates

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GABA, catechol-O-methyl transferase that regulates dopamine (DA), and prolyl endopeptidase (PEP) that regulates vasopressin, arginine, oxytocin, substance P, and angiotensin II [87]. PEP is a serine peptidase that is responsible for maturation and degradation of peptide hormones as listed above. Inhibition of PEP has been shown to improve impaired learning and memory [88,89]. BM has been shown to regulate the level of serotonin by enhancing the expression of synaptotagmin1, a calcium sensor protein present on the membrane of synaptic vesicle that is responsible for exocytosis of neurotransmitter from the synaptic vesicle to the synaptic cleft [90].

Transporters Neurotransmitter release/transportation relies upon factors called transporters. Vesicular glutamate transporter (VGLUT) is one such transporter that transports glutamate, an excitatory neurotransmitter into synaptic vesicles, where they are stored. Reduced VGLUT causes glutamatergic hypofunction that can cause cognitive dysfunction during schizophrenia. BM extract was found to increase VGLUT1, VGLUT2, and VGLUT3 expression in one or more regions (prefrontal cortex, striatum, and CA1-3 region) of brain, thereby restoring cognitive deficit caused during phencyclidine-induced schizophrenia [91e93]. Likewise, BM extract also increased the expression of serotonin transporter (SERT) during development phase of learning and memory [75]. Increase in SERT, a transporter in presynaptic terminal that plays a key role in clearing excess 5-HT in the synapse back to presynaptic neuron, greatly regulates the concentration of 5-HT for signal transmission [94].

Effect of BM on receptors Effect of BM on receptor density Cholinergic receptor BM extract-induced upregulation of muscarinic acetylcholine receptor expression (MUS1) that has effect on cognitive performance [72,95,96]. Serotonergic receptors Contribution of serotonin receptors has been extensively studied in the process of learning and memory. Decrease in the receptor expression leads to impaired cognitive function. BM has been shown to alter the serotonergic (5-HT) receptor, which is known to play an important role in learning and memory. BM was demonstrated to upregulate the expression of 5HT2A, 5HT3A and downregulate 5HT7 in the rat hippocampus. Decrease in 5HT2A is associated with cognitive decline in aging, schizophrenia, and AD while 5HT3 is involved in learning, memory, and attention, both

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directly and indirectly by activating cholinergic system [97e99]. Intervention of BM reversed the effects of impaired cognitive function by upregulating the expression of 5HT3A. BM through 5HT3A also increased the levels of 5-HT, ACh, GABA, glutamate (Glu), and decreased dopamine (DA) levels. Interaction of 5HT3A with serotonergic and cholinergic neurons and other neurotransmitters along with anticholinesterase activity possibly enhances learning and memory [100e104]. Glutamatergic receptors AMPA receptors Diabetes mellitus (DM) is known to cause the risk of dementia and cognitive dysfunction [105e109]. Diabetes induced oxidative stresseassociated memory impairment might be due to altered glucose metabolism and abnormal activation of polyol-sorbitol pathway in neurons, impaired excitatory glutamatergic synaptic transmission, and early LTP (eLTP) [110e112]. BM exhibited antidiabetic activity [113] and its mechanism behind improving DMeassociated memory loss was studied by Pandey et al. [114]. The study concluded that BM extract improved spatial memory loss by upregulating AMPA GluR2 subunit gene expression in CA1 and CA3 of hippocampus and improving oxidative stress in streptozotocin (STZ)-induced DM type 2 (DM2) mice. GluR2 subunit of AMPA, a glutamate-gated ion channel, was thought to play a critical role in Ca2þ permeability and receptor trafficking. This subunit aids AMPA receptor in insertion to synapse and hence synaptic activation. Also, GluR2 has its role in maintaining the stability and assembly of AMPA receptor into the synapse [115]. These facts claim AMPA GluR2 subunit to be important in synaptic plasticity, learning, and memory. BM extract is found to decrease the blood glucose level by reversing the insulin resistance. Antidiabetic activity of BM along with its effect on AMPA GluR2 subunit indirectly reveals that it could regularize glucose metabolism, activation of polyol-sorbitol pathway in neurons, excitatory glutamatergic synaptic transmission, eLTP, and synaptic plasticity [110e112]. BM showing same activity in nondiseased control group revealed that BM could exhibit its activity both in pathological and nonpathological conditions. However, the study failed to explore whether the GluR2 subunit expression increased by BM is edited or unedited because Ca2þ permeability depends on unedited GluR2 subunit which is important for synaptic plasticity [115]. NMDA receptors BM extract has been shown to have its effect on NMDA receptors (NMDAR) at both the subtypes, NR2A and NR2B [116]. NR2A and NR2B are known for neuroprotection and neuronal death, respectively, during NMDAR activation. Alterations in NR2A/NR2B ratio were expected to be associated with modulation of LTP and long-term depression (LDP) functions during synaptic

plasticity in hippocampus [117]. Neuronal nitric oxide synthase (nNOS), an apoptotic factor via nitric oxide (NO), activated by NMDAR also plays critical role in NO-cGMP signaling for cognition. However, excess NO leads to excitotoxicity. BM extract, especially during thioacetamide (TAA)-induced hepatic encephalopathy reversed the altered NR2A/NR2B ratio and normalized the enhanced apoptotic factors (nNOS and NO) level along with Bcl2/Bax ratio [116]. Similar effect of BM extract was studied by Rai et al. and BM extract was found to restore spatial memory by upregulating NMDA GluN2B subunit in prefrontal cortex and hippocampus [85]. BM extract was also demonstrated to reverse the cognitive dysfunction by normalizing the expression of NMDAR in hippocampus and reducing the glutamate receptor binding during epilepsy [118] and the expression in prefrontal cortex and CA1-CA3 during schizophrenia [93,119]. GABA receptors Behavioral deficit and spatial memory deficit associated with decreased GABA receptor in epileptic rats were reversed by BM extract and bacoside A, by reversing the decreased GABA receptor to the normal. BM extract upregulated the decreased expression of GABAAa1, GABAAa5, and GABAAd and downregulated the increased GABAAg5 in hippocampus and cerebellum and likewise upregulated GABAAa1, GABAAg3, and GABAAd and downregulated GABAAa5 in striatum [79,120,121]. Though GABA receptor is a receptor for inhibitory neurotransmitter, there exist some studies that proved GABA receptors also play a role in enhancing learning and memory [122,123]. This statement was supported with studies conducted by Mathew et al., where improved cognitive performance was achieved with BM extract by reversing the decreased levels of GABA receptors [79,120,121].

Effect of BM on second messenger system PKC: PI3K/Akt signaling pathway Glutamatergic neurotransmission is reputed to be an important molecular mechanism for learning and memory formation via synaptic plasticity-related proteins. A study conducted by Matsumoto et al. demonstrated that BM upregulates the phosphorylation of proteins GluR, CaMKII, and CREB by activating PKC signaling pathway mediated by glutamatergic neurotransmission. The study revealed that BM triggers Ca2þ-dependent activation of calmodulin resulting in phosphorylation of CaMKII, a factor that is responsible for converting short-term memory to long-term memory [124]. Mechanistic study conducted by Saraf et al. also proved that BM demonstrated its antiamnesiac activity by PKC-CREB pathway involving calmodulin [125].

Bacopa monnieri for cognitive healthda review of molecular mechanisms of action Chapter | 3

Similarly, BM extract was demonstrated to protect the cognitive function during ischemia via PKC:PI3K/Akt signaling pathway. Treatment with BM extract in ischemiaassociated vascular dementia, nonspatial short-term memory loss, second most common dementia, induced by transient 2 vessels occlusion (T2VO) in mice protected the cognitive function. Also, treatment with bacopaside I, bacopaside N2, and a mixture of bacopaside II and bacosaponin D against oxygen and glucose-deprived ischemia in organotypic hippocampal slice cultures revealed that bacopaside I was the most potent phytocompound. The study concluded that contribution of cognitive protective activity of BM extract was due to more of bacopaside than the other phytoactives. The same study also indicated that the neuroprotective activity of BM during ischemiaassociated cognitive dysfunction was because of its intervention in PKC and PI3K/Akt signaling [126]. PKCε is a calcium independent but diacyl glycerol (DAG)-regulated serine-threonine kinase. PKCε provides protection from ischemia by regulating many pathways such as: (1) phosphorylation of the mitochondria KATP channel [127], (2) increased synaptosomal mitochondrial respiration, (3) activation of extracellular signal-regulated kinase (ERK) pathway [128], via NMDAR [129], and (4) by regulating GABA synapses [130]. However, study conducted by Le et al. stated that the protective action of bacopaside I was due to PKCε-mediated activation of mitochondrial KATP channel (Kir 6.2) and not by ERK. This activation in turn activates voltage gated calcium channels that regulate energy metabolism and thereby cell survival during ischemia [126]. Activity of bacopaside I on energy metabolism in mitochondria during ischemia further confirmed the investigation of Liu et al. [131], which claimed treatment in middle cerebral artery occlusion induced ischemic rats with bacopaside I for 6 days (3 days pre and posttreatment) increased the levels of ATP, energy charge, total adenine nucleotides, NO. The same study also reported that BM increased the activity of Naþ KþATPase and Ca2þMg2þATPase, the signal transducers, that also like Kir 6.2 play critical role in generating nerve impulse and maintaining the resting membrane potential [132]. Bacopaside I also reduced the size of infarct volume and cerebral edema. Activation of PKCε by BM could also have protected the hippocampus by maintaining the CBF during ischemia [130] which was in correlation with the study conducted by Kamkaew et al. [133]. Accumulation of Naþ, Ca2þ, Mg2þ during dysfunction of respective pumps in cells at incidence of neuronal stress, like ischemia, smoking, neurotoxin exposure, and brain injury, leads to catastrophic enzyme activation resulting in irreversible damage to cells. While, pretreatment and posttreatment of BM extract and bacopaside increased the levels of NaþKþ pump and Ca2þ, Mg2þATPase protecting the brain and thereby the memory [134e137].

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PI3K/Akt signaling pathway triggered via either GPCR or tyrosine kinase receptor was considered to play a role in neuronal cell survival and hence the cognitive function. Akt activation by PI3K by phosphorylating at Thr308/Ser473 regulates apoptosis by inhibiting apoptotic proteins like BAD, caspase 9, NF-kB, JNK, GSK3, and enhancing proteins like CREB [138]. BM has been shown to activate PI3K/Akt and level of pAkt and thereby regulate apoptosis, neuron survival, energy metabolism, protein synthesis, neuronal growth, and LTP potentiation [126,139e141].

Effect of BM on regulation of gene expression Regulation of reelin-dependent NMDARBDNF expression Coordination of transcription and translational process is required for LTP and thereby the long-term memory (LTM) formation. A study conducted by Preethi et al. elucidated the mechanism of BM extract in critical steps of reelindependent NMDAR-BDNF expression. BM was found to exert its effect on (1) Methylation of reelin promoter: BM extract elevated the levels of unmethylated reelin DNA, reelin mRNA and decreased the levels of methylated reelin DNA. The enhanced demethylation was attributed to enhanced memory [142]; (2) Splicing of ApoER 2 receptor: BM extract upregulated mRNA expression of ApoER 2 (ex 19) which is very critical for altered reelin to mediate NMDA receptor activity; (3) Phosphorylation of adapter protein, disabled 1 (DAB1): BM extract increased the levels of total DAB1 and p-DAB1, which correspond to the binding of reelin with ApoER 2 (ex 19). pDAB1 is also responsible for the action of Src kinase family (SKF) which phosphorylates NMDAR. (4) Modification of protein: BM extract was found to increase the levels of subunits of NMDAR, NR2A, and NR2B and thereby NR2A/NR2B ratio. (5) Interaction of NMDAR subunit with synaptic proteins: Increased levels of NR2AeSKF and NR2Ae PSD-95 (postsynaptic density protein) showed the interaction of NMDAR and synaptic proteins which activates NMDAR; (6) NMDA activation on methylation of neurotrophic factor promoter: BM extract elevated the levels of unmethylated BDNF DNA and also mRNA expression of BDNF showed that interaction of NMDAR was in coordination with transcriptional and translational activity of BDNF. Thus, BM extract was shown to regulate the gene expression to enhance LTP and the synaptic plasticity through reelin-dependent NMDAR-BDNF expression in support of LTM formation [82].

Regulation of miRNA The microRNAs (miRNAs) are considered as molecular micromanagers that fine-tune gene expression at posttranscriptional phase [143,144]. miRNAs along with

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Nutraceuticals in Brain Health and Beyond

argonaute (AGO) forms a silencing complex called miRISC to regulate the gene expression [145]. The miRNA expression and cognition with respect to neuronal growth and synaptic plasticity are inversely proportional, i.e., downregulation of miRNA enhances cognition [146]. It was found that serotonin greatly downregulated these miRNAs, which in turn enhanced the expression of CREB, a key component for synaptic plasticity [147]. Interestingly BM extract enhanced the cognition through miRNAmediated CREB cascade by enhancing serotonin level. Treatment with BM during brain growth spurt (BGS) (3e 4 weeks postnatal life of rats) downregulated the gene expression of dicer, Ago2, and miR-124 and protein expression of DICER and AGO2; upregulated the gene expression of creb1, total and phosphorylated CREB, and PSD-95 by enhancing 5-HT levels [148]. Reduced dicer, Ago2, DICER, and AGO2 enhance synaptic plasticity, learning, and memory by inhibiting the biosynthesis of miRNAs [145,146,149], whereas, upregulation of synaptic protein, creb1, and pCREB1 (transcription factors) was demonstrated to increase LTM formation and increased expression of PSD-95 proved to regulate architecture of synapses by contributing to localization of receptors, clustering of synaptic signaling proteins, and synapse stabilization [150e153].

Gene ontology analysis A gene ontology analysis based on gene expressions studied by Leung et al. [154] revealed that BM extract regulated (1) Biological processes: that include regulation of protein kinase activity, nervous system development, oxygen transport, synaptic transmission, cellular calcium ion homeostasis, transcription, long-term synaptic potentiation, excitatory postsynaptic membrane potential and potassium ion transport; (2) Cellular components: that include extracellular vesicle, cytoskeletal factors, ribonucleoprotein complex, cell projection, adherens junction, hemoglobin complex, axon, synaptic membrane, and dendrite; and (3) Molecular functions: that include RNA binding, substrate specific transporter activity, oxidoreductase activity, transcription factor binding, heme binding, core promoter binding, transcription core pressor activity, tubulin binding, NADH dehydrogenase activity, and chromatin DNA binding.

Effect of BM on structural factors and neuronal connections Synaptic plasticity LTP is a phenomenon of synaptic plasticity that plays a role in learning and in formation of LTM by inducing long lasting signal transmission between pre- and postsynaptic neurons. BM when measured for its excitatory postsynaptic

potential in hippocampus of rat brain was shown to enhance LTP magnitude, which revealed the ability of BM to strengthen the learning-dependent hippocampal synaptic response [155]. The study was in correlation with the activity of BM where increased synaptic plasticity could be possibly by PKA/ERK-CREB pathway. Enhanced expression of NMDAR2A and NMDAR2B receptors, phosphorylated ERK, CREB, transcription coactivator (p300), acetylated histones (H3, H4) and BDNF expression and downregulated expression of histone deacetylases (HDAC1, HDAC2) and protein phosphatases (PP1a, PP2A) supported that pathway involved in LTP could be the PKA/ERK-CREB pathway [155,156]. Additionally, the effect of BM on synaptic plasticity was confirmed in another study where BM extract was shown to upregulate the expression of fmr-1 gene that encodes for Fragile X mental retardation protein, the mRNA-binding protein that is present on dendritic spines, and is reputed to contribute to synaptic plasticity [157,158].

Neuronal density and dendritic arborization Dendritic arborization is considered to contribute to cognition enhancement and neuronal plasticity [159,160]. It has been shown that alteration in dendritic morphology in hippocampus [161] and amygdaloid [162] are involved in learning process. BM increased dendritic arborization in CA3 region of hippocampus [163] and amygdala neurons [164] thereby increased neuronal plasticity during the phase of learning. BM also demonstrated to enhance neuronal density in CA2 and CA3 region of hippocampus, which was thought to be a reason for cognitive improvement in schizophrenia-induced rat brain [119].

Beta-amyloid and tau proteins The extracellular accumulation of the beta-amyloid fragments (called beta-amyloid plaques) and intracellular accumulation of abnormal form of the protein tau (called tau tangles) are two of several distinctive brain changes associated with cognitive decline as in AD. Beta-amyloid (Ab) plaques are believed to contribute to cell death by interfering with interneuron communication at synapses, whereas intracellular toxic protein tau accumulation collapses the stability of microtubules and blocks the transport of nutrients and other essential molecules inside neurons [165]. Lack of impairment in the functional activity during initial stages might be due to compensatory mechanism of the brain. As neuronal damage increases, the brain can no longer compensate for the changes and individuals show subtle cognitive decline. Later, neuronal damage is so significant that individuals show obvious cognitive decline, including symptoms such as memory loss or cognitive impairment.

Bacopa monnieri for cognitive healthda review of molecular mechanisms of action Chapter | 3

BM was shown to enhance the neuronal cell viability against Ab25e35 by neutralizing the induced toxicity [166]. In another study Malishev et al. proved the efficacy of bacoside A in ameliorating the toxicity of Ab42 by interrupting at membrane interaction level [167]. Consistent to these studies the other similar studies also proved the ability of BM in enhancing cognition by mitigating Ab levels [168e170]. Ternchoocheep et al. proved the efficacy of BM in attenuating the expression of both total tau and phosphorylated tau in isolated cell system [171].

Effect of BM on CBF BM has been shown to increase the CBF in rat cerebral cortex independent of blood pressure. Chronic administration of BM was demonstrated to improve cognitive function [172] by increasing quiescent CBF up to 25% compared with controls, which implied cerebrovascular dilation [133]. It was hypothesized that the BM acts as a vasodilator by releasing nitric oxide from the endothelium and inhibiting calcium fluctuations in and out of the sarcoplasmic reticulum [173].

Effect of BM as neuroprotective agent BM as an antioxidant Brain is highly vulnerable to oxidative stress and free radicals, causing damage to DNA, proteins, and lipids [174e176]. Role of oxidative stress in relation to diseaseassociated cognitive dysfunction was well established in the past for diseases like AD, Parkinson disease (PD) [177], amyotrophic lateral sclerosis [178], and in conditions like aging [90,179] and cerebral ischemia [180,181]. BM and its phytocompounds exerted antioxidant activity by two major actions: (1) by exhibiting ferrous ion chelation and thus inhibited further reaction in free radical release [182,183] and (2) by increasing antioxidant enzymes to counter the free radicals. Intervention of BM to reduce free radicals by increasing antioxidative enzymes has been well studied in protecting the brain and its cognitive function against oxidative stress and related neuronal damage [90,183e188]. The BM extract was found to demonstrate neuroprotective activity by exhibiting antioxidant property by reducing lipid peroxidation in hippocampus during oxidative stress in diabetic rats. BM was also demonstrated to inhibit poly (ADP-ribose) polymerase (PARP), which could reduce the generation of free radicals [87]. This was in correlation with cell-free assay, where BM extract exhibited free radical scavenging activity that was indicated by inhibition of DPPH and inhibition of NADH oxidation. Also, BM was found to exhibit protective effect on DNA cleavage induced by UV photolysis of H2O2 by suppressing free radical generation. The same was confirmed with in vitro assay

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conducted in human immortalized fibroblast cells where BM extract was shown to inhibit H2O2-induced DNA damage greatly up to 65% compared to untreated group and was also found to inhibit H2O2-induced cytotoxicity [189]. A study conducted in vivo in diabetic rats showed that BM extract could increase antioxidant defense system by increasing SOD, CAT, GPx and GSH levels [185]. In another study, BM extract was shown to increase antioxidant enzyme SOD, CAT and GPx in all three major critical regions of brain involved in cognitive function, frontal cortex, hippocampus and striatum [190]. Study conducted by Shinomol et al. showed that pretreatment with BM extract in mice administered with 3-nitropropionic acid, a fungal toxin, completely abolished the elevation of oxidative markers (MDA, H2O2 levels and protein carbonyls) in striatal region of brain and reduced the depletion of thiols and glutathione levels. The same effect that was found in mice was also proved in N27 dopaminergic human cells [191]. Treatment with BM extract was found to normalize the depleted levels of SOD levels in diazepam-induced amnesiac mice [192]. Also BM extract was found to downregulate expression of hypoxia inducible factor-1 (HIF-1a) in hypoxic condition, which confirmed the activation of mitochondrial antioxidants and suppression of mitochondrial ROS system by BM [158,193]. In few studies, the antioxidant activity was attributed to bacosides [190,194]. However, the holistic dried crude powder also showed the activity and proved to prevent DNA damage [191]. By these mechanistic roles in oxidative cycle, BM appears to exhibit neuroprotective activity over several neuropathological conditions by maintaining redox homeostasis.

BM as antiapoptotic agent Bacosides and BM extract have been demonstrated to exhibit neuroprotective activity against oxidative stresse associated apoptosis by increasing the levels of cytochrome c oxidase, ATP, neural cell adhesion molecules (NCAM), g-glutamylcysteine synthetase (g-GCS), and thioredoxin1 (Trx1), and by decreasing chaperon heat shock protein (Hsp70, Hsp90), cytochrome enzyme activity (CYP450), caspase-3 activity, and glutamate dehydrogenase activity [134,194e198]. Also, BM was found to strengthen the synaptic plasticity and dendritic arborization during oxidonitrative stress by countering the apoptotic factors [197]. Additionally, BM extract in a cell-free assay was shown to inhibit caspase-1, caspase-3, and matrix metalloproteinase3, the enzymes that mediate apoptosis cascade [199].

BM as antiinflammatory agent Neuronal injury or accumulation of Ab causes activation of microglial and astrocytic cells mediated by concomitant release of proinflammatory cytokines and thereby

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Nutraceuticals in Brain Health and Beyond

activating apoptotic pathway which could lead to neuronal death. BM exhibited neuroprotective activity by inhibiting proinflammatory cytokines. BM extract and bacoside A were found to inhibit the release of TNF-a and interleukin6 from activated microglial cells [199]. In correlation with this study, BM extract was revealed to ameliorate agerelated neuroinflammation. BM was demonstrated to inhibit proinflammatory cytokines IL-1b, TNF-a, along with iNOS, that were elevated as age increases. Additionally, neuroprotective activity of BM in age-related neuroinflammation was confirmed by reduction in lipofuscin accumulation, an aging biomarker. This study proved that BM could promote healthy brain aging possibly by delaying the age-related cognitive decline [200].

Summary Extensive research has been carried out on BM and vits phytoactives toward understanding the neuronal molecular mechanisms involved in cognitive health benefits. To summarize, the research studies reveal that BM has effects on major pathways and factors involved in signal transduction underpinning the complex cognitive processes. The studied preclinical effects of BM on signal transduction can possibly explain, at least in part, the beneficial effects on cognition observed in human clinical trials. Moreover, effect of BM on CBF, balancing neuronal metabolism, and improving cerebral function by regulating signal transduction, along with its neuroprotective activity, appear to indicate a holistic effect on brain functions unlike chemical drugs that work by single mechanism of action. The existing scientific evidence strongly substantiates the traditional use of Bacopa monnieri for cognitive benefits and justifies its use in dietary and food supplements.

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upregulation of Fmr-1 gene expression in hippocampus. Evid base Compl Alternative Med 2015;2015. Rao BS, Desiraju T, Raju T. Neuronal plasticity induced by selfstimulation rewarding experience in ratsda study on alteration in dendritic branching in pyramidal neurons of hippocampus and motor cortex. Brain Res 1993;627(2):216e24. Bindu B, Alladi P, Mansooralikhan B, Srikumar B, Raju T, Kutty B. Short-term exposure to an enriched environment enhances dendritic branching but not brain-derived neurotrophic factor expression in the hippocampus of rats with ventral subicular lesions. Neuroscience 2007;144(2):412e23. Mahajan D, Desiraju T. Alterations of dendritic branching and spine densities of hippocampal CA3 pyramidal neurons induced by operant conditioning in the phase of brain growth spurt. Exp Neurol 1988;100(1):1e15. Vyas A, Mitra R, Rao BS, Chattarji S. Chronic stress induces contrasting patterns of dendritic remodeling in hippocampal and amygdaloid neurons. J Neurosci 2002;22(15):6810e8. Vollala VR, Upadhya S, Nayak S. Enhanced dendritic arborization of hippocampal CA3 neurons by Bacopa monniera extract treatment in adult rats. Rom J Morphol Embryol 2011;52(3):879e86. Vollala VR, Upadhya S, Nayak S. Enhanced dendritic arborization of amygdala neurons during growth spurt periods in rats orally intubated with Bacopa monniera extract. Anat Sci Int 2011;86(4):179e88. Swerdlow RH. Pathogenesis of Alzheimer’s disease. Clin Interv Aging 2007;2(3):347e59. Limpeanchob N, Jaipan S, Rattanakaruna S, Phrompittayarat W, Ingkaninan K. Neuroprotective effect of Bacopa monnieri on betaamyloid-induced cell death in primary cortical culture. J Ethnopharmacol 2008;120(1):112e7. Malishev R, Shaham-Niv S, Nandi S, Kolusheva S, Gazit E, Jelinek R. Bacoside-A, an Indian traditional-medicine substance, inhibits beta-amyloid cytotoxicity, fibrillation, and membrane interactions. ACS Chem Neurosci 2017;8(4):884e91. Holcomb LA, Dhanasekaran M, Hitt AR, Young KA, Riggs M, Manyam BV. Bacopa monniera extract reduces amyloid levels in PSAPP mice. J Alzheimers Dis 2006;9(3):243e51. Li Y, Yuan X, Shen Y, Zhao J, Yue R, Liu F, et al. Bacopaside I ameliorates cognitive impairment in APP/PS1 mice via immunemediated clearance of b-amyloid. Aging (Albany NY) 2016;8(3):521. Kottapalli S, Choudhary B, Nazir A. In: Impact of bacopa and elytrigia bioactives on effects associated with B-amyloid plaque formation: a three-tiered approach employing in silico, in vitro and C. elegans based studies; February 3, 2020. 2020. Ternchoocheep K, Ingkaninan K, Yasothornsrikul S. Tau protein attenuation ability of Bacopa monnieri exract on nerve growth factor-deprived PC12 cells in normal-serum and serum-free medium. Chiang Mai Med J 2012;51(3):59e69. Uabundit N, Wattanathorn J, Mucimapura S, Ingkaninan K. Cognitive enhancement and neuroprotective effects of Bacopa monnieri in Alzheimer’s disease model. J Ethnopharmacol 2010;127(1):26e31. Kamkaew N, Scholfield CN, Ingkaninan K, Maneesai P, Parkington HC, Tare M, et al. Bacopa monnieri and its constituents is hypotensive in anaesthetized rats and vasodilator in various artery types. J Ethnopharmacol 2011;137(1):790e5.

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[174] Siesjö B, Agardh C-D, Bengtsson F. Free radicals and brain damage. Cerebrovasc Brain Metab Rev 1989;1(3):165e211. [175] Jesberger JA, Richardson JS. Oxygen free radicals and brain dysfunction. Int J Neurosci 1991;57(1-2):1e17. [176] Smith C, Carney JM, Starke-Reed P, Oliver C, Stadtman E, Floyd R, et al. Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease. Proc Natl Acad Sci U S A 1991;88(23):10540e3. [177] Giasson BI, Ischiropoulos H, Lee VM-Y, Trojanowski JQ. The relationship between oxidative/nitrative stress and pathological inclusions in Alzheimer’s and Parkinson’s diseases. Free Radic Biol Med 2002;32(12):1264e75. [178] Halliwell B. Role of free radicals in the neurodegenerative diseases. Drugs Aging 2001;18(9):685e716. [179] Poon HF, Calabrese V, Scapagnini G, Butterfield DA. Free radicals and brain aging. Clin Geriatr Med 2004;20(2):329e59. [180] Murakami K, Kondo T, Kawase M, Li Y, Sato S, Chen SF, et al. Mitochondrial susceptibility to oxidative stress exacerbates cerebral infarction that follows permanent focal cerebral ischemia in mutant mice with manganese superoxide dismutase deficiency. J Neurosci 1998;18(1):205e13. [181] Essick EE, Sam F. Oxidative stress and autophagy in cardiac disease, neurological disorders, aging and cancer. Oxid Med Cell Longe 2010;3(3):168e77. [182] Tripathi YB, Chaurasia S, Tripathi E, Upadhyay A, Dubey G. Bacopa monniera Linn. as an antioxidant: mechanism of action. Indian J Exp Biol 1996;34(6):523e6. [183] Dhanasekaran M, Tharakan B, Holcomb LA, Hitt AR, Young KA, Manyam BV. Neuroprotective mechanisms of ayurvedic antidementia botanical Bacopa monniera. Phytother Res 2007;21(10):965e9. [184] Simpson T, Pase M, Stough C. Bacopa monnieri as an antioxidant therapy to reduce oxidative stress in the aging brain. Evid base Compl Alternative Med 2015;2015. [185] Kapoor R, Srivastava S, Kakkar P. Bacopa monnieri modulates antioxidant responses in brain and kidney of diabetic rats. Environ Toxicol Pharmacol 2009;27(1):62e9. [186] Velaga MK, Basuri CK, Robinson Taylor KS, Yallapragada PR, Rajanna S, Rajanna B. Ameliorative effects of Bacopa monniera on lead-induced oxidative stress in different regions of rat brain. Drug Chem Toxicol 2014;37(3):357e64. [187] Jyoti A, Sharma D. Neuroprotective role of Bacopa monniera extract against aluminium-induced oxidative stress in the hippocampus of rat brain. Neurotoxicology 2006;27(4):451e7.

[188] Deb DD, Kapoor P, Dighe R, Padmaja R, Anand M, D’souza P, et al. In vitro safety evaluation and anticlastogenic effect of BacoMindÔ on human lymphocytes. Biomed Environ Sci 2008;21(1):7e23. [189] Russo A, Izzo AA, Borrelli F, Renis M, Vanella A. Free radical scavenging capacity and protective effect of Bacopa monniera L. on DNA damage. Phytother Res 2003;17(8):870e5. [190] Bhattacharya S, Bhattacharya A, Kumar A, Ghosal S. Antioxidant activity of Bacopa monniera in rat frontal cortex, striatum and hippocampus. Phytother Res 2000;14(3):174e9. [191] Shinomol GK. Bacopa monnieri modulates endogenous cytoplasmic and mitochondrial oxidative markers in prepubertal mice brain. Phytomedicine 2011;18(4):317e26. [192] Prabhakar S, Saraf MK, Banik A, Anand A. Bacopa monniera selectively attenuates suppressed superoxide dismutase activity in diazepam induced amnesic mice. Ann Neurosci 2011;18(1):8. [193] Sanjuán-Pla A, Cervera AM, Apostolova N, Garcia-Bou R, Víctor VM, Murphy MP, et al. A targeted antioxidant reveals the importance of mitochondrial reactive oxygen species in the hypoxic signaling of HIF-1a. FEBS Lett 2005;579(12):2669e74. [194] Hota SK, Barhwal K, Baitharu I, Prasad D, Singh SB, Ilavazhagan G. Bacopa monniera leaf extract ameliorates hypobaric hypoxia induced spatial memory impairment. Neurobiol Dis 2009;34(1):23e39. [195] Chowdhuri DK, Parmar D, Kakkar P, Shukla R, Seth P, Srimal R. Antistress effects of bacosides of Bacopa monnieri: modulation of Hsp70 expression, superoxide dismutase and cytochrome P450 activity in rat brain. Phytother Res 2002;16(7):639e45. [196] Mohanty IR, Maheshwari U, Joseph D, Deshmukh Y. Bacopa monniera protects rat heart against ischaemiaereperfusion injury: role of key apoptotic regulatory proteins and enzymes. J Pharm Pharmacol 2010;62(9):1175e84. [197] Pandareesh M, Anand T. Neuroprotective and anti-apoptotic propensity of Bacopa monniera extract against sodium nitroprusside induced activation of iNOS, heat shock proteins and apoptotic markers in PC12 cells. Neurochem Res 2014;39(5):800e14. [198] Singh M, Murthy V, Ramassamy C. Neuroprotective mechanisms of the standardized extract of Bacopa monniera in a paraquat/ diquat-mediated acute toxicity. Neurochem Int 2013;62(5):530e9. [199] Nemetchek MD, Stierle AA, Stierle DB, Lurie DI. The ayurvedic plant Bacopa monnieri inhibits inflammatory pathways in the brain. J Ethnopharmacol 2017;197:92e100. [200] Rastogi M, Ojha RP, Devi BP, Aggarwal A, Agrawal A, Dubey G. Amelioration of age associated neuroinflammation on long term bacosides treatment. Neurochem Res 2012;37(4):869e74.

Chapter 4

Indian medicinal plants as drug leads in neurodegenerative disorders Rohit Sharma1, Neha Garg2, Deepanshu Verma3, Preeti Rathi3, Vineet Sharma1, Kamil Kuca4 and Pradeep Kumar Prajapati5 1

Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India;

2

Department of Medicinal Chemistry, Faculty of Ayurveda, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India; 3School of Basic Sciences, IIT Mandi, Mandi, Himachal Pradesh, India; 4Department of Chemistry, Faculty of Science, University of Hradec Králové, Hradec Králové, Czech Republic; 5Department of Rasa Shastra and Bhaishajya Kalpana, All India Institute of Ayurveda, Delhi, New Delhi, India

Chapter outline Abbreviations Introduction Methodology Etiopathology of neurodegenerative disorders Ayurvedic herbs: traditional usages in brain disorders

31 31 32 32 32

Abbreviations ACh acetylcholine AChE acetylcholinesterase AChR acetylcholine receptor ARE antioxidant response element Ab amyloid beta CaMKII/IV Ca2þ calmodulin kinase II/IV CAT choline acetyl transferase Ch Choline ChT Choline transporter (carrier) CoA coenzyme A CREB cyclic adenosine monophosphate response element binding protein DAT dopamine transporter ERK extracellular signal-regulated kinases GABA gamma aminobutyric acid GSH glutathione GSK3b glucose synthase kinase-3b IkB inhibitory kappa B JNK c-Jun N-terminal kinase KEAP-1 Kelch-like ECH-associated protein-1 LPS lipopolysaccharide MAO-A monoamine oxidase-A MAO-B monoamine oxidase-B

Nutraceuticals in Brain Health and Beyond. https://doi.org/10.1016/B978-0-12-820593-8.00004-5 Copyright © 2021 Elsevier Inc. All rights reserved.

Role of Indian ayurvedic herbs in neurodegenerative brain disorders Conclusion Acknowledgments References

32 42 44 44

MAPK mitogen-activated protein kinase MEK mitogen-activated protein kinase MMP mitochondrial membrane potential mTOR mammalian target of rapamycin NF-kB nuclear factor-kappa B NO nitric oxide Nrf2 nuclear factor e2-related factor 2 PI3K phosphatidylinsoitol-3-kinase PKC protein kinase C PL-Cg phospholipase Cg ROS reactive oxygen species SOD superoxide dismutase TH tyrosine hydroxylase TLRs tolllike receptors Trk tyrosine kinase receptor Ves vesicle

Introduction Plants are serving all living organisms in sustaining their life from ancient time. In Ayurveda, many plants are used for their medicinal properties. Ayurveda (traditional Indian system of medicine), in its armamentarium has rich evidence-based and time-tested traditional knowledge of

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bioactive natural products of herbal origin having putative roles in brain disorders as neuroprotective and nootropic. These medicinal herbs are widely practiced in different regions of India and have been described as neuroprotective agents. These herbs have been reported to exhibit encouraging bioactivities in neuropsychiatric and neurodegenerative changes associated with aging. Common neurodegenerative disorders are Alzheimer or Parkinson disease, which are characterized by progressive loss of structure and function of neurons or nerve cells. Neurodegenerative diseases are a major cause of disability and mortality, affecting a huge population worldwide with no permanent cure, posing a great challenge to the medical system. This chapter is an attempt to discuss the role of Indian medicinal plants and their bioactive phytocompounds in the prevention and management of neurodegenerative disorders, alongside understanding of their modes of action.

Methodology The data was collected from available published information in various online sources including PubMed, ScopeMed, ScienceDirect, Scopus and all other allied databases, and official publications from the fields of pharmacology, biochemistry, medicinal chemistry, biomedicine, and health. References were also searched from related and relevant review articles. The search was focused to probe the roles of Indian medicinal plants in neurodegenerative brain disorders in light of their ethnomedicinal uses and contemporary scientific evidences. The search combined the terms Ayurveda, Traditional medicine, Herbal medicine, Indian medicine, Neurodegenerative disease, Parkinson disease, Schizophrenia, Alzheimer disease, and Dementia. This search was undertaken in between July 2019 and February 2020. Searches were limited to the literature available in English.

Etiopathology of neurodegenerative disorders Many neuropsychiatric and neurodegenerative disorders, such as depression, dementia, Alzheimer disease, schizophrenia, Parkinson disease, neuronal impairment, multiple system atrophy, amyotrophic lateral sclerosis, and Huntington disease are predominantly appearing in the current era due to the stressful lifestyle and other multiple familial, occupational, or social factors. Key etiologies involved in neurodegenerative disorders are illustrated in Fig. 4.1. Common neurodegenerative disorders along with involved mechanisms and associated physio-biological changes are stipulated in Table 4.1 [1,2]. Oxidative stress and free radicals have been associated primarily in the development

FIGURE 4.1 Biological factors leading to neurodegenerative disorders.

of pathophysiology of neurodegenerative changes in brain tissues. The free radicals generated can trigger multiple pathological processes such as inducing the formation of advanced glycation end products, nitration, lipid peroxidation adduction products, and also the carbonyl-modified neurofilament protein and free carbonyls, eventually leading to neuronal death. The pathological involvement of oxidative stress and acetylcholinesterase in degenerative changes of neuronal tissues is illustrated in Fig. 4.2.

Ayurvedic herbs: traditional usages in brain disorders Since ancient times traditional practitioners in India have been using several herbs to alleviate wide range of psychological ailments; and these herbs are part of these practitioners’ Ayurvedic prescriptions. In Ayurveda, Rasayana herbs are advocated to to attain long age, healthy aging, intelligence, youthfulness, ideal strength of psychosomatic tissues and sense organs and enhance intellect and memory [3]. Aging-related neurodegeneration can be controlled in a systematic manner with the help of Rasayana treatment. Many single and compound Rasayana drugs of Ayurveda possess multifaceted roles like immunomodulation; free radical scavenging; and adaptogenic, rejuvenating, nootropic, and nutritive effects. Rasayana herbs are well reported to modulate the neuronal, endocrinal, and immune systems. These botanicals serve as a rich source of active antioxidants; reestablish youthfulness; enhance and improve recall memory, intellect, and cognitive abilities [4,5]. Comprehensive discussion on these herbs are beyond the scope of this report; thus, traditional Ayurvedic treatments including these herbs have been detailed in Table 4.2 [6].

Role of Indian ayurvedic herbs in neurodegenerative brain disorders Except neuropsychiatric disorders of genetic origin, these traditional herbs have been successfully practiced in

TABLE 4.1 Neurodegenerative disorders: associated pathophysiological changes and manifestations. Pathophysiological changes in brain

Aggregated proteins

Protein form

Alzheimer disease

Continuous loss of intellectual capabilities, viz., thinking, memory, and socio-occupational functioning

Neuronal loss and brain atrophy, primarily in basal fore brain and hippocampus

Ab, hyperphosphorylated tau

Amyloid plaque, neurofibrillary tangles

Multiple system atrophy

Slowed movement, tremors, rigidity, incoordination, impairment of speech, a croaky, quivering voice, orthostatic hypotension-induced fainting, poor bladder control

Progressive loss of function and death of different types of neurons in brain and spinal cord

a-synuclein

Glial cytoplasmic inclusion

Parkinson disease

Tremors; inability to balance; stiff, slow, and shuffling gait.

Declined neurotransmitter (dopamine, 5- hydroxytryptamine, acetylcholine, nor-epinephrine) levels - mainly in substantia nigra and corpus striatum

a-synuclein

Lewy bodies

Amyotrophic lateral sclerosis

Muscular weakness, loss of motor functions, paralysis, breathing problems

Degeneration of motor neurons

Superoxide dismutase-1

Hyaline inclusions

Huntington disease

Uncontrolled and involuntary movements (aka chorea). Progresses to rigidity and dystonia

Progressive breakdown of nerve cells, basal ganglia region of brain is affected

Huntington

Neuronal inclusions

Prion disease

Can be manifested as Creutzfeldt-Jakob disease, Variant Creutzfeldt-Jakob disease, Gerstmann-StrausslerScheinker syndrome, fatal familial insomnia

Misfolding of a normal cell-surface brain protein called cellular prion protein

Prion protein

Prion plaques

Schizophrenia

Delusions, hallucinations, thought disorder, and neurocognitive dysfunction

Neurodevelopmental or neurodegenerative disorder where imbalance of dopamine and glutamate may be involved

e

e

Indian medicinal plants as drug leads in neurodegenerative disorders Chapter | 4

Modes of manifestation/ presentation of symptoms

Neurodegenerative diseases

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FIGURE 4.2 Effect of oxidative stress and acetylcholinesterase in development of neurodegeneration.

various parts of India to manage several brain disorders. The herbs belong to distinct botanical families. Some are wild; some are cultivated; and some of them are herbs, vines, shrubs, or trees. Most of the herbal treatments include more than one part of plant and some prescriptions are given in combination with certain adjuvants or other herbs. This suggests the synergistic approach of judicious herbal combinations of the majority of Ayurvedic drug therapies. Several Ayurvedic herbs which are widely practiced in Indian traditional system are now validated in light of scientific evidences and globally recognized. There is a long list of promising Indian single herbs that are proven to be effective in Alzheimer and Parkinson disease. The active phytocompounds with their possible mechanism of action are detailed in Table 4.3. Chemical structures of isolated phytocompounds that are found effective in neurodegenerative ailments are illustrated in Figs. 4.3 and 4.4. A number of Indian medicinal plants are being explored in recent years with their phytocompounds having antioxidant and anticholinesterase activities (Fig. 4.5), beneficial to manage neurodegenerative changes of brain [7,8]. Several natural antioxidant biomolecules are isolated from Indian herbs, such as: epigallocatechin gallate from green tea, resveratrol from grapes, curcumin from turmeric, chrysotoxine from dendrobium species; mangiferin and morin, specifically enriched in fruit, vegetables, plants such as Mangifera indica; Paeonol from

Paeonia officinalis, ursolic acid from Punica granatum, Duchesnea indica, and Eucalyptus; salidroside from Rhodiola imbricate, asiaticoside from Centella asiatica, polydatin from grapes, Biochanin A from botanicals such as Oroxylum indicum and Cassia fistula, gypenosides from Gynostemma pentaphyllum, nerolidol from Chrysanthemum cinerariaefolium, quercetin and kaempferol from several herbs such as onion, carrot, etc., peonol from Paeonia officinalis, hesperetin and naringenin from several citrus fruits, and myricetin from Indian globe thistle. A number of reports are available ascertaining their potential roles in managing Parkinson disease through various mechanisms such as modulating mitochondrial functions, activating intracellular antioxidants, mediating metabolism of dopamine, and decreasing iron metal levels (Fig.4.6) [9]. Few Indian botanicals are also suggested to have potential role in managing neurodegenerative disorders such as amyotrophic lateral sclerosis and Huntington disease. These are stipulated in Table 4.4 [10]. Based on available reports a schematic representation of mechanistic pathways for Indian herbal phytocompounds involved in neuroprotection against Alzheimer and Parkinson disease is portrayed in Fig. 4.7. A compendium of multitargeted mechanisms of action can be postulated based on published studies. It is observed that external stimulus binds to Trk receptor activating PI3K/AKT, Ras/MAPK, and PL-Cg pathways. LPS binds to TLRs activating NF-kB and JNK signaling. External stimulus releases Nrf2 from

TABLE 4.2 Traditional usages of Indian medicinal plants in brain disorders. Common name

Active constituents

Traditional ayurvedic recommendations

Apamarga

Achyranthes aspera (Amaranthaceae)

Chaff-flower

D-glucuronic

acid, oleanolic acid, hentriacontane, glycosides, amino acids

Snuffed seed powder relieves head heaviness and migraine

Vacha

Acorus calamus (Araceae)

Sweet-flag

Asarone-a and b

Powder with honey; beneficial in anxiety and epilepsy; bark powder is memory enhancer

Vasa

Adhatoda vasica (Acanthaceae)

Adusa

Vasicinone, vasicol, vasicine

Powder with honey cures chronic epilepsy

Shirisha

Albizzia lebbek (Fabaceae)

Shirish tree

Budmunchiamine alkaloids, saponins

Seed powder helps to cure psychosis, insanity, anxiety, hysteria; seeds with black pepper powder when locally applied near eyes cures fainting

Palandu

Allium cepa (Liliaceae)

Onion

Quercetin, allylsulfides

Decoction of its seeds helps to cure insomnia

Akarkara

Anacyclus pyrethrum (Asteraceae)

Pellitory

Pyrethrin

Its paste with vinegar when licked with honey helps to cure hysteria intensity; its decoction with “Brahmi” controls epilepsy and mental retardation; massaging its root powder with Mahua oil heals paralysis

Brahmi

Bacopa monniera (Scorphularaceae)

Indian pennywort

Bacosides A, B, C

Its juice taken with Kuth (Costus speciosus root) powder in honey can cure hysteria

Kushmanda

Benincasa hispida (Cucurbitaceae)

White Gourd

Multiflorenol and its acetate

Its juice taken with Kuth powder in honey can cure hysteria; its juice with Liquorice root can control epilepsy

Rajika

Brassica nigra (Brassicaceae)

Black mustard

Gallic acid, quercetin

Its seeds when ground with pigeon’s droppings and applied on forehead can relieve migraine; massage of its oil reduces fatigue

Lata Karanja

Caesalpinia bonduc (Caesalpiniaceae)

Fever nut

Hematoxylol, stereochenol A

Seeds powder in different combinations when snuffed via nostrils can cure migraine; leaves juice helps to relieve epilepsy

Arka

Calotropis procera (Asclepiadaceae)

Calotrope, Madar

Ursane triterpenoids

Flowers and its milk are useful in epilepsy; leaf powder snuff can relieve migraine; leaves powder mixed with peppermint, camphor, and cardamom when inhaled can relieve migraine

Bhanga

Cannabis sativa (Cannabinaceae)

Marijuana

Tetrahydro cannabinoids

Leaves are beneficial in insomnia; leaves with asafoetida can be used in epileptic women Continued

35

Scientific name

Indian medicinal plants as drug leads in neurodegenerative disorders Chapter | 4

Ayurvedic herb

TABLE 4.2 Traditional usages of Indian medicinal plants in brain disorders.dcont’d Common name

Active constituents

Traditional ayurvedic recommendations

Cassia occidentalis (Caesalpiniaceae)

Negro coffee

Flavonoid glycosides

Decoction can relieve hysteria and epilepsy; snuff of its powders can also relieve hysteria

Chakramarda

Cassia tora (Caesalpiniaceae)

Foetid carria, Ringworm plant

Cassiside, toralactone

Seeds when ground with sour gruel and applied on forehead can relieve migraine pain

Jyotishmati

Celastrus paniculatus (Celastraceae)

Staff tree

Celapanin, celapanigin triglycerides

Seeds powder in combination with almond, pepper, and cardamom is nootropic

Mandukaparni

Centella asiatica (Apiaceae)

Brahmi, Indian pennywort

Asiaticosides

Its powder when formulated in combination is nootropic; powder taken with cow milk can relieve insomnia; powder mixed with honey/pepper/cow ghee can treat anxiety

Indrayan

Citrullus colosynthis (Brassicaceae)

Colocynth, Bitter apple

Cucurbitacins colosynthosides

Its fruit juice or oil when applied on forehead can cure migraine and earache; snuff of its root powder can cure epilepsy

Nimbu

Citrus aurantifolia (Rutaceae)

Lime

Limonene, (E)-caryophyllene

Seeds and fruit juice can relieve insanity and anxiety

Aparajita

Clitorea ternatea (Fabaceae)

Asian pigeonwings, Darwin pea

Triterpenoid, flavonol glycosides, anthocyanins, hirsutene

Powder of seeds and roots when snuffed can relieve migraine pain

Shankhapushpi

Convolvulus microphyllus (Convolvulaceae)

Shankhapushpi

Convoline, convolamine

Roots powder given with milk, honey or ghee is nootropic; its juice with honey relieves epilepsy, psychosis, and insanity

Dhanayaka

Coriandrum sativum (Apiaceae)

Coriander

Linalool, l-terpinene, a-pinene

Its decoction when regularly consumed can relieve vertigo and headache

Dhatura

Datura metel (Solanaceae)

Devil’s trumpet

Hyoscine, hyocyamine

Paste of seeds with black pepper given to treat psychosis

Garjaraka

Daucus carota (Apiaceae)

Carrot

Carotene, Lycopene, Falcarinol

When leaves are cooked with warm cow ghee and given as nasal/ear drops can cure migraine

Bhringaraja

Eclipta alba (Asteraceae)

Trailing eclipta

Widelolactone and glycoside

Its juice mixed with black pepper when applied on forehead can relieve migraine

Vata

Ficus benghalensis (Moraceae)

Banyan tree

Bengalenosides, Leucopelargonidin glycoside

Root bark powder with cow milk and sugar is nootropic

Peepal

Ficus religiosa (Moraceae)

Peepal tree

Pelargonidine glycosides, sterols

Extracts of branches can cure insanity

Yashtimadhu

Glycyrrhiza glabra (Fabaceae)

Licorice

Glycyrrhizin, glycyrrhetic acid, isoliquiritin, isoflavones

Powder of roots with cow ghee can cure epilepsy

Japa

Hibiscus rosa sinensis (Malvaceae)

Rose mallow, China rose

Friedelin, amyrin, cynaroside, apigetrin, quercetin

Leaves powder given with sweet milk to improve memory

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Scientific name

Kaasmarda

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Ayurvedic herb

Hyoscyamus niger (Solanaceae)

Henbane

Hyoscine, coumarinolignans

Few drops of its oil when taken with water at frequent intervals can relieve hysteria in women

Madyantika

Lawsonia inermis (Lythraceae)

Hina, henna tree

Lawsone, lawsoniaside

Seeds given with honey or decoction of its flowers given to relieve giddiness

Shobhanjan

Moringa oleifera (Moringaceae)

Drum stick plant

Moringine, Moringinine

Bark juice instilled in nostrils or given orally to cure meningitis; Decoction of roots can cure epilepsy and hysteria in women

Jatamansi

Nardostachys Jatamansi (Valerianaceae)

Spikenard

Jatamansone and terpenoids

It can relieve hysteria and epilepsy when given with ghee

Ahiphena

Papaver somniferum (Papaveraceae)

Opium poppy

Morphine, codeine, noscapine, papaverine

Helps to cure delirium, insomnia, and convulsions

Pippali

Piper longum (Piperaceae)

Pipli

Piperine, Piperlongumine

Root powder with jaggery can cure insomnia; when mixed with “Vacha” it can cure migraine

Maricha

Piper nigrum (Piperaceae)

Round pepper

Piperine and related alkaloids

When given with “Vacha” on empty stomach can treat hysteria

Agastya

Sesbania grandiflora (Fabaceae)

Sesbane

Leucocyanidin, cyanidin, triterpenoids

Its leaves when ground with black pepper and cow urine and given to inhale can relieve epilepsy; its leaf or flower juice instilled in nostrils can cure migraine pain

Bala

Sida cordifolia (Malvaceae)

Country mallow

Sidasterone A and B

It is boiled in milk with Achyranthus aspera and given to alleviate excessive anxiety

Kantakari

Solanum surratense (Solanaceae)

Kanteli

Carpesterol, solanocarpin, solasonine, solamargine

Paste of its roots, poppy seeds are made in child’s urine and instilled in nostrils to relieve epilepsy

Gorakhmundi

Sphaeranthus indicus (Asteraceae)

East Indian globe thistle

Sterols, sesquiterpenoids

It is given with clove powder to treat Parkinson disease

Tagar

Valeriana jatamansi (Valerianaceae)

Valerian

Jatamansone, jatamansinol

Its juice with honey can be given to treat hysteria, epilepsy and delirium

Nirgundi

Vitex negundo (Verbenaceae)

Five-leaved chaste tree

Negundoside, nishindaside, casticin

Powder of fruits can help to cure mental weakness

Draksha

Vitis vinifera (Vitaceae)

Grapes

Flavonoids, procyanidin, organic acids

Grapes given with Emblica officinalis and ginger powder can relieve fainting and dizziness

Ashwagandha

Withania somnifera (Solanaceae)

Indian ginseng, winter cherry

Withaferin A, withanolide A

Its root powder can improve overall body strength and relieve stress

Indian medicinal plants as drug leads in neurodegenerative disorders Chapter | 4

Paarseek Yavani

37

TABLE 4.3 Traditional Indian herbs beneficial in Alzheimer and Parkinson disease. Common name

Part used

Phytoconstituent

Possible action

References

Mucuna pruriens (Fabaceae)

Cowitch

Seed

L-dopa

(precursor to the dopamine, norepinephrine, and epinephrine)

Neuroprotective, antioxidant, scavenge 1,1-diphenyl-2-picryl-hydrazyl radicals and reactive oxygen species

[11]

Nirgundi

Vitex negundo (Verbenaceae)

Five leaved chaste

Leaves, seeds

Casticin, isoorientin, chrysophenol D, luteolin, pehydroxybenzoic acid

Antioxidant, enhance the response to GABA, antipsychotic, anxiolytic

[12]

Alasi

Linum usitatissimum (Linaceae)

Flaxseed, linseed

Seed, seed oil

Alpha-linolenic acid, Eicosapentaenoic acid, Docosahexanoic acid

Role of omega 3 as neuroprotective, antioxidant

[13]

Nimba

Azadirachta indica (Meliaceae)

Neem, margosa

Fresh leaf

Meliacin- nimbolide, quercetin, kaempferol

Neuroprotective, antioxidative, and antiapoptotic effects

[14]

Sarpaganda

Rauwolfia serpentinia (Apocynaceae)

Indian snakeroot, serpentine wood

Dried root

Reserpine, ajmaline, serpentine

Anxiolytic, tranquilizing

[15]

Dhatura

Datura metel (Solanaceae)

Devil’s trumpet

Seeds, flowers

Hyoscyamine, scopolamine

Antipsychotic effect

[16]

Shankhapushpi

Convolvulus pluricaulis (Convolvulaceae)

Shankhahuli

Whole plant

Convolamine, scopoletin, convoline

Improves learning, memory and recall, AChE inhibition, nootropic

[17] [18]

Guggulu

Commiphora whighitti (Burseraceae)

Gugul

Resin

Guggulsterone, guggulipid

Anti-dementia, AChE inhibition, nootropic

[19]

Ardraka

Zingiber officinale (Zingiberaccae)

Zinger

Rhizome

Zingerone (4-(4-hydroxy3-methoxyphenyl)-2butanone)

Improves recall, retention, and acquisition

[20]

Amlaki

Phyllanthus emblica (Phyllanthaceae)

Indian gooseberry

Fruit mesocarp

Ascorbic acid, emblicanin A and B

Antioxidant, nootropic, improves memory

[21]

Ashwagandha

Withania somnifera (Solanaceae)

Indian ginseng

Root

Withanolides, withaferins, isopelletierine, anaferine, cuscohygrine, anahygrine

Anti-inflammatory, antioxidant, Ab inhibition, AChE inhibition, regeneration of axons, dendrites, and synapses, [dopamine and glutathione level

[22]

Brahmi

Bacopa monniera (Scorphularaceae)

Indian pennywort

Leaves, roots

Bacosides, brahmi

Antioxidant, enhance memory, attenuate a-synuclein aggregation, attenuate apoptosis, enhance mitochondrial function and cognition

[23]

Nutraceuticals in Brain Health and Beyond

Scientific name

Kapikacchu

38

Herb

Gilo, Gado

Stem

Tinosporine, tinosporide, giloin, magnoflorine

Antioxidant, antipsychotic, neuroprotective, memory enhancer, ACh synthesis

[24]

Haridra

Curcuma longa (Zingiberaceae)

Turmeric

Rhizome

Curcumin, b-sesquiphellandrene, curcumenol

Anti-amyloidogenic, antiinflammatory, anti-ChE, anti- b-secretase, improve mitochondrial complex-I activity and striatal dopamine level, inhibit a-synuclein aggregation, antioxidant

[25]

Shigru

Moringa oleifera (Moringaceae)

Drum stick plant

Leaves

Isothiocyanate, kaempferol, beta-sitosterol

Antioxidant, modify levels of monoamines such as norepinephrine, dopamine serotonin

[26]

Jatamaansi

Nardostachys jatamansi (Valerianaceae)

Spikenard

Dried rhizomes and roots

Sesquiterpenes and coumarins

Dopamine enhancing property, improves amnesia

[27]

Jyotishmati

Celastrus paniculatus (Celastraceae)

Staff tree, intellect tree

Seed oil

Triterpenoids and sesquiterpenes

Neuroprotective, antioxidant, improves ACh level

[28]

Jatiphal

Myristica fragrans (Myristicaceae)

Nutmeg

Seed

Myristicin, elemicin, safrole, myristic acid, alpha-pinene

Improve learning, recall, and memory deficit

[29]

Dhaanyak

Coriandrum sativum (Apiaceae)

Coriander

Seed

l-terpinene, linalool, a-pinene

Antiinflammatory, antioxidant, hypolipidemic, improves memory loss

[30]

Kumkum

Crocus sativus (Iridaceae)

Saffron

Stigmas

Crocin, a-crocin, carotenoids

Improves impaired hippocampal synaptic plasticity and fibrilogenesis

[31]

Falgu

Ficus carica (Moraceae)

Fig

Fruit

Umbelliferone, rutin, coumarins

Antioxidant, improves memory deficit and recall memory

[32]

Patha

Cissampelos pareira (Menispermaceae)

Velvet leaf

Whole vine

Hayatine, arachidic acid, bebeerine, berberine

Inhibits AChE, antioxidant, antiinflammatory

[33]

Kushmanda

Benincasa hispida (Cucurbitaceae)

Wax gourd

Fruit

Flavonoids, glycosides, proteins, carotenes, vitamins, minerals, b-sitosterin

Neuroprotective, antioxidant, nootropic

[34]

Mandukaparni

Centella asiatica (Apiaceae)

Brahmi, Asiatic pennywort

Leaves, Roots

Asiaticoside, centelloside, brahmoside

Antioxidant, inhibits AChE

[35]

Nithyakalyani

Catharanthus roseus (Apocynaceae)

Sadabahar, red periwinkle

Dried root

Ajmalicine, lochnerine, dimeric, vinblastine, vincristine

Neuroprotective, antioxidant effect

[36]

39

Tinospora cordifolia (Menispermaceae)

Indian medicinal plants as drug leads in neurodegenerative disorders Chapter | 4

Guduchi

Continued

40

Herb

Scientific name

Common name

Part used

Phytoconstituent

Possible action

References

Puga

Areca catechu (Arecaceae)

Betel nut

Fruit

Arecoline, quercetin, isorhamnetin

Inhibits MAO-A, Muscarineic (M2) binding activity

[37]

Shatavari

Asparagus racemosus (Liliaceae)

Shatavar, Satavar

Tuber

Asparagine, shatavarin

Antioxidant, inhibits MAOA and B

[38]

Shati

Salvia lavandulaefolia (Lamiaceae)

Sage weed

Extracted oil

b-caryophyllene, spathulenol, neomenthol

Inhibits AChE

[39]

Vacha

Acorus calamus (Araceae)

Sweet flag

Rhizome

a and b - asarone

Neuroprotective, improve memory defecits

[40]

Yashtimadhu

Glycyrrhiza glabra (Fabaceae)

Licorice

Root

Glycyrrhizin, glycyrrhetic acid, isoliquiritin

Neuroprotective, antiinflammatory, antioxidant, nootropic, antidementia

[41]

Shalparni

Desmodium gangeticum (Fabaceae)

Sarivan

Root

Pterocarpanoids, gangetin

Inhibits AChE, nootropic

[42]

Aparajita

Clitoria ternatea (Leguminosae)

Asian pigeonwings

Roots

Triterpenoid, flavonol glycosides

Increases ACh level, enhances memory

[43]

Daadima

Punica granatum (Punicaceae)

Pomegranate

Flower, fruits

Ellagic acid, punicalagin, punicalin

Neuroprotective, antioxidant, improve learning abilities and memory retention

[44]

Shyamaparni

Camellia sinensis (Theaceae)

Green tea and black tea

Leaves

Epicatechins, Epigallocatechin, Epicatechin gallate, Epigallocatechin gallate, Theaflavin-3-gallate, theaflavin-30 -gallate and theaflavin-3,30 -digallate

Attenuate apoptosis, inhibit ROS-NO pathway, protects dopaminergic neurons, [ Tyrosine hydroxylase and dopamine transporter expression

[45]

Nutraceuticals in Brain Health and Beyond

TABLE 4.3 Traditional Indian herbs beneficial in Alzheimer and Parkinson disease.dcont’d

Indian medicinal plants as drug leads in neurodegenerative disorders Chapter | 4

41

FIGURE 4.3 Chemical structures of key phytocompounds found effective in neurodegenerative disorders (I).

FIGURE 4.4 Chemical structures of key phytocompounds found effective in neurodegenerative disorders (II).

Nrf2-KEAP-1 complex and activates ARE. Such multitarget roles of Indian medicinal plants may allow them to be a promising and potential therapeutic alternative in

prevention and management of age-associated neurodegenerative disorders. Since the pathophysiology of neurodegenerative diseases involves multiple factors, richness of

42

Nutraceuticals in Brain Health and Beyond

FIGURE 4.5 Indian medicinal plants with their phytocompounds having antioxidant and anticholinesterase activity.

FIGURE 4.6 Natural antioxidant biomolecules from Indian herbs against Parkinson Disease and their possible mechanisms.

multiple bioactive phytocompounds in medicinal herbs could be a torch-bearer to neuroscientists working in the field of drug development.

Conclusion Findings of the present study affirm that many Indian herbs and their various active phytocompounds are well proven for their effective role in neuropsychiatric and neurodegenerative disorders. This detailed information could serve to provide lead to design integrated and effective therapeutic regimen to manage the brain disorders with

prevention and curative approach, though future investigations are warranted to ascertain and validate the bioactivities of phytocompounds and various herbal extracts. Pharma industries are also encountering significant challenges as the drug discovery process for neurodegenerative ailments has now turned very costly, riskier, and critically ineffective. It is hoped that the vast and timetested knowledge of traditional system of medicines coupled with current therapeutic approaches may offer new functional leads for various age-related neurodegenerative diseases.

TABLE 4.4 Possible role of phytoconstituents of Indian herbs in amyotrophic lateral sclerosis and Huntington disease. Common name

Part used

Phytocompound

Possible role

Felmingia vestita

Sohphlang

Root, tuber

Genistein (4,5,7-trihydroxyisoflavone)

Antiviral, anti angiogenic

Camellia sinensis

Green tea

Leaves

Epigallocatechin gallate (Flavan -3 -ol)

Antioxidant, anti inflammatory

Bacopa monniera

Brahmi

Leaves, roots

Bacoside and Bacoposide

Protects the brain against oxidative deteriorative changes

Sesamum indicum

Sesame

Oil

Sesamol

Protective effects against 3-NP induced HD

Tomatoes and tomato-based products

Tomato

Fruit

Lycopene

Antioxidant, additional nitric acid pathway in neuroprotection

Curcuma longa

Turmeric

Tuber

Curcumin

Improves the motor defects and inflation of SDH activity

Several plants particularly grapes

Grapes

Fruit

Resveratrol (3,5,4-trihydroxy trans stilbene)

Antiaging, antiischemic, improves locomotor activity and maze performance

Indian medicinal plants as drug leads in neurodegenerative disorders Chapter | 4

Botanicals

43

44

Nutraceuticals in Brain Health and Beyond

FIGURE 4.7 Schematic representation of mechanistic pathways for Indian herbal phytocompounds involved in neuroprotection against Alzheimer and Parkinson disease.

Acknowledgments The authors express their sincere gratitude to Bharat Ratna Mahamana Pandit Madan Mohan Malviya, the founder of Banaras Hindu University, Varanasi, for his services to humanity, great vision, and blessings.

References [1] Levenson RW, Sturm VE, Haase CM. Emotional and behavioral symptoms in neurodegenerative disease: a model for studying the neural bases of psychopathology. Annu Rev Clin Psychol 2014;10(1):581e606. [2] Kovacs GG. Molecular pathological classification of neurodegenerative diseases: turning towards precision medicine. Int J Mol Sci 2016;17(2). [3] Sharma R, Amin H. Rasayana therapy: ayurvedic contribution to improve quality of life. World J Pharmacol Res Tech 2015;4(1):23e33. [4] Sharma R, Kabra A, Rao MM, Prajapati PK. Herbal and holistic solutions for neurodegenerative and depressive disorders: leads from Ayurveda. Curr Pharmaceut Des 2018;24(22):2597e608. [5] Sharma R, Kuca K, Nepovimova E, Kabra A, Rao MM, Prajapati PK. Traditional Ayurvedic and herbal remedies for Alzheimer’s disease: from bench to bedside. Exp Rev Neurother 2019;19(5):359e74.

[6] Balkrishna A, Misra LN. Ayurvedic plants in brain disorders: the natural hope. J Tradit Med Clin Natur 2017;6:221. [7] Rasool M, Malik A, Qureshi MS, Manan A, Pushparaj PN, Asif M, et al. Recent updates in the treatment of neurodegenerative disorders using natural compounds. Evid base Compl Alternative Med 2014;2014. [8] Kabra A, Sharma R, Kabra R, Baghel US. Emerging and alternative therapies for Parkinson disease: an updated review. Curr Pharm Des 2018;24(22):2573e82. [9] Ding Y, Xin C, Zhang C-W, Lim K-L, Zhang H, Fu Z, et al. Natural molecules from Chinese herbs protecting against Parkinson’s disease via anti-oxidative stress. Front Aging Neurosci 2018;10:246. [10] Rehman MU, Wali AF, Ahmad A, Shakeel S, Rasool S, Ali R, et al. Neuroprotective strategies for neurological disorders by natural products: an update. Curr Neuropharmacol 2019;17(3):247e67. [11] Lampariello L, Cortelazzo A, Guerranti R, Sticozzi C, Valacchi G. The magic velvet bean of mucuna pruriens. J Tradit Complement Med 2012;2(4):331e9. [12] Adnaik R, Pai P, Sapakal V, Naikwade N, Magdum C. Anxiolytic activity of vitex negundo linn. in experimental models of anxiety in mice. Int J Green Pharm 2009;3(3):243e7. [13] Shallie PD, Talabi DJ, Olayinka OO, Babatunde BR, Akpan HB, Otulana OJ, et al. Flaxseed oil as a potential neuro-protective agent on the cerebellum of rotenone mice model of Parkinson’ diseases. Int J Brain Cogn Sci 2017;6(3):43e50.

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[14] Xiang X, Wu L, Mao L, Liu Y. Anti-oxidative and anti-apoptotic neuroprotective effects of azadirachta indica in Parkinson-induced functional damage. Mol Med Rep 2018;17(6):7959e65. [15] Lobay D. Rauwolfia in the treatment of hypertension. Integr Med (Boulder) 2015;14(3):40e6. [16] Ahmed MN, Kabidul Azam MN. Traditional knowledge and formulations of medicinal plants used by the traditional medical practitioners of Bangladesh to treat Schizophrenia like psychosis. Schizophr Res Treatment 2014:10. Article ID 679810. [17] Amin H, Sharma R, Vyas M, Prajapati PK, Dhiman K. Shankhapushpi (Convolvulus pluricaulis Choisy): validation of the Ayurvedic therapeutic claims through contemporary studies. Int J Green Pharm 2014;8(4):193e200. [18] Amin H, Sharma R, Prajapati P, Dwivedi R, Vyas H, Vyas M.  Nootropic (medhya) effect of Bhavita Saṇkhapuṣp ı tablets: a clinical appraisal. Anc Sci Life 2014;34(2):109e12. [19] Saxena G, Singh SP, Pal R, Singh S, Pratap R, Nath C. Gugulipid, an extract of Commiphora whighitii with lipid-lowering properties, has protective effects against streptozotocin-induced memory deficits in mice. Pharmacol Biochem Behav 2007;8:797e805. [20] Gharibi A, Khalili M, Kiasalari Z, Hoseinirad M. The effect of Zingiber officinalis L. on learning and memory in rats. J Bas Clin Pathophysiol 2013;2:2013e4. [21] Vasudevan M, Parle M. Memory enhancing activity of Anwala churna (Emblica officinalis Gaertn.): an Ayurvedic preparation. Physiol Behav 2007;91:46e54. [22] Kulkarni SK, Dhir A. Withania somnifera: an Indian ginseng. Prog Neuro-Psychopharmacol Biol Psychiatry 2008;32:1093e105. [23] Singh HK, Dhawan BN. Neuropsychopharmacological effects of the ayurvedic nootropic Bacopa monniera Linn. (Brahmi). Indian J Pharmacol 1997;29(5):359e65. [24] Sharma R, Amin H, Prajapati P, Ruknuddin G. Therapeutic vistas of Guduchi (Tinospora cordifolia): a medico-historical memoir. J Res Edu Ind Med 2014;XX(2):113e28. [25] Rajakrishnan V, Viswanathan P, Rajasekharan KN, Menon VP. Neuroprotective role of curcumin from Curcuma longa on ethanolinduced brain damage. Phyther Res 1999;13(7):571e4. [26] Obulesu M, Rao DM. Effect of plant extracts on Alzheimer’s disease: an insight into therapeutic avenues. J Neurosci Rural Pract 2011;2:56e61. [27] Karkada G, Shenoy KB, Halahalli H, Karanth KS. Nardostachys jatamansi extract prevents chronic restraint stress-induced learning and memory deficits in a radial arm maze task. J Nat Sci Biol Med 2012;3:125132. [28] Bhanumathy M, Harish MS, Shivaprasad HN, Sushma G. Nootropic activity of Celastrus paniculatus seed. Pharm Biol 2010;48:324327. [29] Parle M, Dhingra D, Kulkarni SK. Improvement of mouse memory by Myristica fragrans seeds. J Med Food 2004;7:157e1661. [30] Mani V, Parle M. Memory-enhancing activity of Coriandrum sativum in rats. Pharmacologyonline 2009;2:827e39.

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[31] Papandreou MA, Kanakis CD, Polissiou MG, Efthimiopoulos S, Cordopatis P, Margarity M, et al. Inhibitory activity on amyloid-b aggregation and antioxidant properties of Crocus sativus stigmas extract and its crocin constituents. J Agric Food Chem 2006;54:8762e8. [32] Saxena V, Ahmad H, Gupta R. Memory enhancing effects of Ficus carica leaves in hexane extract on interoceptive behavioral models. Asian J Pharm Clin Res 2013;6:109e13. [33] Kulkarni PD, Ghaisas MM, Chivate ND, Sankpal PS. Memory enhancing activity of cissampelos pariera in mice. Int J Pharm Pharm Sci 2011;3:206e11. [34] Roy C, Ghosh TK, Guha D. The antioxidative role of Benincasa hispida on colchicine induced experimental rat model of Alzheimer’s disease. Biog Amin 2007;21(1):42e55. [35] Veerendra KMH, Gupta YK. Effect of different extracts of Centella asiatica on cognition and markers of oxidative stress in rats. J Ethnopharmacol 2002;79:253e60. [36] Jyothi P, Sarala KD. Central nervous system protection by Catharanthus roseus leaf extract on streptozotocin einduced diabetes in rat brain. J Pharmacog 2012;3(2):63e6. [37] Houghton PJ, Seth P. Plants and the central nervous system. Pharmacol Biochem Behav 2003;75(3):497e9. [38] Dhingra D, Kumar V. Pharmacological evaluation for antidepressant-like activity of Asparagus racemosus Willd. in mice. Pharmacologyonline 2007;3:133e52. [39] Perry N, Houghton PJ, Theobald A, Jenner P, Perry E. In-vitro inhibition of human erythrocyte acetylcholinesterase by Salvia lavandulaefolia essential oil and constituent terpenes. J Pharm Pharmacol 2000;52(7):1347e56. [40] Vohora SB, Shah SA, Dandiya PC. Central nervous system studies on an ethanol extract of Acorus calamus rhizomes. J Ethnopharmacol 1990;28:53e62. [41] Chakravarthi KK, Avadhani R. Beneficial effect of aqueous root extract of Glycyrrhiza glabra on learning and memory using different behavioral models: an experimental study. J Nat Sci Biol Med 2013;4(2):420e5. [42] Joshi H, Parle M. Antiamnesic effects of Desmodium gangeticum in mice. Yakugaku Zasshi 2006;126:795e804. [43] Rai KS, Murthy KD, Karanth KS, Nalini K, Rao MS, Srinivasan KK. Clitoria ternatea root extract enhances acetylcholine content in rat hippocampus. Fitoterapia 2002;73:685e9. [44] Cambay Z, Baydas G, Tuzcu M, Bal R. Pomegranate (Punica granatum L.) flower improves learning and memory performances impaired by diabetes mellitus in rats. Acta Physiol Hung 2011;98:409e20. [45] Anandhan A, Janakiraman U, Manivasagam T. Theaflavin ameliorates behavioral deficits, biochemical indices and monoamine transporters expression against subacute 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP)-induced mouse model of Parkinson’s disease. Neuroscience 2012 30;218:257e67.

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Chapter 5

Role of nutraceuticals in the management of severe traumatic brain injury Ramesh Teegala Department of Neurosurgery, Anu Institute of Neuro & Cardiac Sciences, Vijayawada, Andhra Pradesh, India

Chapter outline Introduction Traumatic brain injury Nutritional management in TBI

47 47 50

Introduction Traumatic brain injury (TBI) is defined as a nondegenerative, noncongenital insult to the brain from an external mechanical force, possibly leading to permanent or temporary impairment of cognitive, physical, and psychological functions, with an associated diminished or altered state of consciousness [1,2]. TBI is a major global health problem called as silent epidemic [3,4]. Global incidence of TBI is estimated to be 500e800 new cases per 100,000 world population [5]. The highest incidence per population is reported among high income countries like America and European Union countries. The incidence reporting from low and middle income countries is not appropriate; hence, the incidence may appear low compared to high income countries [6]. With such a high incidence, it remains a growing health problem causing severe morbidity and mortality. For clinical evaluation and uniform communication across all medical fraternity, TBI is classified with Glasgow coma score (GCS) scale proposed by Jennette B and Teasdale GM in 1974 and ranges from 3 to 15 [7]. Three is the lowest and 15 is the highest score and outcomes depend upon the score; higher the score better the outcome. According to this scale, TBI can be classified as mild (GCS: 13e15), moderate (GCS: 8e12), and severe (GCS660 g of (nonorganic) vegetables daily [139]. It is likely that the same or greater quantity of vegetables simultaneously upregulated Nrf2, although that was not measured. In an era in which it may not be possible to persuade patients to consume >660 g of vegetables daily, a high sulforaphane-yielding whole broccoli sprout supplement may be an appropriate prescription [126,129].

The microbiota An environment that supports the health of the IEC and immune network will most likely also support the microbiota, assuming that appropriate prebiotics are part of the regular dietary intake. The effect of the diet on the microbiota is influenced by seasonal variations, and this is

The gut microbiome: its role in brain health Chapter | 14

apparent in traditional societies such as the Hadza huntergatherers in Tanzania, who exhibit an exceptionally diverse microbiome. Such seasonal effects are less likely to occur in those consuming a modern Western diet, which contributes to lower diversity [148]. A detailed discussion of the available prebiotics that will enhance proliferation of the butyrate-producers and other desirable microbes is beyond the scope of this chapter and readers are referred to a recent comprehensive review of the subject [46].

Therapeutic interventions Probiotics as therapy Although it is tempting to consider that probiotics might achieve the desired restoration of a dysfunctional gut ecosystem and its target axes, this would address only one-half of the bidirectional relationship between the host and its resident microbiota. Nevertheless, probiotic supplementation is a key intervention recommended by integrative and complementary medicine clinicians for a range of conditions. When considering the rationale for probiotic supplementation, how does one reconcile such therapy in light of the following unanswered dilemmas? (1) Probiotics typically do not colonize the host, leaving no trace in a stool sample within a few weeks of cessation [149]; (2) Diet can rapidly and reproducibly influence the microbiota [45]; (3) A metagenomic analysis can identify species not available as supplements [150]; (4) Post antibiotic therapy, reconstitution of the microbiome has been shown to take 5 months longer with a probiotic than without [151]. Nevertheless, strong evidence supports the hypothesis that the efficacy of probiotics is both strain-specific and disease-specific for a number of diseases and many clinical trials have achieved successful outcomes in this manner [152]. It appears, however, that the potential for a particular strain to provide benefit is commonly conflated with the notion that any probiotic supplement claiming a high microbial count will benefit the host and reestablish the microbiome after antibiotic therapy [153,154].

Antimicrobials as therapy The ready availability of stool microbiome and SIBO breath testing has seen interest in therapies aimed at replacing missing gut microbes and/or eradicating pathogens or pathobionts. Even though IECs are equipped with several specialized mechanisms to actively eradicate undesirable microbes, enhancement of these mechanisms does not appear to be a target of the therapies commonly employed by clinicians.

207

A popular therapeutic approach within the Integrative and Complementary Medicine community is that of “weed, seed and feed,” wherein the first step involves the use of a plant-derived antimicrobial extract or oil to address dysbiosis. The “seed” step follows with the administration of either individual or combinations of probiotics which are “fed” by the use of prebiotic supplements. A Google search using the term “weed seed feed” returns numerous entries but notably, none of these is from a peer-reviewed PubMed publication. As is the case with pharmaceutical antibiotics, no plant-derived antimicrobial is selective for pathogens alone, so that some degree of commensal destruction will occur with resultant compromise of the gut microbial population [155]. The uncertainties in the nature of SIBO and its diagnostic options are highlighted in this 2019 review of SIBO research over the last 3 years [156].

Is it time for a host-centric model? Given that there remain many unanswered questions in relation to the clinical applications of both probiotics and antimicrobials as therapy for addressing dysbiosis and consequent chronic conditions, a model that focuses on restoring homeostasis within the gut ecosystem may more reasonably coincide with the endogenous cellular mechanisms. A diet and lifestyle that is ideal for the host may, with some specific consideration for the prebiotic needs of the commensal microbes, be similarly ideal for the microbiome. Addressing the requirements of a healthy gut ecosystem to harness the various endogenous mechanisms discussed in this chapter should simultaneously provide for all physiological processes, including the gut-brain axis. In the words of Litvak et al., “Because our immune system already has a way to balance the colonic microbiota, harnessing this host control mechanism for therapeutic means could provide an alternative to targeting the microbes themselves for remediation of dysbiosis” [61].

Conclusion In our seemingly insatiable quest to manipulate the composition of the gut microbiome for the enhancement of human health, it is worth contemplating that Nature has sustained human life on this planet for millenniadand all without any of the benefits conferred by modern technology. Clearly, there are processes embedded within human cells that have allowed them to adapt to their ever-changing environments. With a better understanding of these endogenous mechanisms, it may be possible to formulate clinical strategies that resemble those used by Nature

208 Nutraceuticals in Brain Health and Beyond

herself. This chapter suggests that an important piece of the gut-immune health and gut-brain puzzle has been largely overlooked and that a greater focus on restoring the function of the remarkable intestinal epithelial cells is needed in order to redress the balance. The bidirectional interaction represented by the Gut-Microbiome-Brain Axis has markedly changed the way we must continue to consider aberrant function of the human nervous system, not in isolation but in integration with the GI ecosystem of the host in expectation of a favorable impact on human health and behavior.

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Chapter 15

The psychopharmacology of saffron, a plant with putative antidepressant and neuroprotective properties DezsT Csupor1, 2, Barbara To´th1, 2, Javad Mottaghipisheh1, Andrea Zangara3, 4 and Emad A.S. Al-Dujaili5 1

Department of Pharmacognosy, Faculty of Pharmacy, University of Szeged, Szeged, Hungary; 2Institute for Translational Medicine, Medical School,

University of Pécs, Pécs, Hungary; 3Euromed S.A., Barcelona, Spain; 4Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC, Australia; 5Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom

Chapter outline Introduction Traditional and ethnomedicinal uses Chemical constituents Stigma Flowers except stigma Tepal Stamen

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Introduction The genus Crocus, belonging to the Iridaceae family, comprises more than 100 species which are distributed in Eurasia, primarily in Mediterranean Europe and Western Asia. Crocus sativus L., the only species that has commercial importance, is traditionally cultivated in several countries such as Azerbaijan, France, Greece, India, Italy, and recently also in Afghanistan, New Zealand, China, Israel, Japan, and Mexico [1]. However, the majority of world production derives from Iran. The stigma of the plant (saffron) is the most expensive spice in the world. Although it has been used in traditional medicine since ancient times, the importance of saffron crocus as a medicinal plant has increased only in the past decades, after the discovery of its antidepressant effect. The phytochemistry of the stigma has been studied in detail and the mechanism of antidepressant action has been investigated in several preclinical experiments. Clinical efficacy has been confirmed in clinical trials and their meta-analyses. Future perspectives of C. sativus as a medicinal plant include the use of plant parts other than

Nutraceuticals in Brain Health and Beyond. https://doi.org/10.1016/B978-0-12-820593-8.00015-X Copyright © 2021 Elsevier Inc. All rights reserved.

Mode of action Antidepressant effect Neuroprotective effect Anticonvulsant effect Clinical applications Conclusions References

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the stigma, which could reduce therapeutic costs, and extension of its use to other therapeutic areas of central nervous system (CNS) disorders. This review aims to provide a snapshot of the current status of knowledge of the phytochemistry and pharmacology of saffron, and other parts of the saffron crocus flower, with special focus on the psychopharmacological use of the plant.

Traditional and ethnomedicinal uses Saffron has been used in the medicinal systems of regions where it is native and cultivated. Although its contemporary use covers different therapeutic areas, it is applied to treat CNS disorders in different regions of the world. Its use dates back to the second millennium BC, when Assyrians and Babylonians used saffron in treatment of “problems of head” [2]. According to Zakariya Razi, a famous Iranian healer (865e925 CE), the use of saffron led to an elevated feeling of pleasure, close to a psychotic state [3]. Avicenna (980e1037 CE) in his Canon of

213

214 Nutraceuticals in Brain Health and Beyond

Medicine combined the works of Pedanius Dioscorides (40e90 CE) and Galen (129e200 CE) with contemporary Eastern medical practices. In this text, he refers to the sedative and exhilarating effects of saffron [4]. The latter characteristic could indicate its potential use to treat depression. However, from the list of indications determined by Pedanius Dioscorides [5] only the treatment of overindulgence could be somewhat considered as an indication related to the CNS. Considering that Galen in his major work did not mention the medicinal use of saffron, it can be assumed that the application of saffron to CNS indications only became widespread in ancient or medieval Arabic medicine. In China, the dried stigma [Xi Hong Hua (西红花)] is used to relieve anxiety, depression, fear, and confusion, and to treat psychosis [6]. In Ayurvedic medicine, it is used for its relaxant, antistress, and antianxiety effects. In contemporary Iranian folk medicine, saffron is used to strengthen the senses and elevate mood and it is thought that its odor is hypnotic [2].

Chemical constituents Botanically, C. sativus L. is a monocot perennial herb. The flower of C. sativus comprises three stamens and three stigmas (outer sections of carpels) which are the distal ends of the plant’s stalk. Since the petals and the sepals are not distinguishable, those parts are therefore called tepals. It is noteworthy that in several papers, the chemical composition of sepal and petal samples has been reported. Below we use the same names as mentioned in the literature. Phytochemical studies have primarily focused on the compounds responsible for the color and aroma of saffron since these determine the value of the plant as a spice [7e13]. For the same purpose, in a majority of the studies, the stigma was examined [8e10,13e20]. Chemical analysis of C. sativus stigmas has shown the presence of about 150 volatile and non-volatile compounds. The volatiles consist of terpenes (terpene alcohols, and their esters), among which safranal is the main component. Non-volatile compounds comprise crocin, crocetin, picrocrocin, and flavonoids (quercetin and kaempferol) (Fig. 15.1). In recent years, due to increased affirmation of saffron bioactivities, and considering its high price, much effort has been made toward investigating the other parts of C. sativus flowers, which are mainly considered as waste by-products, including the tepals and stamen. C. sativus by-products are rich sources of phenolics [21,22], including flavonoids [21e23] and anthocyanins [22].

Stigma The chemical composition of saffron consists of primary (5% fat, 12% protein, 5% crude fiber, and 63% sugars) [3,24] and secondary metabolites (apocarotenoids, monoterpenoids, and flavonoids) [11]. Among the major secondary metabolites of saffron, carotenoids have been identified as predominant compounds. Apocarotenoids are the products of the oxidative cleavage of carotenoids. The apocarotenoid crocetin (8,80 diapo-8,80 -carotene-dioic acid) (4) is one of the major compounds responsible for the color of saffron, and it is formed by the enzymatic cleavage of zeaxanthin [7]. Crocin (trans-crocetin bis(b-D-gentiobiosyl) ester) (1) is a watersoluble carotenoid pigment. The term crocin refers to members of a series of related carotenoids that are either monoglycosyl or diglycosyl esters of crocetin, including crocin itself, which account for more than 60% of the total crocetin sugar esters [12]. Several studies reported crocins as the main compounds of saffron comprising approximately 6e16% of total dry matter [10,14e20]. Saffron is rich in picrocrocin (2) as the second major compound (1e13% of dry matter) [8,10]. This monoterpene glycoside, responsible for the bitter taste and flavor of saffron, has been assumed to be the precursor of safranal and produced by degradation of zeaxanthin [25]. The aroma of saffron is mainly attributed to safranal (3) as its third main secondary metabolite. Safranal is mostly produced through the hydrolysis of picrocrocin. This aromatic aldehyde is the predominant constituent of saffron volatile oil (30e70%) [9,13]. Apart from safranal and isophorone and its isomers, 4-hydroxy-2,6,6-trimethyl-1cyclohexen-1 carboxaldehyde, along with terpenes, terpene alcohols, and their esters have been documented as the volatile components of saffron [8,25]. In addition to the abovementioned major components, flavonoids (kaempferol, quercetin, isorhamnetin, apigenin, luteolin, and myricetin glycosides), vitamins (B1, C2, C6, C, A, and F), phytosterols (b-sitosterol and stigmasterol), nitrogen-containing compounds (thymine, uracil, harman, and nicotinamide), terpenoids (monoterpenes, tetraterpenes, triterpenoids, and diterpenoids), fat-soluble carotenoids (phytoene, phytofluene, zeaxanthin, lycopene, and a- and b-carotene), and phenolic acids (chlorogenic acid, caffeic acid, and gallic acid) have been characterized in saffron [18,19,26e32].

Flowers except stigma In some studies, the flowers of C. sativus (except stigma) have been phytochemically investigated. Kaempferol-3-O-

The psychopharmacology of saffron Chapter | 15

215

FIGURE 15.1 Characteristic constituents of C. sativus (1: crocin; 2: picrocrocin; 3: safranal; 4: crocetin; 5: kaempferol; 6: quercetin; 7: isorhamnetin; 8: naringenin; 9: kaempferol-3-O-sophoroside; 10: kaempferol-3-O-glucoside; 11: quercetin-3-O-sophoroside).

sophoroside was identified as the major compound [33], among several non-flavonoids including crocetin derivatives, picrocrocin, crocusatin B and C, safranal, and sinapic acid derivatives [16,34,35].

Tepal Most of the studies on C. sativus by-products have focused on the tepals [10,36e45]. Flavonoids, exclusively flavonol aglycons and glycosides, have been identified as the most predominant compounds, whereas safranal is missing from this plant part [45]. The most abundant flavonol aglycons were characterized (in descending order) as kaempferol (5) [36,38,43,45], quercetin (6) [36,43,44], isorhamnetin (7) [36], and naringenin (8) [43]. Kaempferol glycosides were detected as the main secondary metabolites of C. sativus tepals, specifically kaempferol-3-O-sophoroside (9) [40e42,44], kaempferol-3-O-glucoside (astragalin) (10) [10,36,38], and kaempferol 7-O-glucoside [37e39]. From quercetin glycosides, quercetin-3-O-sophoroside (11) [36,41], and from isorhamnetin derivatives, isorhamnetin-3-O-sophoroside were the major component [36,37,39].

Several glycosylated anthocyanins have been identified in tepal samples of C. sativus. These plant parts are rich in delphinidin derivatives (mainly delphinidin-3,5-di-O-bglucoside) [10,41], beside petunidin derivatives [41]. Organic acids were also detected in C. sativus tepals, particularly phenolic acids including p-coumaric acid, vanillic acid, protocatechuic acid, protocatechuic acid methyl ester, 4-hydroxybenzoic acid, and 3-hydroxy-4methoxybenzoic acid [38]. Furthermore, the presence of nitrogen-containing compounds (e.g., tribulusterine, harman, nicotinamide, and adenosine) [38], monoterpenoids (crocusatin-C, -D, -E, -I, -J, -K, and -L), picrocrocin [38], crocin [45], cyclohexadiene derivatives [38], along with kinsenoside, goodyeroside A, and 3-hydroxy-g-butyrolactone [42] was also documented.

Stamen The stamen contains kaempferol-3-O-sophoroside [40,44] and kaempferol-3-O-glucoside [40] in lower concentrations than tepals, as well as other flavonoids and anthocyanins [22].

216 Nutraceuticals in Brain Health and Beyond

Mode of action Most of the preclinical studies have been carried out with saffron (the stigma of the plant) or its secondary metabolites, and have focused mainly on the antidepressant effect. However, several studies have examined the neuroprotective and anticonvulsant effects.

Antidepressant effect Crocin, safranal, and crocetin are the components of the plant that play a role in the antidepressant effect based on the available evidence. A bioactivity-guided study identified crocin as the active component by means of behavioral models of depression [46,47], and this was reconfirmed by similar studies [48]. Efficacy was demonstrated in a clinical study, where crocin (30 mg per day for 8 weeks) reduced the symptoms of depression in subjects with metabolic syndrome compared to the placebo group [49]. As an adjunct treatment, crocin (30 mg daily) increased the efficacy of selective serotonin reuptake inhibitors in patients with major depression [50]. The anxiolytic effect of crocin was demonstrated in animal experiments [51,52]. One further study reported an anxiolytic effect for safranal [53]. In an animal experiment, the antidepressant effects of crocin and crocetin were evaluated in mice after acute and subacute administration where crocetin was observed to be more effective than crocin in the forced swimming (FST) and tail suspension tests [54]. The mechanism of the antidepressant effect has not been fully elucidated. It might be partly mediated by safranal and crocin inhibiting the uptake of dopamine, norepinephrine, and serotonin, as demonstrated in an animal experiment [55]. Crocin is a weak inhibitor of monoamine oxidase (MAO), whereas safranal lacks this effect [56]. The antidepressant activity of crocin might be associated with the suppression of neuroinflammation and oxidative stress, as observed in an experiment in the mouse hippocampus [48]. The aqueous extract of saffron increased the levels of brain-derived neurotrophic factor (BDNF), VGF neuropeptide, cAMP response element binding protein (CREB), and phospho-CREB (p-CREB) in rat hippocampus, which might be related to the antidepressant effect [57]. The effect on CREB might be only a marginal role in the antidepressant activity of crocin, since CREB levels changed only slightly in the rat cerebellum, whereas the levels of brain-derived neurotrophic factor and VGF neuropeptide were unaltered [58]. However, a study reported that crocin prevented the decreasing effect of malathion on BDNF in the rat hippocampus [59]. Crocetin exerted antidepressant activity in animals exposed to chronic stress and also decreased oxidative damage in their brains [60].

It has been demonstrated that saffron can inhibit Nmethyl-D-aspartate (NMDA) and sigma opioid receptors. Since NMDA and sigma receptors can regulate corticosterone release from the adrenal cortex in rats, it can be concluded that saffron and crocin may inhibit corticosterone secretion in stressed mice via blockade of NMDA and/ or sigma opioid receptors located in the adrenal cortex [61]. Both hydro-ethanolic saffron extract and trans-crocetin had an antagonistic effect on NMDA receptors in rat cortical brain slices; however, only the extract was active on kainate receptors [62]. Further, saffron extracts and crocetin had affinity at the phencyclidine (PCP)-binding site of the NMDA receptor and at the sigma-1 receptor, while crocin and picrocrocin were inactive [63]. Since a correlation between hyperhomocysteinemia and depression is proposed, the reduction of homocysteine levels by saffron in patients with major depression might be part of its mechanism of action. The components responsible for this bioactivity have not been identified [64]. It is assumed that the clinical effect is partly related to the antioxidant capacity of the stigma [49]. The antidepressant activities of petals and corms have been studied in animal experiments. The effects of aqueous and ethanolic extracts of saffron stigma and petals were studied using FST in mice: both decreased immobility time in comparison with normal saline [65]. The petroleum ether and dichloromethane fractions obtained from the aqueous ethanol extract of C. sativus corms showed significant antidepressant-like activity in a dose-dependent manner in animal behavioural models of depression [47]. Kaempferol, a major flavonoid of the petals, was reported to have antidepressant activity in mice and rats in the FST [66].

Neuroprotective effect The neuroprotective effect of saffron is partly related to its antioxidant effect. This is supported by animal experiments. The neuroprotective effects of the plant might be exploited in the prevention or treatment of Parkinson disease (PD), Alzheimer disease (AD), or other pathologies. In rats all the alterations (oxidative markers and neurobehavioral activities) induced by cerebral ischemia and reperfusion were significantly attenuated by pretreatment with saffron, most probably by virtue of its antioxidant property [67]. Similarly, crocin had protective effects against ischemic reperfusion injury and cerebral edema in a rat model of stroke [68]. Saffron extract and crocin could decrease glucose toxicity associated with increased reactive oxygen species production in a cell viability assay [69]. Safranal had protective effects on different markers of oxidative damage (redox status, lipid peroxidation, and oxidative DNA damage) in rat hippocampal tissue following quinolinic acideinduced oxidative damage [70].

The psychopharmacology of saffron Chapter | 15

In a study by Vakili et al., coadministration of saffron extract had no effect on cognitive performance of mice, but it reversed significantly the aluminum-induced changes in MAO activity and the markers of lipid peroxidation, reflecting a certain level of neuroprotective potential [68]. Saffron extract improved ethanol-induced impairments of learning behaviors in mice, which was attributed to crocin, whereas picrocrocin was ineffective [71]. In a study on rats, crocins improved working memory and attenuated scopolamine-induced performance deficits in spatial working memory [72]. Treatment of rats with saffron extract or crocin blocked the ability of chronic stress to impair spatial learning and memory retention, and reduced oxidative stress damage. Further, crocin decreased plasma levels of corticosterone, as measured after the end of stress [73]. Saffron extract had only moderate acetylcholine esterase inhibitory activity in an in vitro study, but crocetin, dimethyl crocetin, and safranal were more active, with IC50 values of 96.33, 107.1, and 21.09 mM, respectively [74]. In a rat model of experimentally induced AD, safranal prevented learning and memory decline by ameliorating apoptosis, and reducing inflammation, oxidative stress, and cholinesterase activity [75]. Safranal exerted a protective effect against toxicity and oxidative damage induced by beta-amyloid and hydrogen peroxide in PC12 cells [76]. In neuronal cell culture models of AD, crocin and crocetin reduced the activities of b- and g-secretases, key enzymes of the amyloidogenic pathway, and also amyloid accumulation [77]. In mice with experimentally induced AD, crocin reduced the beta-amyloid content of the brain, increased the level of antioxidant enzymes, and reduced the level of acetylcholinesterase [78]. In AD transgenic mice, crocetin not only significantly reduced inflammation, but also decreased amyloid accumulation in the brain and improved learning and memory deficits [79]. Trans-crocetin enhanced beta-amyloid degradation in monocytes isolated from AD patients by upregulating the lysosomal protease cathepsin B [80]. Crocetin protected the activity of antioxidant enzymes in rats after the administration of 6-hydroxydopamine (6OHDA), a compound that can experimentally induce PD. Moreover, the histopathologic examination of the substantia nigra revealed that crocetin protects neurons from the toxic effects of 6-OHDA or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [81e83]. Crocin reduced neurodegeneration and prevented the decrease in dopamine levels in rats with rotenone-induced PD. This might be explained by the activation of the PI3K/Akt/mTOR axis [84]. The anti-AD effect of crocin and crocetin could partly be explained by the inhibition of E46K a-synuclein fibrillization [85,86].

Anticonvulsant effect Intraperitoneally administered safranal and crocin were evaluated for their anticonvulsant effects in mice with

217

pentylenetetrazole (PTZ)-induced convulsions. Safranal reduced the seizure duration, delayed the onset of tonic convulsions, and protected mice from death, whereas crocin was not active [87]. In three different acute or chronic experimental models in mice, safranal and nanostructured lipid-vehicle-carried safranal showed a dose-dependent effect to relieve or prevent seizures. The nanoformulation of safranal further increased its efficacy [88]. Safranal dosedependently decreased the incidence and latency of both minimal clonic seizures and generalized tonic-clonic seizures following PTZ administration to rats. Since these effects were abolished by flumazenil, it was supposed that the effect of safranal may be mediated through the GABAA-benzodiazepine receptor complex [89].

Clinical applications In this section we provide a brief summary of the clinical evidence on the use of saffron either as an alternative or a complementary therapy for neuropsychological conditions. Fig. 15.2 summarizes the clinical application of saffron. Depression is one of the most studied indications of saffron, since its efficacy and safety have been reported in numerous clinical trials and meta-analysis. Moreover, based on the results of in vitro and animal studies, human clinical studies have been conducted to assess its efficacy and safety in the treatment of patients with cognitive dysfunction and AD (Table 15.1). The clinical efficacy of saffron in the treatment of depression has become of great interest to many research groups worldwide: at least eight meta-analysis have been published on this topic during the past 8 years [99e106]. Despite the fact that the inclusion and the exclusion criteria for these meta-analysis differ (e.g., clinical trials with different comparators, patient population, or setting were eligible for further analysis), and therefore different datasets were used for statistical analysis in each meta-analysis, the conclusions of these articles are quite consistent (Table 15.2). Saffron products (i.e., stigma, petal, extract, and crocin) were proven to be superior to placebo and noninferior to the routinely used antidepressant therapy (e.g., SSRIs, imipramine) at doses varying from 30 to 100 mg based on the Beck Depression Inventory and the Hamilton Depression Rating Scale. Moreover, the metaanalysis by Ghadheri et al. and Marx et al. reported significant anxiolytic effects attributed to saffron [100,104]. In the majority of the trials saffron stigma was assessed; however, the petals or extracts were evaluated in some trials [107e109]. Since petals were effective in these trials, it might be worthwhile to further investigate this underrated and often discarded part of the plant. The optimum dose and duration of saffron treatment is still unclear; however, most of the trials lasted for 4e12 weeks. The vast majority of the trials were conducted in Iran leading to a rather

218 Nutraceuticals in Brain Health and Beyond

FIGURE 15.2 The clinical application of saffron in neuropsychological conditions. BDNF, brain-derived neurotrophic factor; CREB, cAMP response element binding protein; ROS, reactive oxygen species; VGF, nerve growth factor inducible.

homogenous patient population with regard to ethnic background, and therefore the results of the trials and metaanalyses are not unambiguously adaptable to other populations. Apart from the extensive research focusing on the antidepressant effects of saffron, its use in patients with cognitive dysfunction, AD, and PD has been studied to a lesser extent. Based on a comprehensive literature search, no meta-analysis has been performed on either topic; however, several review articles have been published [61,110e114]. Based on few clinical trials, saffron extract and a crocin-containing formulation were effective in the treatment of patients with mild AD or cognitive impairment, which might be due to their antioxidant, antiinflammatory, and antiamyloidgenic effects [110]. In a 22-week, multicenter, randomized, double-blind, controlled trial, the efficacy of saffron stigma extract (30 mg of dried extract) was compared to donepezil (10 mg) in 54 patients with mild-to-moderate AD [115]. Each patient in the saffron group was taking two capsules daily, and each capsule contained 15 mg of saffron extract with 0.13e0.15 mg safranal and 1.65e1.75 mg crocin. Based on the applied AD Assessment Scale-cognitive subscale (ADAS-cog) and clinical dementia rating scalee sums of boxes (CDR-SOB) scores, saffron was found to be as effective as donepezil. Regarding side effects, vomiting occurred significantly less frequently in patients receiving saffron extract. In another randomized study, the effect of saffron on mild-to-moderate AD was compared to that of placebo. Patients in the verum group were required to take 15 mg of saffron extract prepared from the stigma (0.13e0.15 mg

safranal and 1.65e1.75 mg crocin per capsule) twice daily. Based on the ADAS-cog and CDR-SB score results, saffron had significantly better effects than placebo, but the side-effect profiles did not differ significantly [90]. In a 12-month randomized controlled trial, saffron extract was compared to memantine in patients with moderate-to-severe AD [91]. Saffron extract was prepared from the stigma; each capsule contained 15 mg of the extract standardized to crocin (1.65e1.75 mg). Patients were given one capsule of saffron extract or memantine (10 mg) daily for the first month and two capsules afterward. At the end of the trial the authors concluded that the efficacy based on Severe Cognitive Impairment Rating Scale (SCIRS), Functional Assessment Staging (FAST), and Mini-Mental State Examination (MMSE) scores, and the safety of the two treatments did not differ significantly. Based on the clinical evidence, saffron stigma extract is comparable to conventional therapy (donepezil and memantine) and superior to placebo in the treatment of cognitive deterioration in patients with AD. The effect of saffron was studied in a single-blind, controlled trial on patients with amnesic and multidomain mild cognitive impairment [92]. The authors concluded that patients in the saffron group showed improvement in MMSE scores, MRI, EEG, and event-related potential measurements, while deterioration was observed in the control group. Although this study suggests a promising efficacy of saffron that might fill a niche, the study has several flaws regarding the preparation and dose of the saffron product. The effects of saffron-containing combinations on cognitive function were assessed in a crossover trial

TABLE 15.1 Effects of saffron beyond depression. Indication AD

AD

AD

AD

Neurocognitive and CV function

Patients

Intervention(s)

Posology

Multicenter, doubleblind RCT at Iran

Patients with mild-tomoderate AD (MMSE: 15 e26); 55 years of age, N ¼ 54

Saffron stigma extract

15 mg twice daily

Donepezil

5 mg twice daily

RCT in Iran

Patients with mild-tomoderate AD (MMSE: 15 e26); 55 years of age, N ¼ 46

Saffron stigma extract

15 mg twice daily

Placebo

Two capsules daily

Patients with moderateto-severe AD, N ¼ 68 (MMSE: 8e14)

Saffron stigma extract

15 mg once daily for 1 month, twice daily afterward

Memantine

10 mg once daily for 1 month, twice daily afterward

Patients with amnesic and multidomain mild cognitive impairment, N ¼ 35

Saffron

Patients with mild-tomoderate AD (12  ADAS-cog), N ¼ 30

Doubleblind RCT at Iran

Single-blind RCT at Greece Doubleblind, crossover RCT in Iran Doubleblind, crossover RCT in Australia

Healthy adults (MMSE>28), N ¼ 16

Study duration

Reference

22 weeks

Efficacy of saffron did not differ from donepezil on AD and had a better side-effect profile

[90,105]

16 weeks

Saffron showed significantly better effects but its side-effect profile did not differ from that of placebo

[90]

12 months

Efficacy of saffron was comparable to memantine, and their side-effect profiles did not differ significantly

[91]

No information

12 months

Patients given saffron improved, whereas patients in the control group deteriorated

[92]

Cyperus rotundus (500 mg), C. sativus (30 mg), and honey (5 g)

Twice daily

No statistically significant difference observed

[93]

Placebo

Twice daily

Two months and 1 month of washout period

Panax ginseng (27.27 mg ginsenozides), Ginkgo biloba (ginkgo flavoneglycosides), and C. sativus (5.46 mg crocin) containing herbal medicine (Sailuotong, SLT)

Two capsules daily

One week of treatment, and 1 week washout period

SLT may improve cognitive function and working memory in healthy adults

[116]

Placebo

Two capsules daily

Control group Placebo

219

Outcome(s)

The psychopharmacology of saffron Chapter | 15

Cognitive impairment

Study design

Continued

Indication Cognitive decline

Study design Doubleblind, crossover RCT in Italy

Patients

Intervention(s)

Posology

Young elderly (MMSE:20 e27), N ¼ 30

Bacopa monnieri (320 mg), L-theanine (100 mg), C. sativus (30 mg), copper, folate, and vitamins B and D

One capsule daily

Placebo

One capsule daily

Saffron petal extract

30 mg once daily

Placebo

One capsule daily

Crocetin

7.5 mg once daily

Placebo

Once daily

Doubleblind RCT in Iran

Volunteers, N ¼ 20

Doubleblind, crossover RCT in Japan

Healthy adults with mild sleep complaints, N ¼ 30

Obsessive compulsive disorder (OCD)

Doubleblind RCT in Iran

Adults with mild-to-moderate OCD (Y-BOCS:12 e21), N ¼ 50

Saffron stigma extract

15 mg twice daily

Fluvoxamine

100 mg daily

Metabolic syndrome with schizophrenia treated with olanzapine

Triple-blind RCT in Iran

Male inpatients (18e65 years old) diagnosed with schizophrenia receiving olanzapine, N ¼ 66

Saffron aqueous extract as an add-on

15 mg twice daily

Crocin as add-on

15 mg twice daily

Placebo

Two capsules daily

Visual memory

Sleep quality

Study duration

Outcome(s)

Reference

Eight weeks

Nutraceutical combination improved cognitive decline based on the MMSE and PSQ index

[94]

Three weeks

Saffron improved visual memory in healthy adults

[95]

Two weeks with 2 weeks of washout

Crocetin improved sleep quality parameters and enhanced delta power during REM sleep latency without side effects

[96]

10 weeks

No statistical difference observed between both treatment arms regarding efficacy and safety

[97]

12 weeks

Saffron extract could prevent olanzapine-induced hyperglycemia, dyslipidemia, and insulin resistance in patients with schizophrenia

[98]

AD, Alzheimer disease; ADAS-cog, AD assessment Scale-cognitive subscale; MMSE, baseline mini-mental state examination score; OCD, obsessive compulsive disorder; PSQ, perceived stress questionnaire; RCT, randomized controlled trial; REM, rapid eye movement; SLT, Sailuotong; Y-BOCS, Yale-Brown obsession compulsion scale.

220 Nutraceuticals in Brain Health and Beyond

TABLE 15.1 Effects of saffron beyond depression.dcont’d

TABLE 15.2 Meta-analyses on the use of saffron in depression.

Study duration

Saffron (aqueous extract, petals, and stigmas) versus placebo or antidepressants

30e50 mg

Humans regardless of being clinically diagnosed with a mental illness; n ¼ 1237

Any saffron-derived product alone or in combination with standard medications versus placebo or antidepressants

RCTs including crossover and parallel studies; N ¼ 21

Humans; n ¼ 1052

RCTs; N ¼ 8

Patientsa

Intervention(s)

Double-blind RCTs; N ¼ 12

Adults with mild-to-moderate depression; n ¼ 612

RCTs including crossover studies; N ¼ 23

Outcome(s)a

Reference

6e12 weeks

Depression, response rate, remission rate, and adverse effects

[99]

14e450 mg

4e12 weeks

Symptoms of mental illness, and adverse events

[104]

Any saffron-derived product (including crocin) alone or in combination with standard medications versus placebo or antidepressants

22e1000 mg

4e12 weeks

Depression, anxiety, and CRP levels

[100]

Patients with any kind of depression; n ¼ 368

Saffron (stigma, petal, or extract) versus placebo or fluoxetine

30e50 mg

6e12 weeks

Effect of saffron on depression

[102]

RCTs; N ¼ 11

Patients with mild-to-moderate depression; n ¼ 531

Pharmacological doses of saffron (stigma, petal, or extract) versus placebo or antidepressants

30e100 mg

6e12 weeks

Effect of saffron on depression

[105]

Double-blind RCTs; N ¼ 7

Adult patients with major depression disorder; n ¼ 316

Oral monotherapy of saffron (stigma, petal, extract) versus placebo or antidepressants

30e100 mg

6e12 weeks

Effect of saffron on depression

[106]

Controlled clinical trials; N¼6

Outpatients diagnosed with major depressive disorder; n ¼ 230

Saffron (stigma, petal, extract) versus placebo or antidepressants

30 mg

6e8 weeks

Effect of saffron on depression

[103]

RCTs; N ¼ 5

Adults (aged 18 and older) with symptoms of depression; n ¼ 177b

Saffron (stigma, petal, extract) versus placebo or antidepressants

30 mg

6 weeks

Effect of saffron on depression

[101]

a

as defined in the inclusion criteria of the meta-analysis. patients who completed the trial; CRP, C-reactive protein; RCTs, randomized controlled trials.

b

The psychopharmacology of saffron Chapter | 15

Applied daily doses of saffron products

Study designa and number of studies included in meta-analyses

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222 Nutraceuticals in Brain Health and Beyond

conducted in Iran [93]. Thirty patients diagnosed with mildto-moderate AD (ADAS-cog score 12) were randomized into two groups to receive either placebo or a combination of Cyperus rotundus (500 mg), C. sativus (30 mg), and honey (5 g) twice daily for 2 months with a 1-month washout period. The authors concluded that there was no statistically significant difference between the two groups during and after completing the trial. A saffron-containing nutraceutical product improved cognitive function in young elderly patients [94]. In this crossover trial, 30 patients were given a combination of Bacopa monnieri (320 mg), L-theanine (100 mg), C. sativus (30 mg), copper, folate, and vitamins of B and D groups or placebo for 2 months, and significant improvement was attributable to the combination, based on the MMSE and Perceived Stress Questionnaire scores. In another study, 16 healthy adults (MMSE score >28) in Australia were enrolled to complete a randomized, doubleblind, placebo-controlled crossover trial [116]. During the course of the study the patients in each arm received either a herbal combination (Sailuotong) containing Panax ginseng (27.27 mg ginsenosides), Ginkgo biloba (ginkgo flavoneglycosides), and C. sativus (5.46 mg of crocin) twice daily or placebo for 2 months, with a 1-month washout period. The results indicated that the herbal combination might enhance cognitive function and working memory in healthy adults. The effect of alcoholic extract of saffron petal on visual short-term memory (STM) was assessed in a randomized, double-blind, placebo-controlled study [95]. Based on the results of the 20 enrolled healthy volunteers; saffron extract improved STM which might be linked to its previously investigated anxiolytic effects. In a randomized, double-blind, placebo-controlled, crossover study, short-term administration (14 days) of crocetin (7.5 mg per day) in healthy adults improved sleep quality based on objective (EEG data) and subjective (OSA-MA scores) parameters without side effects compared to placebo [96]. In a double-blind, randomized trial, saffron stigma extract (15 mg twice daily) was proven to have comparable efficacy to fluvoxamine (100 mg) in the treatment of patients (n ¼ 50) with mild-to-moderate obsessive compulsive disorder [97]. Schizophrenic patients treated with olanzapine are prone to develop metabolic changes that might lead to metabolic syndrome. In a triple-blind, three-arm, randomized, controlled trial, 66 schizophrenic patients on olanzapine treatment were randomized to receive either aqueous extract saffron (15 mg twice daily) or crocin (15 mg twice daily) or placebo twice daily for 12 weeks [98]. At the end of the trial, none of the patients in the saffron group developed metabolic syndrome, which indicated that saffron might be used as an add-on-therapy in olanzapine-treated patients. In summary, numerous clinical trials and meta-analysis have been published over the past two decades to assess the

efficacy and safety of saffron in the treatment of various neuropsychological conditions. Most of the publications reported favourable effects attributable to saffron. Nevertheless, it is important to highlight that most of these trials had considerable risk bias, and publication bias is also suspected. The effects of saffron on neuropsychological problems other than depression are relatively under investigated; few trials have been designed to answer the same clinical question. It is worth mentioning that saffron was well-tolerated in every clinical trial, and no serious adverse event occurred in the saffron-treated groups. To improve the quality of evidence on saffron and to verify these promising results, further larger trials, involving diverse ethnic populations, are needed.

Conclusions The therapeutic importance of saffron is increasing due to the discovery of its antidepressant and neuroprotective effects. The mechanisms of action and the active constituents behind these effects are not fully known. The recognition that parts of the flower other than the expensive stigma might have clinical value gave new impetus to the scientific studies on C. sativus. The clinical efficacy of the whole plant, and in particular that of saffron, has been studied in several trials, mainly, but not exclusively, in patients with depression. The examination of additional psychopharmacological effects of C. sativus may open up new horizons for future scientific studies.

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Chapter 16

Comprehensive review of Alzheimer’s disease drugs (conventional, newer, and plant-derived) with focus on Bacopa monnieri Kaustubh S. Chaudhari1, 2, 3 Department of Internal Medicine & Neurology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, United States; 2Department of

1

Kayachikitsa, Smt. K.G. Mittal Punarvasu Ayurvedic College, Mumbai, Maharashtra, India; 3Department of Samhita Siddhanta, Smt. K.G. Mittal Punarvasu Ayurvedic College, Mumbai, Maharashtra, India

Chapter outline Introduction Dementia crisis Scope of the chapter Alzheimer’s disease Genetics Pathogenesis Clinical features Current and potential treatments Nutraceuticals in AD Historical origin Scope of the chapter Plant-derived AD drugs Bacopa monnieri Niche and morphology Isolation, extraction, and patent

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Introduction On April 08, 1906, Alois Alzheimer conducted a postmortem evaluation on the brain of Auguste D. She was a 51-year-old woman who had died following 5 years of severe cognitive impairment, paranoid delusions, sleep disorders, social malfunctioning, and progressive aphasia [1]. His findings constitute the beginning of an understanding of one of the most perplexing and unyielding neurodegenerative disorders known. His brain biopsy findings revealed the presence of senile (now called

Nutraceuticals in Brain Health and Beyond. https://doi.org/10.1016/B978-0-12-820593-8.00016-1 Copyright © 2021 Elsevier Inc. All rights reserved.

Active constituent(s) Fundamental and clinical research in B. Monnieri in AD Antioxidant and iron chelation Cholinergic system b-Amyloid plaques Neuroprotectivity (neuronal and glial plasticity) Cerebral blood flow Memory impairment and cognitive defects Clinical trials Bacopa monnieri clinical practice Drug development and current practice Adverse effects and safety Conclusions References

233 240 241 241 242 243 243 243 243 243 243 245 245 246

amyloid) plaques, neurofibrillary tangles, and some arteriosclerotic changes, all of which are recognized today as hallmarks of Alzheimer’s Disease (AD) [2]. Subsequently, there have been extensive studies aimed at understanding the pathomechanisms behind these changes, especially those molecular changes that can aid target drug discovery.

Dementia crisis Dementia continues to plague our recent successes of increasing life expectancy, control of noncommunicable

227

228 Nutraceuticals in Brain Health and Beyond

diseases, and improved geriatric healthcare. Its prevalence shows a meteoric rise from 1% at 60 years to 35% at 90 years in recent decades [3]. AD is a particularly severe and debilitating type of dementia and accounts for 60% of all dementias worldwide [4]. The World Alzheimer’s Report 2015 showed an increase in global spending on Dementia from US$ 604 million (2010) to US$ 818 million (2015) [5]. For people living for more than 60 years, dementia consumed more years with disability (11.2%) than most other insidious illnesses like cerebrovascular accident (9.5%), musculoskeletal disorder (8.9%), cardiovascular morbidity (5.0%), and cancers (2.4%). Also, the disability weight for dementia is more than for most health conditions barring terminal malignancy and spinal cord injury [6]. A century after its clinicopathological recognition, AD still persists as an extremely resilient public health burden with devastating consequences in the elderly. Yet minimal therapeutic interventions exist for AD, most targeted to symptoms rather than the pathology.

Scope of the chapter This chapter utilizes tables (and illustrations) extensively within the text; to complement it rather than to summarize it. Care has been taken to ensure that the content of the tables is sufficiently descriptive and contiguous to link it with the text. Hence, readers are urged to use these tables and charts in conjunction with the text.

Alzheimer’s disease Genetics AD is a chronic neurodegenerative disorder of undetermined etiology. Several genes have been associated with AD, the important ones are summarized in Table 16.1 along with their pathomechanisms [7,8].

Pathogenesis The pathogenesis of AD isn’t clearly understood; however, there have been several attempts to connect our recent knowledge of genes linked to AD and the pathbreaking histopathological findings of Alois Alzheimer to the symptoms of AD. Overproduction and reduced clearance of amyloid-beta (Ab) peptides and accumulation of hyperphosphorylated tau (ps) protein are the key pathomechanisms of AD. Accumulated Ab peptides form diffuse extracellular senile plaques while intracellular ps causes development of neurofibrillary tangles [8]. Histopathologically, AD is characterized by the appearance of diffuse extracellular senile plaques, intracellular neurofibrillary tangles, astrogliosis, and reactive microgliosis in the brain parenchyma [9]. Vascular disease further increases deposits of Ab peptides [10]. These microscopic changes begin in the hippocampus and medial temporal lobe and later proceed to larger areas of the brain [11]. Progress of AD is mainly due to the pathobiological cascades initiated by

TABLE 16.1 Genetics of Alzheimer’s disease (AD). Gene

Chromosome location

Encoded protein

Functions

AD Onset

AD pathomechanism

PSEN-1

14q

Presenilin-1

- Regulate intracellular Ca2þ signaling - Trafficking membrane proteins - Regulate b-catenin stabilization

Early-onset AD

- Mutation results in abnormal cleavage of amyloid precursor protein by g-secretase. - Resulting peptides are highly fibrillogenic and accumulate as Ab plaques in brain.

APP

21q

Amyloid precursor protein

- Production of APP protein cleaved by a-, b-, and g-secretase

Early-onset AD

- Mutation results in abnormal cleavage of amyloid precursor protein by b- and g-secretase. - Resulting peptides accumulate as Ab-plaques in brain.

PSEN-2

21q

Presenilin-2

- Encodes for the transmembrane protein

Variableonset AD

- Mutation causes Ab42 protein accumulation in brain.

APOE

19q

Apolipoprotein E

- Removes Ab proteins and protects neurons

Late-onset AD

- Oxidized ε4 form binds to Ab protein resulting in plaque formation. - Reduce cholinergic activity in brain.

Chaudhari: Bacopa monnieri Neuropharmacology in Alzheimer’s Disease Chapter | 16

these plaques and tangles. These changes cause immunologic and oxidative damage of the brain parenchyma which is progressive, irreversible, and ultimately causes brain atrophy. In an attempt to make the readers’ understanding of AD therapies easier and more target intensive, certain molecular pathomechanisms and immunoinflammatory cascades are explained along with targeting drugs in Table 16.2.

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Clinical features It is seen in old age and rarely before 60 years where it follows an autosomal dominant pattern of inheritance. However, its prevalence doubles every 5 years after the age of 65 [12]. AD often begins with memory impairment. Episodic memory associated with recall of recent events is lost first while working memory associated with programmed motor

TABLE 16.2 Important therapeutic agents for Alzheimer’s disease. Name of drug

Target(s) of action

Additional details

Acetylcholinesterase inhibitors (AChEI): Increase acetylcholine (ACh) levels to counter loss and dysfunctional cholinergic neurons in AD. Donepezil

Reversible and noncompetitive centrally acting AChEI

- Useful in mild, moderate, and severe AD - Slows cognitive decline, rarely improves cognitive function, and improves activities of daily living (ADL) - Available as an oral disintegrating tablet (ODT) - Gastrointestinal cholinergic side effects (lower than other AChEIs)

Rivastigmine

Reversible and noncompetitive inhibitor AChEI and butyrylcholinesterase (BChEI)

-

Galantamine

Reversible and competitive central AChEI

- Useful in mild to moderate AD - Slows cognitive decline - Available as a tablet, extended-release capsule, and oral solution

Useful in mild to moderate AD Also in Parkinson dementia (PD) Slows cognitive decline Available as a capsule and transdermal patch

N-methyl-D-asphartic (NMDA) glutamate receptor antagonist: Blocks excitotoxic effects of glutamate via NMDA receptors in AD. Memantine

NMDA glutamate receptor antagonist

- Useful in moderate to severe AD - Available as a tablet, extended-release capsule, and oral solution

APP secretase inhibitor: APP is initially cleaved at a- and b- sites by a- and b- (b-site APP cleaving enzyme 1 or BACE1) secretases in its juxtamembranous domain. Subsequently, membrane-bound stubs are cleaved at g- and ε- sites by g-secretase. This results in the secretion of nonamyloidogenic p3 fragment and amyloidogenic Ab plaques. Pathologic-accelerated cleavage in AD causes the accumulation of Ab plaques. The idea of drugs targeting secretases is to reduce Ab load in brain. LY2886721

b-Secretase OR BACE1 inhibitor

MK-8931 and E2609 Semagacestat

- Axon guidance defects and hypomyelination due to reduced cleavage of non-APP putative substrates in BACE1 knockout mice g-Secretase inhibitor (GSI)

- Discontinued after phase 3 trials due to worsened cognition and increases risk of skin cancer and infections - Notch (non-APP g-secretase substrate) sparing GSI - Failed to improve cognition - Dermatological and gastrointestinal side effects

Avagacestat (BMS-708163) Tarenflurbil

- First BACE1 inhibitor - Discontinued after phase 2 trials due to hepatotoxicity

g-Secretase modulator (GSM)

- Not found effective after phase 3 trial - Increased frequency of anemia, dizziness, and infections Continued

230 Nutraceuticals in Brain Health and Beyond

TABLE 16.2 Important therapeutic agents for Alzheimer’s disease.dcont’d Name of drug

Target(s) of action

Additional details

Active immunotherapies targeting Ab peptide: Amyloid Hypothesis predicts that most pathological changes in AD are secondary to the accumulation of Ab peptide and the immune and oxidative damage triggered by them. Immunotherapy uses this understanding to develop vaccines against accumulating Ab peptide. AN1792

Vaccine against Ab peptide

- Ab42 with adjuvant QS-21 - First Ab targeted immunotherapy - Aseptic meningoencephalitis

ACI-24

Vaccine against tetra-palmitoylated Ab1-15

- Liposomal vaccine that favors antibodies to b-sheet conformation

UB-311

Vaccine against Ab1e14

- CpG oligonucleotides and aluminum salt formulation - Stimulates Th2>Th1 inflammatory response

ABvac40

Vaccine against Ab C-terminus repeats

- Keyhole limpet hemocyanin and aluminum hydroxide formulation

Lu AF20513

Vaccine against Ab1e12 peptides tri-repeats

- Administered in combination with tetanus toxoid vaccine - Attempt to use immunologic memory of childhood tetanus vaccination to overcome weak response in elderly

Passive immunotherapies targeting Ab peptide: After Ab peptides have aggregated as plaques. Their N-terminal is still exposed while the C-terminal isn’t available to monoclonal antibodies (mAbs), hence mAbs targeting N-terminal are useful only in advanced disease while those recognizing C-terminal are useful to prevent plaque formation. Also, as the antibodies couple with circulating soluble Ab peptides, it alters the Ab equilibrium between brain and blood favoring further drainage of Ab peptides from the brain. This is hypothesized to be the peripheral sink effect. Bapineuzumab

mAbs recognizing N-terminus of Ab (Ab1e5)

- Humanized IgG1 (murine mAb 3D6) - Activates microglial phagocytosis of Ab deposits - Removes Ab peptides by peripheral sink mechanism - Small clearance of fibrillar deposits seen on positron emission tomography (PET) scan but no clinical benefits seen

Solanezumab

mAbs recognizing middle region of Ab (Ab16e26)

-

Gantenerumab

mAbs recognizing N-terminal and middle regions of Ab (conformational epitope)

- Fully human IgG1 - Activates microglial phagocytosis of Ab deposits - No significant clinical benefit seen, but phase 3 trial planned to evaluate amyloid reduction and cognitive improvement in fasted progressors

Crenezumab

mAbs recognizing Ab oligomers > monomers, fibrils and plaques

-

Aducanumab

mAbs recognizing N-terminal Region of Ab (Ab3e6)

- Fully human IgG1 mAb - Reduction in fibrillar Ab on PET scan - Interim analyses showed reduction in clinical progression, phase 3 trials projected for mild AD

Humanized IgG1 (murine mAb m266) Mild to moderate AD Slowed cognitive & functional decline Abandoned after phase 3 trials because it didn’t meet primary endpoint

Humanized mAb IgG4 backbone Stimulates microglia to phagocytose Ab plaques Minimal side effects from vasogenic edema No clinical benefits seen in phase 2 trial, but phase 3 trials with higher doses given for prodromal to mild AD are in progress - Also under testing in carriers of E280A mutation of PS1 gene

Continued

Chaudhari: Bacopa monnieri Neuropharmacology in Alzheimer’s Disease Chapter | 16

231

TABLE 16.2 Important therapeutic agents for Alzheimer’s disease.dcont’d Name of drug

Target(s) of action

Additional details

BAN2401

mAbs recognizing large, insoluble Ab protofibrils

- Humanized IgG1 mAb - Showed good safety and tolerability profiles - Phase 2 trials in progress

Ponezumab

mAbs recognizing C-terminal region of Ab (Ab33e40)

- Humanized IgG2 mAb - No significant cognitive improvement in phase 2 trials, but trials ongoing for cerebral amyloid angiopathy

Gammagard and Gamunex

Polyclonal anti-Ab antibodies

- IVIg from pooled human plasma - Prevention of aggregation and increased clearance of Ab peptides - No benefits seen in clinical trials

Therapies against tau: Tau proteins stabilize the microtubular skeleton of the neurons. Their hyperphosphorylation by glycogen synthetic kinase-3 b (GSK3b) to pTau detaches them from micro skeleton causing formation of neurofibrillary tangles. This is another pathomechanism of AD and below are drugs targeting it. Tideglusib

Inhibits GSK3b phosphorylation

- Prevent GSK3b mediated hyperphosphorylation of tau and thus aggregate formation - First-generation congener (methylene blue) not found effective and second-generation molecule TRx0237 still in phase 3 trial

Epothiline D

Counteract microtubule destabilization

- Not effective for AD

TPI287

Counteract microtubule destabilization

- In phase 1 trial

Active immunotherapies targeting tau: Although tau is an intracellular protein, vaccines/antibodies target them during the proposed extracellular transmission of tauopathies. AADvac-1

Inhibits tau-tau interaction

- Synthetic tau peptide (amino acids 294e305) with carrier KLH and adjuvant aluminum hydroxide - Phase 1 trial showed good safety and efficacy profile and phase 2 trial is in progress

ACI-35

Vaccine against misfolded and phosphorylated tau (pTau)

- Liposomal vaccine with synthetic tau peptide (amino acids 393e408) - Currently in phase 1b trial for mild to moderate AD

Passive immunotherapies targeting tau: Anti-tau antibodies are endocytosed by the neuronal clathrin-dependent FcgII/III receptors-mediated uptake. RG7345

mAbs recognizing ptau phosphoepitope pS422

- Humanized mAb - S422 persists from early through late stages of AD making it attractive immunotherapy - Phase 1 trial discontinued

BIIB092

mAbs recognizing N-terminal fragments of extracellular tau (eTau)

- Humanized IgG4 mAb from pluripotent stem cells of familial AD subjects - Dose-dependent reduction in serum and CSF eTau in phase 1 trial

ABBV-8E12

mAbs recognizing N-terminal fragments of extracellular tau (eTau)

- Humanized mAb - Reduces progression of tau pathology - Phase 2 trials to assess safety and efficacy in progress Continued

232 Nutraceuticals in Brain Health and Beyond

TABLE 16.2 Important therapeutic agents for Alzheimer’s disease.dcont’d Name of drug

Target(s) of action

Additional details

Plant-derived multitargeted agents (refer Table 16.3): Herbal medications have attracted profound clinical interest in recent years due to higher biosafety, alternate and polytarget mechanisms increasing the possibility of future use as a nutraceutical for AD. Herbal molecules

Plants with important Anti-AD biomolecules (Table 16.3): Ashwagandha (Withania somnifera), Haridra (Curcuma longa), Brahmi (Bacopa monnieri), Shankhpushpi (Convolvulus pluricaulis), Gotu kola (Centella asiatica) Jyotishmati (Celastrus paniculatus), Jatamansi (Nardostachys jatamansi), and Guggulu (Commiphora spp.: C. mukul, C. molmol, C. abyssinica, C. Burseraceae, C. wightii) Lesser researched plants associated as AD medication (beyond the scope of this chapter): Mandukaparni (Centella asiatica), Yastimadhu (Glycirrhiza glabra), Guduchi (Tinospora cordifolia), Vacha (Acorus calamus), ginkgo biloba (Ginkgo biloba L.), stinging nettle (Urtica dioica L.), Brazil nuts (Bertholettia excelsa), sage (Salvia officinalis), rosemary (Rosmarinus officinalis), German chamomile (Matricaria recutita), lemon balm (Melissa officinalis), Yashti-madhuka (Glycyrrhiza glabra), common snowdrop (Galanthus nivalis L.), ren-shen (Panax Ginseng), sweet flag (Acorus calamus L.), Laghu Coraka (Angelica archangelica L.), Talauma (Magnolia officinalis), and Monarda (Collinsonia canadensis)

Miscellaneous therapeutic agents: Cytoprotective mechanisms focused on improving blood flow, reducing oxidative stress, etc. Latrepirdine

Antihistaminic, blocks NMDA receptors, improves mitochondrial pathways

- Benefits seen in animal model and phase 2 trial but not in phase 3 trial

Ginkgo biloba

Nootropic, free radical scavenging

- No significant improvement in cognitive function seen in AD and mild cognitive impairment (MCI)

The clinical trial information is compiled from several sources and may not be current esp. for ongoing trials. Hence, the readers are requested to review updated clinical trial information from respective sources.

learning is affected much later in the disease. This is because the former is controlled by the hippocampus and adjacent temporal lobe which is affected first, while the latter is a function of the subcortex which is affected only in severe disease. Factual memory or semantic memory is also affected in later stages but procedural memory is preserved [13,14]. The frequency of neuropsychiatric impairments rises during the later course of the disease and often presents as the direst therapeutic concerns. They include apathy, depression, hallucination, and paranoid delusions. Irritability and agitation stem from the person’s inability to perform tasks they accomplished easily in the past [15]. Besides cognitive decline, neurobehavioral deterioration presents as a significant and comparatively more treatable challenge, especially in advanced AD making a case for institutionalization.

Current and potential treatments In spite of the extensive public health hazard posed by AD, only two classes of drugs have been found minimally effective in the treatment of AD. This is mostly because clinical trials for newer molecules have had a 99.6% failure rate [16]. Existing therapies are aimed at amelioration of symptoms by counterbalancing the impaired synaptic

transmission in affected areas of the brain [17,18]. However, there are no approved agents that can modify the molecular pathologic changes in AD, i.e., there is no disease-modifying therapy that can stall the progress of AD. Hence, although current therapies provide symptomatic relief, it is effective only until the disease has inevitably worsened to a point of no return. That makes a case for research and development of agents targeting the plaques and tangles and/or the neurodegenerative changes caused by them. A summary of the important approved, potential, and withdrawn therapeutic agents for AD is summarized in Table 16.2.

Nutraceuticals in AD Currently, available medications control the symptoms of AD to an extent, but don’t affect the pathology and hence don’t alter the progress of AD. Hence, with the progress of AD, symptom control wears out and the patient inevitably becomes debilitated and dependent on others even for activities of daily living [19]. Therapeutic interventions attempting to block the immunopathological cascade catalysed by the plaques and tangles would be the mainstay in controlling the progressive neurodegeneration in AD in years to come. From

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Table 16.2 it is evident that in spite of precise interruptions in the AD pathologic sequence in laboratory or animal studies, the newer molecules have failed to translate the same effects in clinical trials. While drug discovery shall still continue and prudently so, it has become increasingly important to discover safer biomolecules that target alternate complementary and/or synergistic mechanisms too. Hence, herbal preparations and molecules that have been known to have memoryenhancing effects have garnered tremendous momentum in recent years. Meticulous standardization of the active constituents from these herbs followed by their rigorous efficacy-safety trials have a potential to develop a wide array of therapeutics for AD [19].

Historical origin Ayurveda is a traditional system of medicine in India originating in the Indus Valley Civilization (circa 3000 BC). It has practiced and perfected administration of herbal medications for Vata Dosh (neurological disorders) over several years. The Sanskrit word Vata means air humor and was a part of an ancient belief that nervous impulses to and from the brain are in fact air traveling through the body. Vata Vyadhi (imbalance in air humor) causes neurological disorders like weakness, hypersensitivity, or derangement of the nervous system [19]. Ayurveda literature doesn’t directly mention dementia but Smṛtin asha (memory loss) has been described as a prodrome of jar a (aging) or Jar avasth a (old age above 60 years) [20,21]. Sushruta Samhita, Charak Samhita, and Atharva Veda, the cardinal texts of Ayurveda describe Rasayana (herbal preparations) having prabhava (effect) on Medhya (intellect and memory) as Medhya Rasayana [8]. Classically, Medhya Rasayana (nervines or nootropics) include Yastimadhu, Mandukaparni, Guduchi, and Shankhapushpi. Later several other herbs including Brahmi, Jatamansi, Guduchi, etc., have shown a significant nootropic effect [8,19]. Ancient scholars have been known to consume these herbs to help them memorize lengthy scriptures [8]. This further raises our curiosity about their use as prophylactic nutraceuticals for AD in present times.

Scope of the chapter Identification of the place of Brahmi or Bacopa monnieri among other “significant” Medhya Rasayana is the core object of this chapter. This chapter focuses on the more

233

researched herbal medications while emphasizing that extensive long-term, multicentric clinical trials still need to be done to ensure their long-term efficacy, biosafety, and scope as potential nutraceuticals.

Plant-derived AD drugs The more effective and studied plant derivatives are discussed in Table 16.3 with a focus on their useful parts, bioactive molecules (active agents), target actions, and clinical use [8,19,21-31]. This will help us better understand the comparative scope of B. monnieri as an AD drug.

Bacopa monnieri B. monnieri or Herpestis monnieri (Hindi: Brahmi, ắng) Sanskrit: Aindri, Vietnamese: Rau Ð a is a water hyssop that has been recognized in Ayurvedic medicine as a Medhya Rasayana or nervine tonic thought to have a “memory boosting” action on the brain [8,32-34].

Niche and morphology B. monnieri is a subtropical creeper belonging to the Scrophulariaceae family that grows in the damp marshlands at an altitude of 1500 m above sea level [35]. Although its medicinal uses were originally identified in India, it was also found in other areas of the Indian subcontinent (Nepal and Sri Lanka), Southeast Asia (Taiwan, China, and Vietnam), and also tropical Africa and subtropical United States (Florida and other southern states) [36]. In the United States, it grows in paddy fields and is often confused for weeds. It grows luxuriantly in marshlands close to freshwater aquatic bodies. It is a succulent herb with branched leaves and purple flowers with every part including roots finding a medicinal application [37].

Isolation, extraction, and patent Kahol et al. have perfected and patented the process of extraction, isolation, and concentration of Bacosides from harvested Brahmi leaves to produce a concentrate that is further developed for medicinal purposes. We have illustrated this process graphically in Fig. 16.1 [38].

Active constituent(s) CDRI-08 (CDRI: Central Drug Research Institute) is a standardized extract of B. monnieri (EBm) containing more

Name of plant a/w botanical name Ashwagandha (Withania somnifera) family: Solanaceae

Plant Image

Medicinal part

Biomolecule structure

Bioactive Constituent(s)

Active agents and target actions

Roots

- Withaferin A (Figure), withanolide A (bioavailability 144 times higher in former) - Block Ab peptide production - Nuclear translocation of Nrf2 (increase expression of antioxidant enzymes and neuroprotective hemeoxygenase-1) - Inhibit activation of NF-kb - Reduced apoptosis, dendrite extension, neurite outgrowth, and synapse formation - Increase hippocampal acetylcholine content and cholineacetyl transferase activity

Withanine Withananine Somniferine Sominone Somnine

Clinical details - Improve memory, learning, and cognition - Dose-dependent stress relieving and calming effect, especially in AD - Improved concentration and reduced forgetfulness - Corrects reaction time, social cognition, and auditory-verbal working memory in bipolar cases - Traditionally used as nervine tonic, aphrodisiac, antistress agent (adaptogen) - Side effects: nausea and diarrhea - Potentiates barbiturates and sedatives

234 Nutraceuticals in Brain Health and Beyond

TABLE 16.3 Plant-derived multitargeted agents (botanical images are original while chemical structures have been obtained from PubChm Citations: Withaferin A: PubChem CID 265237, Curcumin: PubChem CID 969516, Bacoside: PubChem CID 92043183, Kaempferol: PubChem CID 5280863, Asiaticoside: PubChem CID 11954171, Pristimerin: PubChem CID 159516, Valeranol: PubChem CID 6429378 and Z-Guggulsterone: PubChem CID 6450278).

Roots

Turmerone oil Curcuminoids

- Curcumin (keto and enol form) (Figure) - Reduced production of Ab plaques and inhibits tau hyperphosphorylation - Neutralize reactive oxygen species (several fold vit E), inhibit lipid peroxidation and interrupt immunoinflammatory cascade - Antiinflammatory actions are by blocking the production of TNF-ɑ, IL-1b and cytokines like IL-8, MIP-1b, MCP-1 in astrocytes and microglia - Modulates modulating the Nrf2-keap1 pathway, promotes Nrf2 nuclear migration (antioxidant enzymes and hemeoxygenase-1) - Elevation of cell glutathione to protect hippocampal mitochondrial against peroxynitrite - Protect neural membrane damage by inhibiting PLA2 and COX2

- Food spice and coloring agent, linked to lower AD incidence in consuming Asian populations - Improves attention and working memory - Improves cognitive function - Cancer chemopreventive - Traditionally used as an antiseptic, to detoxify liver, fight allergies, aid digestion, lower cholesterol, and boost immunity - Black pepper (Piper nigrum) improves curcumin bioavailability by inhibiting glucuronidation

Continued

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Haridra (Curcuma longa) family: Zingiberaceae

235

Name of plant a/w botanical name Brahmi (Bacopa monnieri) Family: Scrophulariaceae

Plant Image

Medicinal part

Biomolecule structure

Bioactive Constituent(s)

Active agents and target actions

Leaves

- Bacoside A (Figure) and B, Bacoposides III to V, Betulininc acid, Bacosaponins A, B, C - Reduces Ab deposition and immunologic hippocampal damage - Scavenges free radicals to prevent cytotoxicity and DNA damage in prefrontal cortex, hippocampus and striatum - Reduces lipid peroxidation - Maintains redox milieu by increasing glutathione peroxidase and chelating iron - Protects hippocampal cholinergic neurons and reduce anticholinesterase activity - Nitric oxide-mediated vasodilation maintains cerebral perfusion

Saponins Triterpenoid Bacosaponins Brahmine Herpestine

Clinical details - Improves total memory score - Significant improvement in paired associate learning, logical and spatial memory - Improves memory acquisition, cognition, delayed recall, and verbal learning - Protects brain against smoking-induced damage - Antioxidant, anti-inflammatory, bronchodilator, cardiopressor, diuretic, antiepileptic, and protects against peptic ulcer - No clinical, hematological, biochemical, teratogenic or genotoxic adverse effects seen

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TABLE 16.3 Plant-derived multitargeted agents (botanical images are original while chemical structures have been obtained from PubChm Citations: Withaferin A: PubChem CID 265237, Curcumin: PubChem CID 969516, Bacoside: PubChem CID 92043183, Kaempferol: PubChem CID 5280863, Asiaticoside: PubChem CID 11954171, Pristimerin: PubChem CID 159516, Valeranol: PubChem CID 6429378 and Z-Guggulsterone: PubChem CID 6450278).dcont’d

Shankhpushpi (Convolvulus pluricaulis) Family: Convolvulaceae

Leaves

Gotu kola (Centella asiatica) Family: Apiaceae

Leaves

Asiaticoside A Asiaticoside B Asiatic acid

- Nootropic and memory-enhancing - Improved spatial learning performance, passive avoidance learning and retention - Traditionally used as nervine tonic for memory and cognition and also for stress, anxiety, mental fatigue and insomnia

- Saponins or triterpenoids like Asiaticoside A (Figure), Asiaticoside B, Asiatic acid, Brahmoside, and Brahminoside - Inhibit Ab accumulation in hippocampus - Prevent H2O2 cytotoxic actions in brain - Quench other free radicals by altering mitochondrial function

- Attenuates neurodegeneration in AD by its antiamyloidogenic properties - Traditionally also referred to as Brahmi and used as a rejuvenating agent with capacity to improve intelligence, longevity, and memory. Also used to purify blood and lower blood pressure. It is also thought to improve sleep and relieve anxiety - Side effects: Drowsiness

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Shankhapushpine Kaempferol Convolamine Convoline

- Shankhapushpine, kaempferol (Figure), convolamine, convoline, triterpenoids, glycosides, anthocyanins, coumarins, flavonoids, sitosterol glycoside, octacosanol tetracosane, hydroxycinnamic acid - Regulate stress by controlling adrenaline and cortisol which has nerve calming effect. - Antioxidant activity to quench free radicals - Reduce cholesterol and LDL cholesterol - Increase hippocampal (CA1 and CA3 area) acetylcholine esterase activity - Functional neuronal growth in form of increased dendritic intersections, branching and dendritic processes in amygdalae

237

Continued

Name of plant a/w botanical name Jyotishmati (Celastrus paniculatus) Family: Celastraceae

Plant Image

Medicinal part

Biomolecule structure

Bioactive Constituent(s)

Active agents and target actions

Seed Seed oil

- Pristimerin (Figure) - Protects neuronal cells against H2O2 toxicity and lipid peroxidation - Induces antioxidant enzymes and promotes free radical scavenging - Increases cholinergic activity in brain

Pristimerin

Clinical details - Sharpens memory, concentration, and cognition

238 Nutraceuticals in Brain Health and Beyond

TABLE 16.3 Plant-derived multitargeted agents (botanical images are original while chemical structures have been obtained from PubChm Citations: Withaferin A: PubChem CID 265237, Curcumin: PubChem CID 969516, Bacoside: PubChem CID 92043183, Kaempferol: PubChem CID 5280863, Asiaticoside: PubChem CID 11954171, Pristimerin: PubChem CID 159516, Valeranol: PubChem CID 6429378 and Z-Guggulsterone: PubChem CID 6450278).dcont’d

Jatamansi (Nardostachys jatamansi) Family: Caprifoliaceae

Roots

- Improvement of learning and memory - Reversal of diazepam induced and age-related amnesia

- Water-soluble gum (30%e60%), alcoholsoluble resins (20%e40%) and 8% volatile biocative oils containing sesquiterpenoids, terpenes, cuminic aldehyde, Eugenol, Z-Guggulsterone (Figure), E Guggulsterone, and Guggulsterols I, II, and III - Scavenge superoxide radicals - Reduce serum cholesterol, LDL cholesterol and triglyceride levels - Antagonize nuclear hormonal receptors to reduce cholesterol effects; this in turn regulates the cellular phospholipid bilayer to protect neuronal and synaptic plasticity from Ab deposits

- Neuroprotective effects in animal models of dementia seen, but larger trials needed to define efficacy and safety in humans

Sesquiterpenoids Valeranol

Guggulu (Commiphora spp. C. mukul, C. molmol, C. abyssinica, C. Burseraceae, C. wightii) Family: Burseraceae

Gum

Guggulsterone

Abbreviations: COX2, Cyclooxygenase type 2; IL-1b, Interleukin 1 beta; IL-8, Interleukin 8; MCP-1, Membrane cofactor protein 1; MIP-1b, Macrophage inflammatory protein 1 beta; NF-kb, Nuclear Factor kappalight-chain-enhancer of activated B cells; Nrf2, Nuclear factor erythroid 2erelated factor 2; PLA2, Phospholipase A2; TNF-ɑ, Tumor necrosis factor alpha.

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- Sesquiterpenes, valeranol (Figure), coumarins, and terpenoids like spirojatamol, nardostachysin, jatamols A and B, calarenol - High superoxide dismutase and low catalase levels in chronic fatigue syndrome were reversed by Jatamansi extract

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240 Nutraceuticals in Brain Health and Beyond

FIGURE 16.1 Kahol’s method for production of Bacopa monnieri extract (Original Image)

FIGURE 16.2 Bioactive Constituents of an extract of Bacopa monnieri (Original Image)

than or equal to 55% bacosides and adequate bacogenins [39]. Phytochemical analysis of the extract has resulted in the detection of several bioactive compounds illustrated in Fig. 16.2 [8,22,32]. Bacoside A is a dammarane-type triterpenoid saponin, which has the most potent of the neuropharmacological actions on EBm [32].

Fundamental and clinical research in B. Monnieri in AD Several pathomechanisms of AD targeted by EBm have been extensively researched in in vitro, animal, and human studies. These mechanisms are described below along with tabular summaries of the major research involving them.

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Antioxidant and iron chelation Oxygen is crucial for functioning of the human brain. However, its excess leads to accumulation of free radicals and reactive oxygen species (ROS) like hydroxyl (OH0 ), hydrogen peroxide (H2O2), peroxynitrite (ONO 2 ), and superoxide free radical (O’ 2 ) which forms the basis for oxidative damage and neurodegeneration in old age [40,41]. Free radical scavenging mechanisms, both enzymatic and nonenzymatic, protect the brain against this damage. Enzymes like glutathione peroxidase (GPx), catalase (CAT), glutathione reductase (GRed), and nonenzymatic mechanisms like coenzyme Q10, vitamins A, C, and E, selenium, and glutathione (GSH) protect against oxidative damage [42]. Brain is particularly vulnerable to oxidative damage owing to higher unsaturated fatty acid content in neuronal cells, higher metabolism, and lesser

241

antioxidants [43]. Free radicals generated due to mitochondrial autophagy further leads to microglial activation, which further generates free radicals that damage the mitochondria. These vicious oxidative cascades are an important factor in neurodegeneration in AD [44]. Extensive in vitro and animal studies have been conducted that demonstrate the free radical scavenging and antioxidant actions of EBm, they are summarized in Table 16.4. [43,46-49] As an antioxidant in AD, EBm increases the level of free oxide scavengers like GSH, GPx, CAT, and SOD. Reduction of free radicals has been linked to improved memory and cognition in AD [50].

Cholinergic system The role of acetylcholine in memory processing and learning has been established in previous studies [51]. Loss

TABLE 16.4 EBm research: antioxidant and iron chelation. Author and year of publication

Model system

Intervention/Experiment

Conclusions

Bhattacharya et al. (2000) [43]

Rats

EBm and antioxidant deprenyl were administered and antioxidant enzymes in brain were compared after 21 days

Deprenyl increased antioxidant enzymes (SOD, CAD, and GPx) in prefrontal cortex and corpus striatum while EBm additionally increased it in hippocampus.

Dhanasekaran et al. (2007) [45]

Human nonimmortalized fibroblasts

EBm was supplemented to fibroblasts exposed to H2O2

EBm protected the fibroblasts against DNA damage by ROS by reduction in lipoxygenase activity and inhibition of H2O2 mediated lipid peroxidation. Iron chelation prevents the immunopathologic cascade initiated by iron Ab protein complex.

Kapoor et al.(2009) [46]

Diabetic rats

Oral EBm administration for 15 days and antioxidant enzyme assay

Increased GPx, GSH, SOD, CAT and decreased lipid peroxidation in brain.

Shinomol et al. (2011) [47]

Prepubertal CFTSwiss mice

EBm was administered to mice whose brain was subjected to 3-NPA induced oxidative stress

EBm administration reversed the corpus striatal mitochondrial damage by 3-NPA as evidenced by reduced levels of malondialdehyde and hydroperoxide in neuronal cytoplasm. The antioxidant properties were further confirmed on DPPH radical scavenging assay, nitric oxide scavenging assay, hydroxyl radical scavenging assay, superoxide scavenging assay, deoxyribose oxidation assay, and iron chelation assay.

Russo et al. (2003) [48]

Astrocytes

Methanolic EBm was administered to astrocytes exposed to nitric oxide donated by SNAP

EBm neutralized the oxidative damage by the resultant peroxynitrite (ONO2-) free radical in 18 hr.

Dwivedi et al. (2013) [49]

Male Sprague Dawley rats

EBm given to rats administered with intracerebroventricular injection okadaic acid for 13 days

Restored antioxidant markers like GCLC, HO1, and Nrf2; reduced neuronal loss and improved memory from reduced latency and path length.

Abbreviations: GCLC, Glutamate-Cysteine Ligase Catalytic subunit; HO1, Heme Oxygenase 1; 3-NPA, 3-nitropropionic acid; Nrf2, Nuclear factor erythroid 2-related factor 2; SNAP, S-nitroso-N-acetyl-penicillamine.

242 Nutraceuticals in Brain Health and Beyond

of hippocampal, basal forebrain, and temporal cholinergic neurons in response to Ab plaques and neurofibrillary s tangles is characteristic of AD. In AD, choline acetyltransferase (ChAT) production reduces to 35%e 50% of normal, and this causes impaired attentional processing and loss of cognition as the ACh reduces with progressing severity of the disease [52]. Reduced choline uptake, deficient ChAT, and increased synaptic AChE are the cholinergic mechanisms of AD [52]. Studies on EBm targeting the above mechanisms are illustrated in Table 16.5 [53-56].

b-Amyloid plaques As explained before APP is initially cleaved by a- and b-secretases and subsequently by g-secretase which results in secretion of amyloidogenic Ab plaques. Any acceleration in this cleavage results in overaccumulation of Ab plaques, which initiate vicious immunoinflammatory cascades which can damage brain parenchyma. Targeting these pathomechanisms is the object of Ab therapy, and the role of EBm in it is discussed in Table 16.6 [57-59].

TABLE 16.5 EBm research: cholinergic system. Author and year of Publication

Model system

Intervention/Experiment

Conclusions

Le et al. (2013) [53]

Mice

OBX mice were compared with Shamoperated mice for hippocampal ChAT expression in response to EBm

EBm reversed the decline in ChAT activity and cognitive function in OBX mice by protecting the cholinergic neurons in median septal nucleus.

Uabundit et al. (2010) [54]

Male wistar rats

Alcoholic EBm administered 2 weeks before and 1 week after intracerebroventricular ethylcholine aziridinium ion injection to rats

EBm reduced cholinergic neuronal loss and improved cognition reflected by enhanced latency on Morris Maze Test.

Rai et al. (2015) [55]

Mice

CDRI-08 (200 mg/kg body weight) administered daily to scopolamine-induced amnesic mice for 7 days

Treatment with EBm improved spatial memory due to its associated increase in expression of GluN2B a subunit of NMDAR and also decrease in ChAT activity in prefrontal cortex and hippocampus.

Saraf et al. (2011) [56]

Male Swiss Albino mice

EBm administered to scopolamine-induced amnesia

EBm reduced spatial memory loss possibly by inhibiting AChE. Reversal of anterograde and retrograde amnesia as evidenced by improved screen muscle coordination (Rotarod test) and spatial orientation (Morris Maze Test).

Abbreviations: GluN2B, Glutamate Receptor Subunit Epsilon-2; NMDAR, N-methyl-D-aspartate Receptor; OBX, Olfactory Bulbectomized.

TABLE 16.6 EBm research: b-amyloid plaques. Author and year of publication

Model system

Holcomb et al. (2006) [57]

Intervention/Experiment

Conclusions

PSAPP mice

PSAAP mice with Swedish amyloid precursor protein and M146L presenilin-1 mutations were given 2 doses of EBm for 2 or 8 months starting at 2 months age

EBm decreased Ab 1e40 and 1e42 levels in cortex and reversed Y-maze and open-field hyperlocomotion.

Limpeanchob et al. (2008) [58]

Cortical cell line culture

EBm was added to a neuronal culture fed with Ab protein and compared with control

AChE was found in control suggesting the EBm protected the test culture against Ab protein-induced damage. EBm also quenched free radicals to improve cell viability.

Malishev et al. (2017) [59]

SH-SY5Y cell line

Cell lines incubated with Ab42 and EBm were assessed spectroscopically and microscopically

EBm prevented fibril formation and membrane interaction of Ab42, thus preventing its cytotoxic effects; however, it didn’t have any direct effect on Ab42 oligomer formation.

Abbreviation: PSAPP, presenilin/amyloid precursor protein.

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Neuroprotectivity (neuronal and glial plasticity) Brain defends itself against metabolic and immunologic stress by restructuring its synapses and neuronal network. Brain-derived neurotrophic factor (BDNF), a neurotrophin, and glial fibrillary acidic protein (GFAP) play an important role in glial plasticity. While BDNF regulates transcription of gene Arc associated with neuronal plasticity, GFAP regulates astrocyte morphology and glial-glial interaction, both clinically preventing amnesia. These mechanisms are summarized in Table 16.7 [60,61].

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Memory impairment and cognitive defects AD is associated with amnesia and cognitive deficit. EBm has shown to reverse these detrimental effects as evidenced by animal studies vide Table 16.9 [65-68].

Clinical trials B. monnieri is one of the most significantly researched herbal nootropics in AD. The major clinical trials and their inferences are summarized in Table 16.10 [69-73].

Bacopa monnieri clinical practice

Cerebral blood flow

Drug development and current practice

The watershed zone in the basal forebrain especially at the hippocampus makes AD more likely when in combination with vascular pathologies like impaired cerebral perfusion and atherosclerosis [62]. Various animal models evaluating the effects of Brahmi on cerebral flow are illustrated in Table 16.8 [63,64].

Brahmi juice or Swarasa is expressed from the leaves using mechanical pressure. It is further extracted (EBm), refined, and standardized as patented by Kahol et al. [38] Clarified butter obtained from cow milk, also called Go Ghrita is liquefied and mixed with Swarasa to produce

TABLE 16.7 EBm research: neuroprotectivity (neuronal and glial plasticity). Author and year of Publication

Model system

Intervention/Experiment

Conclusions

Rastogi et al. (2012) [60]

Female wistar rats

EBm administered for 3 months (200 mg/kg BW)

EBm prevented lipofuscin aggregation, thus was neuroprotective in middle-aged, old-aged, and in SDAT rats. Also, increased acetylcholine synthesis, altered monoaminergic neurotransmitters, and curbed lipid peroxidation.

Konar et al. (2015) [61]

Male Swiss Albino mice

Scopolamine-treated mice given EBm

EBm enhanced BDNF and gene arc but not GFAP to reverse scopolamine-induced neuronal damage.

Abbreviations: BDNF, Brain derived neurotrophic factor; SDAT, Senile Dementia of Alzheimer Type.

TABLE 16.8 EBm research: Cerebral blood flow. Author and year of publication

Model system

Kamkaew et al. (2011) [63]

Kamkaew et al. (2013) [64]

Intervention/Experiment

Conclusions

Anesthetized rats

Intravenous Brahmi was administered and vasodilation was compared with a nitric oxide synthetase blocker L-NAME and phenylephrine

Reduction in systolic and diastolic blood pressures attributed to Brahmi-mediated vasodilation. It increases endothelial NO synthesis and prevents release of Ca2þ from sarcoplasmic reticulum, both cause vasorelaxation.

Rats

EBm, Ginko Biloba, and donepezil were administered to rats for 8 weeks

Cerebral blood flow measured by cerebral laser Doppler was increased with Brahmi (25%) and G. Biloba (29%) but not with donepezil. This also correlated with improved cognition suggesting provascular and nootropic actions of EBm.

ABBREVIATIONS: L-NAME, L-NG-Nitro arginine methyl ester.

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TABLE 16.9 EBm research: memory impairment and cognitive defects. Author and year of Publication

Model system

Intervention/Experiment

Conclusions

Kumar et al. (2015) [65]

Mice

EBm was administered to mice subjected to prolonged (1 month) cold water swim stress and their hippocampi compared histophotometrically with unstressed mice

EBm administration reduced or nearly abolished cold-induced neurodegeneration of the hippocampus in stressed mice.

Saini et al. (2012) (2012) [66]

Male wistar rats

Administration of EBm to mice with memory loss due to intracerebroventricular injection Colchicine

EBm reduced the oxidative damage induced by colchicine reflected by increased retention time on Elevated Plus Maze Test.

Vohora et al. (2000) [67]

Swiss Albino mice

EBm administered to rats with phenytoin induced cognitive impairment

EBm caused reversal of the memory impairment caused by phenytoin as seen on passiveavoidance task, locomotor activity.

Saraf et al. (2008) [68]

Mice

EBm given to mice with diazepam-induced amnesia

EBm administration blocked the GABAergic action of BZDs and thus reversed memory impairment as seen on Morris Water Maze Test.

Abbreviation: BZDs, Benzodiazepines.

TABLE 16.10 EBm research: clinical trials. Author and year of Publication

Model system

Intervention/Experiment

Conclusions

Sharma et al. (1987) [69]

40 healthy children (6e8 years)

Double-blind, placebo-controlled study with test group getting Brahmi 3 tsp (350 mg/tsp) for 90 days

Improved exploratory drive on maze learning test, enhanced reasoning and perception of image patterns and organization.

Calabrese et al. (2008) [70]

Healthy, nondemented adults (>65 years, mean: 73.5 years)

Double-blind, placebo-controlled trial, EBm administered 300 mg/day for 84 days

Improved ability to ignore unnecessary stimuli on Stroop task and improved word recall memory on AVLT. Reduced CESD-10 depression scores over time as well as reduction in anxiety trait.

Kumar et al. (2016) [71]

50 medical students (19e22 years)

Randomized double-blind, placebocontrolled study with test group administered EBm (150 mg/day) for 15 days

Significant improvement in memory and neuropsychologic function as evidenced by improvement in digit span memory task, paired associate task, story recall, nonsense syllables memory recall, finger tapping test, choice discrimination test, and digit picture substitution test.

Dimpfel et al. (2016) [72]

32 adults (50e80 years, mean: 58.63  5.79 years) with MCI

Randomized placebo-controlled study with EBm (120 mg) and ESs (380 mg) administered to test group evaluated on EEG and EOG

EEG recorded a psychometric improvement, with an increase in beta power and attenuation of delta and theta spectral power in MCI cases suggesting a positive shift similar to rivastigmine.

Cicero et al. (2016) [73]

30 elderly (66  3 years)

Randomized placebo-controlled crossover study received multidrug combination with EBm dosed at 320 mg/day for 8 weeks

Improved cognition as seen by improvement on MMSE, PSQ, and SRDS scales.

Abbreviations: AVLT, Rey Auditory Verbal Learning Test; CEDS, Center for Epidemiologic Studies Depression scale; EEG, Electroencephalogram; EOG, Electrooculogram; ESs, Sideritis scardica; MCI, Mild Cognitive Impairment; MMSE, Mini-Mental State Examination; PSQ, Perceived Stress Questionnaire; SRDS, Index and Self-Rating Depression Scale.

Chaudhari: Bacopa monnieri Neuropharmacology in Alzheimer’s Disease Chapter | 16

245

Brahmi Ghrita, a very potent form of EBm. Brahmi or EBm is administered as Ghrita (clarified butter supplement) or Churna (powder) in doses of 1e2 gm/day or as tablet in dose of 250e500 mg/day [8]. Few novel studies on the formulations of EBm are summarized in Table 16.11 [74-76].

liver markers reported by Allan et al. [77] make a case for the study of EBm and hepatocellular injury. Some studies researching the adverse effects of EBm are summarized in Table 16.12 [45,77].

Adverse effects and safety

Far too many times in the history of targeted drug development have plant-derived and often indigenous medicines provided a critical breakthrough in management. Digoxin (Digitalis purpurea), Atropine (Atropa belladonna), and Quinine (Cinchona officinalis) are a few examples. It is for physicians and neuroscientists to uphold with curiosity all possible therapies that can bring relief to their patients.

Considering that EBm use, both for prevention and treatment of AD, is a long-term affair, the chances of sideeffects cannot be ignored. However, there is a dearth of good adverse effect outcome studies on EBm, both in young adults as well as elderly. Further, there are no studies involving use in pregnant and lactating women. Elevated

Conclusions

TABLE 16.11 EBm research: Drug development and current practice. Author and year of Publication

Model system

Intervention/Experiment

Conclusions

Lohidasan et al. (2009) [74]

Rats

MEBM, AGBM, and LEBM were administered to scopolamine-induced AD rats

Greater spatial recognition on 2-trial Y-maze Test was seen with MEBM and LEBM than AGBM. Overall LEBM and MEBM have comparable anti-AD effects.

Jose et al. (2014) [75]

Adult albino Wistar rats

Bacoside A combined with oil-in-water PLGA nanoparticles coated with polysorbate 80 was administered to the rats

SEM showed minimal drugepolymer interaction. Polysorbate 80 promoted crossing blood brain barrier, evidenced by higher brain concentration of Bacoside A.

Habbu et al. (2013) [76]

Male Swiss albino mice and Wistar rats

BPC showing 2 thermal peaks in DSC was administered orally to rats

BPC increased serum concentration of Bacoside suggesting improved bioavailability. Improved cognition and memory in rats.

Abbreviations: AGBM, Ayurvedic ghrita; Bacopa monnieri Extracts, MEBM, methanolic extract; BPC, Bacopa -phospholipid complex; LEBM, Lipid extract; PLGA, Poly-(d, L)-Lactide-co-Glycolide; SEM, Scanning electron microscopy.

TABLE 16.12 EBm research: Adverse effects and safety. Author and year of Publication

Model system

Dhanasekaran et al. (2007) [45]

Intervention/Experiment

Conclusions

Plasmid DNA pBR322

EBm (0e10 mg) incubated with plasmid DNA (1 mg) at 37 C for 1 hr

EBm did not show any genotoxic effect on the index plasmid.

Allan et al. (2007) [77]

Rats

EBm administered at 500 mg/kg to rats for 90 days

Reduced appetite but no weight reduction seen after 3 months. Mild increase in aspartate aminotransferase, urea, albumin, and globulin wrt controls but within normal limits.

Singh et al. (1997) [33]

Humans

Single-dose (20e300 mg) and multiple-dose (100 and 200 mg) administered to 31 males for 4 weeks

No biochemical, haematological, and clinical derangements seen.

Abbreviations: Nil.

246 Nutraceuticals in Brain Health and Beyond

Standardization of active constituents, advanced molecular studies, and metacentric trials aimed at verifying and sharpening our understanding of B. monnieri can provide vital clues to its use as an adjunct if not an alternative to the very limited armamentarium neurophysicians have against AD. Our knowledge of use of Brahmi as a memory-enhancing molecule, as well as its relative biosafety profile, makes a strong case for further research as a preventive agent (nutraceutical) for AD. It’s unlikely that such research may rival the scope of drug discovery by a synthetic chemist; however, it can generate newer and generic biomolecules that could be developed further. In this chapter, I provide an extensive evidence-based outlook on our current understanding of B. monnieri with a hope that it will improve our understanding and widen the scope for further research in this area.

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[48] Russo A, Borrelli F, Campisi A, Acquaviva R, Raciti G, Vanella A. Nitric oxide-related toxicity in cultured astrocytes: effect of Bacopa monniera. Life Sci 2003;73:1517e26. [49] Dwivedi S, Nagarajan R, Hanif K, Siddiqui HH, Nath C, Shukla R. Standardized extract of Bacopa monniera attenuates okadaic acid induced memory dysfunction in rats: effect on Nrf2 pathway. Evid Based Complement Alternative Med 2013;2013:294501. [50] Huang W, Zhang X, Chen W. Role of oxidative stress in Alzheimer’s disease. Biomed Rep 2016;4:519e22. [51] Hasselmo ME. The role of acetylcholine in learning and memory. Curr Opin Neurobiol December 2006;16(6):710e5. [52] Francis PT. The interplay of neurotransmitters in Alzheimer’s disease. CNS Spectr November 2005;10(11 Suppl. 18):6e9. [53] Le XT, Pham HT, Do PT, Fujiwara H, Tanaka K, Li F, et al. Bacopa monnieri ameliorates memory deficits in olfactory bulbectomized mice: possible involvement of glutamatergic and cholinergic systems. Neurochem Res 2013;38:2201e15. [54] Uabundit N, Wattanathorn J, Mucimapura S, Ingkaninan K. Cognitive enhancement and neuroprotective effects of Bacopa monnieri in Alzheimer’s disease model. J Ethnopharmacol January 8, 2010;127(1):26e31. [55] Rai R, Singh HK, Prasad S. A special extract of Bacopa monnieri (CDRI-08) restores learning and memory by upregulating expression of the NMDA receptor subunit GluN2B in the brain of scopolamineinduced amnesic mice. Evid Based Complement Alternative Med 2015;2015:254303. [56] Saraf MK, Prabhakar S, Khanduja KL, Anand A. Bacopa monniera attenuates scopolamine-induced impairment of spatial memory in mice. Evid Based Complement Alternative Med 2011;2011:236186. [57] Holcomb LA, Dhanasekaran M, Hitt AR, Young KA, Riggs M, Manyam BV. Bacopa monniera extract reduces amyloid levels in PSAPP mice. J Alzheimers Dis 2006;9:243e51. [58] Limpeanchob N, Jaipan S, Rattanakaruna S, Phrompittayarat W, Ingkaninan K. Neuroprotective effect of Bacopa monnieri on beta-amyloid-induced cell death in primary cortical culture. J Ethnopharmacol 2008;120:112e7. [59] Malishev R, Shaham-Niv S, Nandi S, Kolusheva S, Gazit E, Jelinek R. BacosideA, an Indian traditional-medicine substance, inhibits b-amyloid cytotoxicity, fibrillation, and membrane interactions. ACS Chem Neurosci 2017;8:884e91. [60] Rastogi M, Ojha RP, Prabu P, Devi BP, Agrawal A, Dubey G. Prevention of age-associated neurodegeneration and promotion of healthy brain ageing in female Wistar rats by long term use of bacosides. Biogerontology 2012;13:183e95. [61] Konar A, Gautam A, Thakur MK. Bacopa monniera (CDRI-08) upregulates the expression of neuronal and glial plasticity markers in the brain of scopolamine induced amnesic mice. Evid Based Complement Alternative Med 2015;2015:837012. [62] Brown WR, Thore CR. Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol 2011;37:56e74. [63] Kamkaew N, Scholfield CN, Ingkaninan K, Maneesai P, Parkington HC, Tare M, et al. Bacopa monnieri and its constituents is hypotensive in anaesthetized rats and vasodilator in various artery types. J Ethnopharmacol 2011;137:790e5.

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[64] Kamkaew N, Norman Scholfield C, Ingkaninan K, Taepavarapruk N, Chootip K. Bacopa monnieri increases cerebral blood flow in rat independent of blood pressure. Phytother Res January 2013;27(1):135e8. [65] Kumar SS, Saraswathi P, Vijayaraghavan R. Effect of Bacopa monniera on cold stress induced neurodegeneration in hippocampus of wistar rats: a histomorphometric study. J Clin Diagn Res January 2015;9(1):AF05e7. [66] Saini N, Singh D, Sandhir R. Neuroprotective effects of Bacopa monnieri in experimental model of dementia. Neurochem Res 2012;37:1928e37. [67] Vohora D, Pal SN, Pillai KK. Protection from phenytoin-induced cognitive deficit by Bacopa monniera, a reputed Indian nootropic plant. J Ethnopharmacol 2000;71:383e90. [68] Saraf MK, Prabhakar S, Pandhi P, Anand A. Bacopa monniera ameliorates amnesic effects of diazepam qualifying behavioralmolecular partitioning. Neuroscience 2008;155:476e84. [69] Sharma R, Chaturvedi C, Tewari P. Efficacy of Bacopa monniera in revitalizing intellectual functions in children. J Res Edu Ind Med 1987;1:12. [70] Calabrese C, Gregory WL, Leo M, Kraemer D, Bone K, Oken B. Effects of a standardized Bacopa monnieri extract on cognitive performance, anxiety, and depression in the elderly: a randomized, double-blind, placebo-controlled trial. J Altern Complement Med 2008;14:707e13. [71] Kumar N, Abichandani LG, Thawani V, Gharpure KJ, Naidu MU, Venkat Ramana G. Efficacy of standardized extract of Bacopa

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[77]

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Chapter 17

Nutraceuticals in neurodegenerative diseases Sharmistha Banerjee, Sayanta Dutta, Sumit Ghosh and Parames C. Sil Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, India

Chapter outline Introduction 249 Role of ROS in the pathology of neurodegenerative diseases 250 Nutraceutical 250 Alzheimer disease 251 Ameliorative effects of various nutraceuticals against the pathogenesis of AD 251 Taurine 251 Curcumin 252 Vitamin C 253 Resveratrol 253 Catechins 254 Huntington disease 254 Parkinson disease 256 Ameliorative effects of various nutraceuticals against the pathogenesis of Parkinson disease 257 Curcumin 257 Taurine 258

Vitamin C Resveratrol Catechins Anthocyanins Morin Quercetin Caffeine Vitamin A Amyotrophic lateral sclerosis Ameliorative effects of various nutraceuticals against the pathogenesis of ALS Vitamin E Vitamin C Curcumin Conclusion References

Introduction

neurodegenerative disease is the formation and accumulation of protein aggregates in the neurons and brain, which leads to aberrant synaptic activity, neurotransmission, and synaptic plasticity. These proteins are required for carrying out of normal physiological activities of brain like transportation, mitochondrial function, and signal transduction. The misfolded forms of the proteins form aggregates and deposition of these aggregated forms gives rise to pathological features associated with neurodegenerative diseases [1]. The tendency of misfolding arises from genetic mutation. For example: PD can be caused due to triplication of a-synuclein locus, HD is attributed to the expansion of CAG stretches at the N-terminal region [2]. Covalent modification of these proteins like aberrant phosphorylation can trigger formation of aggregates. Phosphorylation of synuclein and tau proteins can lead to aggregates and neurofibrillary tangle formation in PD and AD [3].

The term neurodegenerative disease refers to a class of diseases characterized by gradual loss of neuronal function attributed to neuronal cell death. These neurodegenerative diseases are incurable and manifest at older age in its worst pathological form. Till date well-defined neurodegenerative diseases are Alzheimer disease (AD), Parkinson disease (PD), Huntington disease (HD), and Amyotrophic lateral sclerosis (ALS). The common symptoms of these diseases include dementia, problems with movement and coordination, motor disorder, and other psychiatric symptoms like anxiety, depression, and suicidal tendency. These diseases at their initial stages affect particular portion of the brain. For example, AD affects cortex region, PD affects substantia nigra, loss of dopaminergic neuron occurs, and HD affects GABAergic neurons. The main cause of the

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258 258 258 259 259 259 259 259 259 260 260 261 261 261 262

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250 Nutraceuticals in Brain Health and Beyond

These aggregates lead to pathological response in the brain through mechanisms like oxidative stress, neuroinflammation, and apoptosis (Fig. 17.1).

Activation of microglia and consequent neuroinflammation and oxidative stress can lead to neurotoxicity through neuronal cell death.

Role of ROS in the pathology of neurodegenerative diseases

Nutraceutical

ROS and oxidative stress activate redox-sensitive transcription factors like NF-kB that participate in transcription of proinflammatory cytokines and proapoptotic genes [4]. This transcription factor is also required for activation of survival proteins and mitochondrial antioxidants. The finetuning and regulation of its activity depend on the duration of phosphorylated state of NF-kB. ROS inactivates certain phosphatases which dephosphorylates these proteins to regulate their activities. Prolonged activation of JNK during oxidative stress is attributed to oxidative modification mediated inhibition of MAP kinase phosphatase (MKP) [5]. Deposition of misfolded protein aggregates in the brain during neurodegenerative diseases serves as a danger signal for the cells and is recognized by resident immune cells of the brain known as microglia [6]. These microglial cells are activated, which is marked by changes in the morphology of these cells to ramified branched structure. Activation of different tolllike receptors and downstream signaling lead to proinflammatory cytokines production like tumor necrosis factor a (TNF-a), interleukin 1b (IL-1b), IL-6, IL-18, interferon gamma (IFN-g), macrophage inflammatory protein (MIP)-1b, proinflammatory mediators like nitric oxide (NO), prostaglandin E2, and ROS [7,8].

FIGURE 17.1

The term “nutraceutical” was coined by Stephen DeFelice in the year 1989. This term is derived from two wordsd nutrition and pharmaceutical. Nutraceutical covers a wide range of edible items like plant products, vitamins, and minerals present in animal products, pre and probiotics that are beneficial for health [9]. The current definition of nutraceuticals according to Merriam-Webster Online Dictionary 2014 is, “1.a specially treated food, vitamin, mineral, herb etc, that you eat or drink in order to improve your health 2: a foodstuff (as a fortified food or dietary supplement) that provides health benefits in addition to its basic nutrition.” The developmental process of nutraceuticals is a tedious and long one. It requires identification of a food material, separation, and identification of different components with the help of HPLC, NMR, and mass spectra. The biological activities of the separated components have to be determined in vitro and the mechanism of action of the phytochemicals has to be studied. Metabolic profiling and examination of safety mechanism in vivo is a crucial part of the whole process. Finally clinical trial in different diseases will lead to the formulation of a standard nutraceutical to be used as nutria-drug [10]. The difference between dietary supplement and nutraceutical is that the efficacy of nutraceuticals has been clinically proven in various pathological

Molecular mechanisms of neurodegenerative pathophysiology.

Nutraceuticals in neurodegenerative diseases Chapter | 17

conditions and is very close to pharmaceuticals. The concept of nutraceuticals is gaining ground in medical and medicinal-based industrial ground. In this chapter, we will discuss the mechanism of well-known neurodegenerative diseases AD, PD, HD, and ALS and the beneficial roles of different components found in daily food.

Alzheimer disease Alzheimer disease (AD) is one of the common neurodegenerative diseases accompanied by dementia and cognitive impairment [11]. This disease was first observed by German psychiatrist Alois Alzheimer in 1906. Dr. Alzheimer diagnosed a patient named Auguste D. who was suffering from progressive cognitive loss. After Auguste’s death, Dr. Alzheimer examined his brain using histology and observed numerous miliary foci in the cortex of brain tissue. These miliary foci are deposition of neurofibrils which are well recognized today. The pathological response of AD is due to the accumulation and deposition of phosphorylated and ubiquitinated Tau proteins as neurofibrillary tangles. Neurotoxic amyloid-beta precursor protein peptides (AbPP-Ab) deposition also contributes to the miliary foci [12]. This amyloid precursor protein is synthesized in the endoplasmic reticulum (ER) and is translocated to the Trans Golgi network (TGN). Ab precursor is processed by various proteases like a, b, and g proteases [13]. In recent years, the concept of metabolic disturbance in the brain is assumed to be the cause of the disease and the associated neuronal damage through Ab peptide [14]. Glucose is the only energy source for brain tissue. Inability to utilize glucose by the brain has been observed in the AD patients at early stage of the disease, and this deficit of glucose utilization in the brain cortex also co-relates with progressive cognitive disorder [15]. This disturbance in glucose utilization is caused by impaired insulin receptor signaling [16]. Insulin and its receptor mediated downstream signaling help in uptake of glucose into the brain cells for generation of energy with the help of GLUT transporters. Resistance to insulin or disturbance in IGF signaling leads to inhibition of transport of GLUT transporters from cytosol to the plasma membrane, thereby reducing glucose uptake [17]. Deficiency in glucose uptake results in perturbance of energy homeostasis, ROS production, and mitochondrial dysfunction, thereby promoting an inflammatory response [18]. Insulin and IGF signaling helps in apoptosis inhibition, maintaining energy balance, neuron survival, neurites growth, memory, and cognition [17]. Accumulation of ROS and oxidative stress lead to modification of lipid molecules inside brain tissues. Oxysterols are produced through oxidative modification of cholesterol. Oxidative modification of cholesterol produces 24(S)-hydroxycholesterol (24(S), 27-OHC and 7/-Hydroxycholesterol (7/-OHC) which are proinflammatory metabolites [19]. The oxysterols

251

mediate their effects through various receptors like the nuclear receptors, liver X receptors (LXR), and retinoic acidrelated orphan receptors (ROR) [20,21]. They also mediate their effects through G protein coupled receptors [22]. Retinoic acid-related orphan receptors (ROR) are required for activation of inflammatory Th17 cells. Oxysterols might activate inflammatory response in AD through activation of proinflammatory T cells. Since the cause of AD stems from disturbances in insulin signaling resulting in deficiency of glucose utilization in brain tissue followed by oxidative stress, phosphorylation of tau proteins, their accumulation, and inflammation; herefore, nutraceuticals might have a protective role against this neurodegenerative diseases (Fig. 17.2).

Ameliorative effects of various nutraceuticals against the pathogenesis of AD Taurine Taurine is a sulfur containing amino acid produced through the metabolism of cysteine. It is also generated from methionine after methionine is converted to cysteine. Cysteine is converted to cysteine sulfinic acid with the help of cysteine dioxygenase. Cysteine sulfinic acid undergoes decarboxylation by cysteine sulfinic acid decarboxylase to produce hypotaurine which subsequently generates taurine [23]. Kidney and liver are the primary sites of taurine production; moreover, it is also produced in brain, heart, muscles, and blood, especially leukocytes [24]. Taurine possesses antioxidant and antiinflammatory properties in different organ pathophysiological conditions [25e31]. Tauroursodeoxycholic acid (TUDCA) is a bile acid which acts as a neuroprotective agent in mouse model of AD. Administration of TUDCA in APP/PS1 mice reduced Ab deposition, tau phosphorylation, and synaptic function loss. It also mitigated activation of glial cells in the brain of APP/PS1 mice and neuroinflammation by downregulating TNF-a, IL-1b, and IL-6 protein expression. The beneficial role of TUDCA is attributed to the activation of Akt/ GSK3b signaling pathway [32]. TUDCA also modulated apoptosis through E2F-1/p53/Bax pathway in neuroblastoma cell lines having higher level of Ab production and aggregation. TUDCA reduced activities of caspase 2 and 6, downregulated the expression of bax and bcl2 and also reduced nuclear fragmentation [33]. Pretreatment with taurine at a dose of 50 mg/kg of body weight administered orally in ICV-STZ administered rats upregulated the activities of antioxidant enzymes like superoxide dismutase (SOD), catalase, glutathione peroxidase (GPX), glutathioneS-transferase (GST), and glutathione reductase (GR). It also increased glutathione level. Taurine decreased the activity of acetylcholine esterase and also improved the morphology of hippocampal pyramidal neurons. It exerted

252 Nutraceuticals in Brain Health and Beyond

FIGURE 17.2 Ameliorative mechanisms of nutraceuticals in Alzheimer’s disease.

neuroprotective mechanism on STZ induced cognitive impairments in rats [34]. Jang et al. demonstrated that oral administration of taurine ameliorated Ab-induced cognitive deficits in oligomeric Ab-infusion mouse model by directly binding to oligomeric Ab. This binding was proved through surface plasmon resonance [35]. Taurine ameliorated cognitive impairment in intracerebroventricular streptozotocin (ICV-STZ)einduced cognitive disorder in rats through modulation of oxidative stress parameters, secretion of proinflammatory cytokines TNF-a and IL-1b in the hippocampal region and cortex. Choline-esterase activity was also mitigated by taurine [36]. These studies point out the promising nature of taurine for therapeutic purpose.

Curcumin Curcumin is a polyphenol and phytochemical obtained from Curcuma longa, a herb from which turmeric is obtained. Turmeric is used for coloring of food in India and large part of Southern Asia. In Indian Ayurvedic medicine, curcumin has been used for many years for the treatment of various organ pathophysiology [37]. Curcumin exists in two tautomeric forms, keto and enol. It predominantly resides in keto forms in neutral and acidic conditions. Curcumin acts as a good antioxidant and its beneficial role as an antioxidant and antiinflammatory agent has been investigated in diseases like diabetes, cancer and druginduced organ pathophysiology. The antioxidant property of this polyphenol is attributed to the phenolic OH groups which are able to lose protons and the resulting phenoxyl diradical is stabilized by delocalization of electrons. This

resonance stabilized structure helps curcumin to scavenge free radicals, thereby imparting it antioxidant property [38]. Deposition of oligomeric Ab plaques is attributed to the dementia and memory loss in AD. Oral administration of curcumin has been effective in reducing Ab plaque formation in murine model. It downregulated BACE-1 enzyme, the enzyme that converts AbPP to Ab through cleavage of AbPP [39]. Curcumin has been shown to bind to senile plaques (SPs), tau proteins, and cerebral amyloid angiopathy (CAA) in the aging brain of various animal models and also in an AD patient [40]. Administration of curcumin upregulated the expression of BAG2, an endogenous protein which aids in clearing of neuronal tau tangles in primary rat cortical neurons. It also reduced phosphorylated tau levels [41]. Curcumin encapsulated in especially designed exosomes improved solubility, bioavailability, and crossing of the blood-brain barrier through receptor mediated endocytosis in AD models. Curcumin activated AKT/GSK-3b pathway in the brain thereby inhibiting tau phosphorylation and neuronal cell death in vivo in AD. The various challenges associated with curcumin as a therapeutic agent in AD have been extensively reviewed elsewhere [42]. Neuroinflammation is a hallmark phenomenon of AD. Inflammatory response is mainly carried out by activated microglial cells. Proinflammatory cytokines like IL-1b, TNF-a, and IL-6 are produced by activated microglial cells in the brain [43]. Accumulation of these cytokines is also accompanied by ROS production. IL-1b plays a crucial role in the molecular mechanism of AD. IL-1b activates (MAPK)-p38 signaling cascade which ultimately activates the protease, BACE-1. This BACE-1 leads to

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proteolytic cleavage of APP causing Ab deposition [44]. IL-1b also stimulates phosphorylation of tau proteins and aggregation of neurofibrillary tangles (NFT) through p38 activation, thereby augmenting AD pathology [45]. Hyperphosphorylation of tau and its deposition as NFT cause loss of axonal integrity and synaptic connectivity between neurons. IL-1 cytokines also amplify inflammation through activation of NF-kB [46]. Curcumin has been found to ameliorate inflammatory response through modulation of IL-1 family cytokines [47,48].

Vitamin C Vitamin C or ascorbic acid is a well-known antioxidant that exerts its beneficial effects on several physiological functions. It is a water-soluble vitamin. Vitamin C can be synthesized from glucose. Human beings are not capable of synthesizing vitamin C in the body owing to lack of the enzyme, L-gulono-1,4-lactone oxidase, which is required for metabolic transformation of vitamin C from glucose [49]. Ascorbic acid acts as an antioxidant by directly scavenging free radicals or ROS. Loss of one hydrogen gives rise to ascorbate. The resulting ascorbate is converted to ascorbate free radical (AFR) on losing one hydrogen. AFR is converted to dehydroascorbic acid (DHA) through rearrangement of electrons. This DHA can further undergo dismutation to generate ascorbate. DHA can also be converted to ascorbate through GSH dependent reduction and with the help of NADPH oxidase and thioredoxin reductase [50]. Apart from its antioxidant activity, vitamin C also aids in the recycling of other antioxidants namely a-tocopherol and tetrahydrobiopterin [51]. ROS and Oxidative stress are intricately linked with AD. Brain tissue is highly vulnerable to damage mediated by redox perturbation due to higher content of polyunsaturated fatty acids and high oxygen turnover. Brain has the highest content of ascorbic acid and vitamin C is highly enriched in the hippocampus and cortical neurons [52]. Moreover, the concentration of vitamin C in the brain is lower in patients with AD which points to the importance of this antioxidant molecule in AD. Plasma level of vitamin C is also reduced in AD patients [53]. Acute systemic injection of vitamin C in APP/PSEN1 mice ameliorated cognitive impairment [54]. Mitochondrial dysfunction is a hallmark of AD due to accumulation of ROS and progression of oxidative stress. Supplementation of vitamin C reduced mitochondrial dysfunction in 5XFAD mice (an AD model). It also reduced Ab plaque formation and disruption of blood-brain barrier in the brain of 5XFAD mice. Administration of vitamin C at a low dose in KO-Tg mice might contribute to mitochondrial dysfunction due to perturbation in balance of mitochondrial fission and fusion. Vitamin C supplementation at a high dose in 5XFAD mice also prevented accumulation of astrocytes, thereby reducing neuroinflammation in the brain [55].

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Deficiency of endogenous ascorbate level leads to reduced alteration in mitochondrial energy production, mitochondrial membrane potential, mitochondrial respiration, and increased mitochondrial ROS production in the mitochondria isolated from the brain of mice containing both APP/PSEN1 and SVCT2þ/ mutation compared to wild-type isolates. Administration of ascorbate to isolated mitochondria resulted in increased oxygen consumption and reduced ROS formation. The study demonstrated that amyloid plaque and vitamin C deficiency contribute to mitochondrial dysfunction in AD brain, which can be used as biomarker for initiation of AD at early stages [56,57]. Supplementation of vitamin C has been proved to be beneficial in clinical trial reports. Vitamin C supplementation at a dose of 1000 mg/day along with vitamin E (400 IU/day) for 1 year increased the concentration of vitamin C in the cerebrospinal fluid (CSF), as well as in the plasma of AD patients. Moreover this co-supplementation of vitamin C and E also reduced lipid peroxidation in CSF. The course of AD was unaffected by vitamin supplementation [58]. Sixteenweek co-supplementation of vitamin E, C, and carotene significantly improved cognitive behavior and reduced plasma Ab levels in a trial involving 276 elder AD patients [59]. Supplementation of vitamin C, E, and a-lipoic acid to AD patients for 16 weeks reduced F2-isoprostane level, an oxidative stress marker, but did not affect the Ab42 and tau level at CSF [60].

Resveratrol Resveratrol is a polyphenolic compound present in grape, jackfruit, mulberry, and red wine. It is a phytoalexin belonging to the stilbene family and is released to combat environmental stress [61]. Resveratrol exists in two forms: cis and trans. The trans form is more stable than the cis form and possesses biological activities. Trans-resveratrol undergoes several metabolic modifications like glycosylation, methoxylation, oligomerization, and isoprenylation to form trans-piceid, pterostilbene, trans-V-viniferin, and arachidin-3 [61]. Bioavailability of resveratrol is less than1% through oral route on account of its poor water solubility, higher rate of metabolism, and limited chemical stability [62]. Co-administration of resveratrol with alkaloids like piperidine has been found to enhance its pharmacokinetic parameters through inhibition of glucuronidation, thereby also increasing bioavailability of resveratrol [63]. Delivery systems using liposome, colloidal carriers, and resveratrolprotein complexes have been used to increase bioavailability and efficacy of this compound [64]. Resveratrol has been found to be effective against AD. It has been reported to inhibit formation of Ab plaques by binding to Ab in the cortex region [65]. Resveratrol has been found to inhibit BACE1 and g secretase. It has also been shown to inhibit Ab-mediated microglial cell activation in APP/PS1 mice thereby

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preventing neuroinflammation [66]. Neuroinflammation inhibition is attributed to through down regulation of the proinflammatory transcription factor NF-kB, which ultimately reduces secretion of cytokines TNF-a, IL-1b, IL-6, chemoattractants like MCP-1, NO production and prostaglandin E2 formation in AD animal model [67,68]. Accumulation of Ab plaques and activation of microglial cells often leads to ROS production and oxidative stress along with mitochondrial dysfunction. Resveratrol combats oxidative stress by reducing ROS level through activation of glutathione (GSH) that scavenges ROS. It has also been found to activate redox-sensitive transcription factor heme-oxygenase 1(HO-1) in H2O2 induced neurotoxicity [69]. Activation of autophagy through AMPK is another protective mechanism of resveratrol in AD. Autophagy induction has been shown to improve mitochondrial dysfunction in the brain [70]. Resveratrol exerts its effect on brain cell death by modulating bax/bcl2 ratio through JNK activation [71,72]. Moreover, improving cognitive function, memory, and taupathy are a part of AD therapy. Literature reports that resveratrol has profound effect on these pathological phenomena of AD [73].

Catechins Catechins are a major group of flavonoids enriched in tea. The majority of catechins found in tea are epicatechin (EC), ()-epigallocatechin(EGC), ()-epicatechin gallate (ECG), ()-epigallocatechin gallate (EGCG) and the chemical structures suggest much about their biological activities [74]. These catechins differ in the position of hydroxyl group in the B and C ring of basic flavone structure. The ortho-dihydroxyl group in the B-ring contributes to its radical scavenging activity. Presence of a gallate moiety at third position of C ring increases radical scavenging activities. Catechins are metabolized very rapidly, and there are chemical modifications involved in their metabolism. Phase II metabolism of catechins involves glucuronidation, O-methylation, and sulfation by enzymes UDP-glucuronosyltransferases (UGT), catechol-O-methyltransferase (COMT), and phenolsulfotransferases (SULT). The metabolites generated through metabolism of catechins have immense beneficial biological activities. Catechins have been known to exert their effects in various diseases like cancer, diabetes, colitis, etc. [75e77]. Treatment with 0.5% catechins green tea prevented amyloid beta-induced cognitive impairments in rats [78]. Oral and intraperitoneal administration of EGCG at a dose of 50 and 20 mg/kg for 6 weeks suppressed phosphorylation of tau proteins in APPSw transgenic AD mouse model [79]. Catechins have been found to be effective against ROSinduced neuronal damage and inhibit activation of NF-kB [80]. Administration of EGCG restored mitochondrial respiratory rates, mitochondrial membrane potential, ROS production, and ATP level in the mitochondria isolated

from hippocampus, cortex, and striatum in A_PP/PS-1 mice, double mutant transgenic mouse model [81]. Antiinflammatory effect of catechins is attributed to the galloyl and hydroxyl moieties at the 30 position on EGCG. Moreover, catechins also exert beneficial effect in AD pathophysiology through modulation of PKC, MAPK, and AKT pathways [82e84]. Some other nutraceuticals used in treatment of AD are given in Table 17.1.

Huntington disease Huntington disease (HD) is a genetic neurodegenerative disease which manifests at older age. It is an autosomal dominant disorder. HD is characterized by cognitive impairment and motor symptoms. The motor symptoms include irregular muscle jerks which are involuntary in nature (referred to as chorea). Moreover HD is also accompanied by depression and anxiety [95]. The disease has been named after an American doctor, George Huntington, who described the condition and its symptoms. The pathophysiological response of HD is attributed to the mutation in the huntingtin gene (htt). The mutant form is caused by expansion of trinucleotide repeat (CAG)n, which encodes amino acid glutamine located at the N-terminal coding region of huntingtin gene. This glutamine polynucleotide sequence gives rise to mutated form of huntingtin [96]. The function of nonmutated huntingtin gene includes endocytosis, vesicular trafficking, and synaptic transmission. Huntingtin protein also participates in autophagy and transcription of various genes [97]. The mutated HTT (m HTT) causes aberrant disruption in transcription, aggregate formation, and oxidative stress. The extended polyglutamine sequence leads to gain of function of the mutated htt gene which causes toxic effects [98]. m HTT proteins form aggregates in the cytosol and also polyglutamine inclusion in the nucleus. This polyglutamine inclusion contains ordered amyloid fibers with low solubility in detergent and form aggregates [1]. These aggregates also sequester proteins important for transcription of several genes like cell cycle regulation, maintenance of DNA, cellular signaling, protein transport, metabolism, and cellular homeostasis. The interactome of polyglutamine inclusion contains a wide array of proteins covering a vast diversity of cellular functions which make unsurprising facts that the toxic effect of the inclusion will be well pronounced [99]. m HTT has been shown to bind to the outer membrane complex of mitochondria thereby hindering flow of electrons in the ETC and ATP synthesis. This perturbation in the ETC leads to leakage of electrons causing ROS generation and oxidative stress in the brain. m HTT disrupts calcium homeostasis in the mitochondria. It also damages mitochondrial DNA causing mitochondrial dysfunction. These mutated aggregates in the nucleus bind to the promoter region of PGC-1a, thereby hindering its

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TABLE 17.1 Some nutraceuticals used in the treatment of AD. Compounds

Source

Type

Mechanism

References

Anthocyanins

Black rice, black soyabean, and fruits

Polyphenolic flavonoids

1. Prevented Ab aggregation. 2. Prevented Ab induced oxidative stress through modulating Nrf2, Akt/PI3K pathways in H22 cell line and rodents

[85,86]

Morin

Fruits, vegetables, green tea

Flavonoid

1. Promoted Ab degradation, 2. Attenuated tau phosphorylation, 3. prevented Ab-induced impairment of energy homeostasis and mitochondrial dysfunction 4. Reduced activation of astrocytes and microglial cells, thereby preventing neuroinflammation 5. protected synaptic dysfunction and neuronal apoptosis in rodent model

[87,88]

Quercetin

Fruits and vegetables

Flavonoid

1. Improved memory and learning ability, reduced plaque formation, ameliorated mitochondrial dysfunction, and reduced ROS level in APPswe/PS1dE9 transgenic mice. AMPK activity is involved in improvement of cognitive impairment

[89]

Vitamin A

Synthesized endogenously, also obtained from fruits and vegetables

Retinol

1. Prevented Ab plaque formation, inflammatory response by inhibiting binding of microglia to Ab plaque (this binding leads to activation of NF-kB). Reduced proinflammatory cytokines TNFa, IL1b, IL6, and ROS, upregulated activity of choline-acetyltransferase

[90,91]

Caffeine

Coffee beans, chocolate

Polyphenol

1. prevented Ab deposition in the hippocampus of APPsw mice 2. Upregulated PKA expression thereby inhibiting NF-kB mediated activation of (BACE-1) 3. Prevented apoptosis

[92e94]

transcription in the brain. m HTT also binds to PGC-1a and impairs redox defense mechanism downstream [100]. PGC1a aids in the expression of antioxidant genes SOD1, SOD2, and GPx [101]. Lower levels of these antioxidants cause mitochondrial dysfunction, which is a pathological feature in HD and contributes to oxidative stress. m HTT also binds to drp1 which is required for mitochondrial fission and proper execution of mitochondrial dynamics [102]. Impaired mitochondrial fusion and fission leads to accumulation of damaged mitochondria thereby increasing cellular stress and neuronal cell death. Calcium homeostasis is also perturbed in HD leading to cell death through opening of mitochondrial transition membrane pore resulting in release of cytochrome c into the cytosol and activation of caspase 9 and 3 [103,104]. Perturbation of calcium balance and its release into cytosol also generates oxidative stress. Oxidation of pyridoxal kinase leads to decreased availability of active vitaminB6 thereby causing

disturbance in neurotransmitter synthesis [105]. HD is markedly characterized by reduced level of several neurotransmitters in different parts of the brain. Gamino butyric acid (GABA) is significantly reduced in the striatal region of HD patients. The striatal region contains GABAergic, which are the most vulnerable neurons to get damaged during HD [106]. GABA level is also reduced in the cortex and hippocampal regions. Disturbance in acetylcholine is also observed. Cholinergic receptor expression and activity of choline acetyltransferase is also reduced in the caudate region of HD brain [107]. m HTT interferes with the trafficking and expression of brain derived neurotrophic factor (BDNF) which plays a crucial role in the survival of cortical neurons [108,109]. The behavioral changes observed in HD are motor dysfunction, cognitive disorder, and increased risk of suicidal tendency. The nutraceuticals used in the treatment of HD and their mechanisms are given in Table 17.2.

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TABLE 17.2 Some nutraceuticals used in the treatment of HD. Compounds

Source

Type

Mechanism

References

Curcumin

Turmeric

Flavonoids

1. Increased activity of mitochondrial complex proteins 2. mitigated oxidative stress by restoring GSH level reducing lipid peroxidation level, mitochondrial swelling, ROS production 3. activated Nrf-2 to combat oxidative stress 4. improved neuromotor coordination in female Wistar rats 5. ameliorated cell death in HD model in Drosophila

[110,111]

Nonprotein amino acid

1. 2. 3. 4. 5.

Locomotor activity was increased GABA concentration was increased lipid peroxidation in the striatum was reduced GSH level was restored Succinate dehydrogenase activity was improved in male Wistar rats 6. TUDCA reduced striatal neurodegeneration through inhibition of apoptosis of neurons

[112,113]

Polyphenol

1. facilitated degradation of polyQ-Htt aggregates through autophagosome formation, enhanced the stability of redox sensitive factor and autophagosome protein ATG4, prevented ROS formation through aberrant metabolism of dopamine leading to dopamine quinones in SH-SY5Y cells 2. activated Ras-extracellular signal-regulated kinase (ERK) pathway to confer protection against HD in PC12 cell line 3. inhibited cyclooxygenase I (COX I) activity in 3-nitropropionic acid-induced HD model 4. inhibited p53 through deacetylation mediated by SIRT1, thereby preventing neuronal cells from apoptosis

[114e119]

Taurine

Resveratrol

Grapes, red wine

Catechin (epigallocatechingallate)

Tea

1. Inhibited aggregation of m HTT proteins and improves cognitive behavior

[120]

Anthocyanins

Vegetables

1. improved motor dysfunction in R6/1 HD mice, reduced cholesterol oxidation in the cortex of brain

[121]

Quercetin

Fruits and vegetables

1. reversed the inhibitory effect of mitochondrial respiratory complex, prevented mitochondrial swelling and oxidative stress by reducing lipid peroxidation, restored the antioxidant activities of SOD and catalase, improved motor deficit in female Wistar rats 2. Reduced serotonin metabolism, restored microglia and astrocytes, and improved cognitive behavior in HD rat model

[122,123]

Flavonoid

Parkinson disease Parkinson disease (PD) is a neurodegenerative disorder. It is associated with motor dysfunction [124]. It is induced by the loss of dopaminergic neurons in the substantia nigra region of the brain [125]. Deposition of a-synuclein protein in various parts of the brain along with the deposition of neuromelanin and iron lead to the formation of Lewy bodies [126].

Neuroinflammation plays a major role in the gradual loss of nigral dopaminergic neurons. Inflammatory responses are manifested by the elevated release of proinflammatory cytokines, glial changes, and infiltration of T cells. These are important features of PD [127]. Atypical a-synuclein linked dopamine metabolism induces oxidative stress in neural tissue of PD models. This, in turn, activates glial reactions, thereby inducing neuroinflammatory responses [128].

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Mitochondria promote cell death through the generation of toxic ROS [13]. Thus, removal of damaged mitochondria via mitophagy is crucial [129]. Mitochondrial fission, fusion, as well as motility play an important role in maintaining redox balance [130]. Proper maintenance of mitochondrial fission and fusion are disrupted with the progression of PD. Parkin dependent mitophagy is induced in PD models and Drp1 associated Parkin independent mitophagy is also found to occur in brain cells of mammals [131,132]. Apoptosis and autophagy are important cell death pathways linked with the pathogenesis of the disease [133]. While apoptotic and necrotic cell death are important features of PD, the role of autophagy is seemingly anomalous. The atypical form of ae synuclein inhibits its own autophagic clearance thereby augmenting toxic aggregations [134]. Such atypical a-synuclein increases autophagy, which rather than leading to cell survival induces cell death. Autophagy is induced by the mTOR signaling pathway via the autophagy protein Atg1 and also the Vps34-Beclin1 complex promoting cell survival [135,136]. Various nutraceuticals obtained from dietary sources have been reported to exhibit neuroprotective effects against various in vitro and in vivo models of PD. The neurotoxins associated with these models include rotenone, MPTP, paraquat, maneb, 6-OHDA, etc. The nutraceuticals exert their ameliorative effects by modulating various signaling pathways associated with the pathogenesis of PD.

Ameliorative effects of various nutraceuticals against the pathogenesis of Parkinson disease Curcumin Curcumin, a polyphenol obtained from turmeric, has widespread therapeutic effects against the pathogenesis of PD, a neurodegenerative disorder. PD is associated with mitochondrial dysfunctions and related molecular alterations, among various routes of pathogenesis. Curcumin has been reported to exhibit mitochondria-protective effects against various neurotoxins [137]. Pretreatment with curcumin protected the brain mitochondria against complex I inhibition by preventing 3-nitrotyrosine formation in vitro and elevating total cellular glutathione level in vivo [138]. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated PD model developed in SH-SY5Y cells, it has been observed that curcumin exerts its protective effects by enhancing autophagy, upregulating HSP90, and augmenting the clearance of a-synuclein. Curcumin also augmented

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a-synuclein clearance in lipopolysaccharide-induced PD model of rats [139]. It inhibited oligomer formation and opens up mitochondrial ATP sensitive Kþ channels (mitoKATP) to antagonize the effects of mutation or overexpression of a-synuclein [140]. Curcumin protected against homocysteine toxicity, a potent PD model, in rats [141]. It also protected PC12 cells from the neurodegenerative effects of MPTP via Bcl-2-mitochondria-ROS-iNOS pathway and A53T a-synuclein via antioxidant mechanisms, mTOR/p70S6K signaling and recovery of macroautophagy [142e144]. It prevented mitochondrial dysfunction and apoptosis in PINK1 deficient and paraquat treated SH-SY5Y cells [145]. Curcumin ameliorated the deleterious effects of 6- hydroxydopamine (OHDA) model of PD via antioxidant mechanisms, iron chelation, induction of dopaminergic denervation, and Wnt/b-catenin signaling pathway [146e149]. PD is associated with movement disorder, inhibition of hypothalamus-pituitary-gonadal hormones (HPGH), and metabolic shift in the activity of acetyl cholinesterase (AChE). Studies have shown that curcumin promoted HPGH via modulation of AChE and locomotive activities in bisphenol A-treated PD model in rats [150]. Neuroinflammation is an integral part of the pathogenesis of PD. Studies have shown that curcumin alleviates neuroinflammatory and neurodegenerative effects through various mechanisms, i.e., reduction in the level of inflammatory markers (TNF-a, IL-1b, NO, NF-kB), induction of epigenetic changes, etc. [47]. Dopaminergic neuron-specific knockdown of dUCH, a homolog of human UCH-L1 is a novel Drosophila model of PD and is associated with the enhancement of oxidative stress. Treatment of dUCH knockdown flies with curcumin has been reported to improve locomotory activities and decreased ROS level [6]. It ameliorated oxidative damage and death of dopaminergic neurons via Akt/Nrf2 pathway and c-Jun N-terminal kinase pathway, respectively [151,152]. Targeted nanodelivery of curcumin in PD models includes ultrasound microbubble destruction method associated use of polysorbate 80 modified cerasomes and liposomal formulations targeting histone deacetylase (HDAC) (Park 7 knockout PD model in rats) [153,154]. Various derivatives of curcumin also exhibit neuroprotective effects against different PD models: tetrahydrocurcumin inhibited monoamine oxidase B in MPTP treated mice, curcumin bioconjugates like diesters of demethylenated glutamic acid reduced oxidative stress, curcumin glucoside inhibited a-synuclein oligomer formation, glutamoyl diester of curcumin prevented peroxynitrite mediated

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nitrosative stress, demethoxycurcumin alleviated rotenone toxicity, and cyclocurcumin prevented MPTP toxicity [155e160]. However, curcumin mediated induction of PD-associated leucine-rich repeat kinase 2 (LRRK2) in rat mesencephalic cells raises concern and demands further extensive research to confirm its therapeutic effects [161].

Taurine Taurine, obtained from animal tissues, ameliorates paraquat and maneb-induced toxicity associated murine PD model by inhibiting the activation of proinflammatory markers and microglia and the prevention of microglial M1 polarization [162]. Exposure of nigral cell suspensions to taurodeoxycholic acid (TUDCA), a hydrophilic taurine conjugated bile acid, enhanced the survival probability of nigral transplants in rat PD models [163]. TUDCA prevented MPPþ induced JNK phosphorylation and activated the Akt signaling pathway in MPTP treated PD model of rats [164]. It improved locomotory activities as evident through behavioral studies and activated Nrf2 to prevent MPPþ mediated oxidative stress [165,166].

Vitamin C Vitamin C (Vit C), obtained from citrus fruits, helps in reducing oxidative stress induced by Levodopa (L-DOPA), potent therapeutic against PD [167]. Studies in PD patients have also revealed that Vit C can improve L-DOPA absorption in elderly PD patients with poor L-DOPA bioavailability [168]. Vit C being a potent neuromodulator acts as biomarker for progression of PD. Its level decreases in lymphocytes with the progression of the disease [169]. Plasma levels of Vit C also decrease in vascular parkinsonism [170]. Neural stem cell precursors (NSCs) impose a potent therapeutic strategy against PD. Exposure of ventral midbrain derived NSCs to Vit C leads to the decrease of DNA methylation and the activation of a series of developmental and phenotypic genes thereby increasing the survival probability of midbrain type dopaminergic neurons (mDA) after engraftment in PD model of rats [171]. Quenching of superoxide radicals lead to the generation of dopamine (DA)-derived quinones. The subsequently generated oxidative stress is ameliorated by Vit C. However, in the presence of iron, Vit C leads to the enrichment of active Fe(II). In relation to the comparison between Vit C and DA, DA exhibits higher affinity toward iron, leading to the formation of Fe(III)-DA2 complex. Hence, Vit C is unable to reduce the DA bound iron. Thus,

a combinatorial therapy of Vit C and a strong clinically verified iron chelator will be more effective in the treatment of PD [172]. Glutamate toxicity mediated death of dopaminergic neurons involves the activation of AMPA, NMDA, and metabotropic receptors. Vit C is reported to prevent glutamate exposure associated cell death in SH-SY5Y models of PD [173]. L-ascorbic acid delayed the climbing disability of Drosophila model of PD [174]. However, vitamin supplements do not reduce PD risk [175].

Resveratrol Resveratrol, a polyphenolic compound derived from grapes, activated the PI3K-Akt pathway, thereby delaying apoptosis in 6-OHDA model of PD [176]. It acts synergistically with low doses of L-DOPA to generate effects equivalent to higher doses of levodopa, thereby promoting therapeutic effects against PD with reduced risk of sideeffects of the latter [177]. It also improved the cognitive deficits in A53T a-synuclein PD model of mice [178]. It reduced oxidative stress in MPTP treated Drosophila model of PD and alleviated MPPþ induced mitochondrial dysfunction and apoptosis in SN4741 cells via Akt/GSK3b signaling pathway [179]. Resveratrol inhibits SIRT1deacetylated a-synuclein mediated autophagic degradation in MPTP mice model of PD [180]. It activates the SIRT1/ Akt pathway against rotenone toxicity in PC12 cell [181]. It ameliorates ER stress by downregulating CHOP and Grp78 genes, suppresses xanthine oxidase activity, activates Nrf2 signaling and inhibits caspase-3 activity in the brain of rotenone-treated PD model of rats [182]. It modulated rotenone toxicity in SH-SY5Y cells by inducing HO-1 mediated autophagy [183]. Targeted delivery of resveratrol in PD models involves polysorbate 80 coated polylactide nanoparticles and vitamin E-loaded nanoemulsions [184,185].

Catechins Catechins, obtained from tea, are efficient iron chelators and exhibit therapeutic effects against PD [186]. Proteomic analysis has revealed that the mechanism of action of epigallocatechin-3-gallate (EG) involves ATP synthase mitochondrial F1 complex b, protein kinase C ε, HIF-1a, and neurovascular growth factor inducible precursor [187]. It modulated the mTOR/Akt/GSK-3b pathway to prevent apoptosis in the nigral neurons of PD rats and affected the peripheral immune response and NO activity in MPTPinduced mice model of PD [188e190]. It reduced a-synuclein aggregation and oligomer toxicity in PD models

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[191,192]. Dietary supplementation of EG on transgenic Drosophila model of PD reduced oxidative stress and delayed climbing disability [193]. EG suppressed MPTPinduced oxidative stress in PC12 cells via SIRT1/PGC-1a signaling pathway [194]. Catechins improved locomotory abilities in 6-OHDA PD models by virtue of their antioxidant effects and restoration of PKC activity [195].

Anthocyanins Anthocyanins, obtained from berry fruits, attenuated L-DOPA-induced dyskinesia in mice model of PD [196]. Anthocyanin and proanthocyanidin extracts obtained from blueberry, grape seed, China rose, Chinese mulberry, and blackcurrant suppressed rotenone and lipopolysaccharide toxicity in primary cultures of dopaminergic neurons obtained from PD models by attenuating mitochondrial dysfunction and nitrite release [197].

Morin Morin, a flavonol obtained from wine and fruits, suppressed astroglial activation, motor dysfunction, mitochondrial dysfunction, oxidative stress, and inflammation in both MPTP-induced mice and PC12 model of PD [198,199].

Quercetin Quercetin, a natural polyphenol obtained from fruits, beverages, and red onions exerted neuroprotective effects against 6-OHDA model of PD in rats by antioxidant mechanisms [200]. Combination of neuronal growth factor and quercetin loaded in superparamagnetic iron oxide nanoparticles promoted neuronal branching and morphogenesis of PC12 cells. Hence, quercetin has the ability to promote immense therapeutic potential against the pathogenesis of PD [201]. Quercetin in combination with piperine suppressed markers of oxidative stress (nitrite, glutathione, thiobarbituric acid reactive substance, etc.) and inflammation (IL-1b, IL-6, TNF-a, etc.) and induced neurotransmission (dopamine, serotonin, homovanillic acid, etc.) in MPTP-induced rodent model of PD [202]. Quercetin glycosides, i.e., rutin and isoquercetin exerted neuroprotective effects against 6-OHDA-induced toxicity in PC12 cells. Rutin pretreatment attenuated Park-2,5,7 and caspase-3 and 7 genes and upregulated tyrosine hydroxylase gene necessary for dopamine biosynthesis [203]. Quercetin attenuated behavioral impairment, autophagy, and ER stress-induced apoptosis against rotenone toxicity in rodent model of PD [204].

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Caffeine Caffeine, a coffee component, along with eicosanoyl-5hydroxytryptamide, a fatty acid derivative of serotonin, protected brain tissue from a-synuclein toxicity through activation of protein phosphatase A, which dephosphorylates a-synuclein [205]. Caffeine protected against A53T toxicity mediated a-synucleinopathy by regulating macroautophagy (enhances microtubule associated protein 1 light chain 3 and reduces receptor protein sequestosome 1, i.e., SQSTM1/p62) and chaperonemediated autophagy (enhances LAMP2A) [206]. Absolute lower levels of caffeine and its metabolites in the serum act as potential biomarkers of early PD [207]. In MPTP animal model of PD, caffeine exerted neuronal protection by blocking adenosine receptor 2A (A2A). Caffeine is primarily metabolized by cytochrome P450. Consortium studies have shown that some A2A polymorphisms are inversely related to PD risk while slow metabolizers of caffeine, i.e., homozygous carriers of cytochrome P450 polymorphisms exhibit strong coffee-PD association [208]. Though caffeine treatment reduces PD risk in men, its effectivity is inconsistent in women due to postmenopausal hormonal changes [209].

Vitamin A Vitamin A (Vit A), obtained from spinach, carrots, and animal liver destabilize a-synuclein fibrils in vitro [210]. Posttreatment with 9 cis-retinoic acid reduced the loss of dopaminergic neurons in rodent model of PD [211]. Pioglitazone and retinoic acid restored dopamine levels in rotenone model of PD [212].

Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) is a rare type of neurodegenerative disease that primarily affects the neurons which are responsible for regulating voluntary muscle movement. Voluntary muscles are responsible for movements like walking, chewing, speaking, and swallowing. The manifestation and outcome of the disease worsens over time. The clinical treatment options available for ALS are currently limited [213]. ALS belongs to a broader group of motor neuron disorders characterized by gradual neurodegeneration and death of motor neurons. The upper and the lower motor neurons get affected in ALS which subsequently leads to their degeneration and hinder communication with the muscles [214]. These lead to muscle

260 Nutraceuticals in Brain Health and Beyond

function loss and their progressive weakening. The muscles start to twitch and atrophy. Ultimately, the brain fails to initiate and control voluntary movements. Weakness of muscle is observed in the early stages of ALS which eventually affects different voluntary actions like the ability to speak, eat, move, and breathe [215]. Death occurs in ALS patients within 3e5 years on account of respiratory failure. Only 10% of ALS patients survive for 10 years or more. Irrespective of ethnicity, males are more vulnerable to ALS compared to females and it generally affects older people of age group 50e70 years [216]. The pathogenicity of ALS still remains unknown. Only about 5%e10% of patients are reported to have a pedigree of other affected members. The recessive and dominant forms of inheritance of ALS are now recognized. SOD1 (copper/zinc superoxide dismutase gene) mutations are responsible for both familial and sporadic forms. SOD1 gene mutations account for 20% of familial ALS and only 1%e2% of all ALS [217]. Till date, these findings have been a major contribution to our understanding of the ALS mainly for two reasons, primarily there is slight clinical and pathological variance between familial (fALS) and sporadic ALS (sALS). So research outcomes related to the SOD1 mutation may be helpful in sALS. Secondarily, transgenic SOD1þþ mice develop a progressive motor neuron disease (initially in the hindlimbs) like human ALS. This animal model helps in the mechanistic study of the disease and in preclinical screenings [218e222]. Oxidative stress is a major factor related to the diagnosis of ALS and affects machinery involving the presynaptic transmitter [223]. In several ALS mouse models, nerve terminals are found to be more sensitive to ROS. Oxidative stress compromises mitochondrial functioning, amplifies intracellular Ca2þ levels, and also intensifies the presynaptic decline in neuromuscular junction (NMJ) [223]. Ultimately inflammatory outbursts and loss of trophic support lead to neurodegeneration. Protein carbonyl contents have been found to be upregulated in both the motor cortex and spinal cord in sporadic ALS patients. Enhanced levels of oxidative stress marker 3-nitrotyrosine was observed in both sporadic and SOD1 familial ALS patients [224,225]. Immune reactivity of 3-nitrotyrosine was not uniform among wide ventral horn neurons. Protein and lipid oxidation markers were found in reactive astrocytes, motor neurons, microglia, and macrophages in the gray matter of sporadic ALS patients, but absent from spinal cord of healthy individuals [226]. DNA damage marker, 8- OHdG, has also been found to be upregulated in the cervical spinal cord of ALS patients and within the ventral horn. Augmented levels of 8-OHdG (DNA damage), 4-hydroxynonenal (lipid peroxidation),

and ascorbate-free radical have been reported in cerebrospinal fluid (CSF) samples from ALS patients [227,228]. Increased nitrated manganese superoxide dismutase and 3-nitrotyrosine have also been found in CSF samples from ALS patients [229]. Considering, the role of oxidative stress in ALS, antioxidant therapies could be a promising approach. Many natural compounds have antioxidant therapeutic properties. Some of these are easily available, cheap dietary supplements such as vitamins C and E, and are frequently prescribed by doctors for ALS patients [230]. Patients may take specific antioxidants or patented combinations. While the expense of individual agents may be small, the patented combinations are more expensive. It is important to determine the information from these agents for the gain and possible damage.

Ameliorative effects of various nutraceuticals against the pathogenesis of ALS Vitamin E Vitamin E, or a-tocopherol, is a cluster of eight different lipophilic compounds (tocopherols and tocotrienols) synthesized by plants. Vitamin E is a-tocopherol and it acts as an antioxidant [231]. Vitamin E protects cellular proteins, cell membranes, and DNA from oxidation and it also controls cellular homeostasis [232]. Vitamin E easily diffuses into cell membranes due to its lipophilic nature and protects polyunsaturated fatty acids from lipid peroxidation. The redox reaction between tocopherol and harmful lipid peroxide radicals leads to the formation of neutral lipid hydroperoxide and an unreactive vitamin E radical (O2 tocopherol). The reaction between tocopherol and harmful lipid peroxide radicals occurs more rapidly than that of lipid peroxide radicals with nearest membrane proteins or fatty acid chains. Glutathione peroxidase processes the ultimate end product of the redox reaction, the lipid hydroperoxides. Vitamin C (ascorbate) reduces tocopherol and regenerates some of the radicals of vitamin E. Vitamins E and C may thus have harmonizing antioxidant properties [233e235]. Vitamin E treatment increased cell survivability of rat cortical cells (collected from CSF of ALS patients). Reduced level of vitamin E was observed in spinal cord of transgenic SOD1 mice. Vitamin E pretreatment protected mutant SOD1 spinal cord cells of mice against glutamate toxicity [236]. Daily oral administration of vitamin E (dosed200 IU/d) had delayed disease onset and progression over control [237]. Dietary supplementation of vitamin E marginally recovered the vitamin E levels in the spinal cord of transgenic mice [238]. After the chemical

Nutraceuticals in neurodegenerative diseases Chapter | 17

synthesis of vitamin E, it was used for the treatment of encephalomalacia and muscle weakness [239]. It was thought to have a beneficial influence on the neuron. In spite of some contradictory results, the recent findings indicated that the onset of ALS was delayed in mutant SOD1 transgenic mice after vitamin E treatment and tocopherol may provide protection against SOD1 mutations in patients with fALS [240]. Cohort studies of over 1 million individuals from five potential populations recommended that long-term use of vitamin E supplements could mitigate the risk of ALS [241].

Vitamin C Vitamin C (Vit C) is an important antioxidant molecule in the brain. Vit C or L-ascorbate can reach tenfold higher concentrations in the central nervous system (CNS) than plasma due to active transport [242]. At high concentrations, vitamin C works as an antioxidant. In lower concentrations, vitamin C works as a pro-oxidant and induces production of hydroxyl radical in the presence of excess amounts of transition metals (e.g., catalytic iron, Fe) [243]. Vit C helps to maintain normal tissue homeostasis and functioning of the CNS by modulating neuronal differentiation, maturation, synthesis of catecholamine, myelin formation, antioxidant protection, and modulation of neurotransmission [244]. Since ALS is characterized by increased free radical generation and the highest concentration of Vit C in the body is found in the neuronal tissues, it is proposed that Vit C may be used as a potential therapeutic agent. In fALS, excess intracellular copper ion may accumulate due to SOD1 mutations. In a recent study, high dose vitamin C and the metal chelator trientine were used for the treatment of mutant SOD1 transgenic mice. ALS symptoms were delayed by 16 days after this treatment. Different studies have reported beneficial effects of using metal chelators and vitamin C in combinatorial treatment in ALS [245,246]. In a study by Nagano et al., it has been found that Vit C treatment in fALS mice (in both pre and posttreatment condition) increased the rate of survivability by 62%, though that treatment did not affect the mean age of disease onset [247].

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Curcumin Curcumin is a polyphenol found in turmeric (Indian food coloring agent). Curcumin was found to hinder mutant TAR DNA-binding protein-43 mediated excitability of motor neurons in an ALS model [248]. Mutation of TDP-43 was detected in fALS and sALS. Dimethoxy curcumin (DMC) ameliorated mitochondrial dysfunction in mutated TDP-43 transfected cell lines. DMC could be potentially useful as therapeutic agent against neurodegenerative diseases like ALS linked with mutated TDP-43 [249]. Oral curcumin supplementation (600 mg/day) in ALS patients was found to hinder disease progression and improve aerobic metabolism and oxidative damage [250].

Conclusion Currently the exact molecular and cellular mechanism responsible for initiation of neurodegenerative diseases is not fully elucidated. The pathophysiological aspects of neurodegenerative diseases are attributed to mutant protein aggregate formation, their deposition in certain specified brain region resulting in cellular stress response, excessive ROS generation, neuroinflammation, perturbance in neurotransmitter release, and neuronal cell death. The above mentioned mechanisms lead to motor dysfunction, dementia, depression, and other symptoms associated with these diseases. Analysis of the molecular and cellular mechanism provides the idea of using nutraceuticals or dietary items for therapeutic purposes. Many compounds (polyphenols, flavonoids, non-protein amino acids, etc.) found in daily food possess antioxidant and antiinflammatory properties and modulate other molecular crosstalk pathways involved with basic oxidative stress and inflammation. However, certain limitations regarding poor bioavailability, solubility, absorption in the intestine, and metabolism of these polyphenols restrict their use for clinical applications. Attempts are being undertaken to increase their bioavailability using nanocarriers and other suitable methods. Research outcomes of different clinical trials are summarized below in Table 17.3.

262 Nutraceuticals in Brain Health and Beyond

TABLE 17.3 Research outcomes of different clinical trials on use of neutraceuticals. Neurodegenerative disease

Neutraceuticals

Dose

Study outcome

Catechin, epicatechin, epigallocatechin, EGCG

6e9 mL/kg of grape juice, 720 mg of cocoa flavanols, 300 mg EGCG

l

Alzheimer disease

Curcumin

Curcumin C3 Complex 2e4 gr/day

Oral curcumin in a 24-week randomized, double blind, placebo-controlled study indicated limited bioavailability of this compound [254].

Parkinson disease

Caffeine

5 mg/kg/day

Risk of suffering PD and consumption of coffee inversely proportionate [255].

ALS

Vitamin D

2000 I.U./day

Oral vitamin D supplementation in patients with ALS was safe and beneficial [256].

Alzheimer disease

Clinical trials using these molecules have been successful to a certain extent but further detailed studies regarding their ability to cross blood-brain barrier at every stage of the disease and biopharmaceutical analysis are necessary for their clinical applications in future.

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[184] da Rocha Lindner G, Bonfanti Santos D, Colle D, Gasnhar Moreira EL, Daniel Prediger R, Farina M, Khalil NM, Mara Mainardes R. Improved neuroprotective effects of resveratrol-loaded polysorbate 80-coated poly (lactide) nanoparticles in MPTP-induced Parkinsonism. Nanomedicine 2015;10(7):1127e38. [185] Pangeni R, Sharma S, Mustafa G, Ali J, Baboota S. Vitamin E loaded resveratrol nanoemulsion for brain targeting for the treatment of Parkinson’s disease by reducing oxidative stress. Nanotechnology 2014;25(48):485102. [186] Mandel S, Maor G, Youdim MB. Iron and a-synuclein in the substantia nigra of MPTP-treated mice. J Mol Neurosci 2004;24(3):401e16. [187] Weinreb O, Amit T, Youdim MB. The application of proteomics for studying the neurorescue activity of the polyphenol ()-epigallocatechin-3-gallate. Arch Biochem Biophys 2008;476(2):152e60. [188] Zhou W, Chen L, Hu X, Cao S, Yang J. Effects and mechanism of epigallocatechin-3-gallate on apoptosis and mTOR/AKT/GSK-3b pathway in substantia nigra neurons in Parkinson rats. Neuroreport 2019;30(2):60e5. [189] Zhou T, Zhu M, Liang Z. (-)-Epigallocatechin-3-gallate modulates peripheral immunity in the MPTP-induced mouse model of Parkinson’s disease. Mol Med Rep 2018;17(4):4883e8. [190] Choi J-Y, Park C-S, Kim D-J, Cho M-H, Jin B-K, Pie J-E, Chung W-G. Prevention of nitric oxide-mediated 1-methyl-4phenyl-1, 2, 3, 6-tetrahydropyridine-induced Parkinson’s disease in mice by tea phenolic epigallocatechin 3-gallate. Neurotoxicology 2002;23(3):367e74. [191] Xu Y, Zhang Y, Quan Z, Wong W, Guo J, Zhang R, Yang Q, Dai R, McGeer PL, Qing H. Epigallocatechin gallate (EGCG) inhibits alpha-synuclein aggregation: a potential agent for Parkinson’s disease. Neurochem Res 2016;41(10):2788e96. [192] Lorenzen N, Nielsen SB, Yoshimura Y, Vad BS, Andersen CB, Betzer C, Kaspersen JD, Christiansen G, Pedersen JS, Jensen PH. How epigallocatechin gallate can inhibit a-synuclein oligomer toxicity in vitro. J Biol Chem 2014;289(31):21299e310. [193] Siddique YH, Jyoti S, Naz F. Effect of epicatechin gallate dietary supplementation on transgenic Drosophila model of Parkinson’s disease. J Diet Suppl 2014;11(2):121e30. [194] Ye Q, Ye L, Xu X, Huang B, Zhang X, Zhu Y, Chen X. Epigallocatechin-3-gallate suppresses 1-methyl-4-phenyl-pyridineinduced oxidative stress in PC12 cells via the SIRT1/PGC-1a signaling pathway. BMC Compl Alternative Med 2012;12(1):82. [195] Teixeira M, Souza C, Menezes A, Carmo M, Fonteles A, Gurgel J, Lima F, Viana G, Andrade G. Catechin attenuates behavioral neurotoxicity induced by 6-OHDA in rats. Pharmacol Biochem Behav 2013;110:1e7. [196] Fahimi Z, Jahromy MH. Effects of blackberry (Morus nigra) fruit juice on levodopa-induced dyskinesia in a mice model of Parkinson’s disease. J Exp Pharmacol 2018;10:29. [197] Strathearn KE, Yousef GG, Grace MH, Roy SL, Tambe MA, Ferruzzi MG, Wu Q-L, Simon JE, Lila MA, Rochet J-C. Neuroprotective effects of anthocyanin-and proanthocyanidin-rich extracts in cellular models of Parkinson‫ ׳‬s disease. Brain Res 2014;1555:60e77.

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[198] Lee KM, Lee Y, Chun HJ, Kim AH, Kim JY, Lee JY, Ishigami A, Lee J. Neuroprotective and anti-inflammatory effects of morin in a murine model of Parkinson’s disease. J Neurosci Res 2016;94(10):865e78. [199] Zhang Z-t, Cao X-b, Xiong N, Wang H-c, Huang J-s, Sun S-g, Wang T. Morin exerts neuroprotective actions in Parkinson disease models in vitro and in vivo. Acta Pharmacol Sin 2010;31(8):900. [200] Ghaffari F, Moghaddam AH, Zare M. Neuroprotective effect of quercetin nanocrystal in a 6-hydroxydopamine model of Parkinson disease: biochemical and behavioral evidence. Basic Clin Neurosci 2018;9(5):317. [201] Katebi S, Esmaeili A, Ghaedi K, Zarrabi A. Superparamagnetic iron oxide nanoparticles combined with NGF and quercetin promote neuronal branching morphogenesis of PC12 cells. Int J Nanomed 2019;14:2157. [202] Singh S, Jamwal S, Kumar P. Neuroprotective potential of Quercetin in combination with piperine against 1-methyl-4-phenyl1, 2, 3, 6-tetrahydropyridine-induced neurotoxicity. Neural Regen Res 2017;12(7):1137. [203] Magalingam KB, Radhakrishnan A, Ramdas P, Haleagrahara N. Quercetin glycosides induced neuroprotection by changes in the gene expression in a cellular model of Parkinson’s disease. J Mol Neurosci 2015;55(3):609e17. [204] El-Horany HE, El-latif RNA, ElBatsh MM, Emam MN. Ameliorative effect of quercetin on neurochemical and behavioral deficits in rotenone rat model of Parkinson’s disease: modulating autophagy (quercetin on experimental Parkinson’s disease). J Biochem Mol Toxicol 2016;30(7):360e9. [205] Yan R, Zhang J, Park H-J, Park ES, Oh S, Zheng H, Junn E, Voronkov M, Stock JB, Mouradian MM. Synergistic neuroprotection by coffee components eicosanoyl-5-hydroxytryptamide and caffeine in models of Parkinson’s disease and DLB. Proc Natl Acad Sci U S A 2018;115(51):E12053e62. [206] Luan Y, Ren X, Zheng W, Zeng Z, Guo Y, Hou Z, Guo W, Chen X, Li F, Chen J-F. Chronic caffeine treatment protects against a-synucleinopathy by reestablishing autophagy activity in the mouse striatum. Front Neurosci 2018;12:301. [207] Fujimaki M, Saiki S, Li Y, Kaga N, Taka H, Hatano T, Ishikawa KI, Oji Y, Mori A, Okuzumi A. Serum caffeine and metabolites are reliable biomarkers of early Parkinson disease. Neurology 2018;90(5):e404e11. [208] Popat R, Van Den Eeden S, Tanner C, Kamel F, Umbach D, Marder K, Mayeux R, Ritz B, Ross GW, Petrovitch H. Coffee, ADORA2A, and CYP1A2: the caffeine connection in Parkinson’s disease. Eur J Neurol 2011;18(5):756e65. [209] Kim IY, O’Reilly ÉJ, Hughes KC, Gao X, Schwarzschild MA, Ascherio A. Differences in Parkinson’s Disease risk with caffeine intake and postmenopausal hormone use. J Parkinsons Dis 2017;7(4):677e84. [210] Ono K, Yamada M. Vitamin A potently destabilizes preformed a-synuclein fibrils in vitro: implications for Lewy body diseases. Neurobiol Dis 2007;25(2):446e54.

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Chapter 18

Transforming curry extract-spice to liposome-based curcumin: lipocurc to restore and boost brain health in COVID-19 syndrome Simon S. Chiu1, 2, 8, Kristen Terpstra3, Michel Woodbury-Farina4, Vladimir Badmaev5, Josh Varghese6, Hana Raheb1, Ed Lui7, Zack Cernovsky8, Yves Bureau9, Mariwan Husni10, John Copen11, Mujeeb Shad12, Autumn Carriere13, Zahra Khazaeipool14, Weam Sieffien15, Marina Henein16, Brendan Casola17 and Siddhansh Shrivastava18 1

Lawson Health Research Institute, London, ON, Canada; 2Geriatric Mental Health Program, London Health Sciences Centre, London, ON,

Canada; 3Neurological Unit, St Michel’s Hospital Affliliated with University Toronto, Toronto, ON, Canada; 4Department of Psychiatry, School of Medicine, University of Puerto Rico, PR, United States; 5Medical Holdings Inc, New York, NY, United States; 6Marian University College of Osteopathic Medicine, Indianapolis, IN, United States; 7Department of Pharmacology, Schulich School of Medicine, University Western Ontario, London, ON, Canada; 8Department of Psychiatry, University of Western Ontario, London, ON, Canada; 9Department of Psychology, University of Western Ontario London ON, Lawson Health Research Institute, London, ON, Canada; School, Thunderbay, ON, Canada;

10

Department of Psychiatry, Northern Ontario Medical

11

Department of Psychiatry, University of British Columbia, University of Victoria Medical Campus, Victoria, BC,

Canada; 12Department of Psychiatry, Oregon Health Sciences University, Portland, OR, United States; 13Faculty Applied Sciences, Nipissing University, North Bay, ON, Canada; 14University of Western Ontario, London, ON, Canada; 15University of Toronto Faculty of Medicine, Toronto, ON, Canada; Canada;

16

National University of Ireland Galway, Research Institution in Galway, Galway, Ireland;

17

University of Guelph, Guelph, ON,

18

Avalon University School of Medicine, Sta. Rosaweg 122-124 WIllemstad, Curacao, Girard, OH, United States

Chapter outline COVID-19 pandemic Curcumin pharmacology and COVID-19 Nanotechnology, epigenetics, and PK studies of liposomecurcumin

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COVID-19 pandemic Recently, the novel Coronovirus-2 (COVID-19) has reached pandemic scale in terms of both morbidity and mortality on the global level, let alone its devastating impact on disrupting the socioeconomic fabric worldwide. As of June 8, 2020, World Health Organization is reporting 6,931,000 confirmed cases of COVID-19, including 400,857 deaths [1]. The Central Disease Control (CDC), USA, reports confirmed COVID-19 cases to be around 2.3

Nutraceuticals in Brain Health and Beyond. https://doi.org/10.1016/B978-0-12-820593-8.00018-5 Copyright © 2021 Elsevier Inc. All rights reserved.

COVID-19 brain rehabilitation: role of epigenetics diet and exercise Summary References

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million with 11% positive tests and overall mortality exceeding 100,000 in late May 2020 [2]. In Canada with one-tenth the population of USA, the mortality rate has reached 7800 of COVID-19 patients [3]. Mitigation measures and public health surveillance strategies: “stay at home,” “social distancing,” “Personal Protective Envelope,” and ventilator in hospital settings have produced positive results in flattening the curve and stabilized the pandemic crisis, especially in the USA and in Canada. USA

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has the highest reported cases and mortality rate, followed closely by United Kingdom, Italy, and more recently, Brazil. It is noteworthy that COVID-19 has only recently been reported to spread in South America, primarily Brazil, and to a certain extent to Russia and India. The elderly often carry high comorbid medical diagnosis: diabetes mellitus, cancer, hypertension, and cardiovascular disorders. While COVID-19 deaths are primarily related to acute respiratory stress syndrome (ARDS), pneumonia, and sepsis, [4], recent studies have drawn attention to the emergence of CNS involvement. In a recent study of 214 hospitalized patients in Wuhan, China, 36.4% showed neurologic symptoms (headache, dizziness, impaired consciousness, ataxia, acute cerebrovascular disease, and epilepsy), and even full-blown encephalitis syndrome [5]. There is a paucity of data from Europe and North America on extent of neurological impairment. Management of postacute care involves coordination in addressing functional impairment related to muscle weakness, physical deconditioning, cardiopulmonary fitness, gait balance. The landscape of COVID-19 therapeutics is constantly evolving. Conflicting clinical trial findings are reported for the antiviral drug hydroxychloroquine. Hydrochloroquine (HCQ) the antimalaria drug has drawn widespread publicity both for prophylaxis and for the acute treatment of ARDS; however, the multinational registry questions the safety issue of HCQ regarding increased mortality and the occurrence of de-novo ventricular arrhythmias risk [6]. In the study using global big database: the Surgical Outcome Collaborative Registry, from 169 hospitals in Asia, Europe, and North America, to evaluate the relationship of cardiovascular disease and the mortality rate among hospitalized COVID-19 patients admitted between December 2019 and March 2020, the investigators conclude that antihypertensive drugs belonging to the class of angiotensin receptor blockade (ARB) and angiotensin converting enzyme inhibitors (ACEinhibitors), carried no increased risk of death [7]. The issue is whether ACE, angiotensin ACE-2, the coreceptor of the spike protein of COVID-19, regulates the attachment and replication of COVID-19 and sensitive toward ACE-inhibitors and ARB, and whether ACE-inhibitors and ARB therapy should be discontinued amid COVID-19 pandemic. The complexities of cardiovascular control through the renin-angiotensin-aldosterone pathways remain to be delineated better in translational models of gene knockout of ACE-2. The editorial decision of two highly prestigious peer-reviewed journals: Lancet and New England Journal of Medicine to retract both studies within 1 week based on the veracity of data source and clinical trial methodology adds to the overwhelming climate of fear and hypervigilance of the seriousness of the COVID pandemic. Further controlled studies are currently

in progress to evaluate critically the role of HCQ in COVID-19 and to establish the safety profile of ACEinhibitors and ARB in COVID-19 cohort worldwide. Similar apparently discrepant findings from two studies in USA and China are reported with remdesvir (patented product of Gilead Inc. Calif. USA) shown in vitro to inhibit the viral polymerase and the proofreading exoribonuclease [8e10], In the Chinese study, remdesivir use was not associated with a statistically significant difference in time to clinical improvement (hazard ratio 1$23 [95% CI 0$871$75]); however, remdesivir seemed to accelerate improvement rate to a nonstatistically significant degree [8]. On the other hand, the NIH funded USA study [9] found that patients who received remdesivir had a 31% faster recovery than those who received placebo (P < .001). Specifically, the median time to recovery was 11 days for remdesivir-treated patients treated with remdesivir compared with 15 days for those who received placebo. The survival benefit as shown in the mortality rate of 8.0% for remdesivir-group versus 11.6% for the placebo group (P ¼ .059). With regard the convalescent plasma transfusion (CPT), a recent review of five controlled studies [11] found evidence of efficacy of CPT therapy in reducing mortality in critically ill patients [9]. The beneficial effects are most likely related to the increase in neutralizing antibody titers. Disappearance of SARS-CoV-2 RNA was observed in post-CPT therapy. In searching through the pipeline drugs with potential efficacy against COVID-19, we are not able to identify specific drug lead targeting epigenetic signaling in COVID19 while counteracting the treacherous immunity hijacking move by the COVID-19; and furthermore, recruiting nanotechnology to enhance the efficacy and minimizing toxicity. In the concise synopsis, we attempt to characterize the multifaceted pharmacology of curcumin to combat COVID-19 and to describe the transformative roadmap from curry extract and spices extracted from Curcuma longa to US-FDA approved drug lead (Fig. 18.1) earmarked for oncology therapeutics in Phase I clinical trial. Liposome-based curcumin: Lipocurc has the distinct advantage over other anti-COVID drugs under investigation in that it readily penetrates through the BBB: bloodbrain barrier, and is active in translational models of brain disorders including Parkinson disease (PD).

Curcumin pharmacology and COVID-19 In the postgenomic era, there has been escalating interest in epigenetics signaling involved in regulation of gene expression in the context of diverse medical conditions and disorders. In the aging process, epigenetics drift and

Transforming curry extract-spice to liposome-based curcumin Chapter | 18

273

Extraction Purification

Curcumin : Diferuloylmethane IUPAC name: 7-Bis(4hydroxymethoyphenl)-1, 6-heptadiene-3, 5dione

Curry powder

CIVID-19 virus

Liposome-Curcumin Wrapped around Special lipid double layer Phospholipid similar to Natural cell membrane

Patented Nanotechnology formulation Targeted drug delivery Nanotechnology-driven curcumin formulation

Lipocurc Anti-viral Rx FIGURE 18.1

LIPOCURC oncology drug trial in development

Transforming Curry as Lipocurc as novel drug candidate for COVID-19.

senescence explain the genome bias toward aging and carcinogenesis [12]. Since COVID-19 exhibits age-specific effect in triggering relentlessly a cascade of inflammation and tissue damage leading to cell death, as shown by the highest mortality rate in the elderly, the epigenetics mechanisms in neurodegenerative and neuropsychiatric disorders are directly relevant to our understanding of COVID-19. The phenotype of Alzheimer dementia (AD) is not only influenced by AD at-risk genes, but also buffered by AD protective genes. It soon becomes evident that epigenetics dysregulation underlies the pathophysiological mechanisms of brain disorders: AD, PD, schizophrenia, and mood disorders. To reiterate, our overall objective of the drug development platform is to transform curry spice and extract liposome-curcumin (patented Lipocurc pipeline drug candidate SignPath Pharmac. Salt Lake City, Utah, USA) through fusing nanotechnology with epigenetics signaling and to develop an innovative milestone-driven drug development program in the landscape of central nervous system (CNS) and viral therapeutics development. Lipocurc has filed formal FDA patent for both cancer and CNS brain disorders. Very few CNS drugs possess antiviral properties. Converging evidence suggests that curcumin functions as a pan antiviral agent. While curcumin is active against viral replication with reference to hepatitis C, HIV virus, influenza virus, dengue virus, Herpes simplex, prion virus, and SARS-related coronavirus, very little has been invested to

further develop curcumin as a bona fide broad-spectrum antiviral agent exhibiting sustained drug effect against viral resistance [13,14]. With the spread of COVID-19 outside China to Korea, Japan, and Europe, we have data from the two PK studies to determine the maximum tolerated dosage. A pilot Asian study conducted in Taiwan found efficacy of curcumin in reducing replication of SARS-related coronavirus [15]. In the cell-based assay measuring severe acute respiratory syndromeeassociated coronavirus (SARS-COV) based on the cytopathogenic effect on Vero E6 cells, curcumin was found to be a potent inhibitor at concentration of 3.3e10 microM. Curcumin inhibited the catalytic activity of SARS-COV 3CL protease at 40 microM in vitro. The recent identification of ACE2dangiotensin as the coreceptor of S-protein of COVID19 may lead to targeting ACE-2 for another therapeutic avenue [16]. The controversies regarding the benefits versus risks of maintenance antihypertensive therapy with angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin receptor blockade (ARB) amid COVID-19 pandemic underscores the relevance of ACE-2 in pathophysiology of COVID-19. In angiotensin IIeinduced hypertension model, curcumin downregulates angiotensin receptor in A10 cells through blocking angiotensinmediated vasoconstriction. Modulating the function of ACE-2 in COVID-2 represents another novel target of curcumin [17]. A more recent published study from Virology Central Laboratory in Wuhan province, the epicenter of COVID-19

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in China, found evidence for efficacy of curcumin against enteric coronavirus [18]. In the porcine epidemic diarrhea virus (PEDV) model akin to coronavirus model, curcumin was reinforced with uniform and stable cationic carbon dots (CCM-curcumin) for investigating its antiviral properties. The formulated CCM-CDs were pharmacologically active through inhibiting viral entry, suppressing the synthesis of the negative strand RNA of virus, and virus budding. It appears to stimulate the inflammatory cascade involving the interferon stimulating genes (ISGs) and proinflammatory cytokines. It will be intriguing to compare the relative efficacies of CCM-CD and Lipocurc in the standard cytotoxicity, virus yield, and infection rate of COVID-19 virus in vitro. COVID-19 belongs to the same family of betacoronavirus as MERS-COV and SARS-COV. Targeting epigenetics signaling may be the common pathway underling MERS-COV and Influenza A/Vietnam/ 123/2004 (H5N1-VN1203) influenza. Preliminary data showed that both groups of virus: MERS-COV and H5N1/ VN1203 antagonize antigen presentation through epigenetic modulation involving DNA methylation [19]. Lipocurc may be the likely drug candidate to reverse virusinduced antagonism of antigen-presentation of DNA epigenetics pathway. Blockade of viral entry at the epigenetics doorstep can be as efficacious as antagonizing viral polymerase. The ultrarapid rate of spread of COVID-19 remains an enigma. COVID-19 likely adopts the all too familiar “trick” to evade host viral defense through excessive activation of endoribonuclease [20]. Under normal circumstances, viral infection triggers the endogenous antiviral protective innate immune defense system mediated through RNase-L. In COVID-19 overactivation of RNase-L expression can lead to hyperinflammatory condition as the precursor to apoptosis and cell death. In this respect the finding that curcumin inhibited RNase-L-activity through its antiinflammatory and antioxidant properties may be interpreted that the polyphenol counteracts the hijacked immune responses and restores host viral defense. We are not aware of any COVID-19 investigational agents exhibiting the anti-endoribonuclease property. There is growing evidence in support of the central role of interleukin-6 in the “cytokine release storm” in ARDS, the terminal event in COVID-19 [21]. Monoclonal antibody developed against interleukin-6 may hold promise in improving COVID-19 core symptoms and reducing mortality rate. Very few investigators are aware of the findings of studies showing curcumin inhibit interleukin-6 [22]. While many drug trials on COVID-19 are launched to combat COVID-19, few studies have adopted the repurposing paradigm to take advantage of the overlapping immunity , epigenetics and angiogenesis targets in both oncology drugs and anti-viral drugs. We propose to translate the multi-faceted pharmacology of Curry extract from

the Tumeric longata to potential COVID-19 therapeutics through recruiting the novel nanotechnology. More significantly, none of the pipeline antiviral drugs has been shown to cross the BBB and exert beneficial effects on brain health. This aspect of curcumin pharmacology is of prime importance with the increased attention being drawn toward the spectrum of neurological symptoms [23,24], complicating cardiovascular and pulmonary distress leading to death. During the postviral infection era, the neurological and neuro-sequelae of COVID-19 are only beginning to be recognized, let alone the guidelines for navigating through the recovery phase. Our choice of curcumin as an antiviral agent, and the harnessing of nanotechnology to localize the site to the brain regions, with the wealth of CNS studies on the beneficial effects of curcumin in enhancing brain health [25,26] are unique and exceedingly positive as therapeutic potential to restore brain health.

Nanotechnology, epigenetics, and PK studies of liposome-curcumin SignPath Pharma, PA owns the patent of the agent Lipocurc and has agreed to provide the pharmaceutical for our proposed clinical trial in PD. The curcumin component of Lipocurc is originally synthesized at Sami Labs, Bangalore, to 99.2% purity for the treatment of cancer. While SignPath has taken the lead in carrying out oncology trials with Lipocurc, our proposal will be the first in organizing Lipocurc trial in brain disorders. Despite numerous pharmacological studies with curcumin derived from Curcuma longa, L. extract the major drawback in translating the efficacy of curcumin from preclinical models to clinical arena of PD is the low systemic bioavailability of oral curcumin usually available as dietary supplements due to the high first-pass metabolism [27e29]. SignPath Inc. succeeded in utilizing an intravenous liposomal formulation to optimize penetration across the BBB. For the past few years, there has been almost explosive interest in searching for brain-specific drug delivery system for CNS disorders. Nanotechnology through encapsulating the active drug inside biocompatible materialsdliposomes and polymers like hydrogel has taken a highly promising lead in drug development platform [25e29]. Nanotechnology has applications in oncology as well as neurodegenerative disorders [28]. SignPath Pharmac. (Salt Lake City Utah, USA) has succeeded in formulating a patented liposomebased curcumin shown to be bioactive in tumor models and brain disorder models. Curcumin has been identified as a potent modifier of epigenetics signal pathways at multiple sites: HDAC (histone deacetylase) isoforms 1, 3, 8, HAT (histone acetyltransferase), noncoding RNA miRNA-22, miRNA186a, and miRNA-199a [25,26,29]. Curcumin suppresses DNA

Transforming curry extract-spice to liposome-based curcumin Chapter | 18

methyltransferase (DNA MET) and induces global genomic hypomethylation of genes. In addition, curcumin inhibits Class I HDAC (histone deacetylase) isoforms 1, 3, 4, 5, 8; however, curcumin concomitantly activates Class III HDAC(Sirtuin1). Class III HDACs prefer NADþ as a reactant to deacetylate acetyl lysine residues of protein substrates forming nicotinamide, the deacetylated product, and the metabolite 20 -O-acetyl-ADP-ribose. In high throughput epigenetic screening assay using HeLa nuclear extract, curcumin was found to be more potent in inhibiting HDAC than valproic acid and sodium butyrate. The inhibition constant Ki of curcumin (539 nM) was comparable to Ki of trichostatin A (504 nM). Curcumin is more potent than valproic acid (Ki 564 nM) and sodium butyrate (Ki 365 nM). Cross-talks of HDAC with miRNA exert synergistic effects in orchestrating and coordinating multiple gene expression. HDAC inhibitors in controlling epigenetic programming involved in affective regulation, and behavior control, may alter the course of schizophrenia and bipolar spectrum disorders through remodeling chromatin, histonerelated modifications, and even catalyze the access of gene promoters to transcription complex. Pharmacokinetic studies have been completed in three species: rodents, dogs, and humans [30e34]. In the rodent species, rats were given intravenous bolus injections three times a week for 4 weeks (empty liposomes, and 10, 20, and 40 mg/kg Lipocurc) [30]. In our study, we compared the differential brain localization of three nanotechnologydriven curcumin formulations in rats. Our results found that following intravenous administration of liposomal curcumin, polymeric nanocurcumin and polylactic glycolic acid copolymer (PLGA)ecurcumin in rats, these formulations were observed to cross the BBB using a sensitive HPLC assay. All three formulations are localized in specific sites in the brain without observable adverse events. One hour following intravenous injection of 5 mg/kg nanocurcumin or 20 mg/kg PLGAecurcumin or liposomal curcumin, up to 0.5% of the injected material is localized in the brain stem, the striatum, and the hippocampus with varied accumulation and clearance rates. On the other hand, we reported that dogs administered 1 h intravenous infusions at 10 mL/kg/h for 4 weeks (5% dextrose in water, empty liposomes, and 5 and 20 mg/kg Lipocurc) experienced no adverse events [31,32]. For both the canine and rodent species, there were no deaths on the study, and no changes in the clinical signs, body weight, food consumption, clinical chemistries, or organ weights, and no treatment-related adverse effects. In view of the wide safety margin, the NOAEL (no observed-adverse-effect-level: the highest dose at which there was not an observed toxic or adverse effect) for the rat was considered to be greater than 40 mg/kg dosage. For the beagle dogs [31,32] treated with 5 mg/kg Lipocurc, the analysis of all generated datad clinical observations, ophthalmology, ECGs, clinical

275

pathology, gross necropsy and histopathologydconcluded with no treatment-related toxicity. The SignPath research group completed Phase I doseescalating study of Lipocurc recruiting subjects from Europe (Study 1001) [33]. The protocol consisted of dose escalation study of single infusions of Lipocurc over 2 h in healthy volunteers allocated to five subjects/group (4 active drug and l placebo) over nine dosage groups.10, 20, 40, 80, 120, 180, 240, 320, and 400 mg/m2. The results showed that Lipocurc exhibited favorable tolerability and toxicity profile in normal subjects. We have fully characterized the pharmacokinetic parameters of Lipocurc in humans. Blood was collected at baseline, during the infusion at 15, 30, 90 min, at the end of infusion: 0, 5, 10, 15, 30, 45 min and 1, 2, 4, 8, 24, and 48 h for determining the total curcumin and curcumin metabolitedtetrahydrocurcumin after the EOI dose escalation was performed until the highest planned dose (400 mg/m2) was reached. Transient echinocyte formation with no long lasting adverse effects was observed. The infusion of Lipocurc resulted in rapid and dose-dependent development of plasma levels of curcumin with Tmax values ranging from 0.9 to 1.7 h. Cmax ranged between 42  22 ng/mL and 2359  412 ng/mL for 10 and 400 mg/m2. Pharmacologically active metabolites have been reported in previous studies. The findings of a Phase II PK study conducted in Europe reported similar safety and favorable tolerability in a cohort of subjects diagnosed with metastatic tumors [34]. In the Phase I PK, single-center, open-label study, liposomal curcumin was administered as a weekly intravenous infusion for 8 weeks. Dose escalation was started at 100 mg/m2 over 8 h and the dose increased to 300 mg/m2 over 6 h. Results: 32 patients were treated. No doselimiting toxicity was observed in 26 patients at doses between 100 and 300 mg/m2 over 8 h. Of six patients receiving 300 mg/m2 over 6 h, one patient developed hemolysis, and three other patients experienced hemoglobin decreases >2 g/dL without signs of hemolysis. Pharmacokinetic analyses revealed stable curcumin plasma concentrations during infusion followed by rapid declines to undetectable levels after the infusion. Antitumor activity by RECIST V1.1 was not detected. Significant tumor marker responses and transient clinical benefit were observed in two patients. The study concluded that 300 mg/ m2 liposomal curcumin over 6 h was the maximum tolerated dose in the cohort of metastatic cancer patients who were pretreated with chemotherapy for their cancer, and 300 mg/m2 is the recommended starting dose for future randomized anticancer trials. The safety data can instruct and guide Phase II/Phase Ib studies to repurpose Lipocurc from oncology therapeutics development to CNS therapeutics landscape for neuropsychiatric disorders: schizophrenia, mood disorders, AD, and PD, and more recently, COVID-19 infection. Signpath

276 Nutraceuticals in Brain Health and Beyond

Pharmaco. Inc. PA, USA, has essentially overcome the limited systemic bioavailability of oral curcumin, hence creating a drug candidate for launching clinical trials in neurodegenerative disorders and cancer. Our innovative Drug Discovery Platform (DDP) is largely inspired by our earlier synopsis of nutraceuticals hitting overlapping epigenetics targets mediating the vast array of pharmacological activities in AD, PD, diabetes mellitus, anxiety, and depressive disorders [25,26,35]. We embark upon an ambitious plan to transform curry spice to liposome-based curcumin (Lipocurc) through innovative collaboration with SignPath Pharm. Co. (Salt Lake city, Utah, USA). The academic-industry team has for the first time succeeded in formulating liposome-encapsulated curcumin from curry extract and has progressed through vigorous FDA (US) regulatory approval process of securing an IND number. The positive results from PK studies in rodent and canine species and PK Phase I studies are sufficiently encouraging for the academia-industry team to explore therapeutic indications in neuropsychiatric and neurodegenerative disorders.

COVID-19 brain rehabilitation: role of epigenetics diet and exercise We extend to acute lung injury resulting in acute respiratory distress syndrome (ARDS).driven by the cytokine release storm [23,24]. As discussed earlier, recent evidence highlights emerging CNS involvement, as shown in case series studies of COVID-infected patients. Very recently, COVID-19 infection has been found to increasingly involve the CNS. A wide array of neurological and neuropsychiatric symptoms have been described: anosmia, ataxia, epilepsy, altered level of consciousness and delirium, and myalgia [23,24]. Cognitive impairment and mood changes are anticipated to occur following the acute COVID-19 infection. Very few studies have focused on rehabilitation in domains of cognitive, affective, and behavioral domains. Curcumin hits two arms of dysregulated immunity: innate and adaptive immunity, in COVID-19 and will be in a highly favored position to reset the homeostasis mechanisms for both the acute and subchronic phase. As a tumornecrosis factor (TNF) and key regulator of family of cytokines, curcumin is strategically positioned to arrest and reverse the cytokine release storm. Curcumin participates in shifting the phenotype of the main players of inmate and adaptive immunity: macrophages, microglial cells (CNS), and T-cell populations and B-cell populations, toward the antiinflammatory and the antioxidant pathways, which in turn are regulated by the epigenetics signaling [25,26]. The frontier of epigenetics landscape has only recently been

rediscovered as contributing toward the pathological hallmarks of COVID-19: virulence, transmission, and toxicity at the end-organs: the pulmonary system, cardiovascular and cerebrovascular system, and the CNS. We have reviewed extensively the role of curcumin, especially the liposome-based curcumin ad drug lead in PD and AD [25,26]. The cognitive enhancing effects of curcumin in ameliorating the functional decline in both PD and AD are well delineated primary through the signal transduction pathways downstream from the epigenetics hits of Histone deacetylase (HDAC) and DNA methylation. Furthermore, in our study with supercurcumin we have shown that oral formulation of curcumin not only improved the negative symptoms but also the depressive symptoms of schizophrenia [35]. Our results are consistent with the findings of a systematic review of curcumin in depressive symptoms of unipolar depression [36]. A metaanalysis of curcumin in depressive disorder found that curcumin treatment significantly reduced depression symptoms [SMD ¼ 0.34; 95% confidence interval (CI) ¼  0.56, 0.13; P ¼ .002]. It is anticipated that the postCOVID-19 viral syndrome embraces behavioral, cognitive, and mood disturbances. Hence Lipocurc will be the ideal drug candidate for both COVID-19 in the acute phase and in the recovery phase. Since curcumin is the bioactive ingredient of diet and menu in Asia with increased popularity in the Western world, our discussion calls into question whether curcuminenriched diet has beneficial effect in counteracting the cognitive affective and behavioral domains of post-COVID syndrome. Growing evidence suggests that the epigenetics diet (Fig. 18.2) enriched with phenolic compounds extracted from curry overlaps with the Mediterranean diet and DASH diet and ketogenic diet in hitting similar epigenetics signatures modulating oxidative stress and inflammation [12,25,26,37e40] to achieve the three goals: to accelerate the recovery of COVID(þ) exposed and symptomatic individuals via participating in wellness, physical (musculoskeletal), cardiovascular fitness, neurobehavioral programs, to boost their immunological defenses for preventing trapped in cytokine release storm COVID-19 and to enhance cognition and brain-behavioral health, especially in the elderly. We have reviewed evidence from PD studies relating diet and exercises and found that both diet-probiotics-prebiotics and therapeutic dance movements and physical activities can facilitate healthy and cognitive aging, enhance both cardiovascular and metabolic benefits, and prevent motor complications in PD [41,42]. The findings of the gut-microbiome-brain nexus, mediated by neuroimmunity landscape, can equally be applied to acute COVID-19 syndrome and the host of COVID-19-related neurological complications in severe COVID-19-infected

Transforming curry extract-spice to liposome-based curcumin Chapter | 18

277

FIGURE 18.2 Latest newcomer: Epigenomics Diet for cognitive recovery in COVID19.

patients [42]. Taken together, growing evidence strongly suggests that the neurobehavioral sequlae may persist beyond the acute cytokine storm and ARDS. Epigenetics diet and exercisedphysical activitydmodules can be

invaluable partners in COVID-19 rehabilitation phase. Curcumin’s action in reducing culprits in AD: tau and amyloid may equally be applied to COVID-19 recovery phase in restoring synaptic plasticity and neurogenesis (Fig. 18.3).

Hijacking immune systems *Exhausng T-lymphocytes *Dampening endo-nuclease *Shiing T-helper cell sub-types *Mutaon random *disrupts Viral-host defense *impairs adapve immunity *biased interleukins-phenotype *Shiing pro-inflammatory Aberrant host-viral Immune signaling pathway, resulng in * Chaoc epigenomics networks

Curcumin resets adapve and innate immunity via modulang epigenecs network Histone DNA methylaon Non-coding RNA

Cytokine storm

Viral-host epigenome

From periphery to brain Leaky Blood brain barrier Macrophages and dendric cells Cross talk with CNS immunity Cells: glia cells, microglia Sets off brain inflammaon Release of array of mediators Tumor necrosis factor (TNF) Interleukins –apoptosis factors Hyper-inflammaon syndrome Cerebral cytokine storm

Adult respiratory distress syndrome ARDS synergizes with Cerebral cytokine storm Cytokine release syndrome Leading to Neuronal apoptosis Cell death and mortality/morbidity Chius et al 2020

Curcumin reverse ,aenuates Cytokine storm via an-oxidant an-inflammatory acons to rescue from COVID-19

FIGURE 18.3 Model of dysregulation of COVID-19 Genomes/Epigenomics missing key to cerebral Cytokine Storm and Curcumin protection.

278 Nutraceuticals in Brain Health and Beyond

Summary Our choice of curcumin as an antiviral agent, and the harnessing of nanotechnology to localize the site to the brain regions, coupled with the wealth of CNS studies on the beneficial effects of curcumin in enhancing brain health are unique and exceedingly positive as therapeutic potential to restore and enhance brain-behavior functions in the postCOVID-19 period.

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[25] Chiu SS, Terpstra K, Woodbury-Farina M, Mishra R, Badmaev V, Vaughese J, Raheb H, Lui E, Cernovsky Z, Bureau Y, Husni M, Copen J, Shad M, Hou J, Carriere A, Khazaeipool Z, Campbell R, Sieffien W. Transforming curry extract to liposomal curcumin (LipocurcTM) in Parkinson disease (PD) therapeutics landscape: emerging role of epigenetics signaling and nanotechnology. EC Neurol March 2020. Online Pub. [26] Chiu S, Woodbury-Farina M, Terpstra K, Hou J, Bureau Y, Cernovsky Z, Mariwan Husni MUS, Copen J, Hategan A, Seeley Johnson A, Varghese J, Carrie A, Khazaeipool Z, Foskett A. Exploring the architecture of epigenetics in Alzheimer’s Dementia: evidence and promises and challenges. Invited book chapter. USA: SMGroup Publisher; September 2016. www.smgebooks.com. [27] Kunnumakkara AB, Harsha C, Banik K, Vikkurthi R, Sailo BL, Bordoloi D, Gupta SC, Aggarwal BB. Is curcumin bioavailability a problem in humans: lessons from clinical trials. Expert Opin Drug Metab Toxicol September 2019;15(9):705e33. https://doi.org/ 10.1080/17425255.2019.1650914. Epub 2019 Aug 29. [28] Yavarpour-Bali H, Ghasemi-Kasman M, Pirzadeh M. Curcuminloaded nanoparticles: a novel therapeutic strategy in treatment of central nervous system disorders. Int J Nanomed June 17, 2019;14:4449e60. https://doi.org/10.2147/IJN.S208332. eCollection 2019. [29] Boyanapalli SS, Tony Kong AN. “Curcumin, the king of spices”: epigenetic regulatory mechanisms in prevention of cancer, neurological, and inflammatory diseases. Curr Pharmacol Rep April 2015;1(2):129e39. [30] Chiu S, Liu E, Majeed M, Vishwanatha JK, Ranjan A, Maitra A, Dipanker P, Smith JA, Helson L. Intravenous curcumin distribution in the rat brain. J Anticancer Res 2011;31(3):907e12. [31] Helson L, Bolger G, Majeed M, Vcelar B, Pucaj K, Matabudul D. Infusion pharmacokinetics of Lipocurc (liposomal curcumin) and its metabolite tetrahydrocurcumin in Beagle dogs. Anticancer Res October 2012;32(10):4365e70. [32] Matabudul D, Pucaj K, Bolger G, Vcelar B, Majeed M, Helson L. Tissue distribution of (LipocurcÔ ) liposomal curcumin and tetrahydrocurcumin following two- and eight-hour infusions in Beagle dogs. Anticancer Res October 2012;32(10):4359e64. [33] Storka A, Vcelar B, Klickovic U, Gouya G, Weisshaar S, Stegan A, Gordon B, Lawrence H, Michael W. Safety, Tolerability and pharmacokinetics of liposomal curcumin (LipocurcTM) in healthy humans. Int J Clin Pharmacol Therapeut September 2014;23:1e12. [34] Greil R, Greil-Ressler S, Weiss L, Schönlieb C, Magnes T, Radl B, Bolger GT, Vcelar B, Peter P. SordilloA phase 1 dose-escalation study on the safety, tolerability and activity of liposomal curcumin

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(Lipocurc) in patients with locally advanced or metastatic cancer. Published online 2018 Aug 3 Canc Chemother Pharmacol 2018;82(4):695e706. https://doi.org/10.1007/s00280-018-3654-0. PMCID: PMC6132848 PMID: 30074076. Chiu S, Woodbury-Farina M, Terpstra K, Badmaev V, Cernovsky Z, Bureau Y, Raheb H, Husni M, Copen J, Shad M, Jirui H, Campbell R, Khazaeipool Z, Carriere A. Exploratory study of curcumin isolated from turmeric Curcuma longa, the putative histone Deacetylase inhibitor, as added-on strategy to antipsychotics in treating negative symptoms and neuro-cognitive deficits in schizophrenia. ISSN: 2456-1045 Adv Res J Multidisc Discov 2019;40(1). I CHAPTER-2 PUBLISHER: INTERNATIONAL JOURNAL FOUNDATION (IJF). Dalia A-K, Mamoori DAA, Tayyar Y. The role of curcumin administration in patients with major depressive disorder: mini meta-analysis of clinical trials. Phytother Res February 2016;30(2):175e83. https://doi.org/10.1002/ptr.5524. Epub 2015 Nov 27. Chiu S., et al. SMART rehabilitation program blueprint. Caccialanza R, Laviano A, Lobascio F, et al. Early nutritional supplementation in noncritically ill patients hospitalized for the 2019 novel coronavirus disease (COVID-19): rationale and feasibility of a shared pragmatic protocol. Nutrition April 3, 2020:110835. https:// doi.org/10.1016/j.nut.2020.110835 [Epub ahead of print]. Jiménez-Pavón D, Carbonell-Baeza A, Lavie CJ. Physical exercise as therapy to fight against the mental and physical consequences of COVID-19 quarantine: special focus in older people. Prog Cardiovasc Dis March 24, 2020. S0033-0620(20)30063-3. Zhao C, Zhao W. NLRP3 inflammasome-A key player in antiviral responses. Front Immunol February 18, 2020;11:211. https://doi.org/ 10.3389/fimmu.2020.00211. eCollection 2020. Review. Sieffien W, Siddu S, Chiu M, Woodbury F. “Exploring the new frontier of synergy and coupling of music with dance movement to modify the course of Parkinson Disease (PD): synthesis of evidence” XXIV world congress on Parkinson’s disease and related disorders, Montreal, Canada on June 16e19. 2019. Proceedings published in ABSTRACT book. Autumn Carriere, Chiu S, Husni M, Copen J, Shad M, WoodburyFarina M. Exploring emerging role of epigenetics landscape intercepting with mediterranean diet and ketogenic diet and nutraceuticals at gut-microbiota-brain axis in enhancing outcome in Parkinson disease.” to the XXIV world congress on Parkinson’s disease and related disorders montreal, Canada on June 16e19,. 2019. Published in ABSTRACT book.

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Chapter 19

Cognitive health and nutrition: a millennial correlation Arun Balakrishnan, Muralidhara Padigaru and Abhijeet Morde R&D j OmniActive Health Technologies, Mumbai, Maharashtra, India

Chapter outline Molecular signaling of energy metabolism and synaptic plasticity Oxidative damage and cognition Nutrition and neurotransmitters Nutrition and brain well-being Fatty acids n-3 and n-6 Polyphenols Vitamin B family Carotenoids Trace elements Correlation between metabolic diseases and psychiatric conditions

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Diet and cognitive health Early growth stage Adulthood Cognitive enhancers Active sports and cognitive performance: role of nutritional supplements Diet and epigenetics Nutraceuticals as key drivers for brain health Future recommendations References

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Nutrition and diet have long been considered to be building blocks of functional and healthy body. Feeding behavior is closely associated with human civilization, and it is interesting to understand the relationship between food intake and the evolution of cognition pattern across the world [1]. Today, the field of dietary supplements has evolved very rapidly and is a multibillion-dollar industry, with the figures estimated to reach $60 billion by 2020 [2]. Further, advances in cell and molecular biology tools in the past decade have provided biochemical evidence that indicate pivotal role of nutrients in development and functioning of central nervous system. Cognition as such is a broad term that refers to brainrelated processes that facilitate acquiring knowledge and translate it into various emotions [3]. Cognitive health thus relates to learning, memory, attention, consciousness, and integrating all of these in daily activities. Nutrition and dietary requirements have long been associated with mental health, cognition, and neurodegenerative dysfunction and disorders. In the past decade, the importance of nutrition in maintaining neural tissue and membrane structure and in brain signaling pathways is well elucidated.

Nutraceuticals in Brain Health and Beyond. https://doi.org/10.1016/B978-0-12-820593-8.00019-7 Copyright © 2021 Elsevier Inc. All rights reserved.

Nutritional neuroscience has become a major research area wherein there is concerted effort to prevent age-related cognitive decline by advocating specific diet. More and more benefits are attributed to dietary influence leading to cognitive performance such as learning, memory, and intellectual understanding and processing. This is fathomable, given the fact that synaptic functions can influence energy metabolism establishing balance between cognition and somatic functions [4]. In this context, it is key to note that molecular mechanisms of energy metabolism as well as the synaptic plasticity have a direct correlation to the dietary factors that mediate them.

Molecular signaling of energy metabolism and synaptic plasticity Recent studies have focused more toward associating nutrition to cognitive health and brain function at the molecular level. It is well established that the activities of brain consume a significant amount of energy. Mitochondria, which are known as the powerhouse of the cell produce

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energy in the form of ATP, play a critical role in development and functioning of brain cells. In fact, mitochondrial dysfunction has been identified as a cause of several neurological disease conditions including deficient cognitive function [1]. Further, management of energy is orchestrated by interplay of nutrients that is processed and managed by neurons with the aid of signaling molecules (Fig. 19.1). Brain-derived neurotrophic factor (BDNF) is one such signaling molecule that is associated with both energy metabolism as well as synaptic plasticity. Increased BDNF is found in regions of brain with higher metabolic activity (hypothalamus) and cognitive function (hippocampus) [5]. Certain studies have clearly indicated the interrelationship between BDNF and brain-trigger activity. For example, deletion of BDNF gene has resulted in impaired memory [6,7]. Studies have also shown that BDNF modulates a variety of triggers in energy metabolism including glucose levels [8], lipid metabolism [9], insulin sensitivity [10,11], and diminishing appetite [12,13]. Furthermore, it is critical to note that BDNF’s role in energy metabolism and synaptic plasticity is tightly regulated by insulinlike growth factor (IGF-1) which is

synthesized in liver, skeletal muscle, and brain and IGF-1 receptors are primarily expressed in hippocampus [14,15]. In addition to its involvement in regulating plasma insulin levels and insulin sensitivity in brain, IGF-1 is also known to have a role in nerve growth and differentiation, neurotransmitter synthesis and release [16], synaptic plasticity [17], cognitive outcome following brain insult [18], diabetes [19] and aging [20]. IGF-1 also resurrects cognitive function after brain injury [21] or insult and during aging process [22]. Furthermore, BDNF is also known to stimulate peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1a) in neurons. PGC-1a is a mitochondrial activator that plays a critical role in the formation and maintenance of the synapses [23].

Oxidative damage and cognition It is abundantly chronicled that brain is susceptible to oxidative stress and oxidative damage, as it contains large amounts of poly unsaturated fatty acids that are oxidizable, in the plasma membranes of neural cells. In the past decade

FIGURE 19.1 Interaction between feeding and cognition. Neural networks that control feeding also coordinates brain centers involved in energy homeostasis and cognitive function. Ingestion of foods triggers the release of insulin and GLP1 which activates limbic system to activate signal that promote synaptic activity and contribute to learning and memory. Ghrelin released by empty stomach also support synaptic plasticity and cognitive function. Leptin released form from adipose tissue activate receptors in hypothalamus that influences learning and memory. Leptin also elevates BDNF in hypothalamus that can influence food intake and energy homeostasis. IGF1 is produced by the liver and by skeletal muscle in response to metabolism and exercise, activates hypothalamus and influences learning and memory performance. Diet and exercise can affect mitochondrial energy production and release ATP, which activates BDNF and supports synaptic plasticity and cognitive function. The parasympathetic innervation of the gut by the Vagus nerve provides sensory information to the brain, enabling gut activity to influence emotions related to cognition. BDNF, Brain-derived neurotrophic factor; GLP1, Glucagon-like peptide-1 receptor agonist; IGF1, Insulin-like growth factor 1.

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or so, relationship between antioxidants and modulation of cellular mechanisms in brain has been well established through a number of studies [24]. Lower antioxidant levels in elderly institutionalized individuals had a pronounced decline in cognitive performance [25]. Observational studies have specifically shown a link between dietary intake of selenium; carotenoids; vitamins A, C, and E, and supplements known to have antioxidant activities in improving cognitive health [26]. In addition, various micronutrients having antioxidant functions that regulate mitochondrial function, which in turn influences cognitive function. Increased oxidative stress and inflammation are major causes for cognitive decline in aging population. Studies have shown that high energy requirement to maintain brain functions constantly creates oxygen stress in brain leading to neuroinflammation [27]. While reactive oxygen species (ROS) help in cell signaling at physiological levels, exceeding the optimum levels also result in homeostatic imbalance leading to oxidative stress [28].

Nutrition and neurotransmitters Neurotransmitters are endogenous chemicals that transmit signals across synapse from one neuron to another neuron, muscle, or a gland. Amount of neurotransmitter release is generally dependent on changes in the composition of blood plasma. These changes are induced by food intake or extended physical activity. Common neurotransmitters found in humans include acetylcholine (ACh), modified amino acidsdglutamate and a-aminobutyric acid (GABA), biogenic amines like dopamine (DA), serotonin (5-HT), and histamine. Dietary components are capable of affecting the mood, which is due to the availability of neurotransmitter precursors [29]. Fruits, many edible plants, and roots are sources of various neurotransmitters. For example, ACh is found in plants belonging to almost all major economically important plant families: peas, common beans, bitter orange, wild strawberry, radish to name a few [30,31]. In mistletoe (Viscum album), whose traditional use includes hypertensive headache, epilepsy, hysteria and neurological diseases, ACh is found in significant amounts [30]. Glutamate is an important excitatory neurotransmitter that is ubiquitous in food products. Glutamic acid is converted into glutamate at a pH of 7 and is present in foods that are high in protein content [32]. This includes meat, seafood, cheese, mushrooms, spinach, and soy. GABA is yet another inhibitory neurotransmitter found ubiquitously in plants wherein it is synthesized from glutamic acid via glutamate decarboxylase enzyme [33]. GABA levels particularly increase in response to stress conditions such as drought, presence of salt, soaking, and germination [34]. In addition, GABA is found in many

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plant species such as beans, peas, mushrooms, and sweet potato. Consumption of food rich in GABA results in lowering anxiety levels in addition to having analgesic effects. Dopamine is associated with physical coordination of body movements and is also shown to have antioxidant activity [35]. Consumption of leaves of Mucuna pruriens (velvet bean) has been shown to reduce parkinson’s symptoms which is possibly attributed to the presence of high levels of dopamine in it [36]. Dopamine levels are also high in plantain, banana, and avocado [37]. Serotonin (5-HT), while in central nervous system regulates behavior, sleep, and eating patterns, in gut, it is associated with modulation of gastrointestinal motility. Sources of 5-HT include Musa genus (ex: banana), capsicum, hazelnut, tomato, and among fruits, pineapple, plum, and passion fruit [38e40]. Another neurotransmitter, histamine, is a naturally occurring nitrogenous compound present in hypothalamic regions of the brain and is known for regulating arousal, attention, response, and reaction. Histamine is endogenously found in certain foods; in addition, defective processing of food (e.g. cheese, dry meat products) may also result in higher levels of the compound that may lead to amine poisoning [41]. In addition to the natural food sources of neurotransmitters, microorganisms also contribute to dietary availability of neurotransmitters. For example, Lactobacillus species produce ACh [42] and GABA producing strains have been isolated from Italian cheese [43], whole milk [44] and soy sauce [45]. Furthermore, certain bacterial strains such as Escherichia species, Morganella morganii, Klebsiella pneumoniae, and Streptococcus thermophiles [46] are known to produce serotonin. As of now, there are many isolated studies that demonstrate existence of natural sources of neurotransmitters. However, the significance of dietary intake of neurotransmitters needs to be established, as there is a paucity of data with regard to their bioavailability and/or clinical correlation.

Nutrition and brain well-being An increasing body of information has emerged indicating nutrition to be linked to brain health. It needs to be acknowledged that multiple mechanisms such as genetic factors, cell signaling pathways, and dietary factors are intricately regulated, which in turn affect the cognitive abilities. There are studies that have shown the relationship between energy balance and mental health. While nutritional deficiency has undesirable effect on the brain, overnutrition causes increased oxidative damage, decreased synaptic plasticity, and impaired cognitive function [1]. In this context, high energy diet coupled with sedentary

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lifestyle is particularly deleterious leading to obesity and diabetes. These attributes are directly related to impaired cognition and have the potential risk of developing depression and dementia [47]. It is well established that dietary components can influence the brain processes by regulating synaptic plasticity, synaptic transmission, and membrane fluidity [48]. Thus, there is an immediate need to understand the importance of some of the critical nutritional components that are associated with cognitive health and function. Enlisted below are some of the nutritional elements that have a pronounced effect in cognitive health.

Fatty acids n-3 and n-6 Substantial role of fatty acids, a-linolenic acid (18:3n-3), eicosapentaenoic acid (EPA) (20:5n-3), and docosahexaenoic acid (DHA) (22:6n-3), has been enumerated in cognition and mental health. DHA, in particular, is significant in maintaining the brain structure and function [49,50]. DHA is a structural component of plasma membrane of neuronal cells, which is vulnerable to oxidative damage. Thus, availability of DHA in food is crucial for optimal cell signaling in brain. It has been well established that increased levels of brain DHA increases membrane fluidity and protein-lipid interaction thus facilitating neuronal activity and cognition. In contrast, decrease in levels of DHA results in diminished learning and memory due to impairment in neurogenesis and neurotransmitter metabolism [48]. DHA also enhances synaptic plasticity and energy metabolism thus triggering glucose utilization [51] and mitochondrial function [52], while reducing oxidative stress [53]. While role of n-3 fatty acids has been shown to be beneficial to cognitive health, it is also amply demonstrated that trans and saturated fats are deleterious to brain health and cognition [54]. Studies with rodent models have indicated that food containing high levels of saturated fat and glucose are deleterious to cognitive health characterized by diminished memory and learning ability, as well as decreased BDNF-related synaptic plasticity in hippocampus [55]. A study by Hooper et al. [56] showed that n-3 PUFA supplementation had beneficial effects in older adults with low omega-3 index who were at risk of developing dementia. In another study, it was observed that consumption of seafood (containing omega-3 fatty acids) in adults aged 81.4  7.2 years was associated with slower decline in memory, perception, and cognition [57]. Role of n-3 PUFA in improving cognitive health in infants has also been highlighted in a recent study [58]. Diet that provides a-linolenic acid includes vegetable oils such as linseed, soyabean and rapeseed, and meat products. Conversion of linolenic acid to EPA and further to DHA is cumbersome and not recommended due to the suboptimal yields. Thus, direct dietary intake of EPA and

DHA is preferred and the key dietary source of these fatty acids is fish and fish oils. Recent efforts are also directed toward enhancing dietary sources of n-3 fatty acids by developing transgenic plants [59].

Polyphenols Polyphenols constitute a large family of compounds produced by plants that protect them from ultraviolet radiation. Among the known polyphenols, flavonoids and curcuminoids are conclusively linked to brain health and are associated with several neuronal processes including synaptic plasticity and energy homeostasis [60,61]. Flavonols, which belong to flavonoid family are known to have antioxidant effects and are found in a variety of fruits, cocoa, beans, and Ginkgo biloba. By reducing oxidative stress, flavonols also play a role in reducing learning and memory impairment during brain injury as seen in cerebral ischemic rodent model [62]. Yet another plant-derived flavanol epicatechin has the ability to cross the blood-brain barrier and is shown to enhance angiogenesis and spatial memory in experimental murine models. Further, flavanols in conjunction with exercise has proven benefits in improving cognitive health [63]. The active component of plant turmeric, belonging to curcuminoids family, is curcumin, which is handed down as a traditional medicine in India [64]. There has been substantial support to show the beneficial effects of curcumin in counteracting neurodegeneration as seen in brain injury [65] and Alzheimer’s disease [66]. Curcumin is also known to function as an antioxidant and thus protect brain from free oxygen and nitric oxide radicals and lipid peroxidation [67].

Vitamin B family Among the class of vitamins, vitamin B has a substantial role in modulation of brain-specific activities. Vitamins belonging to the B family have a substantial role in enzymatic processes which are key mechanisms in routine functioning of human physiology. B vitamins also serve as important precursors for metabolic substrates; for example, coenzyme A is a cofactor in about 4% of all mammalian enzymes [68]. Furthermore, there is also evidence to show that thiamine and biotin have significant functions in the mitochondrial metabolism of glucose [69] and fatty acids [70], respectively. Studies have thus elucidated B vitamins as contributors in both catabolic and anabolic energy processes [71]. B vitamins influence brain function as they are actively transported across the blood-brain barrier through specific transport mechanisms. Thiamine (vitamin B1) provides structural and functional stability of neurons and neuroglia [72] and modulates the acetylcholine neurotransmitter

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system [73]. Riboflavin (vitamin B2) and niacin (vitamin B3) influence brain function by facilitating energy production, protection from oxidative damage, DNA metabolism and repair, and cellular signaling pathways. Wakade et al. have shown that low-dose supplement of niacin modulates niacin index and ameliorates Parkinson disease symptoms [74]. It can be appreciated that most of the B vitamins (e.g., pantothenic acid, pyridoxine) are involved in the synthesis of multiple neurotransmitters which in turn affect the brain functions. In addition, pyridoxine (vitamin B6) regulates brain glucose levels [75], and in particular, pyridoxal-50 -phosphate is associated with severe inflammation contributing to the pathophysiology of dementia and cognitive decay [76]. Glucose metabolism and homeostasis are brainsensitive functions that are sustained by biotin (vitamin B7) levels [77]. In case of vitamin B9 (folate) and vitamin B12 (cobalamin), it is categorically established that they are interlinked due to their complementary roles in folate and methionine pathways and thus deficiency of vitamin B12 leads to putative deficiency of vitamin B9 [70]. It is believed that folate deficiency leads to reduction in purine/ pyrimidine synthesis and methylation reactions in brain leading to decreased DNA stability and repair, and hippocampal atrophy [78]. It is thus well documented that deficiency of Vitamin B causes multiple dysfunctions in cognitive performance [79]. Mediterranean diet that particularly contain whole grains, eggs, olive oil, nuts, seeds, leafy vegetables, and legumes are natural sources of B vitamins and hence promote cognitive functions.

Carotenoids Carotenoids are phytochemicals that are ubiquitous constituents in food. These have small, but substantial effect, cumulatively, and work in synergy with many other food components that aid in long-term well-being of cognitive health. The brain-related beneficial effects of carotenoids are mainly attributed to their antioxidant effect and antiinflammatory functions. For example, some of the well-known carotenoids are known to exert antiinflammatory response and reduce oxidative stress in some body parts, thus arresting any disease development, such as lycopene in prostate, b-carotene in corpus luteum, lutein and zeaxanthin in neural retina and brain neocortex [80]. Lutein is found in the inner layers of macular region of the eye and is thus essential for visual processing. Retina is part of the central nervous system and lutein also accumulates in brain thus improving the neural efficiency resulting in improved cognition [81]. Lycopene is yet another carotenoid abundantly present in several fruits including tomatoes and watermelon. Lycopene has shown multiple benefits including suppressing the production of inflammatory

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cytokines, accumulation of amyloid plaques [82,83], and accelerating glycolipid metabolism [84], in addition to being a potent antioxidant. Lycopene also confers neurocognitive protection by mediating mitochondrial function and inhibition of neuronal apoptosis [85].

Trace elements Trace elements, an important component of diet, though often overlooked, is well established in improving cognitive health. It is amply shown in research studies that Copper (Cu), Iron (Fe), and Zinc (Zn) play a critical role in neurodevelopment, neurotransmitter synthesis and homeostasis, and signaling [86,87]. Dietary sources of Cu are seafood, nuts, legumes, chocolate, and whole grains while Zn can be found in lean red meat, seafood, and dairy products [88]. Decrease in plasma Cu is associated with cognitive decay in Alzheimer patients [89]. Zinc deficiency is a major concern worldwide and affects 30% of the world’s population. Lack of zinc in diet is associated with cognitive decline in pregnant women [90]. Zn deficiency is also directly linked to impaired memory, learning deficits in children, depression, and cognitive decline [89,91]. For optimal functioning of brain, properly balanced food containing trace elements is key; for example, excess Zn can reduce Cu absorption that may lead to neurological disorders. Among other trace elements, selenium (Se) may be relevant for cognitive health, as it influences hormonal activity and neurotransmitter synthesis in the brain [92].

Correlation between metabolic diseases and psychiatric conditions Perturbations in brain-related energy homeostasis are a cause for the pathobiology of many neurological diseases. Association between metabolic abnormalities and psychiatric disorders is also well documented. The brain with a high rate of metabolism consumes up to 20% of total oxygen available to body while accounting just for 2% of body weight. Such a heightened need for oxygen is attributed to the consumption of large amounts of energy by neurons for maintaining and functioning of neuronal cell membranes and neurotransmission [93]. In addition, neuronal function and survival are critically dependent on mitochondrial function and oxygen supply and thus malfunctioning of mitochondria and oxidative stress lead to serious damage such as in neurodegenerative disorders like Alzheimer and Parkinson diseases [94]. Thus, metabolic disorders such as diabetes and obesity are intricately associated with the pathophysiology of most brain disorders. In this context, it is relevant to note that rodents treated with high fructose diet show increased triglyceride levels and hepatic lipids [95]. It is also worthwhile to note

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that fructose-induced metabolic syndrome reduces synaptic plasticity, learning, and memory, thus compromising cognitive health [96]. Prevalence of diabetes in manic depressive patients has been shown in a study [97] and similarly, diabetes mellitus in schizophrenic population has also been presented previously [98]. All these studies and current trends point to a strong correlation between metabolic diseases and psychiatric disorders although there is no conclusive cause-effect relationship that has been established till date. BDNF is also believed to be a common regulatory factor in both metabolic diseases and psychiatric conditions. For example, low levels of BDNF in the plasma are not only a result of impaired glucose metabolism and diabetes [99] but also are seen in patients suffering from depression [100] and schizophrenia [101,102].

Diet and cognitive health Dietary factors coupled with environmental challenges at various stages of life have a marked influence in cognitive and emotional health in human beings. Obesity in developed countries and poor diet in developing countries are serious concern which could be detrimental to mood and cognition at various stages of human life cycle. It is interesting to note that consumption of high fat diet in early childhood or adulthood can prime the hippocampus to trigger neuroinflammatory response causing memory deficits. On the contrary, intake of food high in polyphenols and antioxidants have the capacity to even reverse age-related cognitive defects by lowering oxidative stress and inflammation.

Early growth stage Early nutritional factors have a long-term influence in modulating incidence of mental disorders in humans. In fact, studies have categorically shown effect of prenatal and postnatal nutrition in development of mental disorders and subsequent passage to further generations [103,104]. It has been observed that children who were breastfed are likely to demonstrate better cognitive performance [105]. This is particularly relevant as neurodevelopment such as proliferation of neuronal elements and neuroblast migration to cerebral cortex occur during such early stages of human life cycle. Thus, early nutrition is a determining factor of cognitive function in later life. Placental insufficiency, increased maternal glucocorticoids, and maternal deficiency in micronutrients are potential factors that can affect cognitive health in adult life [48]. It has also been shown that poor nutrition in utero and in early postnatal life have a lasting impact in metabolic and neural functions including cognitive decay and accelerated brain aging [106]. Early childhood metabolic complications are chief influencers of cognitive development in adolescents. In

this connection, it is important to note that junk food diet containing significant fat content and sweetened drinks result in weight gain and lead to metabolic complications, which in turn result in poor cognition in adulthood [107]. Studies in animal models have proven beyond doubt that high fat diet in rat and mouse during pregnancy and lactation lead to diminished mood, depression, and anxiety, all of which impact cognition [108]. These studies conclusively demonstrate that brain’s high demand for nutrients in early stages of development and dietary imbalance impact neurodevelopment resulting in lasting cognitive dysfunction [109].

Adulthood Monitoring dietary habits in developed countries indicate that there is increased consumption of saturated fats and refined sugars by adults. It has been shown that energy intake in 12% of American adults come from saturated fats while 13% derive energy from added sugars [110], which is significantly higher than what is recommended (5% e10%) or optimal for healthy lifestyle. Such alarming dietary habits have contributed to obesity in young adults in the United States, which is now about three times more than that prevailed in 1960 [111]. Obesity and other metabolic disorders like type 2 diabetes, as seen in earlier section of this chapter, are strongly associated with cognitive impairments and dementia. Research data has pointed to the fact that food containing saturated fats and high sugar content trigger neuroinflammatory responses that may lead to cognitive deficits [112]. Hippocampal region of the brain is especially affected by high fat diet that triggers neuroinflammatory signals impairing hippocampus-dependent memory. In a study by Beilharz et al. [113], rodents were either given a normal (control) diet or a high-fat and/or high-sugar diet. The results showed a marked impairment in memory in the latter two groups as compared to the control. Attention deficit and reduced retrieval of information are also related to high fat diet. Although the mechanism by which the neuroinflammatory responses affect the hippocampus function is not clear, it is believed that high fat diet may sensitize the microglia of the brain, thus triggering the inflammatory response that ultimately compromises the hippocampus [114,115]. Among the immune cells in brain, microglia have a major role in mediating cognitive function. Their key function is to trigger immune response and phagocytose pathogens in injured brain cells [116]. However, excess secretion of inflammatory cytokines by activated microglia may lead to cognitive dysfunction resulting in decrease of neurotrophic factor and IGF-1. Thus, it is abundantly clear that cognitive health is firmly regulated by diet pattern in an adult’s life.

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Cognitive enhancers It is rather antithetical to say that wisdom comes with “age,” but the brain most certainly slows down and cognitive functions decline with aging. Thus, a more recent development is in the field of cognitive enhancers, also called as nootropics or smart drugs, which are believed to fight back the “slowing down” process. Cognitive enhancers include brain training in the form of computer programs, drugs (e.g., modafinil), nutritional supplements, exercise, and meditation. Use of computer-aided video games for improving cognition in children and older adults has been shown in some studies. For example, a multitasking version of a video game played for 12 h over a period of 1 month showed significant enhancement in cognitive tests of sustained attention and working memory [117]. Some of the cognitive functions that have been measured and shown to indicate improvement include visual attention, cognitive control, short-term memory, and processing speed [118]. Although, commercially, video gaming as cognitive enhancer is a burgeoning industry, critiques have been skeptical and have indicated that there is limited evidence supporting the idea of digital media in rendering beneficial effects on real-world cognitive health. With regard to exercise and meditation, these are activities that can discipline the mind resulting in enhanced cognitive performance. But their recommendations are equivocal and are personalized rather than based on evidence. Apart from nutritional supplements that have been discussed in the current chapter, there has not been proven scientific evidence that back the rest of the aspects that are suggested as cognitive enhancers.

Active sports and cognitive performance: role of nutritional supplements Cognitive health is critical for performance in professional sports. For that reason, these cognitive enhancers are also seriously researched in sports science to increase agility, reaction time, focus, and motor skill. Certain nutritional supplements have demonstrated benefits in enhancing motor skill and cognitive health that is discussed here. Branched-chain amino acids such as leucine, isoleucine, and valine are associated with mitigating fatigue during prolonged exercise plausibly by reducing serotonin synthesis in brain [119]. Furthermore, Hassmen et al. have demonstrated that consumption of carbohydrate solution with branched-chain amino acids by runners during competition improved cognitive performance after 30 km as against consuming the one without branched-chain amino acids. It is however interesting to note that such

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improvement is related only to more complex cognitive tasks such as attention and showed no change in lesser physically demanding tasks such as short-term memory [120]. Despite encouraging results, use of branched-chain amino acids benefiting endurance in athletes is still a hypothesis and is not currently recommended as a performance enhancer. Caffeine is a naturally occurring substance chemically identified as trimethlyxanthine and is found in coffee, guarana, chocolate, kola nut, and certain other plants. There are many studies that have pointed to the beneficial effect of caffeine in sports-related activities, especially those related to skill and endurance. For example, passing accuracy in soccer players was vastly improved after consumption of 6 mg caffeine (per kg body mass) as against placebo just an hour before the start of the game [121]. In contrast, certain studies have indicated lack of benefit of caffeine on motor skill performance and reactive agility [122,123]. These were mostly studies related to simulated sports situations, which are notionally different from real-life situations, which may be the reason for the discrepancies. It is likely that the benefit of caffeine is more pronounced in situations where physical or mental fatigue is present, like toward the latter half of the game [121,124]. Ginseng species, some of which include Panax ginseng, Panax quinquefolius, Panax notoginseng, and Eleutherococcus senticosus are triterpene saponins suggested to be involved in modulating performance-enhancing effects on cognition. Effects of ginseng are especially pronounced in active individuals, such as sports persons, who are under physical stress or fatigue [125]. However, conclusive effects are still lacking to recognize ginseng as a supplement in boosting cognitive health, especially in athletes. Among flavanols, cocoa is a plant product primarily containing epicatechin and trace amounts of epigallocatechin. In a crossover study, cocoa flavanols showed beneficial effects with regard to cognition and visual function in cocoa flavanolsefed groups as against the placebo group, when fed to healthy adults at 520, 994 mg, or placebo [126]. Yet another study has reported similar results wherein consumption of dark chocolate (720 mg of cocoa flavanol) improved cognitive performance when compared to ingestion of white chocolate (negligible amount of cocoa flavanol) [127]. It is believed that the mechanism by which cocoa facilitating cognitive performance and visual function may be related to increased brain perfusion [128,129]. Despite encouraging results in certain studies, the evidence to support cocoa as a dietary supplement in improving cognitive performance is still sparse and needs further confirmation. Yet another natural product with flavanol content is G. biloba extract from the leaves of maidenhair tree which is a native to China. Other components in this herb include

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terpenoids and terpene lactones [130]. G. biloba extracts are widely used as nutritional supplements for their suggested activity in increasing cerebral blood flow, reducing blood viscosity and as scavengers of free radicals [131]. However, there is paucity of information with regard to Ginkgo’s effect as cognitive enhancer in active sports. Rhodiola rosea is yet another dietary constituent that facilitates enhanced cognitive function, especially under fatigue and stress conditions. R. rosea has an array of constituents including flavonoids, phenolic acids, triterpenes, and monoterpenes [132] and is shown to improve attention, speed, and accuracy. It also impacts the quality of mental work than the quantity of work completed [133]. The body of literature on the acute effects of R. rosea on physical performance in athletes is sparse and yet to be substantiated with more research data. In addition to the above discussed naturally occurring components, sage (Salvia officinalis), L-theanine, theobromine, and tyrosine are a few other natural supplements that have some effect in improving cognitive health [125]. Except caffeine, most others, however lack scientific support to enable meaningful use as supplements to cognitive performance in active sports.

Diet and epigenetics Among the many research attributes that have delved into brain health, more recent focus has been in the areas of diet and nutrition influencing epigenetic events that potentially transmit across generations. Epigenetic events, including nongenetic components like DNA methylation, control of transcription, histone acetylation, and other posttranslational modifications have the capability to cause phenotypic changes resulting in disease modulation. Studies have been few in this topic, but there has been significant data to show that BDNF can undergo significant changes bringing about epigenetic modulations affecting cognitive functions. Differential expression of specific BDNF splice variants as a result of chromatin modifications has been shown in Alzheimer patients [134]. A recent study in rodent model of depression has shown consistent changes in histone acetylation and methylation at the site of BDNF promoter during depressive state and upon administration of antidepressant [135]. However, the role of diet and lifestyle changes in triggering DNA signaling in brain that impacts cognitive functions is yet to be studied in detail.

Nutraceuticals as key drivers for brain health The above account clearly indicates that many of the food components have a fundamental role in protecting the brain and sustenance of its function. Our daily routine coupled with work-related stress may have damaging consequences

leading to decay of the signaling components associated with neuro transmission. Recent research focus in food science has facilitated development of nutraceutical interventions resulting in related nutraceutical products/supplements. This is also driven by formulation technologies that aid in delivering sufficient quantities of the active components that protect against specific damage causing agent or help in reversing the pathology of the condition. Formulation science also plays a vital role in delivering the active nutraceutical as a single agent or as a combination in a sustained manner that may help in reversing some of the brain-related functions, which are being explored at various scientific levels.

Future recommendations There have been many studies pointing to the relationship between nutrition and short/long-term effects on brain and cognitive health. Collective data obtained in the past decade or so is promising and should be very useful in developing key dietary interventions leading to beneficial cognitive health. Most research data obtained in this area has become the premise for food and nutrition industry to develop highquality products for consumption. The next steps in this area will be to develop evidence-based natural products that can play a direct role in correcting or preventing certain cognitive conditions.

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Chapter 20

Mediterranean diet and its components: potential to optimize cognition across the lifespan Sarah Gauci1, Lauren M. Young1, Helen Macpherson2, David J. White1, Sarah Benson1, Andrew Pipingas1 and Andrew Scholey1 1

Centre for Human Psychopharmacology, Swinburne University, Melbourne, VIC Australia; 2Institute for Physical Activity and Nutrition, Deakin

University, Geelong, VIC Australia

Chapter outline Diet, cognition, and dementia Assessment of Mediterranean diet Mediterranean diet and cognition across the lifespan Mechanisms and food components Olive oil

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Fish Nuts Fruits and vegetables Practical translation into Western countries References

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Diet, cognition, and dementia

Assessment of Mediterranean diet

The role of diet and nutrients in brain health and the risk of developing dementia has been gaining interest over recent years. Early literature focused on how different nutrients and individual food groups were related to cognition [6e8]. Based on evidence from multiple cross-sectional studies various nutrients including B-group vitamins and omega-3 fatty acids have been associated with better cognitive and brain health [9,10]. However, these findings have often not been translated into positive findings following randomized-controlled trials investigating the supplementation of the individual nutrients [11]. Due to the complex interactions that occur when combining different nutrients and food groups, more recent research has focused on whole dietary patterns and cognition [6]. Various dietary patterns have been examined in relation to improved cognitive health. The 2017 Lancet Commission on Dementia Prevention, Intervention and Care [12] highlighted the potential for the Mediterranean diet as an interventional strategy to delay the onset of dementia and slow cognitive decline.

The Mediterranean dietary pattern is characterized by a high intake of fresh fruits, vegetables, fish, breads, cereals, nuts, and legumes. There is a low to moderate consumption of dairy and poultry, while red meat is consumed in low quantities only. Olive oil provides the main source of fat and alcohol is consumed in moderate amounts, normally accompanying meals. The current consensus of the Mediterranean diet is shown in Fig. 20.1. Several assessment tools have been proposed to capture adherence to a Mediterranean diet. The most commonly used measure is the MedDi score [3]. This captures intake on a food frequency questionnaire and scores it against sex-specific group medians. For “MedDipositive” components, including fruit, vegetables, grains, nuts, legumes, monounsaturated fatty acid to saturated fatty acid ratio, consumption above the median is awarded one point and consumption below the median is assigned a value of zero. “MedDi negative” components, including dairy and red meat, are reverse scored with consumption

Nutraceuticals in Brain Health and Beyond. https://doi.org/10.1016/B978-0-12-820593-8.00020-3 Copyright © 2021 Elsevier Inc. All rights reserved.

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294 Nutraceuticals in Brain Health and Beyond

W ee

kly

_ s Sweets 2

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y

Dairy 2 s (preferably low fat)

Olives/nuts/seeds 1-2 s

_2s Vegetables > Fruits 1-2 s Olive oil Bread/pasta/rice/couscous Other cereals 1-2 s (preferably whole grain)

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in

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Water and herbal infusions

FIGURE 20.1 The Mediterranean diet. Adapted from Baich-Faig et al. [102] previously published in Macpherson et al. [103].

lower than the group median awarded one point. In total, individuals are scored on a 10-point scale ranging from zero (low adherence) to nine (higher adherence) [3]. Panagiotakos and colleagues calculated an alternative MedDiet score from a food frequency questionnaire based on frequency of intake, rather than against sex-specific medians. Each component was assessed on a 5-point scale, with a maximum score of 55 indicative of high adherence to a Mediterranean diet. More recently a 14-item questionnaire (MEDAS) has been developed from the PREDIMED trial [13]. This was one of the first questionnaires specifically designed to measure adherence to a Mediterranean diet, and due to its shorter length, offers greater clinical utility.

Mediterranean diet and cognition across the lifespan There is considerable evidence from population-based studies suggesting that the long-term effects of adherence to a Mediterranean-style diet can protect against the development of dementia as well as preserve cognitive and brain function (See Table 20.1). Several epidemiological studies have found that adherence to the Mediterranean diet appears to be protective against developing mild cognitive impairment (MCI) and Alzheimer disease (AD). Findings from the longitudinal Washington Heights-Inwood Columbia Aging Project (WHICAP) demonstrate that higher adherence to the

Mediterranean diet was associated with reduced risk of AD [14] after a follow-up period of 4 years. Similarly, results from the Australian Imaging, Biomarkers, and Lifestyle Study of Aging (AIBL) demonstrate that poor Mediterranean diet adherence was a significant predictor of developing MCI and AD [15]. A more recent study, the Rush Memory and Aging Project, found that highest adherence to a Mediterranean diet was associated with reduced incidence of AD when compared to lower adherence [16]. In addition to reducing the risk of developing AD and dementia, adherence to the Mediterranean diet has also been linked to better cognitive performance in healthy older adults. The Reasons for Geographic and Racial Differences in Stroke (REGARDS) [17] study used a longitudinal design to investigate the relationship between a Mediterranean diet and cognitive performance in healthy adults aged 45 years or older. It was found that higher adherence to the Mediterranean diet was associated with a lower likelihood of cognitive impairment after a 4-year follow-up period. Similar results were found in the Chicago Health and Aging Project (CHAP) [18]. Adherence to the Mediterranean diet was linked to slower rates of cognitive decline as measured by the Mini-Mental State Examination (MMSE) over 7 years. The MMSE is a brief assessment of global cognition that is commonly used for screening cognitive function [19]. Many studies investigating the relationship between cognition and adherence to the Mediterranean diet have used the MMSE [20e22] and found

TABLE 20.1 Longitudinal studies examining the relationship between adherence to the Mediterranean diet and cognition. Participants (n, aged at baseline)

Cherbuin and Anstey [28]

Country

Average follow-up

MedDiet score

Cognitive outcomes measured

n ¼ 1528, aged adults

Australia

4 years

Trichopoulou

Mini-Mental State Examination (MMSE), California Verbal learning Test, symbol digit modalities Test, and purdue pegboard test

MedDiet was not protective of cognitive decline

Fe`art et al. [20]

n ¼ 1410, >65 years

France

5 years

Trichopoulou

MMSE, isaacs set Test of semantic verbal fluency, Benton Visual retention Test of visual memory, Free and cued selective reminding Test of verbal episodic memory

Higher MedDiet adherence was associated with slower decline on MMSE, but not related to other cognitive outcomes, or risk of developing dementia

Galbete et al. [91]

n ¼ 823, >55 years

Spain

8 years

Trichopoulou

TICS-modified

Low & moderate adherence to MedDiet was associated with greater cognitive decline compared to those with high adherence

Gardener et al. [25]

n ¼ 527, >60 years

Australia

3 years

Trichopoulou

Verbal memory, visual memory, executive function, language, attention and visuospatial functioning

Higher adherence to MedDiet (modified for Australian population) was associated with better executive function in APOE e4 carriers

Gu et al. [92]

n ¼ 1219, >65 years

US

3.8 years

Trichopoulou

Incidence of AD

Higher adherence to MedDiet was associated with lower risk for AD

Haring et al. [29]

n ¼ 6425, >65 years, all female, without dementia

US

9.1 years

Fung/Trichopoulou

Incidence of MCI

MedDiet adherence was not associated with cognitive decline.

Hosking et al. [30]

1220, 60e64 years

Australia

12 years

Trichopoulou and panagiotakos

Neuropsychological testing and the MMSE

MedDiet was not protective of developing MCI/dementia

Kesse-Guyot et al. [31]

n ¼ 3083, >45 years

France

13 years

Mediterranean Diet Score trichopoulou

Episodic memory, semantic fluency task, forward and backward digit span task of working memory, delis-Kaplan trailmaking test of mental flexibility

MedDiet adherence was not significantly associated with cognitive function

Koyama et al. [93]

n ¼ 2326, 70e79 years

US

8 years

Panagiotakos

3MS

Higher MedDiet adherence was associated with a slower rate of decline of 3MS score in black participants, but not white participants.

McEvoy et al. [90]

n ¼ 2,621, 18e30 years

UK

30 years

Panagiotakos

Neuropsychological testing: verbal learning, memory, processing speed and executive function

Greater adherence to MedDiet during adulthood was associated with better midlife cognitive performance.

Key findings

Mediterranean diet and its components: potential to optimize cognition across the lifespan Chapter | 20

Authors and year

295

Continued

Authors and year

Participants (n, aged at baseline)

Morris et al. [16]

Country

Average follow-up

MedDiet score

Cognitive outcomes measured

n ¼ 923, 58e98 years

US

4.5 years

Panagiotakos

Incidence of AD

Highest tertile of the MedDiet was associated with AD incidence when compared to lowest tertile score

Psaltopoulou et al. [32]

n ¼ 732, >60 years

Greece

6e13years

Trichopoulou

MMSE

There was a nonsignificant trend between MedDiet adherence and cognition

Qin et al. [94]

n ¼ 1650, >55 years

China

5.3 years

Modified version of trichopoulou

Global cognitive scores and standardized verbal memory scores

The highest tertile of MedDiet adherence was associated with better cognitive performance compared to those in the lowest tertile

Roberts et al. [95]

n ¼ 1233, 70e89 years

US

2.2 years

Trichopoulou

Incidence of MCI and dementia

Higher MedDiet adherence was not associated with risk of MCI/dementia. The odds ratio of MCI decreased with higher intake of fruit and increasing MedDiet score, however this was not statistically significant. There was also a 25% reduced risk of MCI or dementia in subjects in the upper tertile of the MedDiet score at baseline, but this finding did not reach statistical significance

Samieri et al. [96]

n ¼ 16,058, M ¼ 74.3 years

US

13 years

Fung/Trichopoulou

Cognitive battery: TICS, immediate and delayed recalls of the East Boston Memory test, category fluency, digit spanbackward

MedDiet adherence was associated with improved cognitive performance but not with cognitive decline

Samieri et al. [97]

n ¼ 6174, M ¼ 71.9 years

US

5.6 years

Fung/Trichopoulou

Cognitive battery: TICS, immediate and delayed recalls of the East Boston Memory Test, and category fluency

MedDiet adherence was not related to cognitive function. However components of the diet were; a higher monounsaturated-to-saturated fats ratio was related with better cognitive trajectories and wholegrain consumption was related to better global cognition performance

Scarmeas et al. [14]

n ¼ 1880, >65 years

US

5.4 years

Trichopoulou

Incidence of AD

Higher adherence to the MedDiet was related to reduced risk for AD

Scarmeas et al. [5]

n ¼ 2258, >65 years

US

4 years

Trichopoulou

CDR measuring global cognition, DSMeIIIeR for all-cause dementia, NINCDSADRDA for AD

Higher adherence to the MedDiet was associated reduced risk for AD

Key findings

296 Nutraceuticals in Brain Health and Beyond

TABLE 20.1 Longitudinal studies examining the relationship between adherence to the Mediterranean diet and cognition.dcont’d

n ¼ 1393, >65 years

US

4.5 years

Trichopoulou

Neuropsychological battery: memory, orientation, abstract reasoning, language, and construction; CDR measuring global cognition, NINCDSADRDA for AD

Higher MedDiet adherence was associated with a nonsignificant trend for lower risk of developing MCI & MCI converting to AD

Shannon et al. [99]

n ¼ 8009, 40e79 years

UK

13e18 years

Mediterranean Diet Adherence screener (MEDAS); the MEDAS continuous score; MedDiet pyramid (pyramid) score

Global cognitive function: Total score from a Short form extended Mental State exam, Verbal episodic memory, nonverbal episodic memory, Attention, simple processing speed, Complex processing speed and visual deficits contributing to cognitive impairment, Memory

Higher MedDiet adherence was associated with better global cognitive performance

Tangney et al. [18]

n ¼ 3790, >65 years

US

7.6 years

Panagiotakos

MMSE and symbol digit modalities Test

Higher MedDiet adherence were associated with slower cognitive decline

Tangney et al. [21]

n ¼ 826, M ¼ 81.5 years

US

4.1 years

Panagiotakos

19 cognitive tests, summarized as a global measure of cognition and 5 summary measures; episodic memory, semantic memory, working memory, perceptual speed and visuospatial ability

Higher MedDiet score was associated with a slower global cognitive decline

Trichopoulou et al. [22]

n ¼ 401, >65 years

Greece

6.6 years

Trichopoulou

MMSE

Higher MedDiet adherence was associated with less decline on MMSE

Tsivgoulis et al. [17]

n ¼ 17,478, >70 years

US

4 years

Trichopoulou??

Global cognition

Higher adherence to MedDiet was associated with a lower likelihood of incident cognitive impairment in nondiabetic participants only

Vercambre et al. [23]

n ¼ 2504, >65 years, all female

5.4 years

Trichopoulou

Global cognition (TICS), East Boston Memory Test

Higher adherence to the MedDiet was associated with reduced risk for AD

AD, Alzheimer disease; CDR, Clinical dementia rating; MCI, Mild cognitive impairment; MedDiet, Mediterranean diet; MMSE, Mini-Mental State Examination; 3MS, Modified Mini-Mental State; TICS-modified, modified Telephone Interview for Cognitive Status.

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Scarmeas et al. [14]

297

298 Nutraceuticals in Brain Health and Beyond

significant relationships. However, the literature suggests that more sensitive measures of cognition should be used to ensure that the relationship between diet and cognition in the early stages of cognitive decline is also captured [23,24]. An increasing number of recent studies investigating the links between adherence to the Mediterranean diet and cognition have utilized cognitive assessments that are sensitive to the different aspects of cognition that deteriorate with age [21,25e27]. The Australian Imaging, Biomarkers and Lifestyle study used a thorough cognitive assessment battery that included tests of cognitive domains known to deteriorate with age, including verbal memory, visual memory, executive function, language, attention, and visuospatial functioning [25]. The study found that individuals with genetic predisposition to cognitive decline who had higher adherence to a Mediterranean diet adapted to an Australian population had less decline in executive function over a 3-year period. Conversely, those adhering to a more typical Western style diet (higher in processed foods, refined sugars, and red meat) had increased decline in the visuospatial domain. In the Memory and Aging Project (MAP) study, cognitive assessments were made using 19 tests of cognitive performance, with overall higher adherence to the Mediterranean diet related to a slower rate of global cognitive decline [21]. Assessing the different cognitive domains, especially those more associated with age-associated cognitive decline, allows a better understanding of the complex relationship between cognition and diet. Further, the use of age-sensitive measures of cognition may reveal the onset of these relationships and help determine the optimal time window for intervention. Several longitudinal studies have also failed to find a significant relationship between adherence to the Mediterranean diet and cognitive function [28e32]. The heterogeneity of the findings across the different longitudinal studies may be due to the confounding effects of different cognitive outcomes and different scoring methods used. Further, a common limitation of longitudinal trials is the failure to measure dietary intake at follow-up. These studies have used a dietary measure at baseline to observe relationships between baseline Mediterranean diet adherence and cognition at follow-up, typically spanning 5e10 years later. This rests on the assumption that individuals’ diets are consistent over the follow-up period which is often not the case. Particularly in an aging group, dietary modification is common due to loss of spouse, appetite, or disease-instigated changes [33], and therefore may confound the results. Further, some studies fail to measure cognitive performance at baseline, for example, the French Supplementation with Vitamins and Mineral Antioxidants (SU.VI.MAX) only assessed cognitive function at follow-up. This is a common issue in these large population studies, as some may only add cognitive assessment to the cohort at a later stage in the study.

In order to overcome these limitations and explore the mechanisms underpinning the purported benefits of a Mediterranean diet on cognition, a number of randomizedcontrolled trials (RCTs) investigating Mediterranean diet interventions have been conducted. Further, the addition of measures of nutrient status, oxidative stress, and inflammatory biomarkers may help us understand the mechanisms which underlie the relationship between dietary adherence and cognitive and behavioral changes. The RCTs involving Mediterranean diet interventions for cognition are summarized in Table 20.2. A small pilot study by McMillan et al. [34] investigated the effects of a 10-day Mediterranean diet intervention on mood and cognitive performance in healthy young women. Utilizing a between-subjects design, the study found that, in comparison to participants who did not change their diet, those on the Mediterranean diet had improved mood. Cognitive effects were mixed, with improved reaction times for spatial working memory but worse performance on other tasks (numerical working memory and work recognition. In a partial replication of this trial, Lee et al. [35] conducted a 10-day crossover-design Mediterranean diet intervention for healthy young women. This trial supported the mood findings of the pilot study. In this case Mediterranean diet was associated with better performance on word recall tasks (though again, worse performance on a numerical working memory task). Collectively, these findings suggest that the benefit of a Mediterranean diet on cognitive functioning may be more robust in older population, or those with cognitive impairment. More work is needed in younger adults to evaluate whether the Mediterranean diet can optimize cognition in the short-term and potentially acting as a protective factor across the lifespan. In terms of chronic interventions of Mediterranean diet, the PREDIMED trial [36] and associated substudies have been major contributors to our understanding of Mediterranean diet benefits for cognitive function. Based in Spain, participants were selected for having major cardiovascular risk factors and followed the intervention over several years while undergoing periodic cognitive tests and screening for MCI and AD. After 4 years, following a Mediterranean diet supplemented with extra virgin olive oil (EVOO) or nuts was associated with improved composite measures of cognitive function [26]. At 6.5 years, cognitive performance was significantly higher for those with in the EVOO-rich Mediterranean diet group in comparison to the control diet, in addition to significantly less incidence of MCI than controls. As found in longitudinal observational studies, subgroup analyses of the PREDIMED study support the interaction of Mediterranean diet with genetic risk factors for AD. After 6.5 years, a significant interaction was found between adherence to Mediterranean diet and specific genetic risk factors (Apolipoprotein E ε4 allele),

TABLE 20.2 Randomized-controlled trials examining the relationship between adherence to the Mediterranean diet and cognition. Authors and year

Country

Length of intervention

Hardman et al. [40]

N ¼ 102, 60e90 years

Australia

Knight et al. [27]

n ¼ 166, >65 years

Lee et al. [35]

Cognitive outcomes measured

Key findings

6 months

SUCCAB: Simple and choice reaction times, immediate recognition, delayed recognition, congruent and incongruent stroop colourwords, spatial working memory, & contextual memory

There was no significant benefit in overall cognitive performance. However, there was a significant improvement in spatial working memory performance in the combined exercise and diet group when compared to controls.

Australia

6 months

Neuropsychological test battery, summarized into 4 factors: Executive function, memory, speed of processing and visual-spatial memory

There was no benefit of MedDiet intervention for cognitive function.

n ¼ 24, healthy women

Australia

10 days

COMPASS battery, measured using attention, working memory, long term memory and executive function.

There was better performance in the MedDiet compared with the no-change condition for immediate word recall, and incorrect word recall. For the 3-back task, there were fewer correct responses in the MedDiet compared with the no-change condition

MartinezLapiscina et al. [101]

n ¼ 522, selected for CV risk: type 2 DM or 3 major CV risk factors

Spain

6.5 years

MMSE and CDT

Performance on the cognitive assessments was better for participants allocated to the MedDiet þ extra virgin olive oil (EVOO) group in comparison with the control group, while significant differences were not found between the MedDiet þ Nuts group versus the control group.

MartinezLapiscina et al. [66]

n ¼ 285, selected for CV risk: type 2 DM or 3 major CV risk factors

Spain

6.5 years

Incidence of MCI and dementia

Cognitive performance was significantly higher for those with the EVOO-rich MedDiet comparted to the control diet. Participants on the EVOO-rich MedDiet also had significantly less MCI than controls.

McMillan et al. [34]

n ¼ 25, healthy women

Australia

10 days

COMPASS battery, measured using attention, working memory, long term memory and executive function.

Adherence to a MedDiet improved reaction time for spatial working memory tasks compared to the control diet group (no change in diet)

Valls-Pedret et al. [26]

n ¼ 447, selected for CV risk: type 2 DM or 3 major CV risk factors

Spain

4.1 years

MMSE, Rey auditory Verbal learning Test, animals semantic Fluency, digit span subtest from the Wechsler Adult intelligence Scale, Verbal paired Associates from the Wechsler Memory Scale, and the colour trail Test. Cognitive composites: memory, frontal (attention and executive function), and global.

The MedDiet supplemented with olive oil or nuts was associated with improved composite measures of cognitive function.

Wade et al. [41]

n35, 45e80years

Australia

8 weeks

CANTAB: memory, attention, processing speed and planning.

The MedDiet supplemented with pork was found to improved processing speed when compared to the control group

AD, Alzheimer disease; CANTAB, Cambridge Neuropsychological Test Automated Battery; CDT, Clock drawing test; COMPASS, Computerized Mental Performance Assessment System; MCI, Mild cognitive impairment, MedDiet, Mediterranean diet; MMSE, Mini-Mental State Examination; SUCCAB, Swinburne University Computerized Cognitive Assessment Battery.

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Participants

299

300 Nutraceuticals in Brain Health and Beyond

suggesting that the Mediterranean diet may be able to modulate the effects of these genetic risk factors on cognitive decline [37]. This rapidly developing field of epigenetics offers a promising approach whereby the expression of nonmodifiable genes may be altered, and potentially attenuate biological processes underpinning the etiology of AD. At the time of writing, there is an ongoing 12-month Mediterranean diet intervention [38] in individuals with cardiovascular risk factors in Spain. While the primary outcome of this study is to reduce cardiovascular risk, secondary outcomes include cognitive measures, reiterating the importance of Mediterranean diet for cognitive health and recognition of this relationship as gaining traction in the field. To the authors’ knowledge, there have only been three chronic RCTs conducted in nonclinical adults outside of Europe: the MedLey study [27], the Lifestyle Intervention in Independent Living Aged Care (LIILAC) [39,40], and MedPork Randomised Controlled Trial [41]. All three of these trials were conducted in Australia. Interestingly, there was no benefit of a 6-month Mediterranean diet intervention for cognitive function in healthy adults aged 65 years in the MedLey study [27]. The researchers attributed this result to possible ceiling effects for the cognitive outcomes. This study also diverges from PREDIMED in terms of the length of intervention. As the effect of diet is likely cumulative across the lifespan and the effect sizes are relatively small compared to pharmaceutical studies, these factors may have limited the ability to detect a benefit for cognition [24]. However, the 8-week intervention of Mediterranean diet supplemented with 2e3 weekly servings of fresh lean pork was observed to result in improved processing speed when compared to low fat controlled diet in 45e80 year olds [41]. The results of the 6 month LIILAC intervention have just recently been published, while no significant change was observed in overall cognitive performance; performance on the spatial working memory task was improved in the combined exercise and Mediterranean diet group when compared to the control group [40].The LIILAC trial was a pilot for the MedWalk trial; a multisite study investigating the combined effects of a Mediterranean diet and walking intervention in independent living older adults over 2 years. Collectively, the results of the prospective longitudinal and RCTs suggest that Mediterranean diet may help protect against dementia and help maintain healthy cognitive function.

Mechanisms and food components There is a considerable evidence suggesting that the Mediterranean diet has a positive impact on the brain. However, the mechanisms of this relationship are not well understood. It has been suggested that antiinflammatory

and antioxidant properties of the Mediterranean diet improve cardiovascular [1,2,4,42,43] and metabolic health [44], which, in turn, improve cognitive function. There is a well-established relationship between poor cardiovascular health an increased risk factor for later dementia [45]. There is also substantial research linking both hypertension and arterial stiffness to impaired cognitive performance [42,46,47]. While a hallmark of aging, an increase in arterial stiffness reduces the capacity of the vessels to dampen the pulsatile flow created by the heart with each beat [46,48]. The consequence of this increase in blood flow pressure into the smaller capillaries within the brain may cause progressive small vessel damage and cognitive deficits [47]. In addition to arterial stiffness, cerebrovascular disease is another risk factor for cognitive decline and often occurs comorbidly in individuals with AD [49]. As several cardiovascular parameters are risk factors for dementia [45], the beneficial effects of the Mediterranean diet on cardiovascular health may consequently improve brain health into old age. Many studies have suggested that the protective benefits of the Mediterranean diet may be attributed to beneficial effects on oxidative stress and inflammation. Both oxidative stress and inflammation play a role in the pathogenesis of cardiovascular disease and dementia (for a review see Ref. [50]). In addition to poor cardiovascular health, metabolic syndrome has also been linked to cognitive decline and dementia [51,52]. Metabolic syndrome is a clustering of different metabolic disorders including central obesity and any two of the following: raised triglycerides, reduced HDL cholesterol, increased blood pressure, raised fasting plasma glucose [53]. Adherence to a Mediterranean diet has been reported to reduce the incidence and risk of metabolic syndrome [54]. Another metabolic disorder that has been found to impact cognition is the development of type 2 diabetes [55,56]. The connection between the development of type 2 diabetes and the risk of AD is now considered so strong that AD is often considered a neuroendocrine disorder, or type 3 diabetes [57e59]. Further, impaired glucose control even in the healthy range has been linked in increased cognitive decline [60]. A systematic review conducted by Esposito, Maiorino, Ceriello, and Giugliano [61] reported that adhering to a Mediterranean diet may help prevent the development of type 2 diabetes and improve glucose control. Finally, another possible mechanism that the Mediterranean diet may exert benefits on brain function is through Brain-Derived Neurotrophic factor (BDNF). BDNF is a protein that is synthesized in neuronal tissue, vascular endothelial cells, pancreatic cells, and in smooth and skeletal muscle cells. It is thought to play a role in synaptic plasticity, neuronal survival, neuronal health, and differentiation [62,63]. The PREDIMED trial found that

Mediterranean diet and its components: potential to optimize cognition across the lifespan Chapter | 20

adherence to the Mediterranean diet was associated with an improvement in plasma BDNF concentrations in those with depression [64]. Collectively, it appears that there are multiple vascular, metabolic, and inflammatory pathways that mediate the relationship between the Mediterranean diet and cognition [50]. This may be due to the combined effects of a range of components of the Mediterranean diet. The following section will highlight the specific dietary components of a Mediterranean diet that may be particularly important for brain health and underpin these mechanisms (Fig. 20.2).

Olive oil While a broad range of food groups contribute to a traditional Mediterranean diet, olive oil appears to be a significantly important component. It is rich in monounsaturated fatty acids and polyphenols and may be responsible for many of the cardiovascular benefits associated with this dietary profile. A large prospective study of over 40,000 participants found that there was 44% decrease in mortality caused by cardiovascular disease after 13 years in individuals with high olive oil consumption [65]. Further evidence for the protective benefits of olive oil have been described in subset of participants in the PREDIMED study, participants who adhered to the Mediterranean diet intervention with olive oil had performed better on fluency and memory tasks and had lower rates of MCI when compared to the control group [66]. This cognitive improvement was not observed in participants in the Mediterranean diet and nuts condition. The PREDIMED

301

study suggests that a Mediterranean diet rich in EVOO may benefit cognitive health. However, as the study design failed to assess baseline cognitive status, there is a need to replicate these findings.

Fish Oily fish, such as salmon, tuna, mackerel, and sardines are rich in omega-3 fatty acids, which are known to exert antiinflammatory, cardioprotective, and neuroprotective properties [67,68], as well as increased cell membrane fluidity [69]. Long-chain omega-3 polyunsaturated fatty acids (LC-PUFA) include both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). These include long-chain DHA and EPA, which cannot be synthesized efficiently within the body, and therefore it is important that these nutrients are consumed as part of an individual’s regular diet. Fatty acids are a key component of the Mediterranean diet that distinguishes it from other dietary patterns [50]. Overall, there is a great amount of evidence that circulating omega-3 levels in blood and dietary intake of omega-3 are related to cognitive performance [10,70]. However, the evidence from RCTs is mixed [71,72]. These varied findings may be due to the heterogeneity of the cognitive assessments used leading to reduced effect seizes in the meta-analysis [71].

Nuts Tree nuts and legumes are nutrient-dense foods containing monounsaturated (MUFA) and polyunsaturated (PUFA)

FIGURE 20.2 Components of the Mediterranean diet and potential mechanisms that influence cognitive health.

302 Nutraceuticals in Brain Health and Beyond

fatty acid profiles; protein; vitamins; and other nutrients known to have a number of health benefits including cognitive function [73,74]. Participants in the nurses’ Health study (nHs) were found to have modestly better cognitive performance at old age (70þ years), when they had higher nut intake; however, nut intake was not related to cognitive decline [74]. As discussed earlier, the PREDIMED study did not find a significant effect of the Mediterranean diet intervention on rates of MCI when compared to the control group [66]. Overall, there are only a few clinical trials on the effects of nut intake on cognitive function; while nuts may contain essential nutrient compounds, more research is needed to confirm its relationship with cognitive outcomes [75].

Fruits and vegetables A higher intake of fruits and vegetables has been associated with higher blood nutrient levels, lower oxidative stress, and better cognitive function [76]. Increasing fruit and vegetable intake over a period of 3 months was shown to improve nutrient levels in healthy individuals [77]. Consumption of fruits and vegetables or a diet that is supplemented with antioxidants, serum carotenoids, vitamins, fiber, and magnesium has been shown to reduce C-reactive protein [78], a marker of inflammation closely linked to cognition [79]. Furthermore, flavonoids and polyphenols found in fruit and vegetables provide both cardioprotective and neuroprotective properties [67,68]. Research by Devore and colleagues [80] demonstrates that higher intake of food high in flavonoids, such as berries, reduced the rate of cognitive decline in older adults. In a prospective cohort of 921 participants, part of the he Rush Memory and Aging Project (MAP), higher intakes of dietary flavonols were associated with reduced risk of developing dementia after 6 years follow-up [81]. Fruits and vegetables are also high in carotenoids. A recent review of two carotenoids lutein and astaxanthin found that three of the five studies reviewed reported that lutein intake significantly benefited cognitive performance on serval domains [82]. As the Mediterranean diet is rich in these fruits and vegetables, these polyphenols are a possible component of the Mediterranean diet that contributes toward cognitive benefits. Each of these dietary components has been reported to contribute positively to cognition and general health. However, one must consider that dietary patterns such as the Mediterranean are very complex, and the interactions between these food groups, or synergy, may provide benefits to cognition that are not demonstrated to adhere to one component alone. Thus, equal weighting of each food component when scoring adherence to a Mediterranean diet provides an inadequate picture of how the complex nature of diet provides benefits to brain health.

Practical translation into Western countries The dietary pattern typically consumed in Western countries, commonly termed as a “Western diet,” varies greatly from a Mediterranean pattern. Western diets are characterized by a greater amount of processed, discretionary foods which are low in micronutrients. It is therefore unsurprising that adherence to a Mediterranean diet in Western countries such as Australia, the USA, and UK is much lower than traditional Mediterranean countries. To address this, researchers in non-Mediterranean countries have developed several modified interventions which are a hybrid of the Australian Dietary Guidelines and Dietary Guidelines for Adults in Greece [83,84]. In the Framingham cohort, measurement of a Mediterranean-Style Dietary Pattern Score considered not only overconsumption of foods within the Mediterranean diet but consumption of foods not identified as part of the Mediterranean diet [85]. This is an important issue, as traditional scoring methods of Mediterranean diet fail to address other components of diet that may detrimentally impact cognition and therefore “washout” any beneficial aspects from adhering to a Mediterranean diet. That is, an individual may consume high amounts of Mediterranean diet constituents, but also consume large amounts of processed foods, which could have deleterious effects for cognition. In a novel analysis by Shakersain [86], adherence to both a healthy “prudent” diet (high in fruits, vegetables legumes, and fish) in parallel to adherence to an unhealthy “Western diet” (high in sweated beverages, refined grains, processed foods, and sweets) was assessed in 2223 dementia-free participants aged 60 years and older. They then measured cognitive performance 6 years later, reporting the cognitive decline associated with a Western diet was attenuated when individuals also had high adherence to a prudent diet. Thus, detrimental aspects of an unhealthy diet on cognitive health may be reversed when a healthy diet is also adhered to. Born from this concept is a new dietary pattern developed by Prof Morris of RUSH University, termed the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet [87]. As the name suggests, the Mediterranean diet was a model for the MIND diet. However, this diet model considers intake of deleterious foods such as processed foods and sugars. This is particularly important in translation for Western countries where these eating patterns are more prevalent. Preliminary findings from these researchers observed the top tertile of adherence to the MIND diet was equivalent to being 7.5 years younger in age when compared to the lowest tertile [88]. Understanding the mechanisms underpinning a Mediterranean diet is pivotal in order to provide robust evidence for implementation in public health guidelines. The increasing trend for individuals, particularly in Western

Mediterranean diet and its components: potential to optimize cognition across the lifespan Chapter | 20

countries, to use nutraceutical formulations to compensate or “prop up” for nutritional inadequacies not met through diet further complicates the understanding of the relationship between cognitive function and Mediterranean diet. There is a growing consensus that use of dietary supplements may benefit aspects of health, especially in individuals with a suboptimal nutritional status (including psychological and cognitive health). It is therefore important that not only additional supplements are controlled for in future trials, but the baseline nutrient status of participants entering the trial is determined. While dietary supplements are appealing due to their low-effort, the benefits reaped from dietary interventions may be more favorable than supplements due to the synergistic benefits of overall improved diet quality. Further, detailed cost-analysis of a Mediterranean diet intervention for individuals with depression in Australia found that adoption of a modified Mediterranean diet was more financially affordable than a poor-quality diet [89]. Therefore, the applicability of a Mediterranean diet for Western countries is not only feasible, but an important intervention that should be implemented to slow the detrimental impacts of cognitive decline in the aging population.

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[51] Pal K, Mukadam N, Petersen I, Cooper C. Mild cognitive impairment and progression to dementia in people with diabetes, prediabetes and metabolic syndrome: a systematic review and meta-analysis. Soc Psychiatry Psychiatr Epidemiol 2018;53(11):1149e60. https:// doi.org/10.1007/s00127-018-1581-3. [52] Yaffe K, Kanaya A, Lindquist K, et al. The metabolic syndrome , inflammation , and risk of cognitive decline. Am Med Assoc 2004;292(18):2237e42. https://doi.org/10.1001/jama.292.18.2237. [53] International Diabetes Federation. The IDF consensus worldwide definition of the metabolic syndrome. 2006. [54] Studies AM, Panagiotakos DB. The effect of mediterranean diet on metabolic syndrome and its components. J Antimicrob Chemother 2011;57(11):1299e313. https://doi.org/10.1016/j.jacc.2010.09.073. [55] Messier C. Impact of impaired glucose tolerance and type 2 diabetes on cognitive aging. Neurobiol Aging 2005;26:26e30. https:// doi.org/10.1016/j.neurobiolaging.2005.09.014. [56] Lamport DJ, Lawton CL, Mansfield MW, Dye L. Impairments in glucose tolerance can have a negative impact on cognitive function: a systematic research review. Neurosci Biobehav Rev 2009;33(3):394e413. https://doi.org/10.1016/j.neubiorev. 2008.10.008. [57] de la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetesd evidence reviewed. J Diabetes Sci Technol 2008;22(6):1101e13. https://doi.org/10.1177/193229680800200619. [58] Kandimalla R, Thirumala V, Reddy PH. Is Alzheimer’s disease a Type 3 diabetes? A critical appraisal. Biochim Biophys Acta Mol Basis Dis 2017;1863(5):1078e89. https://doi.org/10.1016/ j.bbadis.2016.08.018. [59] Kroner Z. The relationship between Alzheimer’ s disease and diabetes: type 3 diabetes? Altern Med 2009;14(4):373e9. [60] Kaplan RJ, Greenwood CE, Winocur G, Wolever TMS. Cognitive performance is associated with glucose regulation in healthy elderly persons and can be enhanced with glucose and dietary carbohydrates. Am J Clin Nutr 2000;72(3):825e36. http://www.ajcn.org/ content/72/3/825.abstract. [61] Esposito K, Maiorino MI, Ceriello A, Giugliano D. Prevention and control of type 2 diabetes by Mediterranean diet: a systematic review. Diabetes Res Clin Pract 2010;89(2):97e102. https://doi.org/ 10.1016/j.diabres.2010.04.019. [62] Kennedy G, Hardman RJ, MacPherson H, Scholey AB, Pipingas A. How does exercise reduce the rate of age-associated cognitive decline? A review of potential mechanisms. J Alzheimer’s Dis. 2016;55(1):1e18. https://doi.org/10.3233/JAD-160665. [63] Binder D, Scharfman HE. Brain-derived neurotrophic factor. Growth Factors 2004;22(3):123e31. https://doi.org/10.1016/ S0008-6363(95)90141-8. [64] Sánchez-Villegas A, Galbete C, Martinez-González MÁ, et al. The effect of the Mediterranean diet on plasma brain-derived neurotrophic factor (BDNF) levels: the PREDIMED-NAVARRA randomized trial. Nutr Neurosci 2011;14(5):195e201. https://doi.org/ 10.1179/1476830511Y.0000000011. [65] Buckland G, Maye AL, Redondo M, et al. Olive oil intake and mortality within the Spanish population. Am J CLin Nutr 2012;96. https://doi.org/10.3945/ajcn.111.024216.1. Cvd.

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Chapter 21

Centella asiatica (Gotu kola) leaves: potential in neuropsychiatric conditions Prasad Arvind Thakurdesai Indus Biotech Private Limited, Pune, Maharashtra, India

Chapter outline Introduction Psychological disorders Efficacy against mood and depressive disorders Efficacy against anxiety disorders Efficacy against Stress-related disorders Cognitive disorders Efficacy against Alzheimer’s disease Mechanism through b-amyloid Mechanism through neuronal outgrowth promoting action Mechanism through neuronal regeneration

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Introduction Centella asiatica (L.) Urban (family: Apiaceae), popularly known as Gotu kola, is a plant indigenous to Southeast Asia, India, Sri Lanka, parts of China, the Western South Sea Islands, Madagascar, South Africa, Southeast USA, Mexico, Venezuela, Columbia, and Eastern South America [1]. C. asiatica whole plant, mainly leaves (hereafter referred as CA), has been used traditionally as a brain tonic in traditional ethnobotanical medicine [2]. In Indian traditional system of medicine, Ayurveda, CA is mentioned as “Medhya Rasayana” and documented as nerves and brain cells revitalizer [3]. The plant is classified as Class 1 herb (one that can safely be consumed when used appropriately) in the American Herbal Products Association’s Botanical Safety Handbook [4]. CA has been reported to have variety of medicinal properties such as wound healing, antiinflammatory, antipsoriatic antiulcer, hepatoprotective immunostimulant, cardioprotective, antidiabetic, cytotoxic and antitumor, antiviral, antibacterial, insecticidal, antifungal, antioxidant, and for

Nutraceuticals in Brain Health and Beyond. https://doi.org/10.1016/B978-0-12-820593-8.00021-5 Copyright © 2021 Elsevier Inc. All rights reserved.

Mechanism through dendritic arborization Efficacy in animal models of learning and memory Neurological disorders Efficacy against epilepsy Efficacy against neuropathy and spinal cord injury Neurodegenerative and neuroinflammatory disorders Efficacy against drug or chemical neurotoxicity Efficacy against cerebral ischemia Recent advance: nasal delivery of CA extract References

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leprosy and venous deficiency treatments [1,5e16]. This activity profile of CA is extensively reviewed in dedicated monographs published by World Health Organization (WHO) [17] and Committee on Herbal Medicinal Products (HMPC) [18]. Furthermore, comprehensive monographs describing the wide variety of medicinal properties of CA and its phytoconstituents namely European Pharmacopeia Commission E of the German Ministry of Health [3], Alternative Medicine Review [19], and Natural Medicines comprehensive database [20] have been published. Furthermore, pharmacological activity profile of CA as whole plant, leaves, or extract is extensively reviewed in past literature [1,5,6,8,10,13,14,16,21e24]. Review of medicinal properties of separate phytoconstituents of CA (e.g., pentacyclic triterpenoids, ascitic acid) has also been published [12,23,25,26]. CA contains large quantities of pentacyclic triterpenoids and glycosides collectively known as centelloids. These terpenoids are secondary metabolites of CA and include mainly glycosides (asiaticoside, madecassoside, centelloside, brahmoside, brahminoside, thankuniside, sceffoleoside) and their aglycone acids

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308 Nutraceuticals in Brain Health and Beyond

(asiatic-, madecassic-, brahmic-, centellic-) (Fig. 21.1) [22]. These secondary metabolites are suggested to be responsible for a wide range of pharmacological activities of CA [23]. Although, CA is traditionally used for beneficial effects on nervous system such as nervine tonic, rejuvenator, anxiolytic, mental stress reliever, and for producing calmness and enhancing memory and intelligence [24], medicinal potential of CA against neuropsychiatric disorders has not been reviewed in the past except neuroprotective effects [2]. In addition, the extensive medicinal properties and mechanisms of CA against a specific range of neurological and psychological disorders have not been reviewed. The present chapter is the focused review of the published reports of efficacy, safety, probable mechanism of actions of medicinal properties of CA and derived phytoconstituents against a wide range of neuropsychological disorders such as mood, anxiety, epilepsy, stress-related disorders, migraine, cerebral ischemia, neuropathy, and others.

FIGURE 21.1

Psychological disorders Efficacy against mood and depressive disorders The antidepressant activity of ethanolic extract of CA was reported at doses of 100 and 200 mg/kg against forced swimming test (FST) in rodents [27]. The ethanolic and aqueous extract of CA (100 mg/kg, oral, single dose) was reported to have significant, dose-dependent effects of reducing the number of marbles buried without affecting the motor activity in marble-burying model in mice [28]. Marble-burying model is a specific animal model that uses obsessive compulsive disorder (OCD) behavior [29]. Furthermore, OCD is characterized by recurring obsessions and compulsions that significantly interrupt the daily functioning of the patient with comorbidity and major depression considered as an anxiety disorder [30]. Depression frequently accompanies OCD and appears to affect treatment outcome negatively [30]. The antidepressant activity of total triterpenes from CA leaves in FST has been reported [31]. Total triterpenes from

Centella asiatica (L.) Urban leaves and some of its major phytoconstituents.

Centella asiatica (Gotu kola) leaves: potential in neuropsychiatric conditions Chapter | 21

CA leaves reduced the immobility time and ameliorated the imbalance of amino acid levels similar to positive control, imipramine [31]. Additional experiments demonstrated a significant reduction of the corticosterone level in serum and increase of levels of 5-hydroxytryptamine (5-HT), norepinephrine (NE), dopamine (DA) and their metabolites, namely 5-hydroxyindoleacetic acid (5-HIAA), 3-methoxy4-hydroxyphenylglycol (MHPG) in rat brain and amelioration of the function of the hypothalamic-pituitary-adrenal axis as a possible mechanism behind the antidepressant activity of total triterpenes from CA leaves [32]. The potential antidepressant properties of asiaticoside, a major triterpenoid of CA leaves, demonstrated antidepressant-like effects in male mice. On oral administration, asiaticoside (10 and 20 mg/kg) showed significant antidepressant-like effects in terms of augmenting the frequency of grooming behavior splash test in the unpredictable chronic mild stress (CMS) model, and decreased immobility time (tail suspension test, and FST). Antidepressant-like activity of another triterpene constituent from CA leaves, madecassoside, is reported [33]. Acute (3 days) and subacute (21 days) intragastric administration of madecassoside showed reversal of depression-like behavior of mice during FST and reserpine antagonist test at intragastric administration (10, 20, and 40 mg/kg) [33]. Furthermore, the activities of monoamine oxidase-A (MAO-A) and monoamine oxidase-B (MAO-B) in different rat brain regions were also determined. The result indicated that the antidepressant effects of madecassoside through MAO inhibition in the rat brain were stronger with acute administration than chronic administration [33]. The potential of CA leaves extract on the age-related decline in cognitive function and mood disorder in the healthy elderly was shown during the pilot, 8-week, double-blind, placebo-controlled, randomized study [34]. A capsule containing a specialized aerial part of CA extract (containing asiaticoside and asiatic acid) at daily doses of 250, 500, and 750 mg for 2 months was administrated to 20 healthy elderly subjects [34]. Cognitive performance was assessed using the computerized test battery and event-related potential [3,35]. The mood-related parameter was BondeLader visual analog scale [36] that was assessed before the trial and after single, 1, and 2 months after treatment. CA extract showed significant efficacy on cognitive function (shown by the significant increase in event-related potential elicited by oddball at Fz electrode) and mood (increased calmness and alertness) [34]. Asiatic acid, a triterpenoid of CA leaves, at 30 mg/kg dose, on acute, intraperitoneal administration, is reported to be an antidepressant in FST [37]. Asiaticoside, a major triterpene of CA leaves, demonstrated antidepressant-like effects in chronic unpredictable mild stress (CUMS) in C57BL/6 mice [38]. Asiaticoside, on 4 weeks of treatment

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(10, 20, and 40 mg/kg, oral), showed dose-dependent reversal that decreased sucrose preference and increased immobility time shown by CUMS mice. Additional experiments suggested the role of hippocampal braine derived neurotrophic factor (BDNF) signaling activation as a possible mechanism of antidepressant-like action of asiaticoside [38]. BDNF plays a vital role in the neuronal regulation not only in depression but also in suicidal behavior [39]. On the background of evidence of side effects of suicidal tendencies in vulnerable patients by selective serotonin reuptake inhibitors types of antidepressant, the DBNF-derived mechanism of antidepressant action of asiaticoside seems promising. However, the major milestone was reached when the antidepressant activity of the specialized total terpenoidsbased standardized extract of CA leaves (INDCA) was reported in the olfactory bulbectomy (OBX) model in rats [40]. Subacute (14-day) oral pretreatment of INDCA (3, 10, or 30 mg/kg) showed dose-dependent reversal of OBX-induced parameters such as gain in body weight and food intake increase. Similarly, OBX-induced hyperactivity in the open field and elevated plus-maze paradigm was significantly reversed by subacute oral treatment of INDCA [40]. These findings are significant because OBXinduced rat model is a well-validated animal model for depressive disorders [41], which mimics the slow onset of antidepressant action reported in clinical studies [41], and has proven specificity in the mechanism of antidepressant activity [42], especially after chronic administration [43]. In addition, INDCA demonstrated efficacy against depression [40] as well as social isolation, stress-induced depression, and suicidal behaviorerelated traits in laboratory rats [44]. Subacute (14-days) treatment of INDCA (3, 10, and 30 mg/kg, oral) showed a reversal in suicidal behaviorerelated traits (aggression, irritability, active avoidance in learned helplessness) and raised levels of serum cortisol (a stress hormone) [44]. The systematic review of five randomized controlled trials (RCTs) on CA alone and six RCTs of CA containing products were reported [45]. The results suggested positive effects in improving mood by increasing alertness and decreasing anger scores at 1 h after treatment [45]. None of the studies reported adverse effects of CA. However, the result of a systematic review is limited by variation in dose regimen and preparations, thus highlighting the need of standardized extract for the scientific studies for reliable and conclusive evidence [45].

Efficacy against anxiety disorders Anxiety disorders, such as generalized anxiety, panic disorders, phobias, or post-traumatic stress disorder, are common and a significant cause of disability. Anxiety is also a crucial component of many other psychiatric or

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medical conditions [46]. CA has been used in traditional medicines for centuries to treat a range of psychological conditions such as anxiety, and used to provide relaxation to assist meditation [47]. CA has also been documented in Ayurvedic preparations for the treatment of mental fatigue and anxiety [48]. The review of plant-based anxiolytic medicines that provide clinical and/or preclinical evidence [47] listed CA leaves extract as proven anxiolytic on acute as well as chronic administration [49e51]. The preliminary evidence of anxiolytic effects of acute treatment of CA leaves is reported in the year 2000 in a randomized placebo-controlled clinical study [49]. The 20 subjects on CA leaves (12 g, single dose) treatment demonstrated significant reduction in the peak the acoustic startle response amplitude, 30 and 60 min after treatment as compared to 20 subjects on placebo treatment without affecting self-rated mood, heart rate, or blood pressure [49]. The other clinical evidence for anxiolytic action was reported in an open-label clinical study for 70% hydroethanolic extract of CA leaves (500 mg/capsule, twice daily, after meal) on 33 subjects of a generalized anxiety disorder (GAD) [51]. CA leaves extract demonstrated anxiolytic potential in the stress, depression and parameters for willingness for adjustment and cognition [51]. The anxiolytic effects of acute treatment of methanol extract (3047 mg/kg) and ethyl acetate extracts (111 mg/kg) of CA leaves, as well as the asiaticoside (1, 3, or 5 mg/kg, in peanut oil), were reported [52]. Ethyl acetate extract and the methanol extracts were administered orally in 50% condensed milk, and the asiaticoside was administrated in peanut oil. The effect was demonstrated across a variety of anxiety paradigms, including the elevated plus-maze test, open field test, social interaction test, locomotor activity, Vogel test, and novel environment test. Furthermore, the asiaticoside did not affect locomotor activity, suggesting nonsedative nature. Extracts from CA leaves were among few extracts that showed positive GAD stimulatory activity by over 40% at a dose of 1 mg/mL during in vitro rat brain homogenate assays [53]. A large body of published research has demonstrated the role of altered glutamate transmission in anxiolytic action for many different paradigms in preclinical animal and clinical drug trials [54]. The phytoconstituents from CA leaves extract are suggested to interact with glutamic acid decarboxylase to influence brain gamma-aminobutyric acid levels and neurotransmission [53] to demonstrate anxiolytic activity in various animal models [52] and clinical studies [49,51]. The reported dose-dependent increase in g-aminobutyric acid (GABA) levels in rat brain by CA leaves extract during in vivo study [55] is also in line with the postulated role of GABA in anxiolytic action of CA leaves. The anxiolytic efficacy of standardized ethanolic extract of CA leaves (77% triterpenoid fractions of which 43.74%

were madecassoside, and 33.26% was asiaticoside) was reported against 72 h of sleep deprivationeinduced anxiety in male mice [56]. Sleep deprivation is being considered a classic sign and marker for anxiety [57]. On the other, anxiety disorders are known to cause sleep disturbances and disrupted sleep architecture [58,59]. Eight days of treatment at 150 and 300 mg/kg showed protective effects against 72-h sleep deprivationeinduced anxiety-like behavior, oxidative damage, and neuroinflammation with possible involvement of nitric oxide (NO) modulation [56]. Both in vitro and in vivo research have found asiaticoside to be the main anxiolytic constituent [32,52]. Research in rats has linked triterpenes in CA to increased brain levels of 5-HT, NE, and DA together with reduced serum corticosterone levels [32] and cholinergic mechanisms [60]. Triterpenoid glycosidesebased standardized extract of CA leaves is reported to have anxiolytic activity on stress-induced anxiety in chronic immobilization model during ex vivo electrophysiological properties between intercalated cells [61]. The anxiolytic effect was shown to be mediated by increasing activation of excitatory synaptic input to the GABAergic intercalated cells of the amygdala leading to depression of the central nucleus of the amygdala neurons [62]. The asiaticoside (10 mg/kg, oral, single dose) demonstrated the anxiolytic activity in male mice by using experimental paradigms of anxiety namely elevated plusmaze test, light/dark test, and hole-board test without altering the total locomotor activity [50]. Another triterpenoid from CA leaves, asiatic acid, is also reported as anxiolytic by potential modulation of the GABA-A receptor [37]. Acute intraperitoneal pretreatment of asiatic acid (30 mg/kg) alone and in combination with known GABA-A agonist, Flumazenil (3 mg/kg), or a benzodiazepine, Midazolam (1.5 mg/kg), showed significant anxiolytic activity in the elevated plus-maze model in rats [37].

Efficacy against Stress-related disorders Stress and anxiety are often used interchangeably. However, there is an overlap between stress and anxiety. Stress is related to the same “fight, flight, or freeze” response as anxiety, and the physical sensations of anxiety and stress may be very similar. Therefore, it is not surprising that CA has the antistress and anxiolytic potential to relieve different types of stress and anxiety conditions respectively. BDNF is an important mediator of neuroplasticity (neurogenesis and neural remodeling). It is a known protector of the nervous system from the harmful effects of chronic stress [63]. Ethanolic extract of CA leaves is reported to prevent the decrease of hippocampal BDNF concentration in hippocampus upon chronic stress [64]. The subacute administration (28 days) of ethanol extracts of CA leaves (150, 300, and 600 mg/kg, oral) increases

Centella asiatica (Gotu kola) leaves: potential in neuropsychiatric conditions Chapter | 21

memory performance and serum BDNF concentration. It decreases NO levels in rats after chronic electrical stress [64]. The role of restoration of hippocampal BDNF in the antidepressive-like action of chronic asiaticoside treatment against stress-induced depressionlike symptoms in mice has been demonstrated [38]. Furthermore, BDNF is suggested to be a strong link in the relationships between altered cytokine expression [65], as well as stress-induced inflammation with impairment of memory [66,67]. The recent study on subacute administration of ethanolic extract of CA (600 mg/kg, oral) on chronic electrical stress showed lowest levels of proinflammatory cytokines and tumor necrosis factor-a (TNF-a) and highest DBNF levels in the hippocampus [68]. These reports confirmed the anti-stress effects of CA extract through modulating hippocampal proinflammatory cytokines and BDNF [68]. CUMS has been shown to induce depression-like behaviors in rodents, which exhibit similarities to the human form of depression [69]. Decreased expression of BDNF, with altered synaptic morphology and reduced neurogenesis in the hippocampus of rats that were exposed to CUMS, has been reported [70,71]. Asiaticoside was reported to have anxiolytic effects in acutely stressed animals [50,52] and immobilized stress-induced anxiety models [61,62]. Anxiolytic effects of triterpenoid glycosidesebased standardized extract of CA after chronic immobilization stress in mice have been reported [61]. The triterpenoid glycosidesebased standardized extract of CA (30, 100, and 300 mg/kg, oral) and separate phytoconstituent, madecassoside or asiaticoside (10, 20 or 100 mg/kg, oral) showed significant antistress effects in elevated plus-maze test and open arm tests against chronic immobilization stressed mice [61]. However, the extract but not separate phytoconstituents (madecassoside or asiaticoside) could reverse the changes in serum corticosterone levels in stressed mice [61]. Recently, unstandardized CA extract (400 and 800 mg/kg) was shown to reverse the anxiety (open field test and elevated plus-maze test) and depression-like behaviors (FST), amnesic behaviors (maze spontaneous alternation test), and reduced serum cortisol levels in CUMS-induced rats [72]. Ethanolic extract of CA (300 and 600 mg/kg, 4 weeks) is reported to enhance memory function after chronic electrical stress [73]. Triterpenoid-based standardized extract of CA (150 and 300 mg/kg) treatment for 8 days starting 5 days before 72 h of sleep deprivation in mice is reported enhanced locomotor activity, antianxiety-like effect, reversed mitochondrial enzyme complex activities, attenuated corticosterone level as well as improved neuroinflammatory and apoptotic responses, a pyknotic cell density [74]. These mechanisms are thought to be mediated through NO modulation and subsequent cascading effect on mitochondrial insufficiencies, as well as antistress, antiinflammatory, and inactivation of neuro-apoptosis pathways

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[74]. INDCA is reported to ameliorate CMS-induced cognitive impairment in rats [75]. Oral administration of INDCA (3, 10, 30 mg/kg) during the last 2 weeks of CMS showed significant protection from cognitive impairment in object recognition test, object location test, and open field test (OFT). Furthermore, INDCA showed a significant reversal of CMS-induced anhedonia during the sucrose preference test. Potential benefits of CA on diabetes-induced stress in the kidney and brain of rats are also reported [76]. Subacute administration of methanolic extract of CA (500 and 1000 mg/kg, oral) reduced the oxidative stress and proinflammatory markers such as TNF-a and interferon-g (IFN-g), increased antiinflammatory markers interleukin
10 (IL-10) in kidney and brain of streptozotocin-induced diabetic rats [76].

Cognitive disorders Efficacy against Alzheimer’s disease Alzheimer’s disease (AD), a major disorder of the aging population, is becoming a major healthcare problem [77]. The value of the natural products in the treatment of neurodegenerative diseases, including AD, has been reviewed by many researchers in the past [78,79]. Many phytoconstituents namely flavonoids, alkaloids, and triterpenes from diverse natural plant sources have been reported for their possible efficacy against many aspects of cognitive deficits, especially AD [80e82]. An aqueous extract of CA is reported to be effective in preventing the cognitive deficits, as well as the oxidative stress in the intracerebroventricular streptozotocin-model of AD in rats [83]. Twenty-one days of oral treatment at 100, 200, and 300 mg/kg showed a dose-dependent increase in cognitive behavior in both passive avoidance and elevated plus-maze paradigms. A higher dose (300 mg/kg) was reported to reverse the oxidative stress markers in the brain homogenate [83].

Mechanism through b-amyloid Accumulation of extracellular b-amyloid plaques, intracellular hyperphosphorylated tau tangles, generation of reactive oxygen species (ROS) due to mitochondrial dysfunction, genetic mutations, subsequent aberrant signaling, and neuronal cell death reported to cause cognitive defects and behavioral and psychological problems in patients of AD [80]. An important role for b-amyloid in the cascade of events results in the neurodegenerative changes responsible for the memory loss and behavioral changes associated with AD [84,85]. Furthermore, inflammatory responses and autophagy have been implicated in the amyloid-b (Ab) aggregation in AD due to recycling cellular

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waste and eliminating toxic protein aggregates [86]. The CA extract has been reported to impact the amyloid cascade altering many aspects of Ab pathology in the brains and suggested as a possible management option for AD [87e89]. The water extract of CA demonstrated enhanced phosphorylation of cAMP response element-binding protein (CREB) in neuroblastoma and cortical cell cultures [90]. The mechanism of action behind ameliorating the cognitive impairment in rat models of AD by CA extract was suggested from in vitro study in a neuroblastoma cell line expressing amyloid beta Ab(1e42) and in rat embryonic cortical primary cell culture [90]. This significant increase in CREB phosphorylation is in line with other reports on CA extract with increased neuronal dendritic arborization and axonal regeneration in rats [91,92]. CA extract is reported to reduce the amyloid cascade in the brains of PSAPP mice (a type of double transgenic mice) [87]. CA extract (2.5 or 5.0 g/kg/day) on prolonged treatment, starting at 2 months of age before the onset of detectable amyloid deposition and continued up to 8 months, was found to cause significant decrease in Ab (1e40) and Ab (1e42) in enzyme-linked immunosorbent assay (ELISA), reduction in Congo Red stained fibrillar amyloid plaques (microscopy), showed antioxidant activity in vitro, scavenging free radicals, reducing lipid peroxidation, and protecting against DNA damage in brain homogenate [87]. Furthermore, CA extract (25, 50, and 100 mg/mL) was shown to protect PC12 and IMR32 cells against Ab [1e40]-aggregation induced neurotoxicity through to modulation of the antioxidative defense system [93]. The water extract of CA (devoid of the asiatic acid component) was reported in vivo to improve behavioral deficits in a Tg2576 mouse, a murine model of AD with high Ab accumulation [94]. Two weeks of treatment with water extract of CA in the drinking water reported normalizing the Morris water maze and open field behavioral deficits typically observed in aged Tg2576 animals [94]. Notably, the water extract of CA treatment did not alter Ab levels in the brain, suggesting that CA may act downstream Ab formation to mitigate the toxic consequences. Furthermore, protection of SH-SY5Y cells and MC65 human neuroblastoma cells in vitro from toxicity induced by exogenously added and endogenously generated Ab, respectively, are also reported [94]. In the next series of experiments, mono- and dicaffeoylquinic acids (CQAs) in water extract of CA were identified and shown effective in vitro against SH-SY5Y cells and MC65 human neuroblastoma cells against Ab-induced cytotoxicity [89]. These compounds not only showed mitigation of Ab-induced cell death but were able to attenuate Ab-induced alterations in tau expression and phosphorylation in both cell lines similar to water extract of CA [89].

The water extract of CA is also reported to attenuate the mitochondrial dysfunction and oxidative stress in isolated Ab expressing hippocampal neurons [95] and Ab-induced neurodegenerative spine loss and dendritic simplification [96] in Tg2576 mice and wild-type littermates. These reports suggest water extract of CA and several of the compounds found therein can correct many underlying causes of Ab exposure to improve cognitive functions observed in vivo [87,94] and indicate a broader therapeutic utility of the extract beyond AD. The methods, such as fluorescence correlation spectroscopy (FCS), were used to elucidate the mechanism of asiaticoside-induced inhibition of Ab(1e42) fibrillation [97]. The FCS is a proven method that can detect molecular motion at the nanomolar levels [98] and recently attracted interest for investigating the molecular interactions of proteins [99] including Ab(1e42) of fibrillation interactions with molecules [100]. The asiaticoside showed inhibition of the early stages Ab(1e42) of fibrillation, leaving more free Abs in the solution and permitting their rapid diffusion in the confocal volume (FCS study), reduced fiber formation (steady-state) during kinetic ThT fluorospectroscopy, laser-scanning microscopy, and transmission electron microscopy study [97]. Furthermore, in silico molecular docking study showed binding of asiaticoside with Ab intra- and intermolecular amino acid residues, which are responsible for b-sheet formation and longitudinal extension of fibrils [97]. Madecassoside, another major triterpenoid glycoside of CA leaves, is reported to offer neuronal protection through Ab [25e35]-induced inflammatory responses and autophagy in neuronal cells [86]. Aluminum is a ubiquitously distributed environmental toxicant that lacks biological function. However, its accumulation in the brain has been demonstrated to be linked to several neuropathological conditions, particularly AD [101]. A series of reports suggested that asiatic acid could be able to modulate various pathological features of AD and could hold promise in AD treatment. Asiatic acid (10 nM) in vitro is reported to provide neuroprotection against aluminum maltolateeinduced neurotoxicity in human SH-SY 5Y neuroblastoma cells by attenuating DNA damage and apoptosis (Hoechst and dual staining, comet assay; expressions of proapoptotic, antiapoptotic, and signaling indices) via protein kinase B (AKT)/glycogen synthase kinase 3 (GSK-3b) signaling pathway [102]. Furthermore, the neuroprotective potential of oral asiatic acid (100 mg/kg, 42 days) is reported against aluminum chloride (AlCl3)einduced neurotoxicity in rats [103]. Apart from efficacy on learning and memory parameters in the Morris water maze and passive avoidance task, ascitic acid is shown to increase the activity of acetylcholinesterase and attenuated Ab burden and inflammatory markers [103]. A more recent report

Centella asiatica (Gotu kola) leaves: potential in neuropsychiatric conditions Chapter | 21

confirmed the role of Akt/GSK3b pathway activation in downregulation of the expression of cyclin-dependent kinase 5 (CDK 5-enzyme implicated in the phosphorylation of tau proteins), phosphorylated tau (pTau), oxidative stress, and apoptosis as the mechanisms behind the efficacy of ascitic acid against spatial memory deficit, anxiety, and motor dysfunction using AlCl3-induced neurotoxicity model in rats [104].

Mechanism through neuronal outgrowth promoting action Ethanolic extract of CA in drinking water (300e330 mg/kg, daily) reported rapid functional recovery and increased axonal regeneration (larger caliber axons and higher numbers of myelinated axons) suggesting the potential of CA extract for accelerating repair of damaged neurons [92]. A triterpenoid-rich standardized extract of CA has demonstrated neurite outgrowth promoting activity in human IMR-32 neuroblastoma cell line [105]. Furthermore, CA leaves extract and its 45 isolated fractions were evaluated for robust induction in neurite outgrowth and neurofilament expression in cultured pheochromocytoma PC12 cells [106]. The fraction rich in asiatic acid and madecassic acid showed maximum efficacy towards nerve differentiation in vitro, probably through activation of mitogen-activated protein kinase (MEK) signaling pathway [106]. Furthermore, asiatic acid and madecassic acid alone and six combinations (from asiatic acid, madecassic, madecassoside, quercetin, and isoquercetin) on 72 h of exposure to cultured pheochromocytoma PC12 cells showed profound synergistic activation to neurofilaments (NF66, NF68 upregulation) in vitro [107]. Cultured pheochromocytoma PC12 cell line is a widely employed model for studying neuronal differentiation in responding to various treatments [106]. Activation of the MAPKs is known to be an essential step in neurite outgrowth [108,109]. Furthermore, neurofilament 68 (NF68) is the most representative protein as a structural component of the differentiated neurons [110]. NGF is one of the key modulators for the development of neurites. Comparison of individual triterpenoids from CA leaves, namely madecassoside, asiaticoside, madecassic acid, and asiatic acid was made for their neurite outgrowth activities and mechanisms using immunofluorescent cell staining in neuro-2a cells [111]. Neurite outgrowth activity of the glycosides (madecassoside and asiaticoside) was found to involve the activation of sustained ERK phosphorylation leading to CREB activation. At the same time, their aglycones (madecassic acid and asiatic acid) activated only transient signaling of ERK1/2. The role of Akt activation was a suggested probable mechanism of neurite outgrowth activity of CA leaves’ triterpenoid constituents [111]. Recently, the raw extract of CA alone and in combination

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with neurotrophic factors is reported to induce the proliferation of human mesenchymal stem cells (hMSCs) differentiation into Schwann cells and other neural lineage cells [112]. These reports of neurite outgrowth promoting activity of CA or its phytoconstituents is suggested to be mediated through MAPKs [106] and NF68 [107], and/or ERK phosphorylation leading to CREB activation [111] and supported the potential of CA phytoconstituents as an alternative to neural growth factors in the management of neuropsychiatric diseases.

Mechanism through neuronal regeneration For degenerative diseases, such as AD, the restoration of lost neural tissue could be a successful treatment option [113]. Axonal regeneration is vital for functional recovery following nerve damage typically found in neurodegenerative diseases. The regeneration of axonal neurons is one of the recent strategies for the discovery of new options in management of AD [113]. The ethanolic extract CA (100 mg/mL) and asiatic acid (1 mM, 0.5 mg/mL) showed neurite elongation and acceleration of the axonal regeneration and promoted repair of damaged neurons of human SH-SY5Y cells in vitro in the presence of nerve growth factor (NGF) [92]. However, the water extract of CA was found ineffective at the same concentration (100 mg/mL). The difference in CA extract obtained from ethanol extraction showed different efficacy profiles than water extract [88] which is attributed to the presence of asiaticoside in ethanolic extract of CA leaves [92]. Asiatic acid was found orally bioavailable when given as part of a triterpene fraction during clinical studies [114]. These results are supported by a recent study where an ethanolic extract of CA rich in triterpene glycosides, madecassoside, and asiaticoside has been reported reducing the acetylcholinesterase (AChE) enzyme activity and suppressing proinflammatory cytokine/mediators and oxidative stress markers both in vitro (SH-SY5Y and RAW 264.7 cells) and in vivo (PS-induced neuroinflammation in rats) [115].

Mechanism through dendritic arborization Converging evidence indicates that processes occurring in and around neuronal dendrites are central to the pathogenesis of AD [116]. Dendrites play a vital role in the function of the neuronal circuits because of the ability of neurons integration and processing the incoming information [117,118]. The morphology of dendrites, such as branch density and grouping patterns, are highly correlated to the function of the neuron. Dendritic arborization, also known as neuronal branching, is known to enhance learning and memory [119,120]. CA fresh leaf extract, prepared without going for standard (aqueous or

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ethanolic) extraction, at the dose of 2, 4, and 6 mL per day, for 6 weeks, showed dose- and duration-dependent significant increase in the dendritic branching points (a measure of dendritic arborization) and intersections (a measure of dendritic length) of amygdaloid [88] and hippocampal neurons [91,121] and form a basis for learning and memory enhancement efficacy of CA leaves extract.

Efficacy in animal models of learning and memory CA is well known in traditional Chinese and Ayurvedic medicine for the improvement of cognitive function [122]. Therefore, many researchers have focused on the evaluation of the efficacy of neuroprotective effects of CA leavese related compounds. These reports were well-documented with a variety of in vitro and in vivo models of cognitive disorders and were reviewed in the past [2,3,122,123]. Table 21.1 is presenting the existing body of research reports of efficacy of CA and its phytoconstituents against cognitive disorders with possible mechanisms for such activities.

Neurological disorders Efficacy against epilepsy Epilepsy, a common chronic neurological disorder characterized by recurrent spontaneous seizures, is a major health problem that affects 1e2% of the world population [146]. Epilepsy is associated with the alterations in psychological, emotional, and educational parameters. Cognitive problems with abnormal behavioral manifestation are commonly encountered by a majority of epilepsy patients [147]. Moreover, memory improvement is suggested to help improve the quality of life in epilepsy patients [148]. Many plant preparations, including the preparations of CA leaves per se or as a supplement, are suggested to produce fewer undesirable effects with the same effectiveness as to the standard of care [149]. Furthermore, the potential of CA leaves as an adjunctive medication for epileptic patients has been reported by many authors [148,150,151]. The aqueous extract of CA leaves (300 mg/kg, oral) was reported to cause significant prevention of the cognitive impairment and attenuation of the oxidative stress markers in pentylenetetrazol (PTZ) kindled rats [150]. Furthermore, ethyl acetate fraction of CA (EACA) is reported to give additive effects when combined with intraperitoneally administered antiepileptic drugs in terms of protection of mice in the PTZ test [151]. Besides, a combination of gabapentin and EACA demonstrated a broader margin between the effective dose

and the neurotoxic dose [151], which suggests the usefulness of CA leaves in more effective and safer combination in epilepsy patients. The changes in the cholinergic system by CA extract are suggested to be one of the facets of its anticonvulsant activity [146]. Distribution and neurophysiological role of acetylcholine (ACh) and enzyme acetylcholinesterase (AChE) in many regions of the central nervous system during the manifestation of epilepsy is known [152]. Increased acetylcholine content and decreased acetylcholinesterase activity in different brain regions was reported during GABA antagonist, pentylenetetrazol-induced seizures in male rats [146]. Various extracts of CA leaves (n-hexane, ethyl acetate, and n-butanol) are reported to reduce the cholinergic alterations during PTZ-induced epilepsy [146]. Another facet of antiepileptic activity of CA leaves extract is an increase in ATPases activity in epilepsy [153]. In PTZ treated rats, the activities of three ATPases namely ATP Phosphohydrolase, Naþ, Kþ ATPase, and Ca2þ -ATPase activity were reported to decrease in different regions of the brain (cerebral cortex, cerebellum, pons medulla, and hippocampus whereas pretreatment of CA leaves extract showed a significant increase in these ATPases) [153]. However, the more interesting facet of the antiepileptic potential of CA leaves extract’s efficacy extends to postictal pain and depression [154]. Most patients with epilepsy (72%) reported postictal behavioral impairment [155]. Subacute (21-days) treatment of INDCA at an oral dose (10e100 mg/kg, once a day, 21 days) demonstrated anticonvulsant efficacy (decrease in severity and duration, increase in onset time) against PTZ-induced kindling seizures in rats [154]. Besides, INDCA also showed amelioration of symptoms of postictal pain and depression as shown in the tail-flick test and OFT [154]. The brain levels of GABA, 5-HT, Naþ, Kþ -ATPase showed a significant increase, which is in line with past research on CA leaves extract against pentylenetetrazol-induced seizures [153].

Efficacy against neuropathy and spinal cord injury Pentacyclic triterpenoids from CA are reported to be used in traditional medicine for the treatment of diabetes and diabetic complications [12]. Asiatic acid is reported to preserve pancreatic beta-cell mass and mitigates hyperglycemia in streptozotocin-induced diabetic rats [156]. The wound healing potential of asiaticoside in diabetic rats is also reported [157]. Oral treatment of asiaticoside (0.1 and 1 mg/kg/day) at a period of 5 days before and 3 weeks after sciatic nerve crush injury to streptozotocininduced diabetic rats was shown to reverse the enhanced

TABLE 22.1 Potential of CA against cognitive disorders. Material and method

Results and proposed mechanisms

References

1.

2002

Aqueous, extracts of CA leaves at doses 100, 200, and 300 mg/kg, oral, 14 days to normal rats

- Behavioral (Active or passive avoidance with negative (punishment) reinforcement: shuttle box, step-through, step-down, Elevated plus-maze) - Biochemical markers of oxidative stress - Cognitive enhancing effects (learning and memory) through an antioxidant mechanism

[124]

2.

2003

Aqueous extract of CA, orally with 200 mg/kg for 15 days from day 15 to day 30 postpartum (p.p.) to 3 months old male mice

-

[125]

3.

2005

Hydroalcoholic extract from CA, at 100e150 mg/mL, in vitro on AChE from bovine erythrocytes

- Inhibitory activity shows 50% inhibition of AChE

[123]

4.

2007

Fresh leaf juice of CA at 4, and 6 mL/kg, for 6 weeks to normal rats

- Behavioral (T-maze, spontaneous alternation test, rewarded alternation test, and passive avoidance test) - Enhances learning ability and memory retention power

[126]

5.

2008

CA leaves extract asiatic acid, Madecassic acid, asiaticoside, at 1, 5, 10, 100, and 200 mg/mL for 24 h in vitro to mutant N2a neuroblastoma cells

- CREB phosphorylation - Enhanced arborization of neurons and improved cognitive performances - Enhances CREB phosphorylationdED50d 28 mg/mL (extract), 3.75m mg/mL (asiatic acid), 5.7 mg/mL (mecadessic acid)

[90]

6.

2009

Standardized aqueous extract of CA, at 150 and 300 mg/kg, p.o., for 25 days Colchicine-induced memory impairment and oxidative damage in rats

- Behavioral-elevated plus-maze, spatial navigation task - Biochemical tests in brain homogenate (MDA, glutathione nitrite, SOD, catalase, glutathione-S-transferase) - AChE activity - Attenuated memory impairment, oxidative damage, and reversal of increased AChE activity

[127]

7.

2008

Capsules of CA extract at 250, 500, and 750 mg once daily for 2 months, to 28 healthy elderly volunteers, during randomized, placebo-controlled, double-blind study

- The percentage accuracy, word recognition, the reaction time of numeric working memory and spatial memory - 100 component amplitude of the event-related potential - Attenuate the age-related decline in cognitive function and mood disorder

[34]

8.

2005

Ethanolic and aqueous extract of CA leaves (300e330 g/kg in drinking water) to rats with sciatic nerves exposed bilaterally, and crushed twice (for a total of 30 s)

- Behavioral function and morphological measures - More rapid functional recovery and increased axonal regeneration - Larger axons and higher numbers of myelinated axons indicating faster axonal growth

[92]

9.

2011

Standardized aqueous extract of CA at 150 and 300 mg/kg, p.o., 6 weeks to D-galactose-induced cognitive impairment, oxidative and mitochondrial dysfunction in mice

- BehavioraldMorris water maze and elevated plus-maze - Biochemical and oxidative defense, impaired mitochondrial complex (I, II, and III) enzymes

[128]

10.

2011

Asiatic acid (1, 3, 5, 10, 30 mg/kg, intraperitoneal) to normal rats

- Passive avoidance, active avoidance, retention test and blood pressure - Dose-dependently improved memory

[129]

11.

2012

Asiatic acid in vitro in brain homogenate at concentration 1, 3, 10, 30, and 100 mM in 0.05% of DMSO in saline

- Electrophysiology (excitatory-postsynaptic potential)dinhibition of excitatory-postsynaptic potential - The inhibitory effect on brain acetylcholinesterase (AChE)

[130]

Evaluation on the 31st day and 6 months Behavioral (open field, dark/bright arena, hole-board and radial arm maze tests) Biochemical (acetylcholine esterase activity) Histological (dendritic arborization) Dendritic arborization of hippocampal CA3 neurons increased Effects during the postnatal developmental stage to influence the neuronal morphology and promotion of the higher brain function of juvenile and young adult mice

Continued

315

Year

Centella asiatica (Gotu kola) leaves: potential in neuropsychiatric conditions Chapter | 21

Sr. No

Sr. No

Year

Material and method

Results and proposed mechanisms

References

12.

2012

Asiatic acid (0.1, 1, 10, and 100 nmol/L) to human neuroblastoma SH-SY5Y cells in vitro

- The mitochondrial membrane potential inhibition - Reduced ROS, nuclear morphological alterations, and flow cytometric analysis (flow cytometry) - Upregulation of PGC-1a and Sirt1 levels (Western blotting) - Apoptotic cell death (Hoechst 33,342 staining)

[131]

13.

2012

Asiatic acid at 50 and 100 mg/kg, oral suspension, daily, postnatal day-14 for next 30 days to monosodium glutamate (2.5 mg/g)einduced cognitive decline in neonatal mice

- Alleviated glutamate-induced injury and memory retention (Morris water maze test) - Reduced ROS in brain homogenate - Prevents neuronal damage in hippocampus and pyramidal layer structure in the CA1 and CA3 regions (hematoxylin and eosin staining)

[131]

14.

2013

CA as Ghana Satva capsules (1 capsule two times a day, after meals for 6 months) to 25 human subjects (age of 60 years and above) with mild cognitive impairment, open-label study

- Decrease in mini-mental state examination score - Less blood pressure and sleep problems

[132]

15.

2014

Asiaticoside (40 and 60 mg/kg, oral, once per day, 7 days) to transient cerebral ischemia-reperfusion-induced memory impairment in mice

- Ameliorated the memory impairment (Morris water maze task and the step-down passive avoidance test) - Reduced NO, iNOS (biochemical) - Reduced inflammatory cytokine levelsdIL-1b, IL-6, and TNF-a (quantitative real-time polymerase chain reaction (PCR) - Reduced the microglial overactivation and the phosphorylation of p38 MAPK in the hippocampus (Western blot analysis)

[133]

16.

2014

Ethanolic extract of CA (100, 300, 1000, or 1500 mg/kg, p.o., for 8 days) on transient bilateral common carotid arteries occlusion (T2VO) and scopolamine-induced learning and memory impairment in mice

- Ameliorated the learning and memory impairment (Morris water maze and step-down passive avoidance test - Reduced lipid Peroxidation levels

[134]

17.

2014

Aqueous CA leaves extract (100 and 200 mg/kg, oral, four consecutive weeks) on streptozotocin-induced diabetes-related hippocampal dysfunction

- Conserved the hippocampal markers of memory, inflammation, oxidative stress, and neuronal degeneration: - Naþ/Kþ-, Ca2þ- and Mg2þ-ATPases activity (hippocampal homogenate), inflammatory markers TNF-a, IL-6; and IL-1b), oxidative stress

[135]

18.

2015

Asiatic acid (30 mg/kg, orally, 14 or 28 days) to normal rats

- increase the ability to discriminate in a novel object discrimination task, special memory, and hippocampus-dependent spatial memory test - increased doublecortin and Notch1 protein levels in the hippocampus (hippocampal Immunoblotting) - increased number of Ki-67 positive cells in the subgranular zone of the dentate gyrus (Immunohistochemistry)

[136]

19.

2015

Asiaticoside (0.1 and 1 mmol/L) SH-SY5Y cells incubated with high glucose chronically

- Ameliorate the performance in the Morris water maze - Downregulation of intracellular ROS, TNF-a and IL-1b (ELISA) - Up-regulate synaptic proteins expression via modulating phosphoinositide 3-kinase (PI3K)/Protein kinase B(AKT)/Nuclear factor -kappa B (NF-kB)-mediated inflammatory pathways

[137]

316 Nutraceuticals in Brain Health and Beyond

TABLE 22.1 Potential of CA against cognitive disorders.dcont’d

2016

Aqueous extract of CA (2 mg/L in their drinking water) to young (6 weeks) and old (18 months C57Bl/6 mice)

- Improved performance in the Morris water maze - Gene expression by quantitative PCR for oxidative stress pathway, nuclear factor (erythroidderived 2)-like 2 (NFE2L2; NRF2), NAD(P)H dehydrogenase-quinone oxidoreductase 1 (NQO1), glutamate-cysteine ligase, catalytic subunit, heme oxygenase 1 (HMOX1) - Increase expression by qPCR for the genes for mitochondrial pathways-mitochondrially encoded genes-NADH dehydrogenase 1 (Mt-ND1), ATP synthase 6 (Mt-ATP6 encoded cytochrome c oxidase 1 (Mt-CO1), cytochrome B (Mt-CYB), synaptophysin, postsynaptic density protein 95 (PSD95) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH)

[138]

21.

2016

Asiatic acid and madecassic acid (100 mM) on Xenopus laevis oocytes

- Negative modulation of alpha5-containing GABA-A receptors (two-electrode voltage-clamp technique) - Madecassic acid did not affect GABA receptors.

[139]

22.

2018

Ethanolic extract of CA (30 and 200 mg/kg, oral, daily once, 14 days) in normal rats

- Behavioraldimproved hippocampus-dependent with spatial learning and memory, no change in locomotor activity, improved learning, memory, and the memory consolidation phase but did not affect reversal learning (OFT and water T-maze test) - Increased expression of theAMPA GluA1 receptor in the CA1 and CA2 regions of the hippocampus. (Neuronal cell morphology using cresyl violet and apoptosis staining) and GABA-A a1 subunit in the hippocampus (immunohistochemistry)

[140]

23.

2018

Aqueous extract of CA leaves (2 mg/mL in drinking water for 2 weeks) to 20-month-old CB6F1 mice

- Improve multiple facets of age-related cognitive impairment, improved performance in novel object recognition task, object location memory task and odor discrimination reversal learning test - increase in synaptic density of Golgi in tissue homogenate - increased expression of the antioxidant response gene NRF2 as well as the mitochondrial marker porin

[141]

24.

2018

Aqueous extract of CA leaves (2 mg/mL in drinking water for 2 weeks) to b-amyloid overexpressing 7 month old 5FAD female mice

- Attenuates Ab-induced deficits in spatial memory, improves contextual memory, restores executive function (conditioned fear response, object location memory, odor discrimination reversal learning) - Increases hippocampal and cortical gene expression of synaptic, antioxidant, and mitochondria function - Reduces Ab plaques in the hippocampus (immunohistochemistry)

[142]

25.

2019

Triterpenoid glycosidesebased standardized extract of CA (10,30, and 100 mg/kg, oral, twice a day for 30 days) in normal rats

- Significantly promote memory retention (spatial memory performance in Morris water maze task), - Hippocampal long-term potentiation, expression of plasticity-related proteins (NR2A, NR2B, PSD-95, BDNF and TrkB) - Hippocampal long-term potentiation

[143]

26.

2019

CA extract (200, 400, and 800 mg/kg/day) in D-gal/AlCl3induced cognitive deficits in rats

- Improved cognitive impairment (Morris water maze test) - Decreased AChE levels, phosphorylated tau (pTau), malondialdehyde and superoxide dismutase in the hippocampus and cerebral cortex (ELISA) - Attenuated the oxidative stress in hippocampus and cerebral cortex - Prevented ultrastructural alteration of neurons in the prefrontal cortex (transmission electron microscopy, TEM)

[144]

27.

2019

Ethanolic extract of CA (200 and 500 mg/kg/day for 14 days) in scopolamine-induced amnesia

- Spatial memory formation (elevated plus-maze, Morris water maze) - Inhibition of antioxidant enzymes, inflammatory cytokines (IL1b, IL6, TNFa), and enzyme acetylcholinesterase (AChE) in brain homogenate (ELISA)

[145]

Centella asiatica (Gotu kola) leaves: potential in neuropsychiatric conditions Chapter | 21

20.

317

318 Nutraceuticals in Brain Health and Beyond

withdrawal threshold intensity elicited by electrical stimuli and suggested to improve sensory-motor functions [158]. Recently, triterpenes-based standardized CA extract showed efficacy and safety in type-2 diabetes milieus patients with neuropathy (a neuroinflammatory condition) during the randomized, double-blind, placebocontrolled clinical study [159]. The total symptom score of diabetic neuropathies (intensity and frequency of paresthesia, numbness, pain, and burning symptoms self-reported by patients) was significantly reduced by 52-weeks daily oral supplementation of triterpenes, based on standardized CA extract capsules with escalating doses during the study [159]. The impaired neurological function is severe morbidity associated with the spinal cord injury, a neuroinflammatory condition [160]. Spinal cord injury is a serious complication of trauma that leads to sensory and motor dysfunction and high rates of morbidity in terms of neurological functions [161]. Seven days of administration of asiaticoside (15, 30, and 60 mg/kg/day, oral) in an animal model of spinal cord injury showed augmentation of Basso, Beattie, and Bresnahan scores (a measure of improved neurological function), reduction in inflammatory markers (water content of spinal cord, the levels of inducible nitric oxide synthase (iNOS), NF-kB p65 unit, TNF-a, IL-1b, and IL-6), and suppression of the expression of p38-MAPK [162]. Antiinflammatory and antinociceptive activities of asiatic acid have been reported in animal models like carrageenan-induced acute inflammation, acetic acidinduced writhing, and formalin-induced pain in male mice [163]. Asiatic acid decreased the NO, TNF-a, and interleukin-1b (IL-1b) levels in serum and iNOS, cyclooxygenase (COX-2), and NF-kB expressions in the edema paw tissue [163]. Similarly, the madecassic acid, another triterpenoid aglucone, isolated from CA leaves is reported to potently suppress the inflammatory mediators via the downregulation of NF-kB activation in RAW 264.7 macrophage cells [164]. Moreover, the titrated extract of CA, which comprises 29%e30% madecassic acid, effectively inhibited lipopolysaccharides-induced inflammatory responses [165].

Neurodegenerative and neuroinflammatory disorders CA, especially its leaves, has a long history of traditional use as brain or nerve tonic in the traditional literature for neuronal health. Consequently, many researchers have investigated and confirmed the traditional neuroprotective use on a scientific base. Efficacy of CA, its extracts and individual phytoconstituents against many oxidative stress and proinflammatory cytokines [166e173] from animal

models of disease conditions in vivo or against many toxicants in vitro has been reported. The potential of CA on neuroprotective effects of CA extract has been reviewed extensively [2,174,175]. These reviews specially focused on neuroprotective properties of CA through antioxidant mechanisms, neurodegenerative diseases such as PD along with cognitive disease, AD. Therefore, the part of the chapter is focused on the current status of the research of the efficacy of CA or its phytoconstituents against neuroinflammatory disorders where mechanisms other than antioxidant have been suggested. These reports include efficacy in animal models of clinically relevant neuroinflammatory conditions such as neuropathy, cerebral ischemia, spinal cord injury, and others. The recent developments regarding the potential of CA extract and its phytoconstituents against PD and Huntington disease (HD) are presented below. CA extract [176e180] and its phytoconstituents namely asiaticoside [181e183], madecassoside [184], and asiatic acid [165,185,186] are reported to have neuroprotective potential in experimental PD in vitro and in vivo. Drosophila melanogaster has been extensively used as a model, based on loss of function of phosphatase and tensin-induced putative kinase 1 (PINK1), and provides a time- and cost-effective screening tool for potential anti-Parkinson agent discovery [187,188]. PINK1 mutants of D. melanogaster show several similarities with PD, including dopamine neuronal degeneration and locomotor defects [189,190]. The efficacy of CA extract (7 mg/100 g) as a food additive along with five of the classical herbs is reported for the ability to improve the climbing activity of a fruit fly (D. melanogaster) PINK1 mutants, and healthy wild-type flies [177]. Also, CA leaves extract (0.25, 0.50, and 1.0 mL/mL in diet, 24 days) was shown to reverse the loss of climbing ability, activity pattern, and oxidative stress of fruit fly [178]. One of the major etiological factors implicated in PD is a-synuclein aggregation in brain [191,192]. Therefore, inhibition of a-synuclein aggregation has become a major therapeutic target for potential agents against PD [193]. Aqueous extract of CA showed complete inhibition of the a-synuclein aggregation from monomers and oligomer to aggregates and favored the disintegration of the preformed fibrils in the aggregation kinetics study using a thioflavinT assay, circular dichroism, and transmission electron microscopy [180]. Aqueous extract of CA is reported to protect the brain in experimentally induced parkinsonism in animals namely 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)induced [176]. Subacute (21-days) oral treatment of aqueous extract of CA (300 mg/kg/day) reported to decrease in MPTP-induced oxidative stress in corpus striatum and hippocampus in aged rats [176]. MPTP is

Centella asiatica (Gotu kola) leaves: potential in neuropsychiatric conditions Chapter | 21

known to induce selective toxicity to dopaminergic neurons via its metabolite, MPPþ, and induces a Parkinson-like syndrome in animals [194,195]. Treatment with asiaticoside is reported to protect against MPTP neurotoxicity to improve locomotor dysfunction, protect dopaminergic neurons, reverse dopamine loss, increase the B-cell lymphoma 2 (BCL2) to its associated Apoptosis Regulator (Bax) ratio in the striatum of rats [181], and reverses glial fibrillary acidic protein expression in astrocytes, a marker of neuronal damage [182]. Similar effects were observed during 7 days of madecassoside (30 and 60 mg/kg, oral) exposure which showed recovery from early signs of MPTP-induced parkinsonism via reversing the depletion of DA, antioxidant activity, increasing ratio of Bcl-2/Bax, increasing protein expression of BDNF [184]. Asiatic acid reported in vivo neurotrophic efficacy against in MPTP/probenecid (MPTP/p)-induced neurotoxicity via activating MAPK, PI3K-Akt-GSK3b, and mTOR signaling pathways and [186] and in vivo against methamphetaminemediated neurotoxicity in dopaminergic neurons by inhibiting NF-kB/STAT3/ERK and mitochondria-mediated apoptosis [165]. Another animal model that is used for anti-Parkinson agent evaluation is rotenone-induced neurotoxicity in rats [196]. Triterpenoid-based standardized extract of CA (10, 30, and 100 mg/kg, 20 days) showed a significant increase in locomotion together with many dopaminergic neurons in the substantia nigra and striatum (measured by tyrosine-hydroxylase immune-histological staining) in rotenone-induced PD rats probably through the protection of mitochondrial complex I activity, and the enhancement of antioxidant enzyme expression [179]. Pretreatment with asiatic acid (10 nM) offered neuroprotection to the SH-SY5Y cells from rotenone toxicity in vitro (overproduction of ROS, mitochondrial dysfunction, and apoptosis) [185]. Recently, novel phytoconstituents from CA, namely asiaticoside-D, showed monoamine oxidaseB inhibiting potential in rotenone degenerated cerebral ganglions of an earthworm, Lumbricus terrestris [183]. CA is reported to offer protection against 3nitropropionic acid (3-NPA)einduced mitochondrial dysfunctions, viz., reduction in the activity of SDH, electron transport chain enzymes, and decreased mitochondrial viability in the striatum and other brain regions in vitro [197]. Furthermore, a standardized aqueous extract of CA showed a prophylactic efficacy against 3-NPA-induced early oxidative stress and mitochondrial dysfunctions in the striatum and other brain regions [198] and brain of prepubertal mice [199]. A fungal toxin, 3-NPA, is a well-known neurotoxicant which induces selective striatal pathology similar to that seen in HD [198] The various reports of the efficacy of CA against 3-NPA-induced toxicity [197e199] suggest CA as a potential option in controlling HD-related impairments.

319

Efficacy against drug or chemical neurotoxicity Oral supplementation of CA extract during the postweaning period provided significant protection against lead acetateeinduced behavioral impairments and neurotoxicity, probably through increased acetylcholinesterase enzyme levels and antioxidant activity [200]. This report is especially important because of the specificity of the nervous system as a primary target for lead exposure and to the developing brain than the mature brain [201]. Furthermore, the period from gestation through lactation period is sensitive to lead exposure and has long-term consequences for child cognitive development [202]. Recently, methanol extract of CA has been shown to protect the mouse brain and astrocytes from oxidative stress and inflammation induced by paracetamol [203]. Paracetamol is a commonly used analgesic and antipyretic agent. However, its overdose is known to cause vital organ toxicities, including the brain [204]. The methanol extract of CA shows protective action against the damage caused by paracetamol by protecting the tissue architecture, increasing antioxidants, and upregulating antiinflammatory cytokines [203]. Infusion of CA and various fractions (ethyl acetate, n-butanol and dichloromethane) of aqueous extract of CA was found be effective against quinolinic acid, and sodium nitroprusside (SNP)einduced toxicity [205] Asiaticoside was reported to be neuroprotective against N-methyl D-aspartate (NMDA)einduced excitotoxicity through inhibition of decreased neuronal cell loss, restoration of expression of apoptotic-related proteins Bcl-2 and Bax, downregulation of NMDA receptor subtype 2B expression, and calcium influx inhibition [206].

Efficacy against cerebral ischemia Cognitive impairment and memory dysfunction following stroke diagnosis are common symptoms that significantly affect the survivors’ quality of life [207]. Given that the cerebral blood flow or regulation of cerebral circulation is attenuated in the elderly, aging-induced cognitive decline is corelated with the condition of brain ischemia (stroke), especially in elderly subjects [208]. Approximately 30% of stroke patients develop dementia within 1 year of stroke onset [209]. Several studies showed that survivors of childhood arterial ischemic stroke have long-term cognitive impairment [210]. Because of cognitive function enhancing properties of CA and its phytoconstituents, their potential against cerebral ischemia (stroke) has been explored by many researchers. Subacute (21-days) oral supplementation of ethanolic extract of CA (100, 200, and 300 mg/kg/day) showed dose-dependent protection in middle cerebral artery occlusioneinduced ischemia and neurological deficits in

320 Nutraceuticals in Brain Health and Beyond

rats [211]. Subacute administration of total triterpenoidsbased standardized extract of CA showed improved cognition (improved memory and learning flexibility deficits) and hippocampal pathology (ameliorated neuronal damage) after short-term (24 h) and long-term (12 months) induction period of mild chronic cerebral hypoperfusion by permanent right common carotid artery occlusion in rats [212] and transient bilateral common carotid artery occlusion in mice [213]. These effects are supported by in vitro experiments of the neurogenic effect on human neuroblastoma cells by standardized extract of CA [105] and against ischemia-hypoxia in cultured rat cortex neurons by asiaticoside [214]. Asiatic acid, an aglycone form of asiaticoside has also reported efficacy to lower infarct volume in mouse and rat models of focal ischemia [215,216] and focal embolic stroke [217]. In a mouse model of permanent cerebral ischemia, pretreatment of asiatic acid (30, 75, or 165 mg/kg, oral, 1 h pre- and 3, 10, and 20 h postischemia) significantly reduced the infarct volume by 60% (day 1) and 26% (day 7) postischemia, improved neurological outcome, and suggested to act through decreased blood-brain barrier permeability and reduction in mitochondrial injury [215]. In the rat model of stroke, focal cerebral ischemia, asiatic acid (75 mg/kg) treatment was reported to decrease infarct volume and improve neurological outcome, attenuate mitochondrial dysfunction, reduce matrix metalloproteinase-9 induction, and found to have a long therapeutic time window [216]. In addition to asiaticoside, madecassoside, another triterpenoid glycoside from CA, demonstrated protective effects against the focal cerebral ischemia-reperfusion injury in rats, an animal rat model of cerebral ischemia [218]. Madecassoside showed significant efficacy to resolve the neurological deficits, reduce brain infarct area (assessed by 2,3,5-Triphenyl tetrazolium chloride staining), ameliorate neuronal apoptosis (assessed by terminal deoxynucleotidyl transferase-mediated dUTP-nick end labeling (TUNEL) staining), and attenuate production of proinflammatory cytokines, including p65 subunit of NF-kB (assessed by ELISA) [218]. These results are supported by the protective effects of madecassoside against hypoxic-ischemic injuryeinduced cellular toxicity in GT1-7 neuronal cell lines, in vitro [219].

Recent advance: nasal delivery of CA extract Recently, exploration of the intranasal route demonstrated the interesting activity profile of triterpenoid-based standardized extract of CA leaves (INDCA) as a treatment option for neuropsychiatric conditions [220e222]. The CNS diseases and disorders such as migraine, AD, etc., require the presence of the drug to the brain for the

treatment, and the nasal drug delivery system exhibited promising results for the same [223]. The nasal route of administration provides a practical, noninvasive method to deliver therapeutic agents to the brain and spinal cord bypassing the blood-brain barrier and eliminating the potential side effects [224,225]. Subacute intranasal INDCA administration (5, 15, and 50 mg, twice a day) showed promising efficacy against CUMS-induced behavioral anhedonia (sucrose preference test), anxiety (marbleburying test), aggression (resident intruder test) and cognitive decline memory (Morris water maze, Y-maze) in rats probably through stress reduction property (normalizing of elevated cortisol levels) [220]. Migraine is a common debilitating condition with severe recurrent headaches and sensitivity to light and sound, nausea, and vomiting [226]. Nitroglycerin, an NO donor, is the most prominent exogenous algogenic (painproducing) substance that triggers migraine-related features in conjunction with intense pain responses [227]. Acute and subacute pretreatment of INDCA (10 and 30 mg/ kg, oral and 100 mg/rat, intranasal) showed significant antinociception activity, and reversal of the nitroglycerineinduced hyperalgesia (an animal model of migraine) and brain serotonin concentration decline [221]. Furthermore, the effects of subacute administration of intranasal INDCA against nitroglycerine-induced chronic pain are discussed [222]. Subacute (21 days) coadministration of INDCA (5, 15, 50 mg, twice a day) with nitroglycerine (10 mg/kg i.p. alternate days for 11 days) showed dose-dependent prevention of nitroglycerine-induced pain and stress parameters. Intranasal INDCA demonstrated efficacy in terms of preventing pain (facial pain expressions measured by rat grimace scale, RGS), thermal hyperalgesia (using tail flick against radiant heat), mechanical allodynia (using vonFrey apparatus), photophobia (light dark box), and anxiety (elevated plus-maze) parameters. The proposed mechanism of intranasal INDCA against migraine was suggested to be through the prevention of NTG-induced increase in cortisol (serum and brain) and pituitary adenylate cyclase-activating polypeptide (plasma and brain), and NO (serum). The morphology epithelium of the nose turbinate was reported to be unaffected by subacute intranasal INDCA administration [222]. Thus, the intranasal delivery of INDCA is emerging as an optimal way of supportive treatment for neuropsychiatric disorders such as stress-related disorders, tension-type headaches and migraine pain.

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Chapter 22

Big data for clinical trials Nikhil Verma THINQ Pharma-CRO Ltd., Mumbai, Maharashtra, India

Chapter outline Introduction Role of big data in research Technology of big data Life cycle and management of data using technologies

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Introduction Our entire current generation is dependent on information technology and each one of us is bombarded with enormous data points. Oxford dictionary defines Big Data as: extremely large datasets that may be analyzed computationally to reveal patterns, trends, and associations, especially relating to human behavior and interactions. In all areas of disciplines, Big Data may benefit to discover underlying nuances of varieties of phenomena, and further facilitate decision-making.

Role of big data in research The projected three times increase in the incidences of dementia in the coming decades [1] will put immense pressure on the caregivers and healthcare systems. Hence there is a definitive push in the data analytics for developing precise predictive tools to spot early signs of cognitive decline that may develop into full-blown dementias or to slow down progression of the disease. The identification of biomarkers for Alzheimer disease (AD) has paved the way for research into early determinants, with an emphasis on treating patients before the clinical manifestation of the disease [2]. According to a study of the drug development pipeline for AD in 2017, current efforts focus mainly on disease-modifying therapies (DMTs) [3], and most of DMT agents in phase III AD trials (as reported on https://clinicaltrials.gov in 2017) address amyloid

Nutraceuticals in Brain Health and Beyond. https://doi.org/10.1016/B978-0-12-820593-8.00022-7 Copyright © 2021 Elsevier Inc. All rights reserved.

Approach of regulatory agencies Big healthcare data: security and privacy Big data[big prospects References

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targets (15 out of 18) (idem). Yet, the failure rate for these kinds of trials is notoriously high [4]. Chip giant Intel had partnered with Michael J Fox Foundation for Parkinson’s research and they were working on a study that will pull patterns from data collected from patients’ wearable devices. Motion sensors are common today in wearables, watches, and mobile devices for monitoring exercise or step counts. These gross measures of movement, however, do not provide a direct measure of Parkinson’s features such as tremor, bradykinesia, or dyskinesia, as each of those symptoms have very distinct features. The striking differences between old-style health analysis and Big Data health analytics is the heavy use of crossplatform programming in integrating various data touch points. Many healthcare stakeholders trust information technology because of its meaningful outcomesdtheir operating systems are functional, and they can process the data into standardized forms. Today, the healthcare industry is faced with the challenge of handling rapidly developing big healthcare data. The field of big data analytics is growing and has the potential to provide useful insights for the healthcare system. As noted above, most of the massive amounts of data generated by this system is saved in hard copies, which must then be digitized [5]. Big data can bring advancement to healthcare research process and substantially bring down the overall cost, while supporting advanced patient care, improving patient outcomes, and avoiding suspected adverse events.

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Big data analytics is currently used to predict the outcomes of decisions made by physicians, for example, the outcome of a morbid condition based on patient’s demography and health status. Thus, we can say that the role of big data in the research is to manage datasets related to the outcomes and their specific risks, which are complex and difficult to manage if already not identified in the research protocol. This also directly interprets in lowering the insurance cost and patient payouts in case of any serious adverse events. In 2011, organizations working in the field of healthcare had produced more than 150 exabytes of data [6], all of which must be efficiently analyzed to be at all useful to the healthcare system. An algorithm built on levels of metabolites identified in a blood sample can precisely forecast whether a child is on the Autism spectrum of disorder (ASD), based upon a recent study. Instead of looking at individual metabolites, researchers investigated patterns of several metabolites and found significant differences between metabolites of children with ASD and those that are neurotypical. These differences allowed them to categorize whether an individual is on the Autism spectrum, by measuring 24 metabolites from a blood sample, and even to some degree where on the spectrum they land. Big data techniques applied to biomedical data found different patterns in metabolites relevant to two connected cellular pathways (a series of interactions between molecules that control cell function) that have been hypothesized to be linked to ASD: the methionine cycle and the transulfuration pathway. The methionine cycle is linked to several cellular functions, including DNA methylation and epigenetics, and the transulfuration pathway results in the production of the antioxidant glutathione, decreasing oxidative stress [7]. Another case study provides an interesting insight on a unique, population-based observational research initiative aimed at measuring and improving cardiovascular health and the quality of ambulatory cardiovascular care provided in Ontario, Canada, by The CArdiovascular HEalth in Ambulatory care Research Team (CANHEART); with a particular focus on identifying opportunities to improve the primary and secondary prevention of cardiovascular events in Ontario’s diverse multiethnic population. A population-based cohort comprising 9.8 million Ontario adults 20 years in 2008 was assembled by linking multiple electronic survey, health administrative, clinical, laboratory, drug, and electronic medical record databases using encoded personal identifiers. The cohort included z9.4 million primary prevention patients and z400,000 secondary prevention patients. Follow-up on clinical events was achieved through record linkage to comprehensive hospitalization, emergency department, and vital statistics administrative databases. Profiles of cardiovascular health and preventive care are being developed at the health

region level, and the cohort will be used to study the causes of regional variation in the incidence of major cardiovascular events and other important research questions. The CANHEART research initiative will be a powerful Big Data resource for scientific research studies aimed at improving cardiovascular health and health service delivery. It represents a major Canadian effort aimed at creating a learning health system whereby data routinely collected from disparate parts of the health system are brought together and analyzed to generate new insights into how to improve patient outcomes. Linkage of multiple databases will enable the CANHEART study cohort to serve as a powerful Big Data resource for scientific research aimed at improving cardiovascular health and health services delivery. Study findings will be shared with clinicians, policy makers, and the public to facilitate population health interventions and quality improvement initiatives [8].

Technology of big data The architecture of Big Data must be synchronized with the support infrastructure of the organization. To date, all of the data used by organizations are stagnant. Data are increasingly sourced from various fields that are disorganized and messy, such as information from machines or sensors and large sources of public and private data. Previously, most companies were unable to either capture or store these data, and available tools could not manage the data in a reasonable amount of time. However, the new Big Data technology improves performance, facilitates innovation in the products and services of business models, and provides decision-making support. Big Data technology aims to minimize hardware and processing costs and to verify the value of Big Data before committing significant company resources. Professionally managed Big Data are accessible, reliable, secure, and controllable. Hence, Big Data uses can be applied in multifaceted scientific disciplines (either single or interdisciplinary), including atmospheric science, astronomy, medicine, biology, genomics, and biogeochemistry. Below, we briefly discuss data management tools and propose a new data life cycle that uses the technologies and terminologies of Big Data (Fig. 22.1). With the development of computing technology, vast volumes can be managed without the need of supercomputers and high cost. Most tools and methods are available for data management, including Google BigTable, Simple DB, Not Only SQL (NoSQL), Data Stream Management System (DSMS), MemcacheDB, and Voldemort. However, researchers must develop tools and technologies that can store, access, and analyze large amounts of data in real time because Big Data contrasts from the traditional data and cannot be stored in a single dataset. Moreover, Big Data

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Retrieve/reuse/discover

Security

• Searching • Retrieval • Decision making

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Sharing/publishing • Ethical and legal specification • Organization and documentation • Representation

• Privacy • Confidentiality • Integrity • Availability • Governance

Storing • Management plans • Content filtering • Distributed system • Partition tolerance • Consistency • Simple DB • Big table • Hadoop • MapReduce • Memcache DB • Voldemort Collection

Big Data • Raw data

• Cleaning/integration • Log files • Sensing • Mobile equipment • Satellite • Laboratory • Supercomputer

FIGURE 22.1

Filtering/classification • Structure/unstructure • Cleaning/integration • Filtering criteria

Data analysis • Visualization/interpretation • Technique and techno!ogy • Tool selection • Data mining algorithm • Cluster • Correlation • Statistical • Regression • Legacy codes • Indexing • Graphics

Proposed data life cycle using the technologies and terminologies of Big Data [9].

lacks the architecture of traditional data. For Big Data, some of the most widely used tools and systems are Hadoop, MapReduce, and Big Table. These innovations have changed the traditional approach for data management because they effectively process large amounts of data efficiently, cost-effectively, and in a timely manner [9]. Patient monitoring tools relay data to researchers instantaneously by tracking RWE (real-world evidence) in real time via wearable devices, sensors, and smartphones powered by Artificial Intelligence, Big Data, and predictive analytics. (Source: https://www.iconplc.com/ 2018_ICON_Publication_Digital_Health_Whitepaper.pdf.) Myriad types of testing and monitoring can now be done remotely. Wearable devices that are similar in scope and design to commercial fitness trackers as well as skin sensors can collect data on heart rate, blood pressure, ECG (Electrocardiography), skin temperature, breathing rates, and sleep cycles (source https://www.ncbi.nlm.nih.gov/pmc/ articles/PMC6032822/ Wearable Devices in Clinical Trials: Hype and Hypothesis, Izmailova, Wanger and Perakslis). Patients being monitored while in the comfort of their own homes and maintaining their own routines means that the data is providing a complete picture of the patients’ lives and not just a limited time frame within the walls of a doctor’s office. Some of the data collection is passive, with no work required on the part of the patient. For other types of testing, patients must use a mobile phone, paired with the medical device, to send data points forward [10].

Life cycle and management of data using technologies Throughout each stage of the data life cycle, the management of Big Data is the most challenging issue. This problem was first raised in the initiatives of UK e-Science a decade ago. The data were geographically dispersed, managed, and owned by several entities. The new method to data management and treatment required in e-Science is reflected in the scientific data life cycle management (SDLM) model. In this model, present practices are analyzed in different scientific communities. The generic life cycle of scientific data is composed of sequential stages, including experiment planning (research project), data collection and processing, discussion, feedback, and archiving. The proposed data life cycle consists of the following stages: collection, filtering and classification, data analysis, storing, sharing and publishing, and data retrieval and discovery [9].

Approach of regulatory agencies The US FDA is looking at various methodologies to fasttrack innovations in clinical trials, medical product development, and Artificial Intelligence using cost-effective strategies and Big Data. As per the blog by Scott Gottlieb, MD, the Commissioner of the US Food and

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Drug Administration (https://www.fda.gov/news-events/fdavoices/fdas-comprehensive-effort-advance-new-innovationsinitiatives-modernize-innovation), “Our longstanding goal for medical care is to ensure that the right drug or device is delivered to the right patient at the right time. This vision is increasingly possible with the innovative products that are becoming available.” The FDA is implementing a more standardized, efficient, and comprehensive process for review of drug safety. This new process will leverage staff expertise in data analytics to develop more standardized approaches and templates for how to evaluate safety data as part of new drug applications. This process fully leverages the standard datasets that must be submitted in drug applications. It also brings in added quantitative and programming expertise in the conduct of safety analyses to support the medical team’s efforts. As part of this effort, the FDA is looking to make the review process more integrated, multidisciplinary, and problem-focused; and to develop a review document that reflects this multidisciplinary, problem-focused approach. By enhancing efficiency and providing greater support for the application review, they intend to “front load” this process. This approach should result in more time during the review cycle for key discussions, such as on labeling and on post-market requirements and commitments. These new processes should align well with FDA’s ongoing efforts to base our regulatory decisions on an informed assessment of the benefit-risk balancedby providing a deeper understanding of the risks, along with a comprehensive assessment of benefit, incorporating the patient’s perspectives and preferences. As part of these efforts, the FDA is also actively working to evaluate the use of real-world evidence (RWE) to support regulatory decisions. This includes data captured from sources such as electronic health records, registries, and claims and billing data. Real-world evidence can help answer questions that are relevant to broader patient populations or treatment settings where information may not be captured through traditional clinical trials. This is helping the FDA to expand its ability to use RWE for postmarketing safety surveillance and exploring its potential to help support expanded label indications. FDARA provided important funding to evaluate how RWE can be generated, and its potential use in product evaluation. The funding included significant new resources to enhance the FDA’s Sentinel system. To date, Sentinel has been used to assess safety. The FDA is now supporting the first randomized prospective intervention trial that makes use of information in the Sentinel system. To take one practical new example of this application, the IMPACT-Afib trial will test an educational intervention to address the important public health problem of underuse of effective medications to reduce the risk of stroke in patients with atrial fibrillation. This proof-of-concept trial can serve

as a prototype for future RWE trials. At the same time, in another proof-of-concept study, the FDA is also funding a project to examine whether RWE that’s generated using observational data can replicate the results of approximately 30 randomized controlled clinical trials for drugs.

Big healthcare data: security and privacy Big Data has fundamentally changed the way organizations manage, analyze, and leverage data in any industry. One of the most promising fields where Big Data can be applied to make a change is healthcare. Big healthcare data has considerable potential to improve patient outcomes, predict outbreaks of epidemics, gain valuable insights, avoid preventable diseases, reduce the cost of healthcare delivery, and improve the quality of life in general. However, deciding on the allowable uses of data while preserving security and patient’s right to privacy is a difficult task. Big Data, no matter how useful for the advancement of medical science and vital to the success of all healthcare organizations, can only be used if security and privacy issues are addressed. To ensure a secure and trustworthy Big Data environment, it is essential to identify the limitations of existing solutions and envision directions for future research. Security and privacy in Big Data are important issues. Privacy is often defined as having the ability to protect sensitive information about personally identifiable healthcare information. It focuses on the use and governance of individual’s personal data like making policies and establishing authorization requirements to ensure that patients’ personal information are being collected, shared, and utilized in the right way, while security is typically defined as the protection against unauthorized access, with some including explicit mention of integrity and availability. It focuses on protecting data from pernicious attacks and stealing data for profit. Although security is vital for protecting data, it is insufficient for addressing privacy. Whereas the potential opportunities offered for Big Data in the healthcare arena are unlimited (e.g., drive health research, knowledge discovery, clinical care, and personal health management), there are several obstacles that impede its true potential, including technical challenges, privacy and security issues, and skilled talent. Big Data security and privacy are considered huge obstacles for researchers in this field [11].

Big data [ big prospects Big Data has many outcomes for patients, researchers, providers, insurance sector, and other healthcare constituents. It will have a huge influence on how these players engage with the healthcare environment, in particular when

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external data, localization, globalization, mobility, and social networking are involved. The swift, worldwide spread of COVID-19 in the year 2020 has brought into focus the innovative Big Data analytics tools, with individuals from all sectors of the healthcare industry pursuing to examine and reduce the impact of this virus. Apple and Google have been working on a contacttracing tool to help identify potential cases of COVID-19. These two tech companies have now shared more information on the system, including sample interface design for potential apps as well as restrictions on how it will be used. A contact-tracing app is designed to let people know if they have been in close contact with someone who later reports positive for COVID-19. It could pinpoint exactly who needs to be in quarantine and who doesn’t, making it key to easing up social distancing measures. The purpose of the contact-tracing app is to try and track down people and alert them of the need to self-isolate faster than traditional methods. Arogya Setu, the Indian government’s mobile application developed to track COVID-19 patients, has emerged as a powerful tool to curb the spread of coronavirus COVID19 as it helped alert authorities about more than 650 hotspots across the country and over 300 “emerging hotspots” which could have been missed otherwise. Though data privacy and security are a concern, proper handling of data as per the local regulatory guidelines and applying appropriate legal framework would enable the healthcare entities to utilize the enormous real-world data, and this is always going to the big prospect for research in the near future.

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Alzheimers Dement 2013;9:63e75.e2. https://doi.org/10.1016/ j.jalz.2012.11.007 [PubMed] [CrossRef] [Google Scholar]. Huynh RA, Mohan C. Alzheimer’s disease: biomarkers in the genome, blood, and cerebrospinal fluid. Front Neurol 2017;8:102. https://doi.org/10.3389/fneur.2017.00102 [PMC free article] [PubMed] [CrossRef] [Google Scholar]. Cummings J, Lee G, Mortsdorf T, Ritter A, Zhong K. Alzheimer’s disease drug development pipeline: 2017. Alzheimers Dement 2017;3:367e84. https://doi.org/10.1016/j.trci.2017.05.002 [PMC free article] [PubMed] [CrossRef] [Google Scholar]. Canevelli M, Bruno G, Cesari M. The sterile controversy on the amyloid cascade hypothesis. Neurosci Biobehav Rev 2017;83:472e3. https://doi.org/10.1016/j.neubiorev.2017.09.015 [PubMed] [CrossRef] [Google Scholar]. Wu X, Zhu X, Wu GQ, Ding W. Data mining with big data. IEEE Trans Knowl Data Eng 2014;26(1):97e107. Augustine DP. Leveraging big data analytics and Hadoop in developing India healthcare services. Int J Comput Appl 2014;89(16):44e50. Howsmon DP, Kruger U, Melnyk S, James SJ, Hahn J. Classification and adaptive behavior prediction of children with autism spectrum disorder based upon multivariate data analysis of markers of oxidative stress and DNA methylation. PLoS Comput Biol 2017;13(3):e1005385. Tu JV, Chu A, Donovan LR, Ko DT, Booth GL, Tu K, Maclagan LC, Guo H, Austin PC, Hogg W, Kapral MK, Wijeysundera HC, Atzema CL, Gershon AS, Alter DA, Lee DS, Jackevicius CA, Sacha Bhatia R, Udell JA, Rezai MR, Stukel TA. Using big data to measure and improve cardiovascular health and healthcare services. Cardiovasc Qual Outcomes 2015;8:204e12. 2015. Khan N, Yaqoob I, Targio Hashem IA, Inayat Z, Mahmoud Ali WK, Alam M, Shiraz M, Gani A. Big data: survey, technologies, opportunities, and challenges. Sci World J 2014:2356e6140. 712826. Daley ME, Kilgallon M. Healthcare technology & blockchain: positive disruption in clinical trials & patient experience. 2019. Abouelmehdi K, Beni-Hessane A, Khaloufi H. Big healthcare data: preserving security and privacy. J Big Data 2018;5:1. https://doi.org/ 10.1186/s40537-017-0110-7.

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Chapter 23

The multifactorial contributions of PycnogenolÒ for cognitive function improvement Frank Schoenlau Horphag Research (Europe) LTD, Limassol, Cyprus

Chapter outline Introduction PycnogenolÒ as a herbal medication Deteriorating cognitive function in the aging brain

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Introduction The mental process of acquiring knowledge and understanding complex interactions is a privilege of Homo sapiens and related primates. It is commonly suggested that the brain constantly needs challenges, to continuously develop and excel. And indeed the major stimulus to the brain is a persistent, insatiable curiosity. Establishing own opinion from gathered information entertains the brain to think and critically verify compiled information. An own interpretation of assembled data helps establish and maintain own understanding. The routine scrutiny and questioning of information gathered represents an integral part of an individual’s intellectual independence. In our times information may be gathered rapidly and be interpreted in different ways, an invitation to establish an own opinion and engage in discussions. Curiosity killing cats is a myth, curiosity makes them cleverer. Good cognitive skills meanwhile are paramount to live an independent, exciting, and fulfilling life style, from early days throughout the golden years. Muscles perhaps may no longer carry us all that long distances any longer, but there are technical ways to get around, to meet with friends and relatives, to exchange thoughts, interact, and share opinions. A compromised mindset, meanwhile, may prove to be much more of a challenge. Cognitive decline typically proceeds slowly, but may present with periods during

Nutraceuticals in Brain Health and Beyond. https://doi.org/10.1016/B978-0-12-820593-8.00023-9 Copyright © 2021 Elsevier Inc. All rights reserved.

Mechanism of action of PycnogenolÒ PycnogenolÒ as a cognitive enhancer References

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which the forgetfulness accelerates and gets annoying. Habits to downplay the embarrassment with jokes, or changing subject of the conversation, cannot be applied too often, before it gets obvious and stale and seriously embarrassing to everyone present. At worst, an affected person could opt to stay all by his own, which shall be prevented by all means. The causes for cognitive decline are manifold. In earlier days people commonly suffered from deteriorating cognition because of an undiagnosed and untreated hypertension. The risk of cognitive decline attributed by untreated hypertension poses a risk for cognitive health even nowadays. This relationship has recently been corroborated in an article from the Johns Hopkins University School of Medicine, which emphasized the importance of regular blood pressure control [34]. An insufficient oxygen supply to the brain and high oxidative stress are detrimental to a bright cognition. Clinical trials have demonstrated that Pycnogenol enhances domains of cognitive ability. In vitro and in vivo animal and human studies have assessed its mechanisms of action, particularly its strong anti-oxidative properties, as well as antiinflammatory and vascular functions. PycnogenolÒ French maritime pine bark extract (Horphag Research) is gained exclusively from bark of French maritime pine trees, grown in the southwest of France. The

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nutritional preparation is extracted from crushed bark, followed by a patented extraction process [35]. A French independent regulatory and control body assesses the quality and purity of the raw bark. Pycnogenol is ascertained to be generally recognized as safe. This was shown by an independent panel of toxicology experts, who have classified Pycnogenol as generally safe (GRAS) based on clinical safety and preclinical toxicology data.

PycnogenolÒ as a herbal medication The standardized pine bark extract Pycnogenol is composed of phenolic compounds, divided between monomers (catechin, epicatechin, and taxifolin), condensed flavonoids (classed as procyanidins/proanthocyanidins), and phenolic acids (cinnamic acids and other glycosides) [32,50]. After being ingested, these phenolic compounds undergo metabolization and are converted in the colon by microbial enzymes, yielding smaller, bioavailable molecules that are readily absorbable by the colon into the bloodstream. So these phenolic compounds of Pycnogenol can be transported to tissues and organs [46]. Pycnogenol represents the most thoroughly researched dietary ingredient in the world to date, with more than 400 research articles published. Pycnogenol has a long track record related to improving blood flow in arteries, veins, and the most fragile postcapillary venules. Pycnogenol is repeatedly clinically demonstrated, to also benefit vein health and function. The benefits for vein health are related to Pycnogenol strengthening the particularly fragile postcapillary venules, which cannot withhold the gravity force pressure and leak fluids into surrounding tissues. An affected individual may perceive swollen legs or the circumstance that shoes are too tight to wear. Pycnogenol has also a long track record for alleviating common health ailments, predominantly of circulatory- and antiinflammatory nature. Because Pycnogenol stimulates endothelium-derived nitric oxide synthase, an optimal release of nitric oxide into the blood stream sets in, which causes pronounced relaxation of constricted vascular smooth muscle, and arteries hence dilate expanding the diameter of the vessel. The resulting improved endothelial function further contributes to healthier blood pressure and greater perfusion of tissues, with more oxygen and nutrient-rich arterial blood delivered [35]. The elevated arterial dilatation which Pycnogenol supports by increasing nitric oxide availability, and in result, also contributes to a healthier blood pressure. The blood platelets likewise respond to greater presence of nitric oxide in the blood stream, by lowering the platelet alertness for clotting, hence defying the risk for developing a thrombosis.

Pycnogenol metabolites furthermore exert pronounced antiinflammatory activity, which is attributed to Pycnogenol metabolites potently inhibiting inflammation master switch NF-kB. Inflammatory processes in the vicinity of neuronal tissue are particularly harmful to cognition. Human pharmacologic studies have revealed that Pycnogenol metabolites prevent the activation of the inflammation “master switch” NF-kB, in healthy student volunteers [15,16]. Tissue strengthening was further found to be attributed to Pycnogenol inhibiting matrix metalloproteinase enzymes (MMP1, MMP2, and MMP9), thus effectively arresting progression of vein edema to chronic venous insufficiency. Pycnogenol is extensively clinically researched for chronic venous insufficiency and related venous disorders [17]. Based on the circulatory and antiinflammatory modes of action there exist manifold positive activities on various health issues, as demonstrated in the cited studies below: Pycnogenol is used for manifold herbal applications because of its multiple health benefits. Pycnogenol has extensively been studied and has shown to have promising clinical effects in improving conditions including diabetes [25,26,43], cardiovascular health [14,24,49]; asthma [18,38], osteoarthritis [Belcaro et al., 2008a, b], sexual disorders [1,22,44], and venous insufficiency [8,17,32]. Pycnogenol also prevents oxidative stress and side effects in patients with hypothyroidism during levothyroxine treatment [5] and prevents thrombosis [6]. The positive activities of Pycnogenol were specially found for neurological disorders including attention-deficit hyperactivity disorder [10,13,47] and cognitive impairment [28].

Deteriorating cognitive function in the aging brain The aging brain over time is cumulatively and in accelerated intensity impacted by oxidative stress. With time, brain atrophy sets in, which further affects neuronal performance and contributes to increasing oxidative stress to the brain. In turn, oxidative stress may further intensify cognitive decline, which accelerates radical burden to neuronal tissues. A brain mass shrinkage sets in at the age of 60e70 years of age. With onset of atrophy, continuous loss of tissues, such as in the brain, muscles, and essentially body-wide, represents a natural part of the aging processes. There exists no treatment or cure for cerebral atrophy because lost neuronal tissues are not replaced. Brain atrophy involves more than loss of neuronal tissue in the brain, but also the loss of interconnections between neurons [20]. Particularly the apolipoprotein E is assigned to have strong and manifold impacts on cognition. The apolipoprotein E is a proteinaceous lipid carrier, involved in the distribution and metabolization of lipids in the body and

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especially in neuronal tissues. Apolipoprotein E is particularly involved in the transportation and metabolism of fats in the body and particularly the brain. Moreover, apolipoprotein E is implicated in Alzheimer disease [37,45]. Furthermore, the oxidation of apolipoprotein A-I in terms of neurodegeneration is well described by Keeney et al[21]. Reactive oxygen species were considered to be potentially toxic byproducts of aerobic metabolism, which, if not eliminated, may inflict structural damage on various macromolecules, such as, for example, apolipoprotein E. Accrual of such damage over time was postulated to be responsible for the physiological deterioration in the postreproductive phase of life and eventually the demise of the organism [42]. Due to these mechanisms of aging and hallmarks of neurodegenerative diseases, it may be beneficial for senior individuals to consume dietary interventions with antioxidant properties to maintain good cognitive function and reduce the risk of increased oxidative stress [41]. Polyphenols likewise resemble important dietary constituents for spurring cognitive function. Studies found that low urinary polyphenols are associated with cognitive decline in an older population, investigated over a 3-year follow-up period [33]. Not all polyphenols are created equal though. From hundreds of monomeric flavonoid species and their glycosides, an even much greater number of condensed polyphenols are generated in plants [9]. The most extensively clinically researched dietary polyphenol is Pycnogenol, the standardized extract from French maritime pine bark (Horphag Research), manufactured in strict accordance to United States Pharmacopeia definitions [USP]. In light of this assessment, the antioxidant mechanisms of Pycnogenol are further discussed in the section below.

Mechanism of action of PycnogenolÒ Pycnogenol French maritime pine bark extract bears procyanidins, which subsequent to oral consumption are metabolized by omnipresent gut microbiota to bioactive metabolites. It is commonly questioned how Pycnogenol may display such far reaching virtues to the consumer. Pycnogenol represents a textbook example on the fruitful interactions between gut microbiota and plant polyphenols [15,16]. In the small intestine microbiota interacts with Pycnogenol procyanidins flavonoids, generating physiologically potent metabolites such as d-(3,4-dihydroxy-phenyl)-g-valerolactone [15,16]. The latter metabolite distributes in tissues via the insulinindependent glucose transporter GLUT1 [30]. In consequence, Pycnogenol metabolites accumulate in all tissues expressing GLUT1 transporters: erythrocytes, leukocytes, endothelium, and all cells of neuronal lineage [23,30,31]. The transportation via GLUT1 is responsible for

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pycnogenol metabolites passing the blood-brain barrier, which in turn facilitates antioxidant protection to the brain and all neuronal lineage. Pharmacokinetic explorations in healthy student volunteers showed daily Pycnogenol supplementation manifests in a steady state level of Pycnogenol metabolites [15,16]. Metabolites entering endothelium via GLUT1 in turn improve endothelial function, allowing for enhanced nitric oxide generation and more pronounced vasodilatation, and in consequence an optimal brain tissue perfusion, with more oxygenated blood contributing to better cognitive performance. Refer to Fig. 23.1. In a clinical setting daily supplementation with Pycnogenol was demonstrated in healthy subjects to significantly increase blood antioxidant capacity (ORAC), measured after 3 and 6 weeks of daily supplementation. Discontinuation of daily Pycnogenol supplementation led to a progressive loss of antioxidant protection, which finally fainted within 4 weeks of after PycnogenolÒ intake [11]. Another group confirmed the increased blood plasma antioxidant capacity with Pycnogenol, in a double-blind, placebo-controlled protocol, applying the FRAP test for antioxidant capacity monitoring. Durackova and coworkers, studied 21 healthy participants who were monitored for 3 months, with another final evaluation a month after discontinuation (washout). From baseline to the third month supplementation with Pycnogenol, blood antioxidant capacity steadily increased, whereas the placebo group of subjects continued to present with elevated oxidative stress in plasma. The molecular structure of Pycnogenol enables to donate vast numbers of electrons without retaining free radicals [12]. Another group verified Pycnogenol’s antioxidant virtues in subjects presenting with elevated oxidative stress, attributed to cigarette smoking. Daily supplementation with 50 mg Pycnogenol significantly reduced plasma oxidative stress [7]. Pycnogenol antioxidant activity also protects neurons from oxidative harm, and therefore it can be applied as a cognitive enhancer.

PycnogenolÒ as a cognitive enhancer A most recently published peer-reviewed scientific article assessed in detail the mechanisms of action involved with Pycnogenol enhancing cognitive performance. The article, published in 2019 in prominent Frontiers in Pharmacology, by Tamara Simpson PhD and coworkers, at Swinburne University Melbourne, Australia, assessed in detail the efficacy and mechanisms of action related to Pycnogenol for cognitive enhancement [40]. To date the following clinical studies univocally support the notion that Pycnogenol elevates cognitive performance in people at all ages.

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FIGURE 23.1 Pycnogenol improves endothelial function.

Oxidative stress is known since decades to impact cognitive function. Earliest preclinical studies pointed to cognitive function improvements with Pycnogenol [35]. Interestingly, Pycnogenol was shown already in early years to help children focus better at school. Particularly children who suffered with attention deficit challenges were found to particularly well benefit from Pycnogenol supplementation, with greater attention. Verification was carried out by interrupting supplementation with Pycnogenol, which led to considerable worsening of children’s attention. The continuation of supplementing children with pycnogenol correspondingly led again to an improvement of children’s attention. This study in Japan confirmed improvement of children’s attention with Pycnogenol [29], while discontinuation of Pycnogenol supplementation led to worsening of symptoms; yet readministration of Pycnogenol was shown to improve attention again. A most recently published, peer-reviewed scientific article investigated 87 healthy men, aged 55e75 years, who presented with minimal cognitive dysfunction challenges. These men were assigned to either daily supplementation with Pycnogenol, or the control group, over an observational period of 8 weeks. Daily supplementation with Pycnogenol proved to contribute significantly to improved cognitive function, by an average 18%, whereas the control

group meanwhile presented with a cognitive function improvement by meager 2.5% on average [19]. Belcaro showed in a study with 60 healthy professionals aged 35e55 a significant influence of Pycnogenol on cognitive function. The 60 subjects were distributed to one of two groups, one control group and one Pycnogenoltreated group. After 12 weeks the Pycnogenol group showed a reduction of the oxidative stress levels by more than 30% and a significant improvement of cognitive function [3]. Another clinical cognitive function test, The COFU3 study, explored cognitive function benefits of Pycnogenol in individuals of advanced age (55e70 years), who also presented with elevated oxidative stress. Study participants were followed-up over an extended period of 1 year. The outcome presented with significant cognition improvement with Pycnogenol supplementation, whereas the control group did not present with any significant variations. The COFU3 study, published in 2015, showed that regular, continuous supplementation with Pycnogenol significantly improves cognitive function, attention and mental performance, as compared to the control group, which experienced insignificant alterations to their cognitive performance [2,4].

The multifactorial contributions of PycnogenolÒ for cognitive function improvement Chapter | 23

A double-blinded, placebo-controlled study, with healthy senior citizens (aged 60e85 years) as subjects, identified a statistical significant cognition improvement after 3 months of continuous daily supplementation with Pycnogenol. The cognition improvement with Pycnogenol coincided with significant reduction of oxidative stress levels, assessed as F2-isoprostanes. The placebo control group, presenting with comparative baseline cognitive scores, appreciated a cognition performance improvement by a meagre and statistically insignificant 1.2%, whereas the Pycnogenol group presented with significant 8.3% improvement. The oxidative stress level in the Pycnogenol group was reduced by 22.9%, whereas the placebo group presented with a reduction by insignificant 3.7%. Pycnogenol thus is demonstrated to improve memory in healthy, elderly citizens [36]. Moreover, Pycnogenol is demonstrated in another clinical study to significantly improve cognitive function in healthy Students in their twenties. Student participants who supplemented with Pycnogenol for 8 weeks scored significantly better in all six cognition tests, comprising auditory serial addition test, a picture-recall test, mental flexibility test, the “stocking of Cambridge” test, and pattern recognition. Student participants who supplemented with Pycnogenol readily outperformed the control group. This study with healthy students supports the understanding, that Pycnogenol benefits everybody’s cognitive health, irrespective of age, lifestyle, or health situation [27]. Neuronal cells have a vastly different physiology as compared to most other body tissues. The most striking speciality is the circumstance that cells of neuronal lineage depend on glucose as energy source, as they cannot utilize lipids as energy source, as most other tissues readily do. Neurons meanwhile also require vast amounts of oxygen to secure the brain’s high energy demand. Pycnogenol supports better endothelial function by elevating nitric oxide release, which in turn secures greater oxygen and nutrient supplies to performing neurons. The ability of Pycnogenol metabolites to reach into neuronal cells via the GLUT1 transporter (Fig. 23.1), where they extinguish oxidative stress in neurons, explains the tremendous cognition improvements witnessed in clinical trials carried out to date [23]. Therefore neuronal cells receive a privileged, insulinindependent, access to blood glucose reserves via the GLUT1 transporter. Once glucose reserves are exhausted, the ability to concentrate drops quickly, along with the perception of being tired, accompanied by an appetite for something sweet. Because neurons cannot utilize other energy sources than glucose, cells of neuronal lineage have a privileged access to glucose. Glucose transporters, such as GLUT1, channel the valuable blood glucose exclusively to the needful, performing neuronal cells. Tissues other than neurons utilize predominantly lipids.

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The Pycnogenol metabolites, meanwhile, travel in the body in exactly the same transporters as the glucose to active neurons. In consequence, Pycnogenol (metabolites) reaches the blood-brain barrier. In turn, engaged neurons are saved from oxidative harm because Pycnogenol, as nature’s most potent antioxidant, extinguishes radicals swiftly. Engaged neurons depend on continuous, uninterrupted supply streams of oxygen, glucose, and antioxidants. Prolonged intense concentration eventually leads to supply gaps, which is perceived as exhaustion, with difficulty to maintain continued concentration, caused by rising oxidative stress, to which neurons are particularly sensitive, because neuronal cell lineage is void of an inherent antioxidant defense. Oxidative stress is furthermore detrimental to artery function, which in response constrict, hence limiting the nutrient- and oxygen-supply streams to the needful performant neurons. Pycnogenol is capacitated to enhance cognition because it elevates nitric oxide generation [48], which dilates constricted arteries, and hence contributes to increased oxygen and glucose supply streams to performing neurons. A further double-blinded study (ARCLI) is currently ongoing in Australia, which employs neuroimaging and investigates gut microbiota influence further to cognitive performance enhancement [39]]. Pycnogenol may well represent a mainstay cognitive enhancer for everybody who wishes to animate the gray matter: clearer thinking and faster and more successful retrieval of memories. A multitude of studies from across the world point to significantly better cognition with Pycnogenol.

References [1] Aoki H, Nagao J, Ueda T, Strong JM, Schonlau F, Yu-Jing S, et al. Clinical assessment of a supplement of PycnogenolÒ and l-arginine in Japanese patients with mild to moderate erectile dysfunction. Phytother Res 2012;26(2):204e7. [2] Belcaro G, Dugall M, Ippolito E, Hu S, Saggino A, Feragalli B. The COFU3 Study. Improvement in cognitive function, attention, mental performance with PycnogenolÒ in healthy subjects (55e70) with high oxidative stress. J Neurosurg Sci 2015a;59(4):43744e6. [3] Belcaro G, Luzzi R, Dugall M, Ippolito E, Saggino A. PycnogenolÒ improves cognitive function, attention, mental performance and specific professional skills in healthy professionals aged 35e55. J Neurosurg Sci 2014;58(4):239e48. [4] Belcaro G, Dugall M, Ippolitto E, Sagggino A, Feragali B. Improvement in cognitive function, attention, mental performance with PycnogenolÒ in healthy subjects with high oxidative stress. J Neurosorg Sci 2015:436e7. [5] Belcaro G, Cornelli U, Dugall M, Cotellese R, Feragalli B, Cesarone MR. Minerva Endocrinol June 2019;44(2):199e204. [6] Belcaro G, Dugall M, Bradford HD, Cesarone MR, Feragalli B, Gizzi C, Cotellese R, Hu S, Rodriguez P, Hosoi M. Recurrent retinal

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[22] Kobori Y, Suzuki K, Iwahata T, Shin T, Sadaoka Y, Sato R, et al. Improvement of seminal quality and sexual function of men with oligoasthenoteratozoospermia syndrome following supplementation with l-arginine and PycnogenolÒ. Arch Ital Urol Androl 2015;87(3):190e3. [23] Kurlbaum M, Mülek M, Högger P. Facilitated uptake of a bioactive metabolite of maritime pine bark extract (Pycnogenol) into human erythrocytes. PLoS One April 30, 2013;8(4):2013. [24] Liu F, Lau BH, Peng Q, Shah V. Pycnogenol protects vascular endothelial cells from beta-amyloid-induced injury. Biol Pharm Bull 2000;23(6):735e7. [25] Liu X, Wei J, Tan F, Zhou S, Würthwein G, Rohdewald P. Antidiabetic effect of PycnogenolÒ French maritime pine bark extract in patients with diabetes type II. Life Sci 2004a;75(21). [26] Liu X, Zhou H-J, Rohdewald P. French maritime pine bark extract Pycnogenol dose-dependently lowers glucose in type 2 diabetic patients. Diabetes Care 2004b;27(3):839. [27] Luzzi R, Belcaro G, Zulli C, Cesarone MR, Cornelli U, Dugall M, Hosoi M, Feragalli B. PycnogenolÒ supplementation improves cognitive function, attention, and mental performance in students. Panminerva Medi 2011;53(Suppl. 1):75e82. [28] Maimoona A, Naeem I, Saddiqe Z, Jameel K. A review on biological, nutraceutical and clinical aspects of French maritime pine bark extract. J Ethnopharmacol 2011;133(2):261e77. [29] Masami K. Pycnogenol’s therapeutic effect in improving ADHD symptoms in children confirmed. Mainichi Shimbun 2000;10(21):64. [30] Mülek M, Fekete A, Wiest J, Holzgrabe U, Mueller MJ, Högger P. Profiling a gut microbiota-generated catechin metabolite’s fate in human blood cells using a metabolomic approach. J Pharm Biomed Anal 2015;10:114e7. [31] Mülek M, Högger P. Highly sensitive analysis of polyphenols and their metabolites in human blood cells using dispersive SPE extraction and LC-MS/MS. Anal Bioanal Chem 2015;407:1885e99. [32] Petrassi C, Mastromarino A, Spartera C. Pycnogenol in chronic in chronic venous insufficiency. Phytomedicine 2000;(5):383e8. [33] Rabassa M, Cherubini A, Zamora-Ros R, Urpi-Sarda M, Bandinelli S, Ferrucci L, Andres-Lacueva C. Low levels of a urinary biomarker of dietary polyphenol are associated with substantial cognitive decline over a 3-year period in older adults: the invecchiare in chianti study. J Am Geriatr Soc May 2015;63(5):938e46. [34] Keenan WA, Melinda PC, Rebecca GF. The relationship between hypertension, cognitive decline, and dementia: a review. Curr Hypertens Rep. 2017;19(3):24. [35] Rohdewald P. A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Int J Clin Pharmacol Ther April 2002b;40(4):158e68. [36] Ryan J, Croft K, Mori T, Wesnes K, Spong J, Doweney L, Kure C, Lloyd J, Stough C. Examination of the effects of the antioxidant Pycnogenol on cognitive performance, serum lipid profile, endocrinological and oxidative stress biomarkers in an elderly population. J Psychopharmacol 2008;(5):553e662. [37] Shea TB, Rogers E, Oritz D, Sheu MS, Ashline, Apoliporotein E. Deficiency promotes increased oxidative stress and compensatory increases in antioxidants. Free Radic Biol Med 2002;33(8):1115e20. [38] Shin I-S, Shin N-R, Jeon C-M, Hong J-M, Kwon O-K, Kim J-C, et al. Inhibitory effects of PycnogenolÒ (French maritime pine bark extract) on airway inflammation in ovalbumin-induced allergic asthma. Food Cosmet Toxicol 2013;62:681e6.

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[39] Simpson T, Deleuil S, Echeverria N, Komanduri M, Macpherson H, Suo C, Gondalia S, Fard MT, Pipingas A, Scholey A, Stough C. The Australian Research Council Longevity Intervention (ARCLI) study protocol (ANZCTR12611000487910) addendum: neuroimaging and gut microbiota protocol. Nutr J January 5, 2019a;18(1):1. [40] Simpson T, Kure C, Stough C. Assessing the efficacy and mechanisms of PycnogenolÒ on cognitive aging from in vitro animal and human studies. Front Pharmacol 2019b;10:694. [41] Simpson T, Pase M, Stough C. Bacopa monnieri as an antioxidant therapy to reduce oxidative stress in the aging brain. Evid Based Complement Alternative Med 2015. https://doi.org/10.1155/2015/ 615384. [42] Sohal RS, Orr WC. The redox stress hypothesis of aging. Free Radic Biol Med 2012;52:539e55. [43] Spadea L, Balestrazzi E. Treatment of vascular retinopathies with PycnogenolÒ. Phytother Res 2001;15(3):219e23. https://doi.org/ 10.1002/ptr.853. [44] Stanislavov R, Nikolova V. Treatment of erectile dysfunction with Pycnogenol and l-arginine. J Sex Marital Ther 2003;29(3):207e13. [45] Todd M, Schneper L, Vasunilashorn SM, Notterman D, Ullman MT, Goldman N. Apolipoprotein E, Cognitive function, and cognitive decline among older Taiwanese adults. PLoS One 2018b;13(10).

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Chapter 24

Advancements in delivery of herbal drugs for cognitive disorders Nidhi Prakash Sapkal1, 2 and Anwar Siraj Daud2 1

Department of Pharmaceutical Chemistry, Gurunanak College of Pharmacy, Nagpur, Maharashtra, India; 2Zim Laboratories Limited, Nagpur,

Maharashtra, India

Chapter outline Introduction Herbal drugs in neurological health Factors limiting brain delivery of herbal products Advancements in the brain delivery technologies Coadministration of efficacy enhancers Solid polymeric nanoparticles Lipid-mediated carrier systems

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Introduction The recent rise in prevalence of neurological conditions is alarming [1,2]as these conditions now contribute significantly to the global disease burden. According to a study in the Lancet Neurology, neurological disorders are the leading cause of disability-adjusted life years and the second leading cause of death [3]. Although the cases of infectious neurological conditions like tetanus, meningitis, and encephalitis have reduced very significantly, the occurrence of degenerative conditions such as Alzheimer (AD), Parkinson, motor neuron diseases, and CNS cancer, have risen. Several reports about the prevalence and epidemiology of these degenerative disorders show that diseases like AD, other dementia, and Parkinson are higher in older age groups. Thus, it is evident that though neurological diseases caused by microbial infections have become increasingly curable, the age-related diseases that are growing due to increasing life expectancy continue to pose a challenge to the scientific community. In the early days of pharmaceutical research, the focus was on the treatment of infectious diseases as they were a

Nutraceuticals in Brain Health and Beyond. https://doi.org/10.1016/B978-0-12-820593-8.00024-0 Copyright © 2021 Elsevier Inc. All rights reserved.

Miscellaneous nanocarriers Industrial applicability of these novel technologies and commercial viability Regulatory challenges Conclusion References

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major cause of death. However, with time, advancements in technology brought about major socioeconomic and cultural changes. This has led to a remarkable change in our lifestyle, which in turn has resulted in newer diseases. Therefore, the focus of research shifted to treatment of lifestyle diseases like diabetes, hypertension, metabolic syndrome, etc. Further, with increased life expectancy, there is again a shift in the disease pattern to diseases that only emerge beyond a certain age. These age-related degenerative conditions have never been studied as the number of people living beyond 80 years, which is the target age group of sufferers, was never quite as large. It is only now that research efforts are closing the gap to understanding the pathology behind these disorders. The scientific community is still trying to find the exact causes for these age-related pathological changes and connecting them to environmental and societal factors. Meanwhile these diseases are being treated symptomatically or with limited knowledge about the origins and progression of the condition. AD is one such neurological condition, more common in elderly patients, with the risk increasing every year past

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the age of 60. The pathology of this disease is not clearly understood and therefore available treatment options are not effective [3,4]. There are currently only four approved drugs for the treatment of ADddonepezil, rivastigmine, memantine, and galantamine. However, none of these drugs has been found to significantly improve the life or life span of AD patients [4]. Nature has always been a trusted resource for the discovery of new drugs for mankind. Many scientists have turned to studying natural therapies for the treatment of these less understood diseases [5,6]. Several reviews are published on the importance of natural agents as the potential molecules in the treatment of many diseases including neurological disorders [7,8]. Many published studies explain the role of these agents in the treatment of diseases convincingly. However, as in the case of synthetic drugs, the clinical success rate of these herbal drugs is limited. The variability in success rates depends not only on biological effects of the molecules but also on several factors related to physicochemical properties of molecule, route, and mode/method of delivery. Application of drug delivery science may therefore help to convert molecules with limited utility (due to their poor physicochemical properties) into agents of choice in the treatment of many diseases. Researchers are now working on developing effective drug delivery systems for many herbal drugs. In the present chapter we are using AD as the model neurological disorder because of its high prevalence, and we shall discuss the different delivery systems that can help turn herbal drugs into potentially useful agents for the clinical treatment of AD.

Herbal drugs in neurological health Certain herbal drugs have become a treatment of choice due to their efficacy in a particular disease. For instance, in dengue, papaya extract capsules are the only available treatment option. In chemotherapy-induced oral mucositis, curcumin gel is frequently prescribed for the treatment of mouth ulcers; Shankhpushpi and Brahmi are well-known nerve tonics; citrus bioflavonoids are the only known treatment for hemorrhoids. Several other herbal treatment options are available and widely used for purposes such as controlling blood sugar, reversing aging, correcting metabolism, and managing weight. Further, patient acceptance for herbal products is greater than that for synthetic products. Since most herbs and herbal products have traditional use, their safety profile is reasonably established. Therefore, herbal drugs can be launched faster than synthetic drugs. In folklore, several plants have the status of treatment options in managing neurological/nerve health. Now systematic scientific studies validating the efficacy of these plants’ extracts/single constituents as the agents for the

prevention and treatment of neurological diseases have been reported. Since this chapter is focused on the delivery of herbal drugs for cognitive disorders in general and AD in particular, Table 24.1 enlists all those plant extracts/single constituents that have displayed promising ability as a treatment option for AD in various in vitro and in vivo models.

Factors limiting brain delivery of herbal products The information given in Table 24.1 highlights the fact that although many of the herbal drugs have been studied for the treatment of AD in various in vitro and in vivo studies performed in animal models, their utility as a drug product is limited due to the three factors listed in Table 24.2. Firstly, most of these molecules are highly lipophilic, which limits their aqueous solubility. Due to an overall low dissolution of the drug product in the gastrointestinal region, the bioavailability is reduced. Curcumin is the leading example of this phenomenon. Secondly, many of these molecules degrade rapidly not only in the gastrointestinal tract but also after absorption into the systemic circulation. These molecules are prone to phase I and phase II metabolic reactions in the liver. As a result of extensive metabolism, the drug does not reach therapeutic concentration in the body. Rosmarinic acid, ginkgolides, resveratrol, ECG, and chrysin are the examples of drugs that undergo rapid first-pass metabolism. Thirdly, not all drugs can penetrate blood-brain barrier (BBB), an important neuroprotective barrier in the body designed to protect the central nervous system (CNS). This prevents all the large molecules and many of the small molecules from reaching the CNS. Since AD affects CNS tissue, a molecule must cross BBB for efficacy. Though some of the factors that limit molecules as potential drug candidates are easy to address, for instance, poor solubility or metabolic instability, the complexity of developing herbal drug delivery systems for neurological diseases lies mainly in developing systems that enable drugs to cross the BBB and reach the CNS tissue. This limitation affects most potential agents, for example, herbal drugs like curcumin, resveratrol, chrysin, etc., demonstrate great potential in the treatment of brain diseases in various in vitro and in vivo studies, but failed during clinical trials because of the poor brain delivery. The literature is full of established techniques for improving solubility of a molecule. Some techniques for protecting the drug from the metabolism have also been reported such as nanotechnology or use of alternate route of administration. Reported techniques to improve molecular transport across the BBB include use of various active transport mechanisms, nanotechnology, inhibition of efflux

TABLE 24.1 Herbal drugs useful in AD: Pharmacologic actions and limitations. Curcumin (Source: Rhizomes of Curcuma longa) Pharmacological activity: l binds to pleated amyloids [9]; l inhibits tau aggregates, tau-induced neuronal dysfunction in nematodes [10], reduces neuritic abnormalities [11e13]; l corrects defects of heat shock proteins; l oral administration in AD animal models inhibits AÒ deposition. Limitations for brain delivery: l unstable in aqueous solution at pH 7 and above; l very hydrophobic and not water insoluble at acidic pH; l rapid first pass clearance owing to glucuronidation/sulfation of phenolic groups.

2

Resveratrol (Source: fruits of grapes, blueberries, raspberries, mulberries, peanuts, etc.) Pharmacological activity: l antiaging effect in yeast [14], l delays neurofibrillary degeneration in invertebrates and vertebrates [15,16]; l improves moto-neuron functions in mice [17]; l improves learning and memory in mice [18]; l antiinflammatory and protects BBB in AD rats [19]. Limitations for brain delivery: l low aqueous solubility; l poor chemical stability; l rapid first pass metabolism.

3

Chrysin (Source: honey, propolis, passion flowers, flowers of other plants, etc.) Pharmacological activity: l neuroprotective in rats [20]; l improves cognitive/motor deficits and prevents neuronal cell death in rat model [21,22]; l prevents brain damage in mouse model caused by cerebral ischemia [23]; l antiinflammatory activity in the neuronal region [24,25] reduces activation of microglia, inhibits release of nitric oxide and TNF-a, inhibits NO synthase and cyclooxygenase-2 [26]; l prevents age-related memory decline and the activity of biomarkers like reactive species, superoxide dismutase, catalase, glutathione peroxidase, and brain-derived neuropathic factors [27,28]. Limitations for brain delivery: l poor bioavailability; l low oral bioavailability; l extensive metabolism and efflux of metabolites back into the intestine for hydrolysis and fecal elimination [29].

4

Epigallocatechin-3-gallate (Source: Camellia sinensis) Pharmacological activity: l protective against brain edema and neuronal damage after unilateral cerebral ischemia in gerbils [30]; l impairs Ab formation and accumulation by inhibiting APP proteolysis and by inhibiting cAbl/FE65 complex nuclear translocation and GSK3 activation [31e33]; l prevents memory impairment, reduces inflammation, oxidative stress, apoptotic neuronal cell death, and microglia activation [34]. Limitations for brain delivery: l high instability results in low bioavailability although it crosses blood-brain barrier to reach the functional parts of the brain [35].

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Advancements in delivery of herbal drugs for cognitive disorders Chapter | 24

1

TABLE 24.1 Herbal drugs useful in AD: Pharmacologic actions and limitations.dcont’d Ginkgolides (Source:Ginkgo biloba) Pharmacological activity: l improves learning and memory in rats with vascular dementia [36,37]; l mitigates neurotoxicity induced by acrylamide, and promotes neuronal regeneration in the hippocampus of acrylamide-treated mice [38]; l improves behavioral performance [39e41]. Limitations for brain delivery: l poor solubility, low bioavailability ( US$ 800 billion, which translates into 1.1% of global gross domestic product (GDP) [97]. The total cost as a proportion of GDP varied from 0.2% in the low- and middle-income countries to 1.4% in the high-income countries. Dementia can be highly distressing for the families of affected people and for their caregivers [98]. On the other hand, the diseased families frequently experience physical, emotional, and financial pressures that can cause excessive stress to families and caregivers [6]. This necessitates a vital support system in terms of health, social, financial, and legal assistance not only to the patients but also to the affected families [99]. It is often noticed that people with dementia are frequently denied with their fundamental rights and freedoms that are generally available to common citizens. In many countries, physical and chemical restraints are extensively used in care homes for older people. Despite the regulation in place to uphold the rights of people to freedom and choice, many restrictions are imposed in acute-care settings. Therefore, an appropriate support system based on the globally acceptable standards of human rights is required to ensure the appropriate care for people with dementia and their caregivers. World Health Organization (WHO) recognizes dementia as a critical health condition and should be considered as a public health priority. To augment the efforts to minimize the occurrence of dementia, the World Health Assembly has endorsed a Global action plan on the public health response to dementia 2017e2025 [100,101]. The draft of the action plan provides a comprehensive blueprint for policy-makers, international, regional and national agencies for increasing awareness about dementia and the efforts to establish dementia-friendly initiatives for reducing the risk of dementia through accurate diagnosis, treatment, and care as well as support for dementia caregivers, and research and innovation [102].

Management and care of patients suffering with AD As dementia is becoming a global threat for the elderly population, the effort has been all-around to moderate the disease symptoms and provide guidelines for the disease management from time to time. However, AD is growing worldwide as a serious health problem, became the focus for

the evaluation of novel molecules and repurposing of existing therapeutics. For the last 3 decades, tremendous efforts have been channelized toward designing dietary formulations with promising characteristics in the prevention and treatment of age-related diseases. The principal goals for dementia care are [102,103]; 1. Early diagnosis in order to promote early and optimal management, 2. Optimizing physical health, cognition, activity, and well-being, 3. Identifying and treating accompanying physical illness, 4. Distinguishing and treating challenging behavioral and psychological symptoms, providing information and long-term support to caregivers. In the recent past, several chemical substances belonging to the class of natural dietary origin display protective and healthpromoting activities against AD and some age-related neurodegenerative diseases.

Treatment and care At present, there is no effective treatment currently available to cure AD or to alter the progressive neurodegeneration. Numerous new treatments are being investigated, and the therapeutic formulations are in various stages of clinical trials. However, several innovative support systems need to be implemented in order to improve the lives of people with dementia, their caregivers and families. The pharmaceutical industries have not been able to design or discover new drugs that have had a significant impact on the natural history of the disease. Therefore, in the recent past, considerable attention is being paid toward the amalgamation of many nutritional bioactive compounds that can be useful in alleviating the disease symptom in addition to provide fundamental nutrition [104]. These bioactive molecules are frequently isolated and purified directly from diet or supplementation. These compounds may be able to modify physiopathological processes responsible for neurodegeneration and/or to have procognitive properties [105e107]. Such dietary compounds, known as nutraceuticals, act at different biochemical and metabolic levels and have shown different types of neuroprotective properties. The knowledge obtained from numerous observational studies, clinical trials, and Randomized Controlled Trials (RCTs) in humans, suggests that these nutraceuticals can be successfully incorporated routine diet to protect from AD [108]. We report results from studies on flavonoids, some vitamins, and other natural substances that have been studied in AD, and that might be beneficial for the maintenance of a good cognitive performance [109]. Due to the substantial lack of high-level evidence studies, there is no possibility for the recommendation of nutraceuticals in dementia-related therapeutic guidelines [108]. Nevertheless, the strong potential for their neuroprotective action warrants further studies in the field [108].

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Nutraceuticals: an emerging trend in disease management There has been an increasing interest in the past decades about interventions that may help to improve cognitive performance in older age or, at least, delay the onset of dementia. Due to the absence of a cure against dementia and AD, the public health priority has focused more recently on the prevention of cognitive decline [110]. Therefore, lifestyle strategies with beneficial effects on neurodegeneration and vascularitydincluding natural nutrition and nutritional supplementation, cognitive and social activity, physical exercisedhave been identified as possible target options for AD prevention [108]. The effect of a correct diet on human health has been reported in many epidemiological studies and RCTs [108,110,111]. There is clear cut evidence that suggest that the diet rich in specific nutritional components is helpful in reducing the incidence and prevalence of various clinical outcomes, such as cardiovascular diseases, diabetes, cancer, etc. [105]. These specific nutritional food groups are specifically rich in essential micronutrients and vitamins so that they can provide fundamental nutrition and beneficial health-promoting effect similar to pharmaceuticals [112]. Such combinations are often defined as nutraceuticals. Among different types of diet, the Mediterranean diet patterns gain the highest score for their health-promoting effect [113]. Results of large epidemiological and bench studies have shown its high content in nutraceuticals in Mediterranean diets. These diet arrangements are characterized by high consumption of plant foods, fish, olive oil as primary sources of monounsaturated fat and moderate intake of wine. This kind of food intake pattern might be particularly healthy due to the synergistic actions of its components. It is usually believed that the synergistic mechanisms between different food components are responsible for their neuroprotective effects. The onset of several pathological conditions, such as cardiovascular diseases, diabetes mellitus, hypertension, and lipid disorders are highly vulnerable to change in the micronutrient levels. Hence, the nutraceuticals formulations with an appropriate balance of micronutrients and vitamins would have a therapeutic effect. A large number of studies have confirmed that the Mediterranean dietary pattern put forth its beneficial effects against mild cognitive impairment (MCI) and AD [114]. In other words, nutraceuticals are the foods, or the food components, that offer comprehensive medical or health benefits, including prevention and treatment of several diseases [113]. Such preparations or compounds possess antioxidant, antiinflammatory, antimicrobial, antihypertensive, and anticancer properties, as well as they play regulatory roles for intracellular and extracellular signaling pathways [115]. The nutraceuticals market has significantly grown in the last decade due to increased information and awareness about

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these compounds in the prevention and cure of numerous diseases. Evaluating the precise role of nutrition and food supplementation on decreasing the risk of developing AD and other neurodegenerative diseases seems to be quite difficult. Generally, the older population displays poor dietary intake of fruits and vegetables, unhealthy behavior, and higher prevalence of cerebrovascular disease, therefore, the establishment of direct correlations are are the real challenges. Furthermore, the impartial studies, like RCT of nutritional supplementation and its effects on cognition, are very much limited.

Dietary components of nutraceuticals Vitamins As stated previously, the available information for determining the association between cognitive impairment and vitamin intake has some limitations [116]. Vitamins A, C, and E are considered to be robust antioxidants. Since reactive oxygen species (ROS) are associated with neuronal damage in AD, the inclusion of these vitamins could offer a therapeutic effect in AD management [117e119]. Antioxidants in food and supplements have been extensively investigated in relation to prevention and management of AD [120]. These antioxidants include tocopherol (vitamin E), ascorbic acid (vitamin C), and carotenes (vitamin A). Under in vitro conditions, vitamin E decreases lipid peroxidation and oxidative stress and interferes with the inflammation related-signaling cascades [109,119]. Vitamin C is known to prevent the formation of nitrosamines through the reduction of nitrites and may also affect catecholamine synthesis, whereas the presence of carotenes known to adversely affect lipid peroxidation [109,119]. There are several studies with different methodologies relating to the consumption antioxidant and their effect on cognitive impairment. By considering these limitations, there is some evidence from observational studies that advocate dietary intake of antioxidants is associated with the reduction in stroke risk; however, the controlled clinical trials with antioxidant supplementation did not show any decline in the risk of stroke [121]. The same is valid for the antioxidant effect on cognitive decline and dementia. The recent meta-analysis of observational studies concluded that the dietary intakes of vitamin E, vitamin C, and b-carotene can lower the risk of AD, with vitamin E exhibiting the most pronounced protective effect [121,122]. Generally, the plasma concentration of vitamin C < 11 mM is considered to be deficient, 11e28 mM is depleted or marginally deficient, 28e40 mM is adequate, and >40 mM is optimal [123]. Vitamin C is considered to be the most effective antioxidant in body fluid due to its high water solubility and wide range of ROS activities. Since ROS and oxidative stress associated with AD pathophysiology, there

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have been some studies on the possible role of vitamin C is anticipated in AD prevention [124]. Dixit et al. showed that the administration of a single dose of intravenous vitamin C improved short-term spatial memory in middle age (9 months old) APP/PSEN1 mice [125]. The role of vitamin E in alleviating the AD symptoms has been controversial, with several observational studies. Many investigations have shown that vitamin E is helpful in reducing the risk of AD and related dementias. Controlled trials using supplementation of vitamin E have shown a reduction of risk, nevertheless, no noticeable improvement in cognition was observed in healthy older women (>65 years) or in the patients of mild cognitive impairment [126]. On the other hand, supplementation of the vitamin with doses higher than 400 UI is not recommended as it is associated with an increased rate of mortality. In addition, the supplementation of vitamin E displayed antioxidant activities only in half of the treated patients, possibly due to unbalanced monotherapy. Furthermore, the optimum activity of vitamin E requires a water-soluble electron acceptor to expedite the removal of ROS [119]. This can usually be achieved by supplementation of selenium or vitamin C [119]. Two vital studies suggest the beneficial effect of high-dose vitamin E (2000 UI a day) in AD patients. In the first one, Sano et al. claimed to slow down the progression of AD with during 2 years follow up of investigation. In the second study, Dysken et al. suggest that administration of vitamin E was helpful a reducing the deterioration of functional abilities and hence was useful in decreasing the burden of the caregiver of mild to moderate AD patients [127]. Supplementation of b-carotene, a precursor of vitamin A, showed a substantial reduction in cognition impairment [128]. Increased level of homocysteine, an amino acid, is a precursor of methionine and cysteine, often linked with increased risk of cerebrovascular events, poor cognitive performance and commencement of AD. It has been shown that the daily supplementation of vitamin B6, B12, and folic acid reduced the increased levels of homocysteine [129]. A recent meta-analysis study suggested that the supplementation of vitamins B12 and B6 with folic acid resulted in the reduction of cognitive decline, in patients with or without previous cognitive impairment, with or without stroke [130].

Phytochemicals Phytochemicals are secondary metabolites exclusively produced by plants and microbes [131]. They possess neuroprotective potential, and hence, constitute an essential component of nutraceuticals specifically to prevent and cure AD [132]. As previously stated, increased oxidative stress due to the overproduction of ROS is one of the pathological outcomes of AD [133,134]. Hence mitigating

the ROS induced cell damage constitutes one of the core objectives for designing antiAD nutraceuticals [134]. A wide range of well-known nutritional compounds with enriched antioxidant properties including vitamins C and E, carotenoids, flavonoids, polyphenols, and some enzymes (such as catalase, superoxide dismutase, and various peroxidases) [135]. Within these compounds, more emphasis has been given to those biomolecules that have been extensively researched for their antiamyloid and neuroprotective properties [135].

Flavonoids Flavonoids are mostly synthesized by plants as secondary metabolites, and they represent the group of most explored biomolecules for numerous health benefits. They belong to a group of polyphenolic compounds that are commonly found in the routine human diet [131]. Cacao, tea, fruits, vegetables, and other plants are a good source of dietary flavonoids. Depending upon their chemical structures, they can be divided into various subgroups. These molecules have been extensively researched and found to have a beneficial effect on several neurological processes, such as maintenance of neuronal, glial signaling pathways that is essential for neuronal survival and proper function. Flavonoids are also known to increase cerebral blood flow, expression of antioxidant enzymes, and various proteins and signaling molecules, which play a vital role in maintaining synaptic plasticity and neuronal repair [134]. On the other hand, they have also been involved in interfering with several neuropathological processes, which are responsible for AD pathogenesis [136].

Flavanols Flavanols are a main flavonoid group and are found in cocoa and chocolate, as well as in black and in grapes [137] and green tea [138]. Research over the past decade has identified flavanols as showing diverse beneficial physiologic and antioxidant effects, particularly in the context of vascular function. Catechin and epicatechin are the most abundant flavanols in grape seeds and grape juice. A study on supplementation of grape juice from a variety of Vitis vinifera called “Koshu” found to inhibit glutamate excitotoxicity [139]. Few clinical trials in humans suggest that short and moderate-term supplementation with grape juice produces benefits in individuals with cerebrovascular diseases, including increased serum antioxidant capacity, and reduced LDL oxidation, improvement of endothelial function and reduction of platelet aggregation [140,141]. Quercetin is another most studied bioflavonoids, is found in many common foods, such as capers, apples, onions, and green tea. It is a highly potent antioxidant, and hence, useful in preventing endothelial apoptosis caused by

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increased ROS. There are several in vitro studies where quercetin has demonstrated its ability to increase the cell survival under neurotoxic conditions. In vivo studies have demonstrated that quercetin could have a positive role in vascular dementia by decreasing the size of ischemic lesions. Quercetin is reported to improve memory and hippocampal synaptic plasticity in models of cognitive impairment induced by chronic lead exposure. Further, it has the ability to induce repair in neuronal cells damaged by spinal cord injury. Kaempferol is another widely distributed biomolecule and commonly present in the daily human diet in the form of fruits, beverages, tea, and vegetables [135]. Isolated kaempferol possesses the ability to protects PC12 cells against the oxidative stress induced by H2O2 and improves cognitive learning and memory capability in animal models. It was reported that the intake of flavonols, including quercetin, kaempferol, and myricetin has favorable effects on cognitive performance. Traditionally, there are several plants that have been used since time immemorial for the extraction and purification of many vital ingredients with the potential to relieve symptoms of many diseases. Few representative plants and their phytochemicals with neuroprotective and antiamyloid potential are being discussed. Tea (Camilla sinensis) leaves extract: A number of vital phytochemicals have been isolated from the leaves of tea plants. (-)-Epigallocathechin-3-gallate (EGCG) is the key polyphenol extracted from the tea plant (Camilla sinensis) and known to bind a large number of proteins that are usually involved in various protein misfolding diseases and inhibits their fibrillation [138]. It possesses a number of potential health-promoting principles, including antiinflammatory, antioxidant, and anticancer, as well as anti-ageing activities [142]. In recent times the consumption of green tea has been considerably increased due to awareness about its multiple healthpromoting effects. A typical cup of tea containing 2.5 g of tea leaves in 250 mL of hot water usually contains roughly 177 mg of EGCG. Reports that emerged from several studies suggest that EGCG has tremendous antiAD potential. A study (involving murine neuron-like cells (N2a) transfected with amyloid precursor protein (APP) and primary neurons derived from APP-overexpressing mice), showed that the application of EGCG inhibited Ab generation and prevented the learning and memory impairments [143]. Another study also suggested that the oral administration EGCG substantially improved the cognitive losses and reduced the neuronal apoptosis in the APP/PS1 mice [144]. Additionally, daily intake of EGCG by hypertensive rats reduced the progressive increase of oxidative stress and also decreased the concentration of reactive oxygen species on the hippocampus [145]. These results

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are of seminal importance from the point of view of its therapeutic application [134]. In an animal model, EGCG is shown to play a vital role in alleviating vascular-induced loss in learning ability and memory deficit [146]. EGCG is also an established powerful antioxidant, able to sequester iron and copper ions, and hence, neutralize their catalytic activities that lead to the production of ROS [134]. EGCG also displays activity against many inflammatory pathological conditions and able to easily cross the bloodbrain barrier [147], [148]. These properties render the EGCG as potential nutraceuticals that may be systematically implicated for the management of AD and other neurodegenerative disorders that includes oxidative stress insults and inflammation, which subsequently leads to cellular and neuronal death [138]. In addition to EGCG, both black and green teas usually contain a high concentration of other catechins. A number of different catechins demonstrated to have neuroprotective characteristics against various neuropathological conditions, including AD [149]. Despite the lack of clinical trials with tea polyphenols in neurodegenerative diseases, epidemiological observations in US and Finnish populations showed a reduced risk of Parkinson’s disease in high consumers of tea and a reduced risk of cognitive impairment in a Japanese population drinking green tea [149e151]. Ginkgo biloba (Gb) extract Gb extract is commonly used for the prevention and treatment of AD [152]. Extract from Gb leaves, and other preparations mainly consist of terpenoids, flavonol glycosides, and proanthocyanidins. Increased cerebral blood flow and nitric oxide production in vessels and inhibition of platelet-activating factors are thought to be the mechanism of neuroprotection [153]. In studies involving animal models of AD, Gb extract was found to ameliorate Ab(1e42) induced hippocampal neuron dysfunction and neuronal death. However, the clinal trials in the recent past have not yielded encouraging outcomes, and hence, more inclusive studies are needed to rich on decisive conclusion. Turmeric (Curcuma longa) Turmeric is a perennial herb, native to the monsoon forests of south-east Asia and belongs to the Zingiberaceae (ginger) family [154]. It is one of the most frequently used spices in Indian, Asian, and Middle Eastern foods [155e157]. Apart from being used as a cooking spice, it has often been recommended as herbal medicine against several diseases [158e160]. Traditionally, curcumin has been widely used in Indian (Ayurveda), Chinese, and Persian medicines for the treatment of pain associated with inflammation in skin and muscles [161,162]. It has also been regularly used for treatment and cure of asthma,

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allergy, anorexia, cough, sinusitis, hepatic diseases, etc [162,163]. Curcumin is a yellow pigment extracted from rhizomes of the plant and it is considered as one of the most active curcuminoids [164]. The 21st century has witnessed intensive interest in curcumin’s therapeutic properties, which has resulted in considerable scientific enquiry in connection with the development of traditional therapeutic formulations against various diseases. Numerous studies have established its powerful antiinflammatory properties [165]. For example, animal and cell culture studies show that curcumin reduces inflammation in arthritis. Curcumin is also found to be effective in the treatment of irritable bowel syndrome, psoriasis and other skin disorders [166]. Curcumin is also known for its antioxidant properties and acts as a powerful free-radical scavenger [167]. Due to its anti-inflammatory and antioxidant properties, curcumin has extensively been investigated to interfere with the pathways leading to the onset of AD and associated pathological outcomes [168]. Since, increased inflammation and oxidative stress in the central nervous system constitute early pathogenic events of AD, the antioxidant and anti-inflammatory potential of curcumin has logically been explored. As stated before, oxidative stress and inflammation, Ab aggregation, and hyperphosphorylation of Tau are recognized as hallmark pathological characteristics of AD [169,170]. It is also believed that abnormal metabolism of Ab results in the formation of soluble neurotoxic Ab oligomers, which are responsible for increased oxidative stress, inflammation that lead to formation of an AD pathogenic cycle of neurodegeneration [161,171]. In addition to its ability to interfere development of AD pathology through its anti-inflammatory and antioxidant properties, curcumin is known to bind with Ab peptide and interfere with its aggregation and deposition in the form of amyloid plaques [172,173]. Furthermore, it has also been shown to modulate Tau processing and aggregation, which constitutes a key event in AD pathogenesis [174]. While the initiating step of AD yet to be elucidated, the buildup of oxidative stress and inflammatory reactions are thought to begin decades before the first clinical symptoms become visible [175,176]. As stated before, Ab-induced pathological changes are believed to appear early in the disease development process, and the recent findings suggests that interferences that can interject the formation of Ab or aggregation of Ab to form oligomers will be a remarkable strategy for inhibition of aggregated Ab aggregation. Studies based on theoretical mathematical models in people over 60 years suggest that delaying the onset of AD pathology by 1 year may reduce the worldwide burden of the disease by approximately 10%, and 5 years delay could reduce the incidence by almost half [177]. Hence, the early preclinical evaluation and prevention therapy would have a phenomenal impact on interfering with the events that

could lead to buildup of cerebral Ab and Tau pathology, and/or oxidative stress and chronic inflammation. In this way, the delaying the pathological events would play phenomenal role in mitigation of the AD prevalence. Several in vitro studies have suggested that the formation of Ab is significantly reduced in the presence of curcumin [178]. Possibly, curcumin exerts its effect through the involvement in the altering of the APP processing through the secretory pathway. Furthermore, studies with various neuronal cell lines (e.g., pheochromocytoma cells, the PC12 cell line) presence of 3e30 mM curcumin suppressed Ab-induced BACE1 upregulation [179]. Most recently, it is evident that the presence of curcumin was useful in rescuing the flies from the Ab-induced morphological and behavioral defects in an AD Drosophila model [180]. Curcumin is reported to be a suitable metal ion chelator, and therefore, able to prevent the overexpression of APP and BACE1 induced by Cu(II) and Mn [179]. Due to the antioxidant nature of curcumin, it is suggested that it might be influencing the amyloid induced cytopathology, or macrophage processing of amyloid. A recent study suggests that curcumin helped in the reduction of plaque size by 30% after 7 days of intravenous injection of curcumin [181]. It has been reported that curcumin enhances phagocytosis of Ab and help in the restoration of the cognitive function, possibly by upregulating the expression of b-1,4mannosyl-glycoprotein 4b-N-acetylglucosaminyltransferase (MGAT3), which is involved in phagocytosis [182]. Therefore, it is argued that curcumin may be implicated in ameliorating the immune defects and cognitive deficiency in AD patients [183]. Cinnamon (Cinnamomum zeylanicum) (CZ) Cinnamon is a common spice used in different frequently parts of the world, including Sri Lanka, India, Madagascar, and Indo-China countries. Mostly, the inner bark of the tree has frequently been used in ethnic medicines, as well as the flavoring agent in food [184]. The antioxidant and antiinflammatory activity helps in boosting cognitive function [185]. Clinical studies have confirmed its beneficial effect during various complications related to plasma lipids and diabetes [186]. The antioxidant and antiinflammatory properties of cinnamon have been responsible for providing protection against the oxidative disorder by increasing the expression of antioxidants enzymes activities [187]. The antiamyloid nature of cinnamon is established by the inhibition of Tau aggregation and amyloid fibril formation. On the other hand, it stimulates disassembly of Tau fibrils isolated from the brains of those with AD. Interestingly, the normal cellular function of Tau protein was found to unaffected. [188].

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Black pepper (Piper nigrum L.) Black pepper has been used as a traditional medicine in many Middle-Eastern and Asian countries as a potential nerve tonic [189]. Piperine is one of the most abundant alkaloid phytochemicals of the family Piperaceae and has traditionally been used in folk medicine for the treatment of various neurodegenerative diseases such as cognitive impairment, including AD [190]. A recent study revealed that oral administration of piperine can improve memory deficit in a dose-dependent manner. In addition, the other members of the pepper family, including Piper methysticum, Piper submultinerve, and piper betel had been widely considered to have a neuroprotective effect. Mechanistically the black pepper extracts are shown to have an antiAD effect, and mechanistically it has been shown to protect neurons from Ab1-42-induced neurotoxicity. The antioxidant properties of piperine help in reducing oxidative stress in an experimentally induced AD model [191]. Several studies suggest that pepper extract also has the ability to inhibit Acetylcholinesterase (AChE) activity and helps in reducing lipid peroxidation [192]. The pepper extract also has antiamyloid activity. In the animal model, the administration piperine cocktail has shown to help in improvement in Ab-induced memory loss, and reduce the Ab levels in plaque deposition in the brain [193]. Ginger (Zingiber officinale) The rhizome of the ginger plant is known as a valuable source of various phytonutrients, and therefore, it has been extensively used in the preparation of many herbal remedies and formulations [194,195]. Gingerol and zingiberene are essential oils present in ginger, which gives characteristic aromatic aura and a pungent taste [196e198]. It has been reported that gingerol effectively suppressed the aggregation of Ab(25e35), an amyloidogenic fragment of Ab(1e40), reduced the Ab(25e35)-induced intracellular accumulation of reactive oxygen and/or nitrogen species [199]. It has also been anticipated that the treatment with gingerol results in induced expression antioxidant enzymes. 6-Shogaol, obtained from ginger, is known to modulate inflammatory reactions and suppress neuroinflammation [200]. The hexane extract of ginger has also found to inhibit the activities of proinflammatory mediators IL-1b and inflammatory factors, such as nitric oxide, prostaglandin E2 and TNF-a [201]. Other phytochemicals such as flavonoids, tannins, alkaloids, and terpenoids extracted from ginger display inhibitory effects on AChE, and also involved in the prevention of Fe2þ-induced lipid peroxidation [156,202,203]. Therefore, it is quite evident that the phytonutrients in ginger may provide potential leads for the development of novel anti-AD therapeutic strategies [204].

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Conclusions So far, the clinical trials of AD researches have not yielded any curative therapeutic strategies against AD. The major limitations associated with many active ingredients are broadly attributed to poor absorption and bioavailability, and maybe the timing and length of intervention studies. Pathogenesis of AD involves multiple pathways, and hence, a multifactorial approach will constitute a holistic therapeutic strategy. Increasing the bioavailability, bloodbrain barrier penetration, and sustaining the half-life constitutes the center of major attention. Researches pertaining to various oral formulations are lacking, and hence, it is an area for further investigation. On the one hand, the preclinical signs of AD appear decades before its clinical onset, and most of the time, the preventive measure becomes a limited approach. To date, most of the requirement is based on the mature and late-stage AD manifestation. On the other hand, it also opens a new window of opportunities to implicate the molecules that have shown antiAD properties should be incorporated in the daily routine at least for the individual above the age of 40 so that the disease can be prevented or delayed. It is equitable to embrace intervention studies for a longer duration with longitudinal followup by including healthy community-dwelling older adults along with distinctive memory deficient individuals. Moreover, discovery of novel biomarkers related to AD and neuroimaging would be a further addition in rationalizing the clinical significance of nutraceuticals’ efficacy in the prevention of AD-associated cognitive deterioration. Although spices have been essential ingredients of many Indian foods and have been in use for more than 2000 years, their health-promoting properties have been extensively examined recently. Most of the spices contain many active ingredients that show anti-AChE, antioxidants, antiinflammatory properties, which are essential for the development of successful nutraceuticals as novel formulation agents against AD. On the other hand, specific nutrients need to be consumed along with routine diet to allow the stabilization of undesirable biochemical reactions and the formation of toxic substances leading to neurodegeneration and cell death. There is a need for large clinical trials to examine the therapeutic potential of these spices and their contribution in maintaining our cognitive functions as we age.

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[153] Savaskan E, Mueller H, Hoerr R, von Gunten A, Gauthier S. Treatment effects of Ginkgo biloba extract EGb 761(R) on the spectrum of behavioral and psychological symptoms of dementia: meta-analysis of randomized controlled trials. Int Psychogeriatr 2018;30(3):285e93. [154] Nirmal Babu K, Divakaran M, Pillai GS, Sumathi V, Praveen K, Raj RP, Akshita HJ, Ravindran PN, Peter KV. Protocols for in vitro propagation, conservation, synthetic seed production, microrhizome production, and molecular profiling in turmeric (curcuma longa L. Methods Mol Biol 2016;1391:387e401. [155] Kim DS, Park SY, Kim JK. Curcuminoids from Curcuma longa L. (Zingiberaceae) that protect PC12 rat pheochromocytoma and normal human umbilical vein endothelial cells from betaA(1-42) insult. Neurosci Lett 2001;303(1):57e61. [156] Kuo JJ, Chang HH, Tsai TH, Lee TY. Curcumin ameliorates mitochondrial dysfunction associated with inhibition of gluconeogenesis in free fatty acid-mediated hepatic lipoapoptosis. Int J Mol Med 2012;30(3):643e9. [157] Tourkina E, Gooz P, Oates JC, Ludwicka-Bradley A, Silver RM, Hoffman S. Curcumin-induced apoptosis in scleroderma lung fibroblasts: role of protein kinase cepsilon. Am J Respir Cell Mol Biol 2004;31(1):28e35. [158] Irshad S, Muazzam A, Shahid Z, Dalrymple MB. Curcuma longa (Turmeric): an auspicious spice for antibacterial, phytochemical and antioxidant activities. Pak J Pharm Sci 2018;31(6):2689e96 (Supplementary). [159] Hatcher H, Planalp R, Cho J, Torti FM, Torti SV. Curcumin: from ancient medicine to current clinical trials. Cell Mol Life Sci 2008;65(11):1631e52. [160] Prasad S, Aggarwal BB. Turmeric, the golden spice: from traditional medicine to modern medicine. In: Benzie IFF, WachtelGalor S, editors. Herbal medicine: Biomolecular and clinical aspects; 2011. Boca Raton (FL). [161] da Costa IM, Freire MAM, de Paiva Cavalcanti JRL, de Araujo DP, Norrara B, Moreira Rosa IMM, de Azevedo EP, do Rego ACM, Filho IA, Guzen FP. Supplementation with curcuma longa reverses neurotoxic and behavioral damage in models of Alzheimer’s disease: a systematic review. Curr Neuropharmacol 2019;17(5):406e21. [162] Lee KS, Lee BS, Semnani S, Avanesian A, Um CY, Jeon HJ, Seong KM, Yu K, Min KJ, Jafari M. Curcumin extends life span, improves health span, and modulates the expression of ageassociated aging genes in Drosophila melanogaster. Rejuvenation Res 2010;13(5):561e70. [163] Tsuda T. Curcumin as a functional food-derived factor: degradation products, metabolites, bioactivity, and future perspectives. Food Func 2018;9(2):705e14. [164] Sharman MJ, Gyengesi E, Liang H, Chatterjee P, Karl T, Li QX, Wenk MR, Halliwell B, Martins RN, Munch G. Assessment of diets containing curcumin, epigallocatechin-3-gallate, docosahexaenoic acid and alpha-lipoic acid on amyloid load and inflammation in a male transgenic mouse model of Alzheimer’s disease: are combinations more effective? Neurobiol Dis 2019;124:505e19. [165] Kurien BT, Matsumoto H, Scofield RH. Nutraceutical value of pure curcumin. Phcog Mag 2017;13(Suppl. 1):S161e3. [166] Kunnumakkara AB, Bordoloi D, Padmavathi G, Monisha J, Roy NK, Prasad S, Aggarwal BB. Curcumin, the golden

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[184] [185] [186]

[187]

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[194] Langner E, Greifenberg S, Gruenwald J. Ginger: history and use. Adv Ther 1998;15(1):25e44. [195] Montserrat-de la Paz S, Garcia-Gimenez MD, Quilez AM, De la Puerta R, Fernandez-Arche A. Ginger rhizome enhances the antiinflammatory and anti-nociceptive effects of paracetamol in an experimental mouse model of fibromyalgia. Inflammopharmacology 2018;26(4):1093e101. [196] Chrubasik S, Pittler MH, Roufogalis BD. Zingiberis rhizoma: a comprehensive review on the ginger effect and efficacy profiles. Phytomedicine 2005;12(9):684e701. [197] Zhan K, Wang C, Xu K, Yin H. Analysis of volatile and nonvolatile compositions in ginger oleoresin by gas chromatographymass spectrometry. Chin J Chromatography 2008;26(6):692e6. [198] Sharifi-Rad M, Varoni EM, Salehi B, Sharifi-Rad J, Matthews KR, Ayatollahi SA, Kobarfard F, Ibrahim SA, Mnayer D, Zakaria ZA, Sharifi-Rad M, Yousaf Z, Iriti M, Basile A, Rigano D. Plants of the genus zingiber as a source of bioactive phytochemicals: from tradition to pharmacy. Molecules 2017;22(12). [199] Lee C, Park GH, Kim CY, Jang JH. [6]-Gingerol attenuates betaamyloid-induced oxidative cell death via fortifying cellular antioxidant defense system. Food Chem Toxicol 2011;49(6):1261e9. [200] Na JY, Song K, Lee JW, Kim S, Kwon J. 6-Shogaol has antiamyloidogenic activity and ameliorates Alzheimer’s disease via CysLT1R-mediated inhibition of cathepsin B. Biochem Biophys Res Commun 2016;477(1):96e102. [201] Park G, Oh DS, Lee MG, Lee CE, Kim YU. 6-Shogaol, an active compound of ginger, alleviates allergic dermatitis-like skin lesions via cytokine inhibition by activating the Nrf2 pathway. Toxicol Appl Pharmacol 2016;310:51e9. [202] Akinyemi AJ, Adeniyi PA. Effect of essential oils from ginger (zingiber officinale) and turmeric (curcuma longa) rhizomes on some inflammatory biomarkers in cadmium induced neurotoxicity in rats. J Toxicol 2018;2018:4109491. [203] Tung BT, Thu DK, Thu NTK, Hai NT. Antioxidant and acetylcholinesterase inhibitory activities of ginger root (Zingiber officinale Roscoe) extract. J Compl Integr Med 2017;14(4). [204] Azam F, Amer AM, Abulifa AR, Elzwawi MM. Ginger components as new leads for the design and development of novel multitargeted anti-Alzheimer’s drugs: a computational investigation. Drug Des Dev Ther 2014;8:2045e59.

Chapter 29

Nutraceuticals in brain health Swati Haldar1, Souvik Ghosh2, Viney Kumar2, Saakshi Saini2, Debrupa Lahiri1, 3 and Partha Roy1, 2 1

Centre of Nanotechnology, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India; 2Department of Biotechnology, Indian Institute of

Technology Roorkee, Roorkee, Uttarakhand, India; 3Department of Metallurgical and Materials Engineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, India

Chapter outline Introduction to nutraceuticals Historical perspective of nutraceuticals Origin and definition What all can be considered as nutraceuticals? Nutraceuticals for brain health from around the globe Indian traditional medicine Chinese traditional medicine Japanese traditional medicine African traditional medicine (ATM) Traditional Korean medicine (TKM) Traditional medicine of Latin America Nutraceutical and overall brain health: Traditional versus modern outlook Pathophysiology of neurodegenerative conditions Effects of nutraceuticals on neurodegenerative conditions Bacopa monnieri (Brahmi) Ginkgo biloba Withania somnifera (Ashwagandha or Indian ginseng) Convolvulus pluricaulis Centella asiatica (gotu kola) Acorus calamus (sweet flag) Celastrus paniculatus Hemidesmus indicus Trapa bispinosa (water chestnut) Holy basil Semecarpus anacardium (Bhallaatak) Nardostachys jatamansi (spikenard or jatamansi)

409 409 410 410 411 411 411 411 411 412 413 413 414 414 415 415 416 416 416 416 416 416 416 416 416 417

Introduction to nutraceuticals Historical perspective of nutraceuticals According to Oxford Dictionary “nutraceutical,” is a portmanteau derived from the words “nutrition” and “pharmaceutical,” and is “another term for functional food” where functional food is “a food containing health-giving additives.” Plants have been used to treat medical conditions throughout

Nutraceuticals in Brain Health and Beyond. https://doi.org/10.1016/B978-0-12-820593-8.00029-X Copyright © 2021 Elsevier Inc. All rights reserved.

Panax ginseng (ginseng) Clitoria ternatea Coriandrum sativum (coriander or cilantro) Curcumin Resveratrol Lycium barbarum (Wolfberry) Dietary supplements Traditional versus modern outlook on nutraceuticals Mediterranean diet (MD) Asian diet Mechanistic insights into nutraceuticals functioning as protectors of brain health Nutraceuticals targeting mitochondrial dysfunction Nutraceuticals targeting misfolded protein aggregation Nutraceuticals targeting oxidative stress Nutraceuticals targeting neuro-inflammation Nutraceuticals as neurotransmitter modulators Nutraceuticals from an evolutionary perspective Cross-talk between brain and gut Brain and gastronomic evolutions were simultaneous Do nutraceuticals have ethnic biasness when it comes to their effectivities? Mode of nutraceutical consumption: Food versus dietary supplements Conclusion References

417 417 417 417 417 417 417 417 420 421 422 422 424 424 426 427 427 428 429 429 429 430 430

human history. Nutraceuticals have their historic roots traceable to apothecary, herbalism, ethnopharmacology, phytotherapy, and alternative medicines. The rational use of medicines made the apothecarist a pharmacist, the quest for principles of drug action ensued and eventually, development of therapeutics and modern drug with clinical trials dawned. The term “drug” has its origin in the French word “drogue” meaning dried herb [1]. 409

410 Nutraceuticals in Brain Health and Beyond

Indian traditional medicine system is a treasure trove of health and medical knowledge and can boast of various healing procedures, namely Ayurveda, Unani, Siddha and Ashtavaidya. Ancient Indian Ayurvedic texts like Charaka Samhita, Susrutha Samhita, and Ashtangahrdayam, dating back to 371e287 BC are still the infallible epitome of medicine and surgery systems [2]. The contents of these texts have survived the trials and tribulations of historical unrest, skepticism of the wave of modern medical science, and gloriously re-emerged as the knowledge base like none other. Recognizing the wealth of knowledge these ancient medicinal systems hold, a Traditional Knowledge Digital Library (TKDL) was created by the Council of Scientific and Industrial Research, Government of India, to ensure their accessibility to the world in comprehensible formats [3,4]. Eastern hemisphere has been truly the cradle of ancient civilizations as evident from a similar and equally enriched medicine system of China recorded by Li Shizhen during the Ming Dynasty (AD 1368e1644) in the Compendium of Materia Medica, traditionally also referred to as Bencao Gangmu or Pen-tsao Kang-mu. The knowledge of Chinese herbal medicine was further developed into Kampo medicine of Japan, known for managing nervous system conditions. Japanese national healthcare system includes herbal medicines as pharmaceutical preparations [1]. Knowledge of nutraceuticals has been always there around the globe in one or the other form of traditional medicinal systems and more importantly, very efficiently integrated into the traditional lifestyles of different human races. However, with modernization, nutraceuticals disappeared from human lifestyle, resulting in serious health issues over time. Thus, it is difficult to demarcate the disappearance and readvent of nutraceuticals in the timeline of modern medicine. Nevertheless, the legendary publications by Jim Joseph and colleagues [5,6], describing behavioral and cognitive improvements due to blueberry, spinach, or strawberry dietary supplements, were instrumental in repopularizing the significance of nutraceuticals to a newer human generation. There has been a gap in the transmission of traditional knowledge down the generations that has cost the human race heavily, and we still do not know for how long and for how many generations we will be paying for this with our health and that of our progenies. This chapter is dedicated towards understanding the role of nutraceuticals in maintaining brain health. Therefore, we will be focusing on the nutraceuticals, in the form of conventional foods and dietary supplements with direct brain health benefits like delayed aging, reduced or no sideeffects, maintained brain activities resulting in increased life expectancy and preserving an overall healthy brain physiology. Over-the-counter as well as prescription drugs used for symptomatically treating brain disorders can be

detrimental to the very purpose they are meant to serve. They can induce oxidative stress leading to a cascade of other deleterious effects like chronic inflammation, mitochondrial dysfunction, DNA damage, and eventual loss of synaptic plasticity [1] (Fig. 29.1).

Origin and definition The term “Nutraceutical” was proposed by Dr. Stephen L. De Felice in 1989, the founder Chairman of the American organization, The Foundation for Innovation in Medicine [7]. Health Canada defined nutraceutical as “a product prepared from foods, but sold in the form of pills, or powder (potions) or in other medicinal forms, not usually associated with foods” [8]. Thus, nutraceuticals have both the medicinal as well as the nutritional values. Ayurveda, the 5000year-old ancient Indian system of medicine, supports this fact till date. The overall health status of the human race is being threatened due to increasing encroachment by a multitude of diseases, some of which are very difficult to treat and some even untreatable. This emergent situation has led to a renaissance in nutrition research exhaustively exploring the disease-fighting potentials of phytochemicals from both food and non-food plants [9].

What all can be considered as nutraceuticals? Nutraceuticals can be herbs, nutrients, or dietary supplements. Thus, nutraceuticals can be both traditional and nontraditional. Traditional nutraceuticals are natural products, with known potential health qualities and are not subjected to any chemical alteration before consumption. These include several fruits, vegetables, grains, soy, tea, chocolate, fish, dairy, and meat products. Nontraditional nutraceuticals result from agricultural breeding, genetic modifications, or added nutrients and/or ingredients. For example, extracted fruit juices with added calcium and cereals with vitamins or other nutrients added. Therefore, nutraceuticals have various sources, like, the food industry, the herbal and dietary supplement market, the pharmaceutical industry, and even, the newly merged pharmaceutical/ agribusiness/nutrition conglomerates. Nutraceuticals can be isolated nutrients, herbal products, dietary supplements and diets, even genetically engineered “designer” foods and processed products such as cereals, soups, and beverages. For example, many food products, categorized as polyunsaturated fatty acids (PUFA), dietary fiber, probiotics, prebiotics, flavonoids, and other herbal extracts are nutraceuticals [10]. The concept of nutraceutical is inspired by the famous saying of the father of medicine, Hippocrates (460e370 BC), “Let food be your medicine, and medicine be your food” [11].

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FIGURE 29.1 Potential benefits of nutraceuticals in brain dysfunction. Nutraceuticals have more than nutritional value. Their synergistic actions subtly influence key cellular signaling that favors improved neuronal function. Medicine is an independent molecule designed to act specifically on one target, is used at higher doses and which over prolonged use adversely affects normal cellular functions, even leading to cellular toxicity. Side-effects of medicines can exacerbate the situation by aggravating dysfunctional bioenergetics, oxidative stress, DNA damage, inflammation, and neuronal injury. These processes contribute to aging and cellular crises, eventually, leading to brain damage. Nutritious food containing molecules with medicinal value can alleviate these disruptive mechanisms by correcting deranged cellular signaling. Thus, nutraceuticals help to repair cellular damage, thereby improving brain health. Reproduced with permission from Williams RJ. Neuro-nutraceuticals: the path to brain health via nourishment is not so distant. Neurochem Int 2015:8e13. https://doi:10.1016/j.neuint.2015.08.012. [Journal, Editorial].

Nutraceuticals for brain health from around the globe Indian traditional medicine Different types of spices like turmeric, garlic, coriander, black pepper, ginger, cinnamon, clove, green pepper and onion; herbs like basil, sage; nuts like almonds are an integral part of Indian diet and are known to be effective against Alzheimer, Parkinson, multiple sclerosis, epilepsy, neuropathic pain, cerebral ischemia, depression, schizophrenia, meningitis, spongiform encephalopathy, and even brain tumor [12e21] (Fig. 29.2).

Chinese traditional medicine The Compendium of Materia Medica by Li Shizhen is the most comprehensive record of traditional Chinese medicine. It is a product of 30 years of rigorous field study enlisting all the plants, animals, minerals, and other natural items with medicinal properties and consists of 1892 entries from 800 other medical reference books [21]. One such medicine is Yi-Gan San (YGS) that consists of seven different extracts, namely, Atractylodes lancea rhizome, Poria sclerotium, Cnidium rhizome, Uncaria thorn,

Japanese Angelica root (Angelica radix), Bupleurum root, and Glycyrrhiza in the proportions of 4:4:3:3:3:2:1.5. YGS has been administered to children for treating restlessness and agitation. It is also useful in treating neuropsychological disorders such as behavioral and psychological symptoms of dementia (BPSD) in the elderly, a number of symptoms of borderline personality disorder, tardive dyskinesia, and psychotic symptoms of schizophrenia [21].

Japanese traditional medicine Yokukansan (YKS), a traditional Japanese Kampo medicine, originated from traditional Chinese YGS. Both, YKS and YGS have similar compositions. YKS is effective against excitatory BPSD (behavioral and psychological symptoms of dementia) such as hallucinations, agitation, and aggressiveness in the patients suffering from Alzheimer’s disease (AD), dementia with Lewy bodies (DLB), and other forms of senile dementia [22].

African traditional medicine (ATM) Ghana boasts of a wide array of medicinal flora and its longstanding cultural use of traditional and alternative medicines (TAMs), as is evident from several published

412 Nutraceuticals in Brain Health and Beyond

FIGURE 29.2 Spices effective against neurodegenerative conditions. Several spices used in Indian and other Asian cuisines have neuroprotective properties. Thus, people of Asian ethnicity receive their required dose of neuroprotective nutraceuticals from their diet itself. This is reflected in low prevalence of brain-related disorders in these parts of the world.

FIGURE 29.3 Commonly used plants in African Traditional Medicine. These plants are endemic to African continent. Courtesy: Mothibe ME, Sibanda M. African traditional medicine: South African perspective. In: Traditional and complementary medicine African; 2019, https://doi.org/10.5772/ intechopen.83790. [Under the terms of the Creative Commons Attribution 3.0 License (CC BY License)].

works on the ethnobotanical use of TAMs in the country [23]. Ageratum conyzoides (Asteraceae) and Ocimum gratissimum (Lamiaceae) are potent analgesics. While Lantana camara is the most popular anxiolytic agent, Cymbopogon citratus (Gramineae), Mangifera indica, Tetrapleura tetraptera (Fabaceae), and Persea americana (Lauraceae) are the most studied anticonvulsants (Fig. 29.3).

mountains of East Asia) is widely used for improving cognitive performance [24]. Galantamine (an alkaloid obtained from the bulbs and flowers of the Caucasian snowdrop Galanthus woronowii) and huperzine A (a sesquiterpene alkaloid found in the fir moss Huperzia serrata) are popular traditional treatments for cognitive impairment [25].

Traditional Korean medicine (TKM)

Interestingly, Korea has the highest percentage (15.26%) of certified doctors practicing traditional medicine in hospitals and clinics in East Asia, followed by Mainland China with 12.63% and Taiwan with 9.69% doctors. It is encouraging to note that traditional medicine

Hanbang, the Traditional Korean Medicine (TKM), is an inseparable component of Korean culture. Ginseng (also known as Korean ginseng or Chinese ginseng, grows in the

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TABLE 29.1 Plant species used in different parts of Mexico to treat depression or sadness. Plant

Family

Location

Use

References

Bougainvillea spectabilis Willd

Nyctaginaceae

Puebla

Sadness in children

[27]

Chenopodium ambrosioides L.

Chenopodiaceae

Epazote

Sadness in children

[28]

Haematoxylum brasiletto Karst

Leguminosae

Chihuahua

Sadness in children

[29]

Cyprus esculentus L.

Cyperaceae

Oxaca, Santa Maria Tecomavaca

Depression

[30]

Cyprus flavescens L.

Cyperaceae

Oxaca, Santa Maria Tecomavaca

Depression

[30]

Chiranthodendron pentadactylon Larreat.

Sterculiaceae

Distrito Federal

Depression, nostalgia

[31]

Porophyllum macrocephalum DC.

Asteraceae

San Luis Potosi

Depression, anguish

[32]

Courtesy: Laura et al. Medicinal plants for the treatment of “nervios”, anxiety, and depression in Mexican traditional medicine. Revista Brasileira de Farmacognosia 2014;24(5):591e608. https://doi.org/10.1016/j.bjp.2014.10.007. [Under Creative Commons Attribution International License (CC BY-NC-ND 4.0)].

is legally institutionalized in Korea and the expenses for its services like acupuncture, moxibustion, and cupping have been covered by National Health Insurance since 1987. Treatments using most herbal extracts are also covered by the Korean health insurances, with the only exception of decoctions of raw herbs [26]. All these factors have placed traditional medicine at par with modern medicine in Korea.

Traditional medicine of Latin America Mexican traditional medicinal system identifies bodily and mental unrest as “nervios,” a folk illness, reported across many countries in Latin America. Nervios is mostly treated with the help of herbal tea made from a combination of Agastache mexicana (toronjil morado), Agastache mexicana subsp. xolocotziana (toronjil blanco), Dracocephalum moldavica (toronjil azul or chino), Cinnamonum sp. (canela), different species of Citrus flowers (flor de azahar), Chiranthodendron pentadactylon (flor de manita), Ternstroemia sp. (tila), Foeniculum vulgare (hinojo), Ipomea stans (tumbavaquero), to name a few. Interestingly, 92 plant species, belonging to eight families, namely, Asteraceae, Rutaceae, Lamiacea, Passifloraceae, Valerianaceae, Rosaceae, Theaceae, and Verbenaceae are used to treat nervios in different parts of Mexico. Likewise, nine plant species from eight families are used to treat depression. People suffering from anhedonia, low self-esteem, mental slowness, and loss of concentration are treated with extracts from Mimosa pudica, Tagetes lucida, Annona cherimola, Byrsonima crassifolia, and Litsea glaucescens. These herbal extracts have been tested for their potential antidepressant properties in animal models of depression [33]. Traditional Mexican medicinal system uses Galphimia glauca, Tilia americana L. var. mexicana, Lippia alba, Ipomoea stans, Casimiroa edulis, Montanoa frutescens, Magnolia dealbata, Valeriana edulis ssp. procera, Annona

diversifolia, Matricaria chamomilla, and Loeselia mexicana for treating anxiety. Anxiolytic effects of these species have been established in anxiety animal models also [33] (Table 29.1). Oxidative stress, acetylcholine deficiency in the brain, and inflammatory processes are associated with AD. In the northeast region of Brazil, various plants are used to treat several diseases associated with these processes. Such plants with positive effects on cognitive disorders, strong acetylcholinesterase inhibitory, anti-inflammatory, and antioxidant activities are potential therapeutics for treating AD [34]. An ethnobotanical survey of northeast Brazil for the major plants with these properties identified Hymenocallis speciosa (mangaba fruits) with the best antioxidant and anticholinesterase properties [35]. These properties are attributable to the presence of antioxidant compounds such as phenols, tannins, flavones, flavonoids, leucoanthocyanidins, and alkaloids [36]. Copaifera langsdorffii also exhibited high acetylcholinesterase inhibitory activity due to its ability to increase acetylcholine, thereby, employing mass production of the substrate to induce substrate-mediated inhibition of enzymatic activity [35]. The currently used hypoglycemic agent, Bauhinia forficata is a potent anticholinesterase and has a high antioxidant capacity. Therefore, it is also being considered as a potential therapeutic against AD [35].

Nutraceutical and overall brain health: Traditional versus modern outlook Before exploring the role of nutraceuticals in maintaining brain health, it is pertinent to have a basic understanding of the physiological changes associated with neurodegenerative conditions. This will help in better appreciation of the precise and meticulous scientific reasoning behind the principles of traditional medicinal systems that form the basis of nutraceuticals.

414 Nutraceuticals in Brain Health and Beyond

Pathophysiology of neurodegenerative conditions The life expectancy of humans has considerably increased in developed and developing countries due to advancements in medical research and discovery of life-saving drugs against several debilitating and life-threatening scourges such as cancer, infectious diseases, and metabolic disorders. However, with the increase in longevity of life, several other lifestyle-associated diseases such as cardiovascular diseases, type-2 diabetes, and various forms of age-associated cognitive decline including neurodegenerative conditions such as AD, Parkinson disease (PD), and amyotrophic lateral sclerosis have been emerging at a high rate [37]. Neurodegenerative diseases are one of the most debilitating conditions and usually associated with mutated genes, accumulation of abnormal proteins, increased reactive oxygen species (ROS), or destruction of the neurons in a specific part of the brain [38e42]. The prevention of neurodegenerative diseases has been one of the primary goals of researchers, but to make prevention feasible, two objectives must be accomplished: (1) individuals at high risk for the disease must be identified before the symptoms become evident, and (2) compounds that are safe and effective in either reducing or slowing the disease progression need to be developed. Improved experimental models, modern research techniques and research in the field of neuroscience have advanced our understanding of the unique mechanisms of the onset and expansion of the neurodegeneration and toxicants-induced neurotoxicity. Among several recognized mechanisms, the damage to neuronal mitochondria, intracellular calcium ion (Ca2þ) overload, uncontrolled generation of ROS, sustained inflammatory condition, or any combination of these are the common busy high-roads for neurotoxicity [43e50]. Although, the causative reason for the onset of neurodegeneration may differ, the progression of toxicant-induced neuronal damage and neurodegenerative disorders largely involves the same shared mechanisms, reinforcing the importance of these pathways as common targets for the intervention strategies. Utilizing the knowledge of the etiology of the neurodegenerative diseases, target-based therapies such as neurotransmitter modulators, direct receptor agonists/antagonists, second messenger modulators, stem cellse based therapies, hormone replacement therapy, neurotrophic factors, as well as regulators of the mRNA synthesis and its translation into disease-causing mutant proteins have been developed [51e58]. Although, these strategies are great tools to mitigate the neurodegenerative processes, such treatments are often associated with adverse effects and long-term unknown consequences [52,55,57,58]. Therefore, treatment options in alternative systems of medicines are being actively explored.

In majority of neurodegenerative diseases, histopathological signs display fibrillar proteinaceous deposits, due to polymerization of specific misfolded, aggregated proteins and peptides (listed in Table 29.2) [59]. The authenticity of amyloid hypothesis in the pathology of neurodegeneration is well established. However, the prevention of fibril formation can only delay the onset of disease pathology. Interestingly, a calorie-sparse, nutrient-dense, plant-based diet rich in nutraceuticals is believed to be effective not only in preventing but curing neurodegenerative diseases.

Effects of nutraceuticals on neurodegenerative conditions Worldwide, annually more than 10 million people suffer from neurodegenerative diseases. Unfortunately, this number is expected to increase. Western countries witness a predominance of neurodegenerative conditions among people aged 70e79 years. The geriatric population in these countries is 3.1% which is prone to neurodegenerative diseases, whereas this figure is significantly, as low as, just 0.7% in places like India. According to accumulating evidence, this difference is majorly because of lifestyle and food habits. From ancient times, Asian countries, particularly India, depend on spices or natural products to cure most of the ailments and have been successfully using them for disease prevention. These spices and natural products have been used not only as medicines but they have been an integrated part of ethnic cuisines of these countries, and thus, have been a part of their regular diets. A spice is usually a dried-up seed, fruit, root, bark, or flower from a plant. Thus, nutraceuticals have been an integral part of Indian and other Asian diets long before even the term was coined. Nutraceuticals can have both prophylactic and therapeutic properties with minimal to absolutely no sideeffects. They have always been a part of traditional and folk herbal medicine. The high metabolic rate and suboptimal free radical scavenging system, relative to the rest of the body, make human brain extremely susceptible to oxidative stress. Probably, because the world’s oldest documented medical systems like Ayurveda, Unani, and traditional Chinese or Asian medicine were aware of this, they prescribed the use of a number of plants with antioxidant activity as therapeutics for neurodegenerative diseases [60]. Medhya (intellectual promoting) herbs have been helpful in cognitive disorders [61]. Nootropic agents proved excellent in improving memory, mood, and behavior [62]. Ayurveda categorizes metabolic defects in three categories based on the particular dosha out of tridoshas, viz., “Vata,” “Pitta,” and “Kapha” being affected. Tridoshas are believed to govern movements and activities, the health and energy levels, and growth and structural modification, respectively [63]. Malfunctioning of any of these driving forces, due to

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TABLE 29.2 Neurodegenerative conditions and their corresponding misfolded protein/peptide components of the fibrillary tangles. S. No.

Disease name

Misfolded proteins/peptides

1.

Alzheimer disease

Amyloid-b peptides

2.

Familial Danish dementia

ADan amyloid peptide

3.

Parkinson disease

a-synuclein

4.

Frontotemporal dementia

Tau proteins

5.

Amyotrophic lateral sclerosis

Superoxide dismutase

6.

Familial British dementia

ABri amyloid peptide

7.

Huntington disease

Huntingtin gene

8.

Spinocerebellar ataxia

TATA boxebinding protein

9.

Cerebellar ataxia

Ataxins proteins

10.

Dentatorubral-pallidoluysian atrophy

Atrophin 1 protein

11.

Hereditary cerebral amyloid angiopathy

Cystatin C protein

12.

Kennedy disease

Androgen receptor

13

Spongiform encephalopathy

Prion

Reproduced with permission from Preethi et al. Chapter 8 e Nutraceuticals in prophylaxis and therapy of neurodegenerative diseases. Nat Prod Drug Dis 2018;359e376. https://doi.org/10.1016/B978-0-12-809593-5.00008-2.

unfavorable environment or improper diet, results in pathologic conditions [64]. Through its major discipline “Rasayana tantra,” Ayurveda focuses on treatments to improve longevity, memory, and physical appearance of an individual. Automatically, this results in well-nurtured cognitive performance and physical strength. Thus, Ayurveda is not just a collection of herbal therapies, but rather a regimen for a healthy, disease-free mode of life [65]. Traditional Chinese and other Asian medicinal concepts are based on “Yin, Yang, and Qi” believed in these traditions to be the components of “vital energy.” These systems of medicine also employ herbs for neuroprotection. The World Health Organization (WHO) estimates almost 70%e80% of the world population to be relying on traditional medicine either directly in the form of diet and herbal extracts, or indirectly as extracted active components used in the modern methods as drugs, otherwise being referred to as nutraceuticals [61,66]. A brief report on a few popularly used herbs as therapeutic agents in traditional or folk medicines for neurological conditions is provided below. These are also the basis for nutraceuticals maintaining brain health.

Bacopa monnieri (Brahmi) Baccopa monnieri traditionally known as Brahmi is well known for its potential to rejuvenate nerve cells and the ability to improve memory power. It is commonly found in India and Australia. Brahmi has two saponins, namely Bacoside A and B, which are made up of Sapogeninsd Bacogenins A1eA4, betulic acid, and various alkaloids.

Among the two main saponins, Bacoside A improves memory power [67]. Besides boosting memory, B. monnieri has antioxidant, antistress, anti-inflammatory, antimicrobial, and smooth muscle relaxant activities [68]. Antioxidant and antistress activities of B. monnieri have been effective against stress mediated dysfunction of nerve cells in Huntington disease (HD) [69]. Antioxidant activity of B. monnieri is modulated by the availability of Glutathion (GSH) and the activity of Glutathion reductase (GR) and is mediated through activation of Hsp70, P450, and superoxide dismutase [70,71].

Ginkgo biloba The leaf extract of Ginkgo biloba, commonly known as living fossil, contains trilactonic diterpenes (ginkgolide AeC, ginkgolide JeM), trilactonic sesquiterpene (bilobalide), and various flavonoids known for their antioxidant properties. It is widely used in traditional Chinese medicine [72,73]. It also prevents aggregation of blood platelets and therefore is potent against ischemic hemorrhage [74]. In addition, this extract inhibits the formation of A-beta from b-amyloid precursor protein, thus, having potential against AD [75]. The active components of the extract compete with free cholesterol to interact with the A-beta and decrease its aggregation. Gingko extract is a potent neuroprotective and antiapoptotic agent that effectively inhibits ROS accumulation by A-beta and reduces neuronal apoptosis which preludes neurodegenerative disease [76e78].

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Withania somnifera (Ashwagandha or Indian ginseng) Withania somnifera or Ashwagandha, as known traditionally, has been since time immemorial used as anti-inflammatory, antioxidant, antistress, neuroprotective, immune boosting, and memory enhancing agent in Ayurvedic system [79e81]. W. somnifera inhibits the release of corticosterone and activates choline-acetyltransferase to inhibit stress-induced NADPH-diaphorase (NADPH-d) activity and consequently boosts serotonin in the hippocampus [82]. The active components of W. somnifera such as withanolide A, withanolide IV, withanolide VI facilitate pre- and postsynaptic reconstruction and axonal and dendritic regeneration [83,84].

Convolvulus pluricaulis Convolvulus pluricaulis is a perennial herb, all parts of which have therapeutic benefits. Indian and Chinese medicinal formulations widely use this plant to cure various diseases like chronic cough, sleeplessness, epilepsy, hallucinations, anxiety, etc. [85]. A wide variety of in vitro and in vivo pharmacological effects like CNS depressant, anxiolytic, tranquilizing, antidepressant, antistress (psychological, chemical, and traumatic), anti-neurodegenerative, antiamnesic, antioxidant, hypolipidemic, immunomodulatory, and analgesic effects have been reported [85]. Other prominent effects of the ethanolic and methanolic extracts of the whole plant include reduced spontaneous motor activity and fighting response, potentiated pentobarbitone hypnosis and morphine analgesia, abolished conditioned avoidance response, antagonized convulsive seizures and tremorineinduced tremors in mice [85].

Among the many ethnomedicinal and ethnobotanical uses ascribed to the rhizomes of A. calamus are treatments of memory disorder, enhancing learning performance, antiaging and anticholinergic activities through traditional Chinese and Indian prescriptions. Active components of Acorus rhizome, a- and b-asarone, possess a wide range of neuropharmacological activities like sedative, CNS depressant, behavior modifying anticonvulsant, acetylcholinesterase inhibitory, memory enhancing, anti-inflammatory, antioxidant, hypolipidemic, immunosuppressive, and cytoprotective to name a few [96].

Celastrus paniculatus Ayurveda recognizes Celastrus paniculatus as “Tree of life,” which has been used since time immemorial to treat brain-related disorders and enhance learning and memory. The “Jyotishmati oil” extracted from the seeds of C. paniculatus is a potent revitalizer of the CNS. Although, native to Indian subcontinent, C. paniculatus grows wildly in China, Taiwan, Cambodia, Nepal, Indonesia, Laos, Malaysia, Myanmar, Thailand, Vietnam, Australia, and several Pacific islands [97].

Hemidesmus indicus Commonly known as Indian Sarsaparilla/Anantamul, this perennial is diffusely twinning or prostrate semi-erect shrub with a woody root stock and numerous slender wiry laticiferous branches with purplish-brown bark [98]. Ayurveda, Siddha, and Unani systems of medicine use H. indicus to treat a variety of diseases including epileptic seizures and chronic nervous diseases [98].

Centella asiatica (gotu kola)

Trapa bispinosa (water chestnut)

C. asiatica is commonly used as a green leafy vegetable, in traditional diets in different parts of the world due to its well-known health benefits. It is widely used in Ayurvedic, Unani, and folk medicines in India, Sri Lanka, Southeast Asian countries, China, and Africa over the centuries [86,87]. C. asiatica possesses neuroprotective, neuroregenerative, immunomodulatory, antidepressive, memory-enhancing, gastroprotective, cardioprotective, radioprotective, anticancer, antimicrobial, wound healing, anti-inflammatory, antidiabetic, and antioxidative properties [86e93]. Traditionally, C. asiatica is popular as a memory enhancer and nerve revitalizer, indicating its potential as a cure for neurodegenerative conditions of the aging population like AD, senile dementia, and PD [94,95].

T. bispinosa is an established neuroprotective herb that has been used as nerve tonic from ages. It reduces D-galactoseinduced oxidative stress by activating glutathione peroxidase and catalase to reduce lipid peroxide [99].

Acorus calamus (sweet flag) This semiaquatic, perennial, aromatic herb with creeping rhizomes is endemic to the northern temperate and subtropical regions of Asia, North America, and Europe [96].

Holy basil It is known since the Vedic age for its immense curative and multipurpose utility. It has anticonvulsion potential, analgesic activity. It can increase motor activity, normalizes neurotransmitter levels in brain, influences the neurochemistry of the brain, and enhances memory [100].

Semecarpus anacardium (Bhallaatak) S. anacardium is an ancient traditional herb mentioned in Valmiki Ramayana, one of the most sacred books of India written before 3000 BC [101]. Medicinal potency of this plant is evident from its popularity as Ardha Vaidya in Ayurveda meaning half-physician. Truly, it could cure

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almost any ailment. Its fruit was considered as a golden acorn during the period of Galen (Greek physician, AD 130e210) and Avicenna (Persian mathematician, AD 980e1037) in Western society [102]. Consumption of S. anacardium without proper detoxification could be lethal. Its strong ROS scavenging activity provides protection against free radicalemediated diseases like cancer and cerebro-cardiovascular disorders [101].

Among its diverse medical properties are anti-inflammatory, antioxidant and immune boosting responses. It facilitates macrophagic clearance of the amyloid plaques formed in AD. Curcumin modulates cerebral microcirculatory function and alleviates hypertension and depression by normalizing the levels of dopamine, noradrenaline, and 5 hydroxyindole acetic acid in the frontal cortex [107].

Nardostachys jatamansi (spikenard or jatamansi) The root extract of N. jatamansi is an aromatic antispasmodic, diuretic, neuroprotective tonic with carminative, deobstruent, digestive, and reproductive stimulant properties. Besides, Ayurveda recommends its application in spasmodic hysteria, other nervous convulsive ailments, nervous headache, epilepsy, and convulsions [103].

Resveratrol (3,40 ,5-trihydroxystilbene), is a natural polyphenol found in grapes, raspberries, blue berries, and mulberries. It is effective against cardiovascular and AD [108e110]. The active compound Piceatonnol (monohydroxylated derivative) blocks Ab-induced ROS accumulation in AD. In addition, it maintains neuronal homeostasis through stimulating AMP kinase [111]. Besides, it can be a strong preventive agent for stroke [112].

Panax ginseng (ginseng)

Lycium barbarum (Wolfberry)

It is a popular medicinal herb of Korean and Chinese origin, known for treating cancer, neurodegenerative disorder, hypertension, and diabetes. The active components of P. ginseng, Ginsenosides, Rb1 and Rg3, possess remarkable neuroprotective activity making it an excellent treatment option for neurodegenerative diseases [104]. Ginsenoside acts on dopaminergic neurons by reducing neural iron levels and concomitantly lowering the expression of divalent metal transporter (DMT1) and potentially increasing that of ferroportin (FP1) in PD [105].

Wolfberry is commonly used in Chinese medicine as antiaging agent. Pretreatment of cortical neuron with L. barbarum extract reduced lactate dehydrogenase release and blocked Ab-peptide activated caspase activities. This protected the pretreated neurons from deleterious effects of Ab peptide [113,114].

Clitoria ternatea C. ternatea is a popular Ayurvedic “Medhya” or brain tonic used for treating “Manasika roga” or mental illness. Extract of C. ternatea improves memory retention and increases acetylcholine content and acetylcholinesterase activity in the different regions of brain, namely, cerebral cortex, midbrain, medulla oblongata, and cerebellum [106].

Coriandrum sativum (coriander or cilantro) A popular cooking ingredient throughout the world, C. sativum improves blood circulation and improves mental concentration and memory capabilities. It has welldocumented free radical scavenging and lipid peroxidation activities. Aqueous extract of coriander seed protects pyramidal cells in the cerebral cortex against neurodegenerative disorders and AD [60].

Curcumin Curcumin or turmeric, the most common spice in Indian cuisines, is known for its cosmetic and medical properties in Ayurveda for many years. It is actually a storehouse of dietary fiber, potassium, magnesium, iron, and vitamins.

Resveratrol

Dietary supplements Consumption of non-nutritive chemicals from plants like terpenoids and flavonoids, rich in antioxidants, reduced lipid peroxidation and increased antioxidant levels in blood plasma. Similarly, a-lipoic acid is another potent antioxidant that plays a vital role in brain function, glucose metabolism in the brain, and stabilizing cognitive function in AD affected brain [9]. Consumption of phytochemicals as dietary supplements promotes health benefits by protecting against chronic neurodegenerative and cognitive disorders. Phytochemicals mainly include secondary metabolites, an array of bioactive constituents capable of improving human health significantly. These supplements could be vitamins, minerals, herbs, or other botanicals, enzymes, amino acids, or other dietary substances. Traditionally these phytochemicals used to be a part of the diet in day-to-day life. However, these days, they are available in different forms like tablets, capsules, liquids, powders, extracts, and concentrates (Table 29.3).

Traditional versus modern outlook on nutraceuticals “We are what we eat” consciously or subconsciously (as a practice or habit). Indeed, it is just the way we consume the nutrients that determines the outlook on nutraceuticals. If

418 Nutraceuticals in Brain Health and Beyond

TABLE 29.3 Spices, the phytochemicals present in them, and the specific ameliorating effects they have on different neurodegenerative conditions. Spice

Phytochemicals

Effects

Extract

Prevents Ab aggregation [12]

Curcumin

Ab insult inhibition [115,116] Protection from Ab-induced damage in vivo (Sprague Dauley rats) [117] Prevents neuroglial cell proliferation [118] Inhibited Ab-induced cytochemokine gene expression and CCR5-mediated chemotaxis of THP-1 monocytes by modulating EGR-1 [119]

Curcumin derivatives

Prevents Ab aggregation [120]

SAC

Reduction of apoptosis in Ab-induced PC12 cells [13]

Extract

Generation of Ab fibril is inhibited in human brain [121] Antiamyloidogenic effects [122]

Linalool

Inhibition of acetylcholinesterase in vitro [14]

Alzheimer disease Turmeric

Garlic

Coriander Sage

Rosmarinic acid

Protection from Ab-induced neurotoxicity in PC12 cells [123]

Ginger

Extract

Ab aggregation blockage [12]

Almond

Morin

Ab fibril destabilization [21]

Angelica

Extract

Protection against Ab-induced memory impairment in vivo [124]

Cinnamon

Extract

Prevents Ab aggregation [12]

Basil

Ursolic acid

Acetylcholinesterase inhibition [125]

Black pepper

Piperine

Alleviates memory impairment and neurodegeneration [15]

Focal cerebral ischemia Liquorice

Isoliquiritigenin

Protection against cerebral ischemia injury [126]

Gamboge

Gambogic acid

Kainic acid-triggered neuronal cell death inhibition and reduced infarct volume in the transient MCAO model of strokes [127]

Angelica

Extract

Reduction of cerebral infarction and neuronal apoptosis in vitro [128]

Z-ligustilide

Lowered platelet aggregation induced by ADP ex vivo and arteriovenous shunt thrombosis in vivo [129]

FBD

Brain ischemia/reperfusion injury prevention [130]

Ferulic acid

Reduction in cerebral infarct area and neurological deficit-score in transient MCAO rats [131]

Turmeric

Curcumin

Plays a role by inhibiting the monoamine oxidase and regulates the release of serotonin and dopamine from the brain [132]

Black pepper

Piperine

Inhibits the growth of cultured neurons from embryonic rat brain [133] Gives protection to the mice from CMS, BDNF upregulation [134]

Ginger

Oil

Induces antidepressant like synergism in vivo [17] Imposes synergistic antidepressant actions in vivo [135]

Black pepper

Piperine

Upregulates hippocampal progenitor cell proliferation and increases BDNF level [134]

Cloves

Eugenol

Induces expression of MT-III in the hippocampus and antidepressant like activity [18]

Quercetin rutoside

Lowers superoxide production [19]

Eugenol

Suppresses neuropathic pain [136]

Depression

Schizophrenia Onion Neuropathic pain Clove

Continued

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TABLE 29.3 Spices, the phytochemicals present in them, and the specific ameliorating effects they have on different neurodegenerative conditions.dcont’d Spice

Phytochemicals

Effects

Curcumin

Inhibits medulloblastoma [137], neuroblastoma [138], and pituitary folliculostellate [139] cells and exerted antitumor effect cell proliferation inhibition, blocked clonogenicity, downregulates bcl-2 and bcl-xL, leading to caspase-mediated cell death, and blocks migration of medulloblastoma cells [140] Sensitization of malignant glioma cells to TRAIL/Apo2L-mediates apoptosis [141] Inhibition of MMP gene expression in human astroglioma cells [142] Suppression of growth and chemoresistance of human glioblastoma cells through AP-1 and NF-kB [143] Antiapoptotic signals suppression and activation of cysteine proteases for apoptosis in human malignant glioblastoma U87MG cells [144] G2/M cell cycle arrest induction in a p53-dependent manner and ING4 expression upregulation in human glioma [145]

Demethoxycurcumin

Upregulation of Bcl-2-mediated G2/M arrest and apoptosis in human glioma U87 cells [146]

Ginger

Shogaols

Neuroprotection in IMR32 human neuroblastoma and normal HUVEC from Ab-insult [147]

Angelica

Extract

Triggers both p53-dependent and p53-independent pathways for apoptosis in vitro, suppressed growth of subcutaneous rat and human brain tumors, reduced the volume of GBM tumors in situ, prolonging survival rate [148] Inhibits tumor growth by reducing the level of VEGF and cathepsin B on brain astrocytomas [149]

Red chili

Capsaicin

Induction of cytotoxicity and genotoxicity in human neuroblastoma cells in vitro [150] Induced apoptosis in A172 human glioblastoma cells [149] Apoptosis induced by redox status-dependent regulation of cyclooxygenases in human neuroblastoma cells [151] TRPV1 vanilloid receptor mediated induction of apoptosis of glioma cells and requires p38 MAPK activation [152] Induces apoptosis in human HepG2 and human neuroblastoma (SK-N-SH) cells [153]

Basil

Ursolic acid

Inhibits IL-1b or TNF-a-induced C6 glioma invasion by suppressing the association of ZIP/p62 with PKC-zeta and downregulating MMP-9 expression [20]

Kokum

Gambogic acid

Binds to TrkA and prevents death due to glutamate toxicity, induces neurite outgrowth in PC12 cells [127] Inhibits growth and induces apoptosis in glioma cells [16]

Black pepper

Extract

Prolonged anticonvulsant activity against audiogenic seizures in vivo (DBA/2) mice and against seizures induced in T.O. mice by NMDLA [154]

Clove

Eugenol

Suppression of epileptiform field potentials and spreading depression in rat neocortical and hippocampal tissues [155]

Tarragon

Anethole

Exert dose- and time-dependent antiseizure activity in maximal electroshock and pentylenetetrazole models of experimental seizures [156]

Celery seed

Apigenin

Seizure phenotype reduction in a Drosophila model of epilepsy [157]

Horseradish

Kaempferol

Seizure phenotype reduction in a Drosophila model of epilepsy [157]

Turmeric

Curcumin

Ameliorated seizures, oxidative stress, and cognitive impairment in pentylenetetrazole-treated rats [158]

Curcumin

Reduction of synuclein toxicity, intracellular ROS, and apoptosis in neuroblastoma cells [159]

Brain tumors Turmeric

Epilepsy

Parkinson disease Turmeric

Continued

420 Nutraceuticals in Brain Health and Beyond

TABLE 29.3 Spices, the phytochemicals present in them, and the specific ameliorating effects they have on different neurodegenerative conditions.dcont’d Spice

Phytochemicals

Effects

Ginger

Zingerone

Prevents 6-hydroxydopamine-induced dopamine depression in mouse striatum and increase superoxide scavenging activity in serum [160]

Clove

Eugenol

Protects mice from 6-OHDA-induced PD [161]

Almond

Morin

Terminates the loss of cell viability and apoptosis in PC12 cells [162] Attenuates behavioral deficits, dopaminergic neuronal death, and striatal dopamine depletion in the MPTP mouse model [162]

Turmeric

Curcumin

Inhibition of differentiation and development of Th17 cells [163] Decreases TLR-4 and TLR-9 expression in CD-4 and CD-8(þ) T cells [164]

Green pepper

Luteolin

Inhibits activated peripheral blood leukocytes from MS patients and EAE [165] Inhibition of mast cells, T- cells [166]

Onion

Quercetin

Modulation of immune responses in peripheral blood mononuclear cells [167]

Multiple sclerosis

Spongiform encephalopathy Turmeric

Curcumin

Resists protease-resistant prion protein accumulation in vitro [168]

Extract

Possesses in vitro fungistatic and fungicidal activity against Cryptococcus neoformans [169]

Diallyltrisulfide

Possess in vitro fungicidal effects [170]

Meningitis Garlic

6-OHDA, 6-hydroxydopamine; ADP, adenosine diphosphate; AP-1, activator protein 1; Ab, amyloid beta peptide; BCL2, B-cell lymphoma 2; BCL-xl, Bcell lymphoma-extra large; BDNF, brain-derived neurotrophic factor; CCR5, c-c chemokine receptor; CD, Cluster of differentiation; CMS, chronic mild stress; EAE, experimental allergic encephalomyelitis; EGR-1, early growth response-1; FBD, a herbal formula composed of Poriacocos, Atractylodes macrocephala, and A. sinensis; GBM, glioblastoma multiforme; HUVEC, human umbilical vein endothelial cells; IL-1b, interleukin-1b; ING4, inhibitor of growth protein 4; MAPK, microtubule associated protein kinase; MCAO, Middle cerebral artery occlusion; MMP, matrix metalloproteinase; MPTP, 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine; MT-III, metallothionein-III; NF-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; PKC zeta, Protein kinase C, zeta; ROS, Reactive oxygen species.; SAC, S-allylcysteine; TLR, tolllike receptor; TNF-a, tumor necrosis factor-alpha; TRAIL/Apo2L, tumor necrosis factor (TNF)-related apoptosis-inducing ligand; TrkA, tyrosine receptor kinase; TRPV, transient receptor potential vanilloid; VEGF, vascular endothelial growth factor. Reproduced with permission from Kannappan et al. Neuroprotection by spice-derived nutraceuticals: you are what you eat! Mol Neurobiol 2011;44(2):142e159. https://doi:10.1007/s12035-011-8168-2.

the nutrients are taken as supplements in the form of tablets, capsules, etc., it is more of a modern practice. However, if the dietary regime is defined to include these nutrients in the form of food taken, as has been the case with ethnic food habits, it will be a traditional outlook on nutraceuticals. Which out of these two practices is a more effective way of consuming nutraceuticals, remain undecided. When nutraceuticals are consumed as a part of the food eaten, they are not taken alone; rather, the body receives a combination of several nutraceuticals. This can prove to be more beneficial than consuming specific nutraceuticals individually. In combination, bioavailability of nutraceuticals may improve and synergism may be expected. Evolution of human food habits has been a function of several factors acting simultaneously to help the fittest combination to survive, surface, and stabilize. Therefore, the human digestive system can be expected to be more in tune with dietary combinations of nutraceuticals rather than dietary supplementation of the same. Two classic cohort studies on

effects of Mediterranean and Asian diets in preserving brain health in aging populations will justify this perspective.

Mediterranean diet (MD) MD is attributed to better cognitive functions in aged people: 9 out of 12 eligible studies confirmed lower rates of cognitive decline and reduced risk of AD in people adopting the MD [171]. Similar results were reported by the PREDIMED study (PREvencio’n con DIeta MEDiterra’nea) carried out on a cohort of 578 subjects [172]. These subjects conformed to the traditional MD and were evaluated for their cognitive performance and total urinary polyphenol excretion [172]. This study showed that higher intakes of extra virgin olive oil (EVOO), coffee, walnuts, and wine significantly improved memory and global cognition due to their high polyphenolic contents. A new large randomized controlled trial, the NU-AGE, has recently been launched with the rationale that a 1 year intervention with MD to reduce inflammation and aging

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(the so-called “inflammaging”) in 65- to 79-year-old subjects, will improve their physical and cognitive status [173e175]. The MD-associated benefits result from complex association and interaction of diet and habits. Thus, great efforts have to be deliberately made to individuate nutritional factors endowed with specific healthy biological activities so that these studies can provide useful information for drug design, diet integration, or food fortification.

Asian diet A similar study in Hisayama was conducted on 1006 subjects aged 60e79 years from 1988 to 2005 [176]. Through correlations between diet and incidence of various types of dementia (and other age-associated diseases), this study identified a dietary pattern that was associated with a reduced risk of dementia in a general Japanese elderly population. This pattern was characterized by high intakes of soybeans and soybean products, vegetables, algae, milk and dairy products, and a low intake of rice. Rice was not deleterious in itself, but a high intake of it restricted consumption of those foods that are potent in preventing dementia [176]. Another interesting case of correlation between dietary habits and brain health is the Okinawan diet from Japan. Okinawan population has strikingly higher longevity and low risk of age-associated diseases (including AD) relative to the rest of the Japanese population [177]. Interestingly, when people emigrated from Okinawa to other countries and adapted the local dietary pattern, the incidence of

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various forms of dementia, including AD, increased in aged people and became similar to that of the surrounding populations [178]. This is compelling evidence that established the relevance of dietary factors over genetic ones in this case. Okinawan diet differs from MD in a much lower intake of calories from fat. Calorie requirements of Okinawan diet are met by carbohydrates from sweet potatoes (roots and leaves), and not rice. Both the Okinawan and the MD diets are based on high vegetable and legume intake (though in the former these are essentially soybeans) and scarce in meat [179]. So, the Okinawan diet clearly coveys that the healthiest foods are those which are poor in calories and rich in nutrients, for example, sweet potatoes, they are extremely rich in antioxidants (mostly vitamin A and C, and also phenolic compounds). They have significant antiinflammatory, antihyperglycemic, and lipocholesterolemic effects; are good sources of B vitamins, including folate, thiamine, riboflavin, and vitamin B6 [9,180,181]. Interestingly, folate and vitamin B6 convert homocysteine into cysteine. High homocysteine is associated with an increased risk of cardiovascular disease and dementia. Thus, the Okinawan diet reduces risks of cardiovascular mortality and dementia. Serum homocysteine levels are particularly low in Okinawan people. Besides sweet potatoes, other ingredients of this diet like turmeric, accounts for its particular healthiness. Turmeric is a popular spice both in Okinawa and in India. Its long-term consumption in India is associated with a 4.4-fold reduced rate of AD incidence compared to the USA [182]. Therefore, it is the diet again that manifests the health benefits (Table 29.4).

TABLE 29.4 Vitamins that can provide neuroprotection or alleviate neurodegeneration. Name of the Vitamin

Common Name

Vitamin B1 Vitamin B6

Essential Function performed in relation to brain health

Effects due to deficiency

Thiamine

Cognition

Cognitive deficit and encephalopathy

Pyridoxine

Brain development (in kids), synthesis of neurotransmitters

Impaired fetal brain development, autonomic dysfunction

Vitamin B9

Folic acid

Overall functioning of the brain

Cognitive impairment, depression, increases chances of Alzheimer’s Disease and vascular dementia

Vitamin B12

Cyanocobalamin

Maintains healthy nerve cells, prevents brain atrophy

Memory loss

Vitamin C

Ascorbic acid

Protects brain from oxidative stress and inflammation

Impaired oxidative stress management, higher risk of neurodegeneration

Vitamin D

Ergocalciferol (D2), Cholecalciferol (D3)

Brain development, synaptic plasticity, calcium signalling, neurotransmission, neuroprotection, maintaining brain vasculature

Cognitive dysfunction, autism, epilepsy, enhanced risks of stroke, Alzheimer’s disease, Schizophrenia and Parkinson’s disease

Vitamin E

Tocopherol

Protects brain from oxidative stress

Increased risk of neurodegeneration

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Mechanistic insights into nutraceuticals functioning as protectors of brain health Genetic mutations, accumulation of abnormal proteins, increased ROS, and/or destruction of the neurons in a specific part of the brain are associated with the debilitating conditions of neurodegenerative diseases [38e42]. Among the well-understood mechanisms behind the etiology of toxicants-induced neurotoxicity and neurodegeneration observed in case of AD, PD, HD, MS, and ALS, the salient ones are neuronal mitochondrial dysfunction, intracellular Ca2þ overload, unrestrained generation of ROS and prolonged neuroinflammation individually or in combination [183e186]. Improved experimental models, techniques, and exhaustive on-going research in the field of neuroscience have been instrumental in identifying the aforementioned mechanisms [43e50,187]. Ca2þ homeostases across the cellular, endoplasmic reticular (ER), and mitochondrial membranes are critical for normal cellular physiology. Maintenance of Ca2þ homeostasis across different membrane systems is coordinated precisely through several specialized mechanisms. Naturally, any perturbation to these mechanisms disrupts the fine coordination between different levels Ca2þ homeostasis, resulting in unfettered increase in the intracellular and intraorganellar (ER and mitochondria) Ca2þ concentrations. This calcium overloading eventually leads to neurodegenerative pathogenesis [188e190]. ROS-induced mitochondrial dysfunction during neurodegeneration not only impairs cellular energy production but also triggers deregulation of Ca2þ homeostasis. In addition, mitochondrial failure enhances generation of ROS through a positive feedback loop [191]. Such in-depth understanding of disease mechanism led to significant development in target-base therapies involving stem cells, hormone replacement, modulation of neurotransmitter, and expressions of pathogenic alleles [51e58]. Particularly, great hopes are laid on neural transplantation and stem cellsebased therapies against the range of neurodegenerative diseases [192e194]. However, these treatments come with sideeffects both known and unknown, some of which could be long term as well [52,55,57,58]. Therefore, an emergent need to identify safer alternative treatment options, particularly, those employable for longer duration was felt. Thus, nutraceuticals capable of multitargeting to improve the overall neuronal health with minimal or no side-effects became an attractive option [195e200]. Improved understanding of neurodegenerative etiology led to several target-based therapeutic options. However, as mentioned earlier, these options have several adverse sideeffects, and thus are not suitable for chronic use, which sometimes is an absolute requirement. There are encouraging outcomes from quest for safe, side-effect-free alternative

natural remedies, with both prophylactic and curative properties. Such protective strategies including nutraceuticals have gained popularity, since the coining of the term “Nutraceutical” by Dr. Stephen DeFelice, in 1989 [7]. These are food-based remedies to prevent and/or treat a wide variety of diseases and disorders [201]. Nutraceuticals can simultaneously act on multiple cellular pathways. Being part of the diet or a dietary supplement, nutraceuticals are suitable for prolonged administration. Both these attributes make them most favorable for treating neurodegenerative ailments, which often being chronic, require long-term treatments. Popular nutraceuticals, like, resveratrol, a-lipoic acid, coenzyme Q10 (ubiquinone), b-carotene, lycopene, astaxanthin, and curcumin are potent antioxidants that can neutralize oxidative stress and boost endogenous antioxidant levels. In the process, they stabilize mitochondrial functions. Mitochondrial dysfunction is an important reason behind neurodegeneration. Thus, the inherent nature of these nutraceuticals makes them most suitable remedies for neurodegeneration [198e200,202e205]. Neuroprotective effects of nutraceuticals are not just due to their ability to scavenge free radicals, chelate transition metals, improve antioxidant reserve, and reduce inflammation, rather, their capability to modulate various signaling pathways plays an important role in this. These nutraceuticals modulate Nrf2/ ARE, mitogen-activated protein kinase (MAPK), protein kinase C (PKC), Janus kinase-Signal Transducer and Activator of Transcription (JAK-STAT), MEK/ERK/CREB, PI3K/AKT and insulin-signaling pathways which are important for cell survival and stress response [206e213]. Nutraceuticals affect multiple molecular pathways. Therefore, in addition to treating neurodegeneration, nutraceuticals are anticipated to improve overall neuronal health. Epidemiological studies of World Health Organization, carried out by Professors Doll and Peto in the 1980s, suggested that approximately 35% of cancer deaths can be prevented through appropriate nutrition. Even 90% of certain cancers can be avoided by dietary supplementation [214]. This is indeed an encouraging observation for considering nutraceuticals in treating neurodegenerative conditions. This section of the chapter will cover the various molecular pathways targeted by nutraceuticals in alleviating neurodegenerative conditions.

Nutraceuticals targeting mitochondrial dysfunction Neurons are vulnerable to mitochondrial damage [183,215]. Among the nutritional supplements explored for their potential role in preserving mitochondrial functions, curcumin, a-lipoic acid, astaxanthin, and coenzyme Q10 are quite efficient. Curcumin is extracted from turmeric, a very common spice used in Indian recipes. It ameliorated

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FIGURE 29.4 Nutraceuticals targeting mitochondrial dysfunction. (A) Curcumin prevents 6-hydroxydopamine-induced neurotoxicity by increasing the level of Cu-Zn SOD. Cu-Zn SOD helps to check the increase in intracellular ROS generation. Curcumin also inhibits nuclear translocation of NF-kB, a potent transcriptional regulator involved in several proinflammatory pathways. (B) a-lipoic acid is a potent mitochondrial stabilizer that can protect neurons from hypoxia and other toxicant-induced neurotoxicity by improving the mitochondrial functions. It is also responsible for decreasing ROS generation. (C) Astaxanthin acts through PPARg mediated pathway to protect mitochondria from detrimental effects of ROS generation. It also inhibits the ubiquitin mediated proteosomal degradation of IkBa to prevent the nuclear translocation of NF-kB. (A) Reproduced with permission from Wang J, Xu H, et al. Rg1 reduces nigral iron levels of MPTP-treated C57BL6 mice by regulating certain iron transport proteins. Neurochem Int 2009;54(1):43e48. https://doi:10.1016/j.neuint.2008.10.003; (B) Courtesy: Deveci et al. Alpha lipoic acid attenuates hypoxia-induced apoptosis, inflammation and mitochondrial oxidative stress via inhibition of TRPA1 channel in human glioblastoma cell line. Biomed Pharm J 2019;111:292e304. https://doi:10.1016/j. biopha.2018.12.077. [Under Creative Commons Attribution International License (CC BY-NC-ND 4.0)]; (C) Courtesy: Kim SH, Kim H. Inhibitory effect of astaxanthin on oxidative stress-induced mitochondrial dysfunction-a mini-review. Nutrients 2018;10(9):1e14. https://doi:10.3390/nu10081137. [Under Creative Commons Attribution International License (CC BY-NC-ND 4.0)].

6-hydroxydopamine-induced neurotoxicity in MES23.5 cells. Curcumin treatment partially restored the mitochondrial membrane potential (DJm) in these cells. The levels of Cu-Zn superoxide dismutase (Cu-Zn SOD) were increased. This suppressed intracellular ROS levels. Curcumin also inhibited nuclear translocation of NF-kB, a transcription-factor involved in inflammation [216] (Fig. 29.4A). a-Lipoic acid is a naturally occurring fatty acid found in foods like spinach, broccoli, potatoes, yeast, and organ meats such as liver and kidney. It is very efficient in stabilizing neuronal mitochondria, both in vitro and in vivo against hypoxia and other toxicants-induced neurotoxicity. It improves mitochondrial functions and physiology [218] (Fig. 29.4B). Clinical trials on use of a-lipoic acid in patients with diabetic and cancer chemotherapy associated peripheral neuropathies have been

conducted [219,220]. Astaxanthin is a ketocarotenoid that imparts pink or red pigmentation in salmon, trout, lobster, shrimp, and other seafood. Studies showed that astaxanthin can protect mitochondria in cultured nerve cells and boost cellular energy production. It also restrained production of ROS [217,221,222] (Fig. 29.4C). Coenzyme Q10 (CoQ10) is a vitamin-like substance found ubiquitously in the body, with higher proportions in heart, liver, kidney, and pancreas. Although meats and seafood are its dietary sources, it can be synthesized in the laboratory and therefore, can be made available as dietary supplement. CoQ10 is a powerful mitochondrial antioxidant. It can efficiently preserve mitochondrial functions during stroke and epilepsy. Besides, it can protect neuronal cells from striatal excitotoxic lesions produced by the mitochondrial toxin (complex II inhibitor) and neurodegenerative disorders

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[223e226]. Clinical trials of CoQ10 have demonstrated its beneficial effects in neurodegenerative disorders [227,228]. These evidences confirm that nutraceuticals are potent preservers of mitochondrial functions, and thus are efficient in fighting against the pathophysiology of neurodegenerative disorders.

Nutraceuticals targeting misfolded protein aggregation Resveratrol inhibits amyloidogenic cleavage, thereby enhancing clearance of Ab, eventually reducing Ab aggregation. [229e231] (Fig. 29.5). Several nutraceuticals such as resveratrol, curcumin, ginsenosides, gallic acid, etc., are reported to have inhibitory effect on a-synuclein

assembly and concomitant neurotoxicity [232]. Calcium dyshomeostasis underlies disease progression in AD [233]. Blueberry extract can antagonize increase in intracellular calcium. It can also prevent aggregated Ab-induced ATP leakage. These properties of blueberry impart protection to neurons from calcium-overload-induced neurotoxicity. Not many reports on calcium-overload antagonizing effect of nutraceuticals are available [234]. A thorough mechanistic screening of nutraceuticals for potential inhibitors of intracellular calcium overloading is required.

Nutraceuticals targeting oxidative stress Nutraceuticals like resveratrol, quercetin and berberine act as antioxidants by scavenging ROS and upregulating cytoprotective

FIGURE 29.5 Nutraceuticals targeting aggregation of misfolded proteins. (A) Resveratrol acts against Alzheimer disease by decreasing the amyloidogenic cleavage of the amyloid precursor protein (APP), thereby, enhancing clearance of amyloid beta (Ab) peptides and concomitantly, their aggregation. Resveratrol also protects neuronal functions through its antioxidant properties. (B) Phytochemicals/plant extracts act as neuroprotective agents by targeting different key stages of a-synculin oligomerization and fibrillation. (A) Courtesy: Jia Y, Wang N, Liu X. Resveratrol and amyloid-beta: mechanistic insights. Nutrients 2017;9:1e13. https://doi:10.3390/nu9101122. [Under Creative Commons Attribution International License (CC BY-NCND 4.0)]; (B) Reproduced with permission from Javed H, et al. Plant extracts and phytochemicals targeting a-synuclein aggregation in Parkinson’s disease models. Front Pharmacol 2019;9:1e27. https://doi:10.3389/fphar.2018.01555.

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FIGURE 29.6 Nutraceuticals targeting oxidative stress. (A) Ginsenoside inhibits Ab-triggered mitochondrial apoptotic pathway by attenuating Ab-evoked reactive oxygen species (ROS) production, apoptosis signal-regulating kinase 1 (ASK1) phosphorylation, and JNK activation. In addition, it also affects pathway. (B) Sulforaphane (SFN) protects brain against oxidative stress by activating on Keap1-Nrf2 responsive genes. SFN causes conformational alterations in Keap1 by interacting with numerous cysteine residues in it. This eventually releases Nrf2, which gets translocated to nucleus, subsequently, and binds to Maf proteins and transactivates ARE in the promoter of genes coding for antioxidant and detoxifying enzymes. (C) Schematic representation of natural products involved in neuroprotection against Alzheimer disease by managing oxidative stress. (D) Rosmarinic acid showed neuroprotective effect by scavenging ROS. (A) Courtesy: Liu M, et al. Ginsenoside Re inhibits ROS/ASK-1 dependent mitochondrial apoptosis pathway and activation of nrf2-antioxidant response in beta-amyloid-challenged SH-SY5Y cells. Molecules 2019;24(15):1e16. [Under Creative Commons Attribution International License (CC BY-NC-ND 4.0)]; (B) Reproduced with permission from Uddin S, et al. Emerging promise of sulforaphanemediated Nrf2 signaling cascade against neurological disorders. Sci Total Environ 2020; 707:135624. https://doi:10.1016/j.scitotenv.2019.135624; (C) Courtesy: Shal B, et al. Anti-neuroinflammatory potential of natural products in attenuation of Alzheimer’s disease. Front Pharmacol 2018;9:1e17. https://doi:10.3389/fphar.2018.00548. [Under Creative Commons Attribution International License (CC BY-NC-ND 4.0)]; (D) Courtesy: Cui H, et al. Rosmarinic acid elicits neuroprotection in ischemic stroke via Nrf2 and heme oxygenase 1 signaling. Neural Regen Res 2018;13(12):2119e2128. https:// doi:10.4103/1673-5374.241463. [Under Creative Commons Attribution-Non-Cpmmercial-Share Alike 4.0 License].

genes in Nrf2-dependent manner. Nrf2-antioxidant response element (Nrf2/ARE) signaling pathway is a potent therapeutic target for neurodegenerative diseases [198e200,235e237] (Fig. 29.6A and B). L-Sulforaphane is an isothiocyanate compound found in broccoli and other cruciferous vegetables. Studies show that it can inhibit dopamine quinone-induced neuronal death by reducing the accumulation of ROS, preventing membrane damage, and DNA fragmentation in dopaminergic cell lines and mesencephalic dopaminergic neurons. LSulforaphane and tert-butylhydroquinone also stimulated Nrf2/ ARE transcriptional pathway against H2O2-induced oxidative

stress in a mixed neuron-astrocyte culture system Nrf2/ARE pathway and upregulates various antioxidant genes like g-glutamylcysteine ligase (GCL), MnSOD, hemeoxygenase, and NAD(P)H:quinine reductase. GCL is the rate-limiting enzyme in the synthesis of glutathione (GSH), an important factor in ROS scavenging [238,240,241]. Blueberry targets ROS signaling through CREB and MAP-kinase signaling pathways [236,242] (Fig. 29.6C). Likewise, curcumin imparted neuroprotection by decreasing ROS and proapoptotic signaling in mouse models of encephalitis [180,243]. Carnosic acid and rosmarinic acid also scavenged ROS to protect neuronal cells in vitro and in vivo

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[180,239,244] (Fig. 29.6D). Resveratrol provides neuroprotection by modulating Ab processing and upregulating sirtuin 1, the longevity-linked gene [245]. Similarly, aged garlic extract was found potent against Ab peptide-induced apoptosis. It suppressed generation of ROS, attenuated caspase-3 activation, prevented DNA fragmentation, and PARP cleavage [13]. Eugenol, a nutraceutical obtained from cloves, increased GSH levels and inhibited lipid peroxidation in 6-hydroxydopaminetreated mouse striatum. This also prevented 6-hydroxydopamineinduced reduction in dopamine levels [161]. Epidemiological studies strongly correlate antioxidant-rich foods with reduced risk of developing PD. However, conclusive clinical trials in support are yet unavailable [246].

Nutraceuticals targeting neuro-inflammation Phospholipase A2 links prooxidants and proinflammatory cytokines with the release of arachidonic acid and eicosanoid synthesis. Arachidonic acid and eicosanoid are important mediators of inflammation. Anthocyanins inhibit phospholipase A2 to alleviate neuroinflammation [247,248]. Anthocyanins are naturally occurring pigments belonging to flavonoid group of polyphenols. Anthocyanins are very common in berries. Blueberries modulated expressions of the genes involved in inflammation to impart

neuroprotection [249]. Curcumin inhibited inflammation by suppressing NF-kB activation. This also helped in preventing Ab-induced cell death in a human neuroblastoma cell line [48]. Green tea flavonoid, epigallocatechin-3-gallate, and mustard oil glycoside also inhibit proinflammatory signaling through NF-kB or toll-like receptor modulation to stabilize the blood-brain barrier in MS [250]. Retinoic acid is a metabolite of vitamin A that can balance T-lymphocyte populations in peripheral blood, which results in increased tolerance and decreased inflammation. Thus, it is also anticipated to improve plasticity, neural regeneration, cognition, and behavior in patients with MS [251]. Vitamins D and E reduce inflammation in patients with MS, PD, and AD [252]. Vitamin E supplementation also suppressed neuronal degeneration occurring due to kainic acid-induced status epilepticus in rat brain. The levels of astrocytic and microglial antigens (GFAP and MHC II, respectively) and proinflammatory cytokines such as IL-1b and TNF-a were significantly reduced after vitamin E supplementation [253]. Omega-3 polyunsaturated fatty acid can target behavioral dysfunction, hippocampal neuronal loss, inflammation, demyelination, and impulse conductivity. Thus, omega-3 supplementation promoted neurologic recovery in traumatic brain injury by attenuating the deleterious effect on white matter [254,255] (Fig. 29.7).

FIGURE 29.7 Nutraceuticals targeting inflammation. Schematic figure showing the antiinflammatory effects of resveratrol on LPS-induced microglial activation through (1) inhibition of reactive oxygen species production; (2) suppression of MAPK signal transduction pathways; and (3) activation of Sirt1, which in turn suppresses the activation of NF-kB signaling pathway. The overall effects reduce the production of proinflammatory mediators, eventually resulting in neuroprotection. Reproduced with permission from Zhang Z, et al. Morin exerts neuroprotective actions in Parkinson disease models in vitro and in vivo. Acta Pharmacologica Sinica 2010;31(8):900e906. https://doi:10.1038/aps.2010.77.

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Nutraceuticals as neurotransmitter modulators Some nutraceuticals possess neuromodulatory activities that can be beneficial for treating neurodegenerative disorders. Mitochondrial membrane potential (DJm) dissipation ultimately leads to mitochondrial instability. The flavonoid apigenin present in celery seeds can protect neurons from copper-induced Ab-mediated toxicity by relieving mitochondrial DJm dissipation [256]. It also modulates GABAergic and glutamatergic transmission in the cultured cortical neurons [257]. Soy isoflavones influence the brain cholinergic system to restrict age-related neuronal loss and cognitive decline in male rats [258,259]. Resveratrol acts as an antidepressant by increasing 5-HT [260] (Fig. 29.8).

Nutraceuticals from an evolutionary perspective Nutraceuticals are surfacing as the future for managing diseases with challenging epidemiologies. Nutraceuticals or dietary supplements, as they are now known, do not have any geographical restrictions, courtesy rapid globalization of almost everything in modern life. However, nutritional history of human race shows something interesting: geographic variations of diets prepare the local populace for

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a particular geophysical environment. Conversely, endemism of natural resources shaped the dietary portfolio of human populations across the world for centuries. The overall decline in the global food quality owing to rushed commercialization of the global food market has brought almost the global population on the same platform. From here, now, we have started tracing back the secrets of long and healthy lifespans of our ancestors. Among several anticipated factors, food habit is emerging to be the most important one behind this. Therefore, ancient food habits have been extensively explored in recent years that have resulted in identification of dietary items with very high medicinal values. Including these items in daily diets as supplements, regardless of their geographic origin, is trending as the dietary regimes of wealthy countries. So far, this chapter provided the readers with a comprehensive understanding of the role of nutraceuticals in maintaining overall health of human brain. There are many reports, reviews, articles, book chapters, and even entire books dedicated to this topic that has enhanced our general knowledge and understanding of the functioning of brain nutraceuticals. However, to the best of our knowledge, there is no report that offers the readers a historical perspective of gradual evolution of nutraceuticals across the geographical habitats of different human races. Proteomic

FIGURE 29.8 Nutraceuticals as modulators of neurotransmitters. Flavonoids bound to receptors for neurotransmitters either stimulate or inhibit them and thus mediate their actions via modulation of gene expression or phosphorylation. Subsequently, they modulate the synaptic protein synthesis, neuronal plasticity, and other morphological changes responsible for neurodegenerative disorders and impairment in cognition. Courtesy: Ayaz M, et al. Flavonoids as prospective neuroprotectants and their therapeutic propensity in aging associated neurological disorders. Front Aging Neurosci 2019;11:1e20. https://doi:10.3389/fnagi.2019.00155. [Under Creative Commons Attribution International License (CC BY-NC-ND 4.0)].

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and metabolomic profiles of a population are the functions of geographical conditions. So, it is quite possible that nutraceutical requirements of a given population to ensure brain health could be quite specific and spelt out by these profiles. The current section is dedicated toward understanding this complex coordination between racial genetic makeup and their dietary requirements.

Cross-talk between brain and gut The “gut-brain axis” is a rather new and somewhat unusual concept connecting brain functions to gut microbiota. Elderly individuals were found to have altered “gut-brain axis,” which is believed to be responsible for systemic inflammation in the aging population. Besides, altered “gut-brain axis” is also indicated as a possible marker for early onset of frailty in younger population. According to this concept, probiotic consumption is healthy for gut microbiota and positively influences brain functions pertaining to behavior and cognition. The authenticity of this concept has been put to clinical trials for addressing the relationship between gut microbiota and CNS and psychiatric disorders. One such study aims at investigating the correlation between composition of gut microbiome, permeability of intestinal barrier, and systemic inflammation in patients with dementia [261]. The enteric nervous system can function autonomously and handle reflexes in the absence of CNS input. It communicates with CNS parasympathetically via vagal nerve and sympathetically via paravertebral ganglia. In addition, it is susceptible to neurotrophic and neuromodulatory signaling. Thus, Dr. Michael Gershon has rightly identified gut as “the second brain” [262]. Intestinal flora of an individual is a unique signature decided by the mode of delivery at birth, genetic predisposition, age, nutrition, food habits, physical activity, environmental factors, stress, infections, other diseases, and the use of antibiotics [263]. Interestingly, the gut microbiota influences CNS through synthesizing molecules mimicking neuroactive factors like acetylcholine, catecholamine, g-aminobutyric acid (GABA), histamine, melatonin, and serotonin [264]. Conversely, emotional and psychological stress influences the composition of gut microbiota, resulting in reduction in benevolent Lactobacilli population and a rise in pathogenic Clostridium species [265e267]. Therefore, gut-brain axis is inclusive of the intestinal flora, and hence the term is extended to “microbiota-gut-brain axis.” The idea of “microbiotagut-brain axis” gained popularity since the early 2000s, following a study reporting an exaggerated hypothalamuspituitary axis (HPA) response to stress in germ-free (GF) mice as compared to normal ones [268]. The gut-brain communication is maintained by vagus nerve signaling and specific bacterial species [269e271]. GF mice lived significantly longer than their normal counterparts. This is

likely to be due to reduced pathological infections. However, a converse effect is not ruled out, since, aging is known to adversely affect gut lining like it does to brain cells. In fact, microbial diversity and stability of intestinal microflora reduce with age [272,273]. Interestingly, reduction in brain function and cognitive abilities accompanied the age-related loss of intestinal flora [274,275]. Aging leaves its imprints on almost all types of cells, and its manifestations share common denominators like genomic instability, epigenetic alterations, and oxidative stress [276]. Even the gut microbiota is not spared from the effects of aging: the composition alters, which in turn affects brain physiology and function. Fecal microbiota transplantation experiments in rats linked gut microbiota with depression, anhedonia, and anxiety through modifications in tryptophan metabolism. This strongly implicated the role of gut microbiota in neurobehavioral changes [277]. Metabolization of dietary glutamate through certain strains of Lactobacillus and Bifidobacteria resulted in dysregulated GABA signaling and concomitant reduction in anxiety and depression-related comportment in mice [277]. This age-related alteration in gut microbiota homeostasis led to imbalance between symbionts and pathobionts. Consequently, intestinal barrier function was reduced leading to a state of dysbiosis relatable to subsequent metabolic and inflammatory disorders, visceral pain, and altered brain functioning [278]. Nutraceuticals, alternatively identified as food or food products with medical or health benefits, are essentially active compounds effective against many diseases [279]. So, neuro-nutraceuticals are, by extrapolation, active compounds that exert effects on the CNS. Since CNS health is also a function of intestinal flora, therefore, food ingredients responsible for maintaining latter are counted in neuro-nutraceuticals. Some of these might be “nondigestible food ingredients” like prebiotics that selectively stimulate the growth of symbionts like Bifidobacteria and Lactobacilli in the colon [280]. Chemically, prebiotics are fructo-oligosaccharides. They are enzymatically processed in the colon to generate short-chain fatty acids that positively impact commensal flora, which help both in maintaining integrity of epithelial barrier and brain metabolism [281]. Prebiotics lowered triglycerides and cholesterol levels in blood, which is beneficial for blood-brain barrier integrity and brain lipid metabolism [280]. The viable microorganisms in the intestine with positive health effects are called probiotics [282]. Bacterial species belonging to genii Lactobacillus, Bifidobacterium, Escherichia, and Bacillus are the most common probiotics. Saccharomyces cerevisiae, commonly known as the baker’s yeast, is also a probiotic [283]. Probiotics can modify the gut microbiota and thus directly affect tryptophan levels. Tryptophan is a serotonin precursor and hence, the observed anxiolytic effects of probiotics [261].

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Brain and gastronomic evolutions were simultaneous Cooking, meat eating, and domestication of plants and animals have the critical driving forces behind the major dietary shifts during hominin evolution. Decades of devoted and exhaustive anthropological research elucidated that these shifts in dietary history were associated with major anatomical and cultural changes along hominin evolution such as the increase in relative brain size and the advent of modern civilization via agriculture. However, this reconstruction proved more crucial for understanding the evolutionary context of our modern diets and the diseases often associated with them. Changes in food availability and diet composition during hominin evolution likely created strong selection pressures on multiple biological processes that mediated the effect of dietary risk factors for common diseases, such as diabetes, hypertension, and cancer. Morphology of the digestive system has also adapted to dietary shifts [284]. The gut microbiome shows strong individual specificity as a result of genetic polymorphisms introduced by selection pressures like eating habits, living environment, and antibiotic usage [285]. In fact, the diversity and stability of gut symbionts protect us from several diseases like obesity, cancer and even mental disorders [286,287]. Thus, alterations in the gut microbiome lead to several diseases. Gut microbiome in normal individuals shows great diversity due to genetic and environmental factors and of course the eating habits that give the individual specific uniqueness proving the aphorism “We are what we eat.” [288]. Naturally, gut microbiota varies in different countries due to eating habits, culture and genetic variations reflecting racial in addition to spatial distribution [285,289]. Genome interacts with the environmental factors, such as diet, through epigenetic changes. This concept was proposed by the British biologist Conrad Waddington (1905e1975) in 1942 to describe the interplay between genes and the environment in determining the phenotype of an organism. The epigenetic changes are not restricted to embryonic developmental stage only; rather they are active throughout the lifetime of an organism. Dietary and other environmental factors are known to induce epigenetic changes like DNA methylation and histone modifications that not only lasted the lifetime of an individual but also passed on to the offspring through non-Mendelian inheritance. Evidences of diet-induced heritable epigenetic changes have been accumulated [290]. In fact, there are conclusive evidences that the genes that underwent epigenetic changes in response to diet had diverged humans from chimpanzees in the evolutionary tree. The genes directly affected by dietary changes were under strong selection pressure, favoring crucial morphological and functional changes. According to the expensive-tissue hypothesis, a

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switch to a high-quality diet allowed a reduced gut size and an increased brain size driving human evolution [291,292]. Introduction of cooking in the food habits of evolving humans made this switch possible. A diet of raw food difficult to digest could not sustain the high-energy requirements of the human hunteregatherer. Cooking is believed to have allowed reduction in tooth and jaw sizes, led to a smaller gut, thereby, creating room for brain enlargement. Anthropologists noted that cooking was discovered independently by various human populations sufficiently long ago for the current phenotypes to evolve. Thus, epigenetic inheritance acted as an engine of evolution that played an important role in species divergence.

Do nutraceuticals have ethnic biasness when it comes to their effectivities? Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the main components of omega-3 fatty acid, are particularly found in salmon fish muscles [293]. Omega-3 fatty acid and PUFAs are associated with decreased chances of anxiety and depression [294]. Japan is the major consumer of salmon fish, which corroborates longer lifespan of Japanese as compared to other ethnicities [295]. But, can people from other ethnicity, with different gastric profile, digest salmon and get as much benefits as Japanese? Similarly, Asian countries that consume spice are less prone to develop neurological disorders as compared to the Western countries. But can the genetic profile of people from other ethnicities handle the extent of spices used in Indian food? It is difficult to have case-by-case answer to these questions. But like the digestive profile, our allergic profile is also governed by our genetic constitution. Therefore, it is likely, very likely, that food sources of nutraceuticals need to be customized to the genetic profile of the individual’s ethnic background. Lactose intolerance is a genetic trait shaped by the evolutionary forces that show ethnic distribution [296].

Mode of nutraceutical consumption: Food versus dietary supplements Since, gastronomic profile plays a crucial role in deciding the nutrition that will ultimately enter the body, therefore, nutraceuticals taken as food might not be the best option always. Moreover, digestive profile unique to particular human race/s as shaped by the natural selection pressure in the form of food availability (as seen is the case of lactose intolerance) may pose hindrance in accepting or adapting to a different food habit, regardless of the richness of that diet in nutraceuticals. Besides, several cultural, ethical and religious beliefs are known to affect food habits. For example, vegetarian populations are restricted from eating fish, and thus cannot enjoy the benefit of body receiving

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omega-3 directly from the food. For them, cod liver capsules are alternative option. Thus, consuming isolated active components from different food items has gained popularity due to ease of availability and acceptance. Nutraceuticals work in “groups” on “group of targets”. So, there is no one-on-one protocol when nutraceuticals are at work. This teamwork might be required for their intestinal absorption or subsequent assimilation or even performing their functions or a combination of all of these. Food items are stash pools of nutraceuticals in themselves. Therefore, when nutraceuticals are consumed as food, the teamwork is automatically taken care of. However, if nutraceuticals are taken as isolated active compounds, this facility will be missing unless a combinatorial prescription is made. In that case also it is quite unlikely that the natural composition can be reproduced. So, nutraceuticals in the form of tablets, syrups, etc., might perform only suboptimally compared to when taken as food items. Dietary supplements are generally considered safe. Dietary supplements can be easily brought to the market without the support of clinical trials although not totally without risk. There is a lack of systematic studies of their adverse effects and so their use is not absolutely free of risk. Dietary supplements are concentrated or purified products, which can achieve higher plasma levels than respective food sources. These food sources are complex mixtures of bioactive proteins, peptides, and phytochemicals. High plasma levels can pose health risks as seen in case of isoflavones when taken as dietary supplements. As an example, cases of endometriosis have been associated with isoflavones [297]. So, it is difficult to preferentially recommend one mode of nutraceutical consumption to other. Nevertheless, considering the possible number of permutations and combinations gone into natural selection of the fittest traits, it is advisable to adopt food habits compatible with one’s genetic constitution.

Conclusion “Let thy food be thy medicine” is the idea behind the current popularity of nutraceuticals in the Western countries. Asian food habits have always been based on this principle. Ayurveda, the Indian traditional system of medicine, in particular emphasizes the overall health of mind and body through medications in form of food. So, eating healthy food is not a new concept. Thus, nutraceuticals in form of food is actually a readvent of a traditional practice recognized worldwide. However, isolating the active compounds present in the food items and making them available in concentrated forms is definitely something new and more efficient, at least initially; but as discussed earlier, such pure ingredients might not be as beneficial as thought to be. Nutraceuticals, when taken as food, tend to target multiple pathways. Interestingly, these

are major signaling pathways involved in the processes responsible for many diseases. It is fascinating to observe how precisely the nutraceuticals can handle multitargeting. Such precision is difficult to be reproduced through combinatorial administration of active components isolated from the same food items. This chapter has exhaustively reviewed various ethnic medicinal systems and the nutraceuticals identified in them that are involved in maintaining brain health and the tentative pathways they target. From all these a clear correlation between food habits and the prevalence of neurological disorders emerges. This has already led to an unbridled consumption of dietary supplements, which are actually isolated nutraceuticals from various food items but supplied in a very concentrated form. Such supplements are available over the counter, which worsens the situation, since in general consumption is not correlated to requirement. Quite often, the body is left to cope with the overloading of such dietary supplements. Being derived from food items, their possible toxicity never occurs to mind, which sometimes has been the case. Thus, a strategy needs to be put in place to reduce unrestrained intake of dietary supplements. One such approach is, including these supplements under prescription. But, in countries like USA, with less affordable medical systems, such a measure is unlikely to be successful. Therefore, alternative strategies, like, encouraging people to adapt healthier food habits can be an excellent solution. Such food habits might not be ethnic to a particular population, nevertheless, they can always be tempered to enhance their palatability.

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Chapter 30

Ayurveda and Brain health Bhushan Patwardhan and Hema Sharma Datta Interdisciplinary School of Health Sciences (ISHS), Savitribai Phule Pune University (SPPU), Pune, India

Chapter outline Introduction - The brain and the nervous system Ayurvedic perspective of the nervous systemdMajja dhatu and Majjavaha srotas Brain patterns and Dosha type Brain agingdModern and Ayurvedic perspective Neurodegeneration Alzheimer’s disease (AD) Parkinson’s disease (PD) Autism (ASD)

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Introduction - The brain and the nervous system The brain, spinal cord and the nerves, together make up the nervous system. The nervous system has three main functions - Sensory function (gathering information from both inside and outside the body), Integration function (transmitting and processing the chemical inputs in the brain and spine) and Motor function (sending signals to the muscles, glands and organs to respond appropriately). The nervous system has two main divisionsdCentral Nervous System (CNS) and the Peripheral Nervous System (PNS). The CNS comprises of the brain and spinal cord whereas the PNS consists of all the nerves that branch out of the brain and spinal cord. The PNS has two main divisions, the somatic system that regulates voluntary responses of the body, and the autonomic system that regulates the involuntary responses of the body. The autonomic nervous system is further divided as sympathetic nervous system (SNS) that promotes emergency response commonly known as ‘fight of flight’ response, and parasympathetic nervous system (PSNS) that promotes normal response commonly known as ‘rest and digest’ response of the nervous system. The CNS is responsible for cognition, movement, senses, and emotions. Neurons are the structural and functional units of the nervous system. There is a network of billions of

Nutraceuticals in Brain Health and Beyond. https://doi.org/10.1016/B978-0-12-820593-8.00030-6 Copyright © 2021 Elsevier Inc. All rights reserved.

Attention deficit hyperactivity disorder (ADHD) Neuroprotective and regenerative strategies Neuronutrients (Medhyarasayana) Detoxification (Panchakarma) Diet (Ahara) Rejuvenation (Yoga and Nidra) Discussion and way forward References

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neurons in the CNS that transmits and stores information. There are three basic parts of neuron, the cell body, dendrites and axon. Dendrites of the neurons receive stimulus and carry its impulses to the cell body whereas axon fibers (covered with a dense lipid layer called myelin sheath) carry the impulses away from the cell body. Neurotransmitters are the chemicals that cross the gap in the synapses and continue the nerve impulses. The CNS has limited capacity for self-repair. As it is encased in bony structures (skull and vertebrae), the accessibility to it is difficult; it also has a special vascular system that serves as a barrier to prevent entry of harmful substances. CNS diseases/disorders include neurodegenerative diseases, neurodevelopmental diseases, and traumatic injuries which result in permanent functional impairment [1,2]. Brain is one of the largest organs in the body and majorly comprises of fat. Brain size is generally proportional to the body size but that does not correlate with the intelligence. The major parts of the brain comprise of the cerebrum, cerebellum, diencephalon, and brain stem. Cerebrum is the largest portion of the brain comprising of about 60% of brain mass and it consists of two hemispheres. The gray matter (cerebral cortex) comprises of the cell bodies and synapses but no myelin and the folded bulges of the cortex (gyri). The white matter (medullary body) consists of the myelinated axons. Cerebrum is 441

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responsible for emotions, thoughts, creativity, communication, planning. Cerebellum coordinates movements and balance. Diencephalon (Epithalamus, Thalamus, Hypothalamus) manages internal environment, moods, memory, regulates pituitary gland and sleep. Brain Stem (Midbrain, Pons, Medulla), the smallest region, manages the basic bodily functionsdvegetative functions and involuntary responses. Essential fatty acids (EFAs) are the most important molecules that help in maintaining the integrity and functioning of the brain. EFAs, especially the omega-3 fatty acids, are important for brain development during the gestation as well as postnatal period. EFAs cannot be synthesized by the body and hence are to be obtained from dietary sources, deficiency of which can lead to impaired brain performance and diseases. As EFAs are involved in the synthesis and functions of brain neurotransmitters, and in the molecules of the immune system their continuous bioavailability throughout the life span is desired. Neuronal membranes contain phospholipids that helps in the synthesis of specific lipid messengers on neuronal stimulation or injury, which in turn participate in signaling cascades that can either promote neuronal injury or neuroprotection. Myelin has a much higher lipid content about 80% t compared to white matter where it’s about 60% and gray matter where it’s about 40%. Myelin contains higher cerebroside’ cerebroside sulfate and cholesterol, and lower ethanolamine glycerophosphatides and choline glycerophosphatides than gray matter. Serine glycerophosphatides and sphingomyelin are about the same in each tissue. The extra-myelin portion of white matter has lipid composition that is similar to myelin, but different from gray matter. The molar ratio of protein amino acids to polar lipids in myelin is approx. 2.38 to 1. Brain uses about 20% of the total blood and 20% of the total oxygen that is circulating through the body at any given time. If blood supply to the brain is cut off for more than 8e10 s, it can lead to unconsciousness, however the human brain can survive for about 5 to 6 minutes without oxygen [3,4].

Ayurvedic perspective of the nervous systemdMajja dhatu and Majjavaha srotas According to Ayurveda “srotamayam hi shariram” means the whole body is composed of channels. Srota refers to macro and micro channels of circulation in the body through which the basic building elements of the body (dosha, dhatu, and mala) circulate. Dosha regulates all physiological functions of the body and dhatu provides the

nourishment to the body, while mala are the waste matter of the body metabolism. Charaka explains thirteen srota as depicted in Table 30.1. Seven srota for dhatu i.e. rasa (life sap or plasma), rakta (blood), mansa (muscle), meda (fatty tissues), asthi (bones), majja (bone marrow and nervous tissues) and shukra (semen or regenerative tissues). Three srota for mala, i.e. mutra (urine), purisha (faecal matter), and sweda (sweat). Three srota for prana (life forces), anna (food) and jala (water). Hence Srota are responsible for movement of bodily humors, nourishment of body tissues and purity in psychological feelings. Dushti (impairment) in these channels cause derangements and is responsible for various physiological and neurological disabilities. Srota are considered as modification of the Panchamahabhoota in which different elements undergo transformation, transmutation, circulation and transportation. The human body is an expression of Panchmahabhoota (five great elements) that includes five basic elements of nature, earth, water, fire, space and sky. Their combination and proportion determine the prakriti (constitution) of the individual that is referred as the dosha type as Vata (air and ether), Pitta (fire and water) and Kapha (water and earth). In Ayurveda, the majja dhatu is considered as an unctuous part present in the bone casing. It is associated both with the bone marrow which is present inside the bones and the nervous system comprising of the brain in the skull casing and spinal cord in the vertebrae. s Majja originates from its previous dhatu-meda (fatty tissues) and it is formed from ahara rasa (the essence of food). The quality and quantity of ahara rasa thus determines the quality and quantity of majja dhatu. Majjavaha srota are channels that carry the nutrients to the bone marrow and nervous system. The marga (channel of influence) of majjavaha srota is suggested to be central, sympathetic, and parasympathetic nervous system while the mukha (origin of influence) of majjavaha srota is suggested to be considered as the synaptic spaces. Constitution of majja dhatu has a predominance of jala mahabhuta (water element) and has kapha like characteristics however for proper formation and functioning of the majja dhatu, air and water should be in balance. The balance of air helps regulate the flow of nerve impulses and water helps provide a counter balance to air hence protecting the nerve against excessive motion and agitation. The food that provokes vata generally leads to poor formation of majja dhatu and hence is responsible for various neurological and degenerative disorders. Vitiation of pitta leads to inflammation and over a long period of time can burn out the myelin and nerve tissue. Vitiation of kapha may slow down nerve conduction, decrease the rate of processing information and cause blockages resulting in the aberrant flow of nerve impulses. The depletion of

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TABLE 30.1 The channels of circulation in the human body as per Ayurveda

Macro and Micro Channels of Circulaon in the Body (Thirteen SROTA)

Seven for Body tissue (DHATU)

Three for

Three for Body waste (MALA)

Vital forces

for Plasma (RASA)

for Urine (MUTRA)

for Life force (PRANA)

for Blood (RAKTA)

for Faecal maer (PURISHA)

for Food (ANNA)

for Muscle (MANSA)

for Water (JALA)

for Fat (MEDA) for Bone (ASTHI) for Marrow & Nerves (MAJJA) for Regenerave ssue (SHUKRA)

Nervous System (MAJJA VAHA SROTA)

Channel of Influence (Marga) CNS + PNS

Origin of Influence (Mukha) Synapc Space

majja dhatu known as majja kshaya, with aging, can be the cause of various neurological disorders hence affecting the intellectual and psychological status of a person [5e8].

Brain patterns and Dosha type Dosha plays an important role in determining the quality of dhatu and hence the brain pattern. All the seven dhatu of the body contains their own fire (agni) for metabolizing the nutrients supplied through srota. The state of agni determines the quantity and quality of the tissues that are formed. The health of the majja dhatu is dependent upon the state of the majjagni (one of the seven tissue fires called dhatvagni). Majjagni resides within the majja dhara kala (the membranes or layers in the body). Infiltration of the kala by vata dosha, makes the agni variable, infiltration of the kala by kapha dosha lowers the agni, and infiltration of the kala by pitta dosha, leads to increased agni Variable agni results in irregular tissue formation and the tissue is

very fragile. Movement of prana is irregular and may result in hyperactivity or hypoactivity. Jerky motions and tremors are also co related with this. Aggravated vata dosha may result in drying and thinning of the nervous tissues. Low agni may result in excessive tissue formation of low quality making the majja dhatu denser and thicker which in turn leads to slow movement of nerve impulses (prana), slow processing of sensory information and slow response times. When kapha dosha increase further it may block the flow prana entirely. Increased agni may result in minimal to moderate tissue formation that may be very efficient which in turn leads to the effective movement of prana through the nervous system with faster processing and response time. When pitta dosha increases too much, the tissue formed become prone to inflammation and excessive metabolism which may lead to deterioration of the myelin sheath and disturbance of neurological structures. This may occur in some cases of Parkinson’s disease and dementia.

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Vata dosha brain pattern is associated with a great range of functioning of the brain and nervous system; it is characterized by highly variable behavior. People with this type exhibit high range of prefrontal functioning, get overstimulated easily, like multitasking, tend to learn and forget quickly. They can give creative solutions to problem solving but have trouble sleeping soundly. Due to high sympathetic nervous system activation, the peripheral blood flow is less that leads to cold limbs. They are very sensitive to pain and cold temperatures. They have a high range of digestive power leading to an irregular appetite and bowel movements. Their limbic system is highly sensitive to changes in the environment. Their emotions are highly variable, they can have excessive fear and phobias. Their hypothalamus is constantly changing the state of the mind and body. Pitta dosha brain pattern is associated with fast, passionate responses of the brain and it is characterized by dynamism. The sympathetic response turns on to a high level and then returns to resting levels again. People with this type have their autonomic response tied to purposeful goal-oriented behavior, where it turns on to reach the goal and then turns off. They have strong digestion and frequent bowel movements. Their hypothalamus has a strong on and off switch and it maintains a higher core body temperature and dynamic mental and physical activity. When Pitta dosha becomes excessive it can lead to irritability and anger. Kapha dosha brain pattern has stable activity pattern of the brain and nervous system and is characterized by steadiness. People with this type have high parasympathetic response and have methodical thinking and action. They prefer routine and need stimulation to get going. The sympathetic response is not easily evoked in them. They are calm, easy going, not easily perturbed, always smiling, and rarely in a hurry. They are sensitive to cold and dampness. The hypothalamus maintains a slower metabolism rate [9e11].

Brain agingdModern and Ayurvedic perspective The brain undergoes continuous structural and functional changes from conception to old age, more than any other part of the body. The brain development starts early in the life of a foetus, and it grows at a rate of about a quarter million neurons per minute in the first trimester. After birth during first few weeks, the brain volume is about 35% of adult volume and almost doubles during the first year, and increases to 15% to 80% of the adult size in subsequent years. The amount of brain stimulation a child receives can affect brain growth by almost 25%. During the first few years of life, more than one million new neural connections are formed every second and the size of the brain increases fourfold at 3e5 years. It reaches around 90% of adult

volume by the age of 6 years, though the brain growth continues till 18 years of age. Grey and white matter have different growth trajectories. The frontal lobes, responsible for executive functions, such as planning, working memory, and impulse control, are among the last areas of the brain that mature, and they may not be fully developed until the age of 30e35 years. The sensation-seeking trait (dopamine levels) develops during adolescence. Impulsivity and sensation-seeking have different trajectories of development from age 12 to 24 [12,13]. In Ayurveda, aging is known as Jara. It is defined as that which becomes old by the act of wearing out, jiryati iti jara; it is synonymous with vardhakya meaning increasing age. Ayurveda divides human life into childhood up to the age 16 years; youth and middle age, from 16 to 60 years (Charaka) or 70 years (Sushruta) and exhibits progressively the traits of growth vivardhamana (16e20 years of age), youth youvana (20e30 years), maturity sampoornata (30e40 years), deterioration parihani (40 years onwards which gradually sets in up to 60 years); old age, wherein after 60e70 years the body elements, sense organs, strength, and so forth begin to decay. While describing aging, Ayurveda takes in consideration Prana (life energy that performs respiration, oxygenation, and circulation). It governs two other subtle essence ojas and tejas. Ojas (the essence of the seven dhatus or bodily tissues) is responsible for the autoimmune system and mental intelligence; it is necessary for longevity. Displaced ojas creates the kapharelated disorders and decreased ojas creates vata-related reactions. Tejas (the essence of a very subtle fire or energy) governs metabolism through the enzyme system. Agni (central fire or energy source in the body) promotes digestion, absorption, and assimilation of food. Tejas is necessary for the nourishing and transformation of each dhatu. Aggravated tejas burns away ojas reducing immunity and overstimulating pranic activity. Aggravated prana produces degenerative disorders in the dhatus. Lack of tejas results in overproduction of unhealthy tissue and obstructs the flow of pranic energy. Just as it is essential to maintain balance among the tridoshadvata, pitta, kapha principles of motion, metabolism, structure, respectively, the dhatus and the three malas (bodily wastes); it is important for maintenance of health and longevity that prana, ojas, and tejas remain in balance. The tridosha play a very important role in the maintenance of cellular health and longevity. Kapha maintains longevity on the cellular level. Pitta governs digestion and nutrition. Vata, which is closely related to pranic life energy, governs all life functions. Proper diet, exercise, and lifestyle can create a balance among these three subtle essences [6,14]. The dosha, dhatu and mala constitute the basis of the physiological and pathological doctrines of Ayurveda and body can function normally when they are balanced and in equilibrium. The diminishing agni in older age leads to

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decrease in quantity and quality of all dhatus. Pathologies of the nervous system are termed vatavyadhi such as pain and alterations of motion. On a psychological level, when majjadhatu is healthy, there is a sense of fullness and completion; when deficient, there exists a feeling of emptiness; and in excess, there is the feeling of stagnation and lack of motivation. According to Charaka, factors that lead to vitiation of majjavaha srotas include virrudha ahara (eating wrong combinations of food), lack of sleep, stress, fractures, suppressed emotions, etc. The symptoms of vitiation include lack of stability and equilibrium, loss of memory, anxiety, ringing ears and dark circles around the eyes, talk disorder as stuttering, and the associated diseases could be Bell palsy, Alzheimer’s disease, Parkinson’s disease etc. According to Ayurveda, the process of brain aging begins in the fourth decade of life, which includes neurodegeneration. The contemporary biosciences also register similar views on brain aging considering it an inevitable phenomenon. The weight and volume of the brain decreases by 5% between ages 30 and 70 years, by 10% by the age 80 years and by 20% by the age of 90 years. With aging degenerative changes like physiological disturbances of neurotransmitter secretions, blunting of dendrites and synapses and formation of beta amyloidal plaques occur; this process of neurodegeneration when enhanced can lead to AD and other types of dementia [12,15].

Neurodegeneration Due to aging, the brain size, vasculature, and cognition change, and there are changes in levels of neurotransmitters and hormones. Incidence of stroke, white matter lesions, and dementia also rises. The shrinking of the gray matter, decrease in dendritic synapses, decrease in white matter, deterioration of myelin sheath after the age of 40 is most common. Brain changes do not occur to the same extent in all brain regions, the frontal lobes are most affected by white matter lesions, the prefrontal cortex is most affected and the occipital least. This correlates with the cognitive changes seen in aging. The frontal and temporal lobes are most affected in men as are the hippocampus and parietal lobes in women. Mapping structure to function and change because of aging is a complex task; however, there are studies that show links between volume and neuropsychological function where association between increasing age, a reduction in prefrontal cortical volume, increased subcortical white matter lesions, and an increase in perseverative behavior were seen. The most common cognitive change associated with aging is that of memory. Memory function can be broadly divided into four sections, episodic memory, semantic memory, procedural memory, and working memory. The first two of these are most important with regard to aging. Episodic memory is defined as ‘‘a form of memory in which information is stored with

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‘mental tags’, about where, when and how the information was picked up.” Episodic memory starts declining from middle age and is associated with memory loss seen in AD. Semantic memory defined as ‘‘memory for meanings’’ also declines from middle age leading to slower reaction times, lower attentional levels, and slower processing speeds. According to Ayurvedic pathophysiology majority neurodegenerative disorders may be a result of Beeja Dosha (genetic factor), Ahara Dosha (deprived diet), Agni Dushti (digestive fire disturbance), Medha (cognition) problems and Vata Dushti (vitiation or disturbance of Vata) Table 30.2 summarizes the neurological diseases and disorders [12,15e17].

Alzheimer’s disease (AD) AD is the most common subtype of dementia (a disorder in which mental functions deteriorate and breakdown), followed by vascular dementia, mixed dementia, and dementia with Lewy bodies. By 2050 an estimated 135 million people worldwide will have dementia. According to the National Institute of Neurological Disorders and Stroke, AD is a progressive, neurodegenerative disease that occurs when nerve cells in the brain die. The disease often results in impaired memory, thinking, and behavior, confusion, restless, impaired judgment, impaired communication. Brains affected by AD often show presence of neurofibrillary tangles and neuritic plaques. There is reduced production of certain brain chemicals necessary for communication between nerve cells, especially acetylcholine, norepinephrine, serotonin, and somatostatin. The National Institute on Aging enumerates the suspected causes are age and family history, certain genes, abnormal protein (amyloid b-protein (Ab)) deposits in the brain, environmental factors and immune system problems [17,18]. As per Ayurveda, mind, body, and soul should be in perfect synchronization for overall health. A balanced interaction and coordination of atma (soul), indriya (cognitive organs), manah (psyche), and indriyartha (sense organs) governs the learning process; functioning of these in turn is governed by a balance of tridosha (vata, pitta, kapha) and triguna (sattva, raja, tama). Vata regulates the functioning of the buddhi (intellect), cognitive organs and psyche. Pitta enhances intellect; and Kapha nurtures dhee (intelligence), dhriti (fortitude), and smriti (memory). Any disturbance in tridosha and triguna can disturb the functioning of cognitive organs, psyche and intellect that can result in impaired memory. The progressive gradual decline of memory, judgment, and daily functioning describes AD that finally leads to loss of bodily functions and ultimately death. The cause and mechanism for AD is explained through the concept of smritibhramsha (disturbed memory). This condition arise due to the depletion of dhatus and

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TABLE 30.2 Neurological diseases and disorders.

NEURODEGENERATION

Alzheimer’s disease (AD)

Parkinson’s disease (PD)

Autism spectrum disorder (ASD)

Attention deficit/ hyperactivity disorder (ADHD)

Similarity to

Similarity to

Similarity to

Similarity to

Smritibhramsha

Kampvata, Vepathu

Unmada, Manovikara

Dhee, Dhriti, Smriti Vibramsha

Prevepana, Sirakkampa

Spandin, Kampana

imbalance of vata dosha which arises due to consumption of diet dominant in tamas (obscurity) and rajas (passion), and irregular physical activities that affect the mind and body. The concept of beeja dosha (genetic defects) explains the genetic causes due to vitiated doshas. The vitiation of vata dosha is mainly caused due to tissue wasting (dhatukshaya) and obstruction of the channels (margavarodha). Margavarodha is caused by the formation of ama (accumulation of waste or toxins) due to improper digestion of food or defective process of metabolism. It’s associated with protein aggregation that disturbs the equilibrium and finally leads to degenerative changes and AD. This degeneration further vitiates Vata and results in a repetitive circle of degenerative events. The concept of pranaavrita samana is explained as difficulty in speech, slurred speech, and dumbness. The concept of vital forces of life is explained in terms of five types of life force viz. Prana vayu (inward moving energy), Apana vayu (outward moving energy), Udana vayu (energy of head and throat), Vyana vayu (circulation of energy) and Samana vayu (digestion and assimilation). If vyana vata is occluded by prana vata, then there can be memory loss as well as loss of strength. According to Charaka there are eight factors for improving smriti; nimitta (knowledge of cause and effect), rupagrahanth (knowledge of form), saadrashya (knowledge of similarity), saviparyayat (knowledge

of contrast), sattvanubandha (knowledge of mind), abhyasa (repetition), jnana yoga (attainment of metaphysical knowledge), and punahshrutat (subsequent partial communication) [16e19].

Parkinson’s disease (PD) PD is a progressive neurological disorder characterized by a large number of motor and nonmotor features described under the acronym TRAP: Tremor at rest (trembling in hands, arms, legs, jaw, and face), Rigidity (stiffness of the limbs and trunk), Akinesia (or bradykinesiaeslowness of movement), and Postural instability (or impaired balance and coordination). In addition, flexed posture and freezing (motor blocks) is included. According to the National Institute of Neurological Disorders and Stroke, PD belongs to a group of conditions called motor system disorders, which are the result of the loss of dopamine-producing brain cells. PD generally affects people over the age of 60, and it affects men and women equally. Depression, difficulty in swallowing, chewing, and speaking, urinary problems, constipation, skin problems, and sleep disruptions are the other associated symptoms. In PD there is loss of the nerve endings that produce norepinephrine, the main chemical messenger of the sympathetic nervous system, which controls many automatic functions of the body, such

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as heart rate and blood pressure. The brain cells also contain Lewy bodies and unusual clumps of the protein alpha-synuclein. There are studies being done to understand the functions of alpha-synuclein, its relationship to genetic mutations that impact PD and lewy body dementia [20,21]. In Ayurvedic literature PD and similar conditions are referred by various names, viz., kampavata (tremors due to vata), vepathu (generalized involuntary movements of all parts of the body or of the head), prevepana (excessive shaking), sirakkampa (head tremor), spandin (quivering), and kampana (tremors). PD is generally referred as kampavata, which is associated with vata disturbances, which results in vitiation of rasa dhatu. The pathogenesis involves dry skin; further vitiated vata affects meda and majja dhatus, which block channels and lead to stiffness, rigidity of muscles, and tremors. As the age advances the sanchaya (accumulation) of apana vayu occurs, which leads to constipation and when this combines with vata it results in vyana vayu disturbance in rasa dhatu, leading to dryness of the body membranes. Vitiated vata relocates to any dhatu that is weak; in this case it’s the degenerative tissue of the brain. Vayu (prana, samana, and vyana) in the majja dhatu results in the damage of brain portions that lead to altered coordination and tremors whereas vyana vayu in mamsa dhatu causes rigidity and diminishes the vital force of life leading to depression. Disturbed vata dries out kapha (cellular structure) in majja dhatu that creates an open space for entrance of vitiated vata. Though the condition has majorly vata pathology, pitta may also contribute as its excessive heat can burn the cellular structure causing diminished kapha (kapha kshaya) in the majja dhatu and can initiate neurological disturbances [22,23].

Autism (ASD) ASD is a commonly used term for a class of neurodevelopmental disorders characterized by a triad of deficits in social reciprocity, impaired verbal or nonverbal communication, and repetitive restricted patterns of behavior. Other features generally seen in autistic children are obsessive behavior, reduced muscle tone, compromised digestive system. Onset of ASD occurs during the first 3 years of life and has an approximate ratio of five males to one female. Around 20%e30% of people with ASD have epilepsy and about 50% have intellectual disability. Its pathogenesis commences at a very early age, during embryonic development. The reasons for ASD include genetic basis, gastrointestinal pathology, autoimmune complications, inflammation, extreme oxidative stress, and decreased ability of the body to detoxify toxins [24,25]. Autism is the world’s third most common developmental disorder. In Ayurveda it’s nearest similarity exists with unmada (insanity). The clinical features of autism find some similarity with the lakshanas (features) described in

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unmada due to the vitiation in vata. The causes of autism defined are genetic factors (beeja dosha), pre and postnatal insult to brain, diet (ahara dosha), digestive tract changes, and poisoning (dushi visha). It is the result of khavaigunya (divergence in channels); further vitiated doshas may exacerbate the khavaigunya. Prajnaparadha (actions against one’s self-conscious) at various stages of pregnancy by the pregnant mother is another cause which may lead to manovikara (dysfunction of mind) in the neonate and may result in ASD. In the fourth month of pregnancy, the fetus heart (the seat of consciousness) becomes active, and expresses its desires through the mother, which if not honored, may lead to various physical and psychological abnormalities. To avoid complications like prolonged delivery, injury to fetal skull, hypoxia, and asphyxia which may vitiate vata dosha, enough precautions should be taken during delivery and neonatal period. Diminished ojas is the result of manovaha srotas dushti that leads to poor immunity, infections, and uncommon behavioral symptoms. If agni is corrected it ensures detoxification, facilitates proper nutrition to dhatus, proper functioning of manovaha srotas, and formation of ojas [26].

Attention deficit hyperactivity disorder (ADHD) ADHD is a behavioral disorder of children that is characterized by inattention, increased distractibility and difficulty in sustaining attention, poor impulse control, and decreased self-inhibitory capacity, as well as motor overactivity and motor restlessness. About two to four times more boys are affected than girls. The children with ADHD have slower reaction times or attention span than the general population, for which a weak or underdeveloped cerebellum is majorly responsible as the cerebellum is related to making quick responses. Childhood ADHD is a vata-dominant disease of manovaha srota wherein vyana-vayu is occluded by pranavayu and then there is loss of all the senses, loss of memory, as well as strength. It may also result from Beej Dushti (genetic deformity) during conception or Garbhaja Kaaranas (causes in the prenatal period) [27]. National Institute of Mental Health (NIMH) and National Institutes of Health (NIH) suggests that ADHD may be caused by interactions between genes and environmental or nongenetic factors, cigarette smoking, alcohol use, drug use during pregnancy, exposure to environmental toxins, low birth weight, and brain injuries [28]. In Ayurveda, the characteristics of ADHD can be correlated with the abnormal presentations that are manifested due to disturbances in the normal functions of manahddhee, dhriti, smriti, vibramsha. Mana is responsible for indriyabhigraha (control of sense organs), svanigrahah (self-control), uhya (hypothetical thinking), and vichara (analytical thinking). Dhee (knowledge of judging

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correctly), dhriti (controls manah) and smriti (memory power) are the three main faculties which enable the mind to work at its best; in contrary, in the absence of the same, mind fails to make the right decision. This situation of mind is called as dhee, dhriti, and smriti vibramsha and finally resulting in manasika vikaras (improper functioning of mana) like kama (passion), krodha (anger), lobha (greed), moha (infatuation), irshya (grief), mada (arrogance). Due to this the manah loses its capacity of concentration, attention, and learning as observed in ADHD. Hyperactivity includes restlessness, uneasiness and nervousness in behavior frequently on every day and every time. In Ayurveda, this is referred as cheshta (conduct or behaviour) that is executed by vyana vayu (one of the five divisions of life force that empowers the distribution and communication system of the body) and the vitiated vyana vayu leads to abnormal, improper, and unsteady activities manifested in the form of hyperactivity and impulsivity (kayacheshta and vakcheshta) [29].

Neuroprotective and regenerative strategies Today many people are turning to the alternative and complementary medical sciences, especially Ayurveda, in search of solution for the problems for which modern medicine has not been able to provide a solution or cure. Ayurveda, the Indian traditional system of medicine that advocates the use of medicinal plants and has customized treatment approaches can provide important leads for new treatments and can result in improved clinical outcomes, if investigated by well-designed long-term studies. As discussed previously in this chapter, Ayurveda understands the nature of human brain in a completely different manner from modern day’s psychiatric and physiological theories; hence it can offer newer ways for prevention and management of neurodegenerative disorders and diseases. The procedures by which dhatus are brought into equilibrium condition is called chikitsa; this further includes the processes for expulsion of vitiated doshas from the body (shodhana) and the treatment with drugs that bring normalcy of doshas (shamana). Yuktivyapashraya chikitsa encompasses herbal supplementation, yoga, panchakarma and usage of specific and controlled diet that can help in preventing or resolving the health condition of the patient. To correct, the imbalance in the metabolic fire (agnivikara) the hypo functioning of the digestive fire is corrected by application of appetizers (deepana dravya). Panchkarma therapy, the protocol for removing toxins from the system, to nourish and to energize the cells is also helpful. Yoga therapy that includes pranayam (breathing technique), Asanas (postures), and Mudras (relaxation and meditation) help in promoting the physiological and psychological processes that calm the state of mind and improve sensory responses, attention, and immunity. As preventive therapy

regimen for pregnant women (Garbhiniparicharya) is of major importance. The concept of vayasthapana in Ayurveda deals with preserving the youthfulness of a body irrespective of its age and restricting progression toward senescence, along with enhancement of longevity, intellect, physical and mental strengths, and prevention from diseases. Rasayana tantra, one of the eight branches of Ayurveda, is dedicated to rejuvenation, regeneration, immunomodulation, and healthy aging. The scope of rasayana therapy is not restricted to herbs or formulations alone, but includes nonpharmacological interventions lifestyle interventions, panchkarma therapies, and personal and social behavioral conduct too. All these measures that assist in the maintenance of healthy body tissues. The major being kutipraveshik rasayana (Ayurvedic therapy for rejuvenation that is carried out while staying in isolation in a specially constructed cottage) and achara Rasayana (Ayurvedic strategy for regulating the behavioral social conduct, which ensures a healthy life in a healthy society). As per Ayurveda there is a natural dominance of vata dosha in old individuals hence vata-dominant diseases are expected more. The degenerative and debilitating diseases like AD, PD, stroke are commonly seen in older populations. Application of medhyarasayana (CNS rejuvenators) to restore the body’s harmony and improve the balance between brain and nervous system has been widely used. It can help reduce the progression of diseases, strengthen the sense organs, increase the digestive power and provide a better quality of life. The most commonly suggested herbs include mandukaparni, brahmi, sankhpushpi, and guduchi as memory enhancers. Ethnopharmacology and natural product drug discovery remain a significant hope in the current scenario. Considerable research on pharmacognosy, chemistry, pharmacology, and clinical therapeutics has been carried out on Ayurvedic medicinal plants. Several preclinical and clinical studies have examined cytoprotective, immunomodulatory, and immunoadjuvant potential of Ayurvedic medicines. The ethnopharmacology knowledge, its holistic and systems approach supported by experiential base can serve as an innovative and powerful discovery engine for newer, safer, and affordable medicines [6,30,31].

Neuronutrients (Medhyarasayana) Medhyarasayana refers to Ayurvedic drugs that are used to help improve memory and cognitive functions, while promoting intellect (medhya). Medhyarasayana are extensively used for the ailments of mental and cognitive disorders, as they correcting the dhatus (tissues), there by normalizing their functions and prevent the early aging process. It helps in improvement of mental faculties dhee, dhriti, smriti and gives resistance against diseases. Shodhana (purification therapies) acts at the level of doshas but

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rasayana acts at the level of dhatus or at subcellular level. When severe vitiation of dhatus leads to neurodegeneration such as AD, rasayana chikitsa is very helpful. The mechanism of action of rasayana includes nourishment and maintenance of cell, new cell growth, immunomodulatory action, antioxidant action, and preserving the balance between mind and body. Allopathic treatment for PD includes the drugs supplying the brain with L-DOPA to increase striatal dopamine levels with precursorsubstitution and/or reduce its breakdown but higher doses can cause motor complications of dyskinesia and dystonia and compromise medical treatment. The seeds of Mucuna pruriens (atmagupta or kapikachhu) used in Ayurvedic medicine to manage neurodegenerative diseases like PD are mentioned as the natural source of levodopa that is converted to dopamine in the brain. Some clinical studies suggest pharmacokinetic profile of this natural form distinct from synthetic levodopa, which is likely to reduce the untoward motor complications. It has also shown some neuroprotective benefits, which are unrelated to levodopa. Withania somnifera and Curcuma longa are other commonly mentioned medicinal plants in management of PD that have directionally shown promising results. For the management of ADHD, trials with Brahmi (Bacopa monnieri) and Ashwagandha (Withania somnifera) have shown some positive effect on cognition, memoryenhancing effect, nootropic effect, anxiolytic and antidepressant activity. Apart from Brahmi and Ashwagandha Mandukaparni, Shankhapushpi, Madhuyashti, Jatamansi, Jyotishmati, and Guduchi are considered as potential herbs that can help to improve the brain functions, the sensory and motor functions, and ultimately can help in the management of various cognitive disorders by restoring the balance in tridosha and triguna [32e34]. Ayurveda suggests the use of brahmi, Bacopa monnieri (family: Scrophulariaceae) in different mental conditions and various studies have documented its potential for improvising memory and learning abilities, and symptomatic relief to AD patients. In children with ADHD improvements in sentence repetition, logical memory, and paired associate learning tasks have been reported. To obtain the scientific evidence whether brahmi can enhance cognitive performance in humans the scientific testing through various randomized controlled human clinical trials, is being undertaken. Recent reviews indicate that brahmi trials in adults and adolescents may show improvements in memory, attention, cognition, and mood. Whereas in children increased exploratory drive, improved perceptual images of patterns and organization, and reasoning ability has been indicated. Various preclinical research studies have demonstrated various central nervous system actions of brahmi including antioxidant, antidepressant, and nootropic effects; along with direct and indirect links to changes in dopamine, serotonin,

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noradrenaline, and acetylcholine neurotransmitters. The main active constituents of brahmi includes brahmine, herpestine, nicotine, hersaponin, and monnierin. The nootropic effects are proposed to be associated with the presence of bacosides A and B where bacosides possess enhanced antioxidant defense system and memoryenhancement activity. The mechanisms of action appear to act on the CNS and can modulate cholinergic densities, acetylcholine levels and has b-amyloid scavenging properties. Some clinical studies suggest that the treatment with brahmi continuously for about 6 months or more and its evaluation on various neuropsychological parameters may give beneficial effect in improving memory and attention span, decreasing the rate of forgetting of newly acquired information and associated behavioral problems among the aged suffering from dementia, AD [35e37]. In India, mandukaparni or gotu kola, Centella asiatica (family: Apiaceae/Mackinlayoideae) is popularly known as a brain food. It is a tropical medicinal plant native to Southeast Asian countries, and it is one of the best herbs known for anti aging properties due to its antioxidative effects. It’s possesses neurotonic effects, improves memory and stimulus reflex. Various reviews on scientific studies pertaining to gotu kola indicate its role to protect against neurodegenerative diseases in animal models. Multiple studies have suggested the effectiveness of gotu kola extract in preventing oxidation of proteins, lipid peroxidation, and pro-oxidant processes due to its neuroprotective activity and it is found to be helpful in PD. Some research study results with C. asiatica indicate a correlation and neural basis between improved learning capacity and increased dendritic arborization in amygdaloidal nucleus. Its postulated that the components in Centella extract, such as asiatic acid, asiaticosides, polyphenolic compounds may be helpful for accelerating repair of damaged neurons by their antioxidant and anti inflammatory, and therefore may be effective in preventing the cognitive deficits, as well as the oxidative stress [38e40]. Some recent reviews suggest about 54 Convolvulaceae species to display CNS efficacies historically, about 46 species that have been evaluated for their CNS efficacies and about 67 compounds from 16 Convolvulaceae species are suggested to possess CNS efficacies. Ayurvedic practitioners find the use of Shankhapushpi (Convolvulus pluricaulis) to be helpful in increasing acquisition efficiency of the brain. Its scientific potential in CNS depression, anxiolytic, tranquilizing, antidepressant, antistress, neurodegenerative, antioxidant, hypolipidemic, immunomodulatory, analgesic, anti fungal, antibacterial, anti diabetic, anti ulcer, anti-catatonic, and cardiovascular activity has been found to be promising and the plants are reported to contain several types of alkaloids, flavonoids, and coumarins as active chemicals that bring about their biological effects [41e43].

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Madhuyashti or liquorice, Glycyrrhiza glabra (family: Fabaceae) is a traditional medicinal plant used in various ancient medicine systems and documented across the globe for its ethnopharmacological value to cure varieties of ailments. The central cholinergic pathways play a prominent role in the learning and memory processes. Acetylcholinesterase is an enzyme that inactivates acetylcholine. The extract of G. glabra has been proposed to show acetylcholinesterase-inhibiting activity. Glycyrrhizin the major active constituent obtained from liquorice roots, is one of the most widely used in herbal preparations for the treatment and management of chronic diseases. Several studies have been reported for the beneficial effects of G. glabra in co morbidities associated with CNS. High phenolic content compounds present in G. glabra are thought to be responsible for its strong antioxidant activity and some studies have reported that liquorice flavonoids have 100 times strong antioxidant activity when compared with antioxidant activity of vitamin E. G. glabra is known to possess and show promising effect as a memoryenhancing agent on learning and memory and also have anti-depressant and anti-stress activity. Anti depressant-like effect of liquorice extract is generally attributed to the restoration of brain monoamines, like norepinephrine and dopamine levels [44,45]. Jatamansi, Nordostachys jatamansi (family: Valerianaceae) has been traditionally used for management of neuro psychiatric disorders and few researches show its protecting action against chronic stressinduced impairments in hippocampus-dependent spatial learning and memory. Jatamansi causes an overall increase in the levels of central monoamines and inhibitory amino acids and has been found to have strong antioxidant activity [46,47]. Since time immemorial, a traditional ayurvedic herb called Jyotishmati Celastrus paniculatus, a has been used to address cognitive deficits in mentally retarded children. Jyotishmati has been reported to have neuroprotective and antioxidant activities. It’s seed oil may produce antidepressant like effect by interaction with dopamine receptors, serotonergic and GABA receptors, and hence may serve as an aid to help increasing the levels of brain dopamine and serotonin, as well as decreasing the levels of GABA. Studies also suggest that jyotishmati preferentially affects learning and recall of memory [48,49]. For centuries in India, Ashwagandha or Indian ginseng, Withania somnifera (family Solanaceae) has been used as a broad-spectrum remedy for various neurological and immunological conditions but today it is gaining recognition globally as a promising future herb for the management of anxiety and stress. Ashwagandha is categorized as an anti-inflammatory and antioxidant herbal supplement. The herb also can help regulate physiologic processes and hence stabilizing the body’s response to stress exerting an anxiolytic effect in animals and humans. Investigation for

immune modulation mechanism has so far identified major five bio actives that are capable of regulating 15 immune system pathways through 16 target proteins by bioactivetarget and protein-protein interactions, and hence indicating the potential of withanolide-phytosterol combination as an effective immunomodulator. Recent reviews on ashwagandha suggest its extensive potential as neuroprotective in various brain disorders and are supported by relevant preclinical studies, clinical trials and published patents. However, to promote ashwagandha as a drug, more studies are warranted as today there is still vague understanding of the mechanistic pathways involved in imparting the neuroprotective effect. The phytoconstituents of ashwagandha that are attributed with neuroprotective properties and pharmacological effects in anxiety, AD, PD, ASD, ADHD are sitoindosides VIIeX, withaferin A, withanosides IV, withanols, withanolides A, B, D, anaferine and beta-sitosterol [50e52]. Guduchi, Tinospora cordifolia (family: Menispermaceae) is a large deciduous climbing shrub found mainly in tropical parts of India. It has been widely used in the traditional Indian system of medicine for its general adaptogenic and immunomodulatory activity in fighting infections. It’s known to possess anti-inflammatory, antistress action and improves learning and memory and its antioxidant property is known to prevent/protect neurodegeneration. T. cordifolia is a medicinal plant popular mainly for immunomodulatory activity. Its therapeutic activity may be attributed to protoberberine alkaloids such as jatrorrhizine, palmatine, and berberine [53,54]. On the similar lines of benefit Haridra or Turmeric, Curcuma longa (Family; Zingiberaceae) and Guggulu or Commiphora wightii (Family: Burseraceae) also find a frequent mention along with the above stated herbs. Their neuroprotective efficacy along with anti-inflammatory, antioxidant and anti-protein activities are complemented with a very good safety profile. Dietary curcumin is a strong candidate for the management of major disabling age-related neurodegenerative disorders. Guggulu contains ferulic acids, phenols, and other non phenolic aromatic acids which are potent scavengers of superoxide radicals and can be important for the management of neuro degenerative disorders that are associated with oxidative stress [55,56].

Detoxification (Panchakarma) Panchakarma is a fivefold treatment modality in Ayurveda which is basically divided as purva karma (preparatory procedure), Pradhan Karma (main operative procedure), and Pacchat Karma (postoperative regimen). Panchakarma is majorly a biocleansing procedure which detoxifies the body and helps in increasing bioavailability of drugs and diet. Purva karma includes carminative

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(Deepan), digestive (Pachan), oleation (Snehan), and medicated steam therapy (Swedan). These are beneficial for lubricating, liquefying of toxic waste products/metabolites accumulated in various channels of the body and helps for easy elimination from the body through nearest route. Pradhan Karma includes therapeutic emesis (vamana) and therapeutic purgation (virechan) followed by medicated enema (basti) and medicated nasal drops administration (nasya). Pacchat Karma (postoperative regimen) is a special dietary regimen to be followed to restore the normalcy of body systems. Panchkarma is given depending upon the prakriti and dosha type of a person. The treatment of vata disturbance through oleation using oils medicated with Ashwagandha (Withania somnifera) and Bala (Sida cordifolia) are used to pacify vata. Oxidative stress plays a vital role in the pathogenesis of degenerative disorders of the brain. Thermal therapy is known to enhance antioxidant functions and svedana may also facilitate a similar action. Shirodhara is suggested to have anxiolytic, sympatholytic, and immunopotential effects. Ashwagandha and Bala are known antioxidants and may contribute to prevent the pathogenesis. Bala is also the chief ingredient of Dhanvantaram tailam. After treatment with a polyherbal formulation containing Ashwagandha and Bala, improved mobility may be witnessed [57,58].

Diet (Ahara) As per Ayurveda, food or diet (ahara) plays a major role in nourishing the body, mind, and soul. It also defines certain rules that should be followed for preparation, combination, and consumption of food. Modern science describes food in terms of its nutritional values, vitamins, minerals, proteins, fats, carbohydrates, whereas Ayurvedic diet varies for every individual based on factors like age, gender, dosha type (vata, pitta, kapha) and the level of ama (toxins) in the body. Ayurveda advocates satvik diet (fresh, juicy, light, nourishing diet) to keep the mind calm and relaxed. Rajasik diet (very spicy, salty and sour taste, stimulants like refined sugar and caffeine) should be avoided as they aggravate pitta and vata which in turn increase restlessness, anger, and irritability. Tamasik diet (stale, frozen, preserved, and highly processed foods with preservatives and synthetic additives) should not be consumed, as they diminish the digestive fire and produce toxic substances [59,60].

Rejuvenation (Yoga and Nidra) Yoga is necessary for good health, as it helps in rapid healing of the body and brings peace to the mind. Although yoga has been used as a complementary health approach for enhancing wellness and addressing a variety of health issues, very few studies report yoga as either the primary intervention or one component of a multicomponent

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intervention in people with mild cognitive impairment or dementia. Yoga may affect cognitive functioning through improved sleep, mood, and neural connectivity. There are several limitations of the existing studies, including a lack of intervention details, as well as variability in the frequency and components of the yoga interventions. A further complicating issue is the role of various underlying etiologies of cognitive impairment. Despite these limitations, yoga is considered safe and potentially beneficial complementary health approach for people with dementia. Some research studies suggest that yoga may have a positive effect on CNS like improving the wave frequencies, glucose metabolism, neurotransmitter activity, and the autonomic nervous system. Yoga uses asanas (physical postures), pranayama (breathing exercises), and deep relaxation techniques to calm the senses, decrease hyperactivity, enforce discipline, decrease the temper outbursts, emotional instability, and mood swings. Yoga asana s that may be helpful in ASD include Trikonasan, Veerbhadrasan, Shahsakasana, Parvatasana, Sukhasan, Shavasana. The practice of mantra meditation that involves closing the eyes and mentally chanting a mantra for 10e20 min helps in developing a state of deep relaxation and can be helpful in children with ADHD as it controls stress, manages anxiety, and improves memory and attention. Recitation or attentive listening to “Omkar” also proves beneficial. In the subtle body, the majja dhatu is dependent upon the flow of prana primarily through svadhisthana (lower abdominal center) and (heart center) anahata chakras. Through these chakras the qualities of water and air circulate, respectively [61-64]. Ayurveda considers nidra (sleep) to be a basic building block for healthy mind and body. Sleeping on the right side is the most relaxing and on the left, it is most digestive. Sleep deprivation can cause diminished mental performance and hence a good night sleep is vital for proper brain function and helps in reducing stress and depression [64].

Discussion and way forward Ayurveda, the Indian traditional system of medicine advocates the use of medicinal plants and has customized treatment approaches that can lay the foundation for new modern day treatments. Considerable research on pharmacognosy, chemistry, pharmacology, and clinical therapeutics of Ayurvedic medicinal plants has been carried out, and many preclinical and clinical studies have shown cytoprotective, immunomodulatory, and immunoadjuvant potential of Ayurvedic medicines. It can thus serve as an innovative and powerful discovery engine for newer, safer, and affordable medicines. To reinforce natural product drug discovery, the clinical outcomes should be validated by multiple well-designed long-term studies. Ayurveda

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considers neurological disorders (AD, PD, ASD, ADHD) as the result of a vata dosha disorder. Mind, Body and Soul must be in perfect synchronization for overall health. Ayurveda advocates life style and behavior, nutrition, and the use of medicinal plants and has components of customized treatment approaches that can provide important clues and leads for new treatments. The treatments and remedies involving Rasayana (micronutrients) specific to brain tissue are called Medhyarasayana that helps in delaying brain aging, regeneration of neural tissues and are known to help produce antistress, memory improvization, and adaptogenic effects. The popular Medhyarasayana are Brahmi (Bacopa monnieri), Mandukaparni (Centella asiatica), Shankhapushpi (Convolvulus pluricaulis), Madhuyashti (Glycyrrhiza glabra), Jatamansi (Nordostachys jatamansi), Jyotishmati (Celastrus paniculatus), Ashwagandha (Withania somnifera), and Guduchi (Tinospora cordifolia). Panchakarma, Ahara, Yoga, and Nidra can help attain a balance of tridosha & prana, ojas, tejas and can help lead a healthy life and avoid neurodegenerative disorders.

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Index Note: ‘Page numbers followed by “f ” indicate figures and “t” indicate tables.’

A Acorus calamus, 109e110, 416 Active constituent(s), 233e240 Active sports, 287e288 Acute respiratory stress syndrome (ARDS), 272 Adenosine triphosphate (ATP), 58e59 Adulthood, 286 African traditional medicine (ATM), 411e412 Agantuj karan, 82 Age-dependent neuronal loss, 133e134 Age-related changes in cognitive function, 1 Aging brain, 336e337 Aging population, 57e58 Aging-related neurodegeneration, 32 Alkaline phosphatase, 200e201 Alzheimer disease (AD), 38te40t, 44f, 329, 343e344, 369, 373e374, 380 active constituent(s), 233e240 amyloid b (Ab) hypothesis, 393e394, 394f b-amyloid plaques, 242, 242t antioxidant, 241, 241t iron chelation, 241 apolipoprotein E (APOE), 394e395 Ayurveda, 445e446 Bacopa monnieri, 233e240 brain-derived neurotrophic factor (BDNF), 395 care of patients, 396 cerebral blood flow, 243, 243t cholinergic system, 241e242 clinical features, 229e232 clinical research, 240e243 clinical trials, 243 cognitive defects, 243 dementia, 391e392 dementia crisis, 227e228 dietary components, 397e401 black pepper, 401 cinnamon, 400 flavanols, 398e401 ginger, 401 Ginkgo biloba (Gb) extract, 399 phytochemicals, 398e401 tea (Camilla sinensis) leaves extract, 399 turmeric, 399e400 vitamins, 397e398 extraction, 233 fundamental, 240e243 genetics, 228, 228t

historical origin, 233 iron chelation, 241 isolation, 233 management, 396 memory impairment, 243 mitochondrial hypothesis, 395 morphology, 233 neurodegenerative diseases, 251e254 ameliorative effects, 251e254 catechins, 254 curcumin, 252e253 resveratrol, 253e254 taurine, 251e252 vitamin C, 253 neuroprotectivity, 243, 243t niche, 233 nutraceuticals, 232e233, 397 patent, 233 pathogenesis, 228e229 plant-derived AD drugs, 233 signs, 392e393 social and economic impact, 396 symptoms, 392e393 tau protein, 394 therapeutic agents, 229te232t treatment and care, 396 treatments, 229te232t, 232 vascular dementia, 391e392 vascular hypothesis, 395 Ameliorate brain function, 6, 7t Amino acid tyrosine, 5e6 Amino acids, 6 AMPA receptors, 20, 165 Amukkara, 385e386 Amyloid b (Ab) hypothesis, 393e394, 394f b-Amyloid plaques, 242, 242t Amyotrophic lateral sclerosis (ALS), 43t, 382 neurodegenerative diseases, 259e261 ameliorative effects, 260e261 curcumin, 261 vitamin C, 261 vitamin E, 260e261 Analysis of variance (ANOVA), 147 Angiotensin-converting enzyme inhibitors (ACE-I), 273 Anidra, 86 Antiapoptotic/maternal dietary supplement fetal alcohol syndrome disorder (FASD), 159e160 health in adult disease, 161e162

Lung, 160 malaria, 160e161 perinatal brain injury, 159 placenta, 158e159 schizophrenia, 161 sulforaphane protection pathway (Nrf2/ ARE), 157e158 Anticonvulsant effect, 217 Antidepressant effect, 216 Antihypertensive medication, 58 Antiinflammatory agent, 23e24 Antimicrobials as therapy, 207 Antioxidant, 241, 241t iron chelation, 241 Antioxidant agent, 23 Antioxidant defenses, 60, 61f Antioxidant therapies, 3 Anuchit bramhacharya, 82 Apasmara, 86 Apolipoprotein E (APOE), 394e395 Asatmendriar-thasamyoga, 82 Ascorbic acid in healthy brain aging, 130e131 Asian diet, 421, 421t Attention deficit hyperactivity disorder (ADHD), 447e448 Autism spectrum disorder (ASD), 181, 330, 447 Ayurveda Alzheimer disease (AD), 445e446 attention deficit hyperactivity disorder (ADHD), 447e448 autism spectrum disorder (ASD), 447 brain aging, 444e451 detoxification, 450e451 diet, 451 dosha type, 443e444 drugs, brain disorders, 86 herbs, 32 in brain health-medhya rasayan herbs, 86e110 Majja dhatu, 442e443 Majjavaha srotas, 442e443, 443t medicine, 382 nervous system, 441 neurological disorders, 445e448 neuronutrients, 448e450 neuroprotective/regenerative strategies, 448e451 Parkinson disease (PD), 446e447 rejuvenation, 451 Ayurvedic principles of brain health, 81e83

455

456 Index

B Bacopa monnieri, 171e172, 233e240, 415 adverse effects, 245 cognitive defects, 244t cognitive health, 19 approved drugs as cognition enhancers, 18 on CBF, 21e22 cognition, 15e18 factors influencing signal transduction cerebral blood flow, 18 genes and their expression, 17e18 neurotransmitters, 16 receptors, 16e17 second messenger system, 17 structural factors and neuronal connections, 18 as neuroprotective agent, 22 on neurotransmitters enzymes/protein regulating neurotransmitters, 19 transporters, 19 nutraceuticals for cognitive performance, 18 on receptors, 19e20 on regulation of gene expression, 21e22 on second messenger system, 20e21 signal transduction, cognition, and cognitive impairment, 16 on structural factors and neuronal connections, 21 current practice, 243e245 drug development, 243e245 linn, 99e101 memory impairment, 244t safety, 245 Basal energy expenditure (BEE), 50e51 “Beehive theory”, 48e49 Behavorial outcomes, 186t Beta-amyloid and tau proteins, 22e23 Bifidobacterium infantis, 180, 185 Bifidobacterium spp., 10 Big data Alzheimer’s disease (AD), 329 Autism spectrum of disorder (ASD), 330 big healthcare data, 332 big prospects, 332e333 CANHEART research, 330 COVID-19, 333 privacy, 332 regulatory agencies approach, 331e332 research, 329e330 scientific data life cycle management (SDLM) model, 331 security, 332 technology, 330e331 data management, 331 life cycle, 331 Big healthcare data, 332 Bilateral uterine artery ligation (BUAL), 156 Biochemical and cardiovascular measures, 147 Biological factors influencing cognitive aging, 58e59

Biophenol-rich fruits, 142 Black pepper, 401 Blood-brain barrier (barrier system), 181, 199e200 Blood pressure, 145 Brain aging and associated neurodegenerative diseases, 126e134 Brain and mental health in ayurveda ayurvedic drugs in management of brain disorders, 86 ayurvedic herbs in brain health-medhya rasayan herbs, 86e110 ayurvedic principles of brain health, 81e83 brain type Prakriti, 83, 84t Mana (mind), 82e83 Manas roga, 84e86 medhya rasayana herbs Acorus calamus (Vacha), 109e110 Bacopa monnieri linn., 99e101 Celastrus paniculatus Willd. (Jyotishmati), 108 Centella asiatica (Mandukaparni), 101e102 Clitoria ternatea Linn. (Aparajita), 109 Convolvulus pluricaulis Choisy., 102e103 Glycyrrhiza glabra (Yastimadhu), 106 Nardostachys jatamansi (Jatamansi), 106e107 Tinospora cordifolia (Guduchi), 105e106 Valeriana wallichii (Tagar), 107e108 Withania somnifera (Ashwagandha), 103e105 Brain communication, 178e180, 179f Brain-derived neurotrophic factor (BDNF), 51, 177e178, 205, 281e282, 395 Brain disorders, 32e42 Brain rehabilitation, 276e277 Brain type Prakriti, 83, 84t Brain well-being, 283e285 Branched chain amino acids (BCAA), 51 Brassica nigra (L.) Koch, 114

C Calcium, 363 Caloric restriction (CR), 132e133 Calorie restriction mimetic in healthy brain aging, 132e134 Cancer stem cells, 164 CANHEART research, 330 Cardiometabolic disease altered glucose metabolism, 359 atherosclerosis, 360 brain and cognitive health, 358e361 brain health, 359e361 cardiometabolic profile, 360e361 Coenzyme Q10, 364 cognitive function, 361e364 diet low glycemic index diet, 361 mediterranean diet, 361 reduce sugar, 361 vegan diet, 361 vegetarian diet, 361

westernized diet, 361 fibrinogen, 359e360 hemostasis, 359e360 high-density lipoprotein (HDL) cholesterol, 358 inflammation, 360 insulin resistance, 359 management aims, 361 minerals, 363e364 calcium, 363 iodine, 363 iron, 363 magnesium, 363 selenium, 363e364 zinc, 364 N-acetyl cysteine (NAC), 364 omega-3 polyunsaturated fatty acids, 364 optimum nutrition, 358 oxidative stress, 360 polycystic ovary syndrome in females (PCOS), 358 thrombosis, 360 thyroid function, 360e361 vascular endothelium, 360 vitamins folate, 362 vitamin B1, 362 vitamin B2, 362 vitamin B6, 362 vitamin B12, 362 vitamin C, 362 vitamin D, 362e363 vitamin E, 363 vitamin K2, 363 Carotenoids, 67e70, 285 Celastrus paniculatus, 416 Celastrus paniculatus Willd. (Jyotishmati), 108 Cellular defense mechanisms induction of, 204 Centella asiatica, 383e384, 416 cognitive disorders aluminum, 312e313 Alzheimer’s disease (AD), efficacy against, 311 b-amyloid, 311e313 dendritic arborization mechanism, 313e314 learning/memory animal models, 314 neuronal outgrowth promoting action mechanism, 313 neuronal regeneration mechanism, 313 potential of, 315te317t definition, 307 Mandukaparni, 101e102 medicinal properties, 307e308 nasal delivery, 320 nervous system, 308 neurodegenerative disorders, 318e320 cerebral ischemia, 319e320 drug/chemical neurotoxicity, 319 neuroinflammatory disorders, 318e320 cerebral ischemia, 319e320 drug/chemical neurotoxicity, 319

Index

neurological disorders epilepsy, efficacy against, 314 neuropathy, efficacy against, 314e318 spinal cord injury, efficacy against, 314e318 phytoconstituents, 308f psychological disorders antidepressant-like activity, 309 anxiety disorders, efficacy against, 309e310 chronic mild stress (CMS) model, 309 depressive disorders, efficacy against, 308e309 monoamine oxidase-A (MAO-A), 309 mood disorders, efficacy against, 308e309 stress-related disorders, efficacy against, 310e311 Central nervous system (CNS), 273, 344 Cerebral blood flow, 243, 243t Cerebrospinal fluid (CSF), 48 Cerebrovascular disease, 58 Certain nonfermented foods, 4, 5t Chicago Health and Aging Project (CHAP), 294e298 Chinese traditional medicine, 411 Choline facilitators, 18 Cholinergic receptor, 19 Cholinergic system, 241e242 Chronic traumatic encephalopathy, 381 Cinnamomum verum J.Presl, 114 Cinnamomum zeylanicum Blume, 114 Cinnamon, 400 Circadian rhythm, 201 Clitoria ternatea, 417 Clitoria ternatea Linn. (Aparajita), 109 Cobalamin, 370 Coenzyme Q10, 63e64, 364 and oxidative stress, 64 potential treatment for cognitive decline, 64 Cognition, 282e283, 293e300, 295te297t reducing oxidative stress, 63 Cognitive aging, 58 Cognitive decline, 370e373 Cognitive defects, 243 Cognitive disorders Centella asiatica aluminum, 312e313 Alzheimer’s disease (AD), efficacy against, 311 b-amyloid, 311e313 dendritic arborization mechanism, 313e314 learning/memory animal models, 314 neuronal outgrowth promoting action mechanism, 313 neuronal regeneration mechanism, 313 potential of, 315te317t herbal drugs Alzheimer (AD), 343e344 brain delivery technologies, 348e351 central nervous system (CNS), 344 commercial viability, 351, 351t deoxycholate (DOC), 349

efficacy enhancers, coadministration of, 348 factors, brain delivery, 344e348 industrial applicability novel technologies, 351 limitations, 345te348t lipid-mediated carrier systems, 349e350 liposomes, 349e350 nanocarriers, 350e351 nanostructured lipid carrier (NLC), 350 neurological health, 344 pharmacologic actions, 345te347t phosphatidylcholine (PC), 349 poly (lactide-co-glycolic acid) (PLGA), 349 quercetin liposomes, 350 regulatory challenges, 351e352 scientific community, 343 solid polymeric nanoparticles, 348e349 Cognitive enhancers, 287, 337e339 Cognitive function assessment, 147 Cognitive health, Bacopa monnieri for, 19 approved drugs as cognition enhancers, 18 on CBF, 21e22 cognition, 15e18 factors influencing signal transduction cerebral blood flow, 18 genes and their expression, 17e18 neurotransmitters, 16 receptors, 16e17 second messenger system, 17 structural factors and neuronal connections, 18 as neuroprotective agent, 22 on neurotransmitters enzymes/protein regulating neurotransmitters, 19 transporters, 19 nutraceuticals for cognitive performance, 18 on receptors, 19e20 on regulation of gene expression, 21e22 on second messenger system, 20e21 signal transduction, cognition, and cognitive impairment, 16 on structural factors and neuronal connections, 21 Cognitive performance, 287e288 Commercial viability, 351, 351t Common neurodegenerative disorders, 32 Computerized Mental Performance Assessment System (COMPASS), 145 Convalescent plasma transfusion (CPT), 272 Convolvulus pluricaulis, 416 Convolvulus pluricaulis Choisy., 102e103 Coriandrum sativum, 417 COVID-19 pandemic, 333 acute respiratory stress syndrome (ARDS), 272 angiotensin-converting enzyme inhibitors (ACE-I), 273 brain rehabilitation, 276e277 central nervous system (CNS), 273 convalescent plasma transfusion (CPT), 272

457

curcumin pharmacology, 272e274 dysregulation model, 277f epigenetics, 274e276 epigenomics diet, 277f Histone deacetylase (HDAC), 276 hydrochloroquine (HCQ), 272 liposome-curcumin, 274e276 mitigation, 271e272 nanotechnology, 274e276 severe acute respiratory syndromeeassociated coronavirus (SARS-COV), 273 Crocetin, 217 Crocin, 216 Crocin in healthy brain aging, 131 Crocus sativus L., 114e117, 214 Curcumin, 126e127, 272e274, 417

D Danavgrahayukta, 85e86 Default mode network (DMN), 59 Dementia, 370e373, 391e392 Dendritic arborization, 22 Dendritic cells, 199 Deoxycholate (DOC), 349 Detoxification, 450e451 Diet, 281, 286, 288 Ayurveda, 451 cardiometabolic disease low glycemic index diet, 361 mediterranean diet, 361 reduce sugar, 361 vegan diet, 361 vegetarian diet, 361 westernized diet, 361 components, 397e401 black pepper, 401 cinnamon, 400 flavanols, 398e401 ginger, 401 Ginkgo biloba (Gb) extract, 399 phytochemicals, 398e401 tea (Camilla sinensis) leaves extract, 399 turmeric, 399e400 vitamins, 397e398 fat, 206 fish consumption, 7e8, 7t indigestible prebiotics, 206 protein, 206 Dietary polyphenols, 169e170 neuroprotective effects of curcumin, 170 of EGCG isolated from green tea, 171 of resveratrol, 170e171 polyphenolic compounds in human central nervous system functions, 171e172 Diferuloylmethane, 71 Disability-adjusted life-years (DALYs), 1 Double-blind placebo-controlled crossover trial, 141e151 calculation of composite domain scores, 145e146 methods and materials, 142e145 potential mechanisms, 151

458 Index

Double-blind placebo-controlled crossover trial (Continued ) results, 147e148 statistics, 145e146 Drosophila melanogaster model, 170 Dysbiosis, 195 Dysfunctional gut ecology to chronic disease, 203 Dysregulation model, 277f

E Eicosapentaenoic acid (EPA), 429 Ellagic acid in healthy brain aging, 131e132 Endogenous antioxidant defense systems, 60 Endoplasmic reticulum (ER) stress, 164 Energy metabolism, 281e282 Enteroendocrine cells (EECs), 199 Enzymatic antioxidants, 61t Enzymes/protein regulating neurotransmitters, 19 Epigallocatechin gallate (EGCG) in healthy brain aging, 132 Epigenetics, 274e276, 288 Epigenomics diet, 277f ERK pathway, 164 Eugenia caryophyllata Thunb., 119 Extra virgin olive oil (EVOO), 298

F Fatty acids, 284 Fermented foods, 4 Fetal alcohol syndrome disorder (FASD), 159e160 Fetal inflammatory response (FIR), 156e157 Fish, 301 Flavanols, 398e401 Flavonoids, 52, 70e72 Flowers, 214e215 Folate, 370 Food components, 300e301 Food/food component in brain health, 3e4 cognition beyond foods, 8 diet, aging, and neurodegenerative diseases, 8e9 diet, cognition, and epigenetics, 9 energy status and brain health, 4 food “liking” versus food “wanting”, 8 microbiota-targeted functional foods for brain health, 9e11 neuroactive in foods, 4e6 omega-3 and phytochemicals, 6e8 thinking outside the brain, 11 Food “liking” versus food “wanting,”, 8 Frontotemporal lobar degeneration, 381 Fruits, 302

G GABA receptors, 20 Gandhavagrahayukta unmad, 85e86 Gastrointestinal (GI) system, 48e49 Gene ontology analysis, 22 Germ-free animals, 197

Ginger, 401 Gingerol in healthy brain aging, 127e128 Gingko biloba, 18, 52, 141e142, 399, 415 healthy brain aging, 128e129 Ginseng, 52 healthy brain aging, 129 Ginsenoside Rg1, 129 Glasgow coma score (GCS) scale, 47 Global incidence of TBI, 47e48 Glucoraphanin, 155 Glucosinolates, 155 AMPK and SFA toxicity and protection, 165 antiapoptotic/maternal dietary supplement, 157e162 background and significance, 156e163 cancer stem cells, 164 effect on HDAC enzymes, 163e164 endoplasmic reticulum (ER) stress, 164 ERK pathway, 164 NrF2-ARE signaling pathway, 165 proapoptotic/anticancer, 162e163 redox signaling, 163 signaling apoptosis through extrinsic pathway, 163 SMYD3 genes, 164e165 tumor suppressor genes, 164 Glutamatergic neurotransmission, 20 Glutamatergic receptors, 20 GLUT1 transporters: erythrocytes, 337 Glycyrrhiza glabra (Yastimadhu), 106 Goblet cells, 199 Gotu kola, 383e384 G proteins, 17 Green tea catechins (GTCs), 132 Gut barrier, 199 Gut-brain axis, 9e10, 176e177, 176f, 428 biochemical influences on neural function in, 204e205 Gut ecosystem communication, 203e204 Gut microbiome, 193e194 biochemical influences on neural function in gut-brain axis, 204e205 blood-brain barrier, 199e200 dysbiosis, 195 germ-free animals, 197 GI tract and its microbiome as ecosystem, 196e197 gut barrier, 199 history of microbiome research, 194 host cells, 206 human gut microbiome, 194e196 human microbiome project, 194e195 intestinal epithelial cell, 198e199 intestinal microbes communicate with host, 202e204 linking, 195e196 linking gut microbiome to brain, 195e196 microbiome analysis, 195 microbiota, 206e207 microbiota shift rapidly with dietary change, 196e197 microorganisms constitute gut microbiome, 195

modern links between microbiome and human behavior, 195 nutrition-specific requirements of host and its microbiota, 205e206 shifting therapeutic emphasis, 197e201 therapeutic interventions, 207 tight junction, 200e201 Gut microbiota, 175e176 affect brain, 180e181 brain communication, 178e180, 179f on CNS, 177e178, 178f and gut-brain axis, 176e177, 176f microbiota-gut-brain axis and autism, 181e184 microbiota-gut-brain axis and depression, 181 prebiotics and probiotics, 184e185

H Harnessing modern lab technology, 194e195 HDAC enzymes, 163e164 Health in adult disease, 161e162 Healthy brain aging, nutraceuticals in, 125 ascorbic acid in healthy brain aging, 130e131 brain aging and associated neurodegenerative diseases, 126e134 calorie restriction mimetic in healthy brain aging, 132e134 crocin in healthy brain aging, 131 curcumin in healthy brain aging, 126e127 ellagic acid in healthy brain aging, 131e132 epigallocatechin gallate (EGCG) in healthy brain aging, 132 gingerol in healthy brain aging, 127e128 Gingko biloba in healthy brain aging, 128e129 ginseng in healthy brain aging, 129 quercetin in healthy brain aging, 129e130 resveratrol in healthy brain aging, 130 a-tocopherol in healthy brain aging, 131 Hemidesmus indicus, 416 Herbal drugs, cognitive disorders Alzheimer (AD), 343e344 brain delivery technologies, 348e351 central nervous system (CNS), 344 commercial viability, 351, 351t deoxycholate (DOC), 349 efficacy enhancers, coadministration of, 348 factors, brain delivery, 344e348 factors limiting brain delivery, 344e348 industrial applicability novel technologies, 351 limitations, 345te348t lipid-mediated carrier systems, 349e350 liposomes, 349e350 nanocarriers, 350e351 nanostructured lipid carrier (NLC), 350 neurological health, 344 pharmacologic actions, 345te347t phosphatidylcholine (PC), 349 poly (lactide-co-glycolic acid) (PLGA), 349 quercetin liposomes, 350

Index

regulatory challenges, 351e352 scientific community, 343 solid polymeric nanoparticles, 348e349 Herbal medicines, 113, 336 individual herbs, 114e120 polyherbal formulations and synergistic effects, 120 Herbs and traditional medicines, 52 Histone deacetylase (HDAC), 276 Holy basil, 416 Homocysteine, 370 Homocysteine hypothesis, 370e373 Host cells, 206 nourishing, 205 Host-centric model, 207 Human central nervous system functions, 171e172 Human gut microbiome, 194e196 Human microbiome project, 194e195 Huntington disease, 43t, 254e255 Hydrochloroquine (HCQ), 272 Hyperglycemia, 201

I IEC signaling molecules, 199 Impaired autophagy, 59 Indian ayurvedic herbs, 32e42 Indian botanicals, 34 Indian herbal phytocompounds, 44f Indian medicinal plants, 34, 35te37t, 42f Indian traditional medicine, 411 Individual herbs Brassica nigra (L.) Koch, 114 Cinnamomum verum J.Presl, 114 Cinnamomum zeylanicum Blume, 114 Crocus sativus L., 114e117 Eugenia caryophyllata Thunb., 119 Lavandula stoechas L., 117 Melissa officinalis L., 117e118 Phyllanthus emblica L., 118 Piper nigrum L., 118 Syzygium aromaticum (L.) Merrill & Perry, 119 Terminallia chebula Retz, 119 Zingiber officinale Roscoe, 119e120 Industrial applicability novel technologies, 351 Insanity/psychosis/mania (Unmada), 84e86 Intestinal bacteria, neural regulators synthesized by, 181 Intestinal epithelial cell, 198e199 Intestinal microbes communicate with host, 202e204 Intestinal mucosal barrier, 181 Intra-cerebroventricular injection of streptozotocin (ICV-STZ), 64 Iodine, 363 Iron, 363 chelation, 241 Isolation, 233

J Japanese traditional medicine, 411

K Kapha dosha, 83 Kaphaj Unmad, 85 Ketogenic dietary approaches, 8

L Lactobacillus casei, 8e9 Lactobacillus helveticus, 185 Lactobacillus johnsonii, 52 Lactobacillus spp., 10 Lavandula stoechas L., 117 Lemon balm, 117e118 therapeutic effects of, 118 Lipid-mediated carrier systems, 349e350 Lipopolysaccharide (LPS)-induced AD model, 127, 203 Liposome-curcumin, 274e276 Liposomes, 349e350 Low glycemic index diet, 361 Lung, 160 Lunuvila, 384e385 Lycium barbarum, 417

M Magnesium, 363 Majja dhatu, 442e443 Majjavaha srotas, 442e443, 443t Malaria, 160e161 Malondialdehyde-modified low-density lipoprotein, 132 Mana (mind), 82e83 Manas roga, 84e86 Man-shik Dharniya vega, 83 Medhya rasayana herbs Acorus calamus (Vacha), 109e110 Bacopa monnieri linn., 99e101 Celastrus paniculatus Willd. (Jyotishmati), 108 Centella asiatica (Mandukaparni), 101e102 Clitoria ternatea Linn. (Aparajita), 109 Convolvulus pluricaulis Choisy., 102e103 Glycyrrhiza glabra (Yastimadhu), 106 Nardostachys jatamansi (Jatamansi), 106e107 Tinospora cordifolia (Guduchi), 105e106 Valeriana wallichii (Tagar), 107e108 Withania somnifera (Ashwagandha), 103e105 Medhya rasayanas, 86 Mediterranean diet, 8, 361, 420e421 assessment, 293e294 Chicago Health and Aging Project (CHAP), 294e298 cognition, 293e300, 295te297t dementia, 293 extra virgin olive oil (EVOO), 298 fish, 301 food components, 300e301 fruits, 302 mechanisms, 300e301 mild cognitive impairment (MCI), 294 nuts, 301e302 olive oil, 301

459

practical translation, 302e303 randomized-controlled trials, 299t vegetables, 302 Western countries, 302e303 Melissa officinalis L., 117e118 Memory impairment, 243 Mental diseases, 85f Metabolic diseases, 285e286 Metabolites, 6 Metal-catalyzed protein oxidation, 60 Microbiome human behavior, modern links between, 195 Microbiome analysis, 195 Microbiome research, 194 Microbiota, 206e207 nourishing, 206 Microbiota-gut-brain axis, 183e184 aging, 181e182 autism, 181e184 depression, 181 obesity, 182e183 Microbiota Gut Brain (MGB) axis, 48e49 Microbiota-targeted functional foods, 9e11 Microorganisms constitute gut microbiome, 195 MicroRNAs (miRNAs), 21e22 Mild cognitive impairment (MCI), 181e182, 294 Minerals cardiometabolic disease, 363e364 calcium, 363 iodine, 363 iron, 363 magnesium, 363 selenium, 363e364 zinc, 364 Misfolded protein aggregation, 424, 424f Mitigation, 271e272 Mitochondria, 58e59 Mitochondrial dysfunction, 58e59 Mitochondrial oxidative respiration, 63f Monounsaturated fatty acids (MUFA), 6e7 Morphology, 233

N N-acetylaspartate (NAA), 372e373 N-acetyl cysteine (NAC), 364 Nanocarriers, 350e351 Nanostructured lipid carrier (NLC), 350 Nardostachys jatamansi, 417 Nardostachys jatamansi (Jatamansi), 106e107 Natural antioxidant biomolecules, 42f Neural function, 204e205 Neural regulators synthesized intestinal bacteria, 181 Neuroactive compounds, 4, 6 nonfermented foods, 4, 5t potential positive and negative health effects of, 4, 6t Neuroactive in foods, 4e6 Neuroanatomical pathways, 180 Neurobehavioral diseases, 203 Neurodegenerative diseases, 203

460 Index

Neurodegenerative diseases (Continued ) Alzheimer disease (AD), 251e254 ameliorative effects, 251e254 catechins, 254 curcumin, 252e253 resveratrol, 253e254 taurine, 251e252 vitamin C, 253 amyotrophic lateral sclerosis (ALS), 259e261 ameliorative effects, 260e261 curcumin, 261 vitamin C, 261 vitamin E, 260e261 definition, 249e250 Huntington disease, 254e255 nutraceutical, 250e251 Parkinson disease, 256e259 anthocyanins, 259 caffeine, 259 catechins, 258e259 curcumin, 257e258 morin, 259 quercetin, 259 resveratrol, 258 taurine, 258 vitamin A, 259 vitamin C, 258 ROS, 250 Sri Lankan medicinal herbs Alzheimer disease (AD), 380 Amukkara, 385e386 Amyotrophic lateral sclerosis (ALS), 382 Ayurveda system of medicine, 382 Centella asiatica, 383e384 chronic traumatic encephalopathy, 381 frontotemporal lobar degeneration, 381 Gotu kola, 383e384 Lunuvila, 384e385 Parkinson’s disease, 380e381 phenolic and polyphenolic substances, 383 primary lateral sclerosis, 381e382 therapeutic targets in, 382e383 traditional medicine, 382 Vishnukranti, 386e387 Wanduru Me, 386 Neurodegenerative disorders, 31e32, 33t, 58 ayurvedic herbs, 32 biological factors leading to, 32f Centella asiatica, 318e320 cerebral ischemia, 319e320 drug/chemical neurotoxicity, 319 etiopathology of, 32 etiopathology of neurodegenerative disorders, 32 Indian ayurvedic herbs in, 32e42 Indian medicinal plants in brain disorders, 35te37t methodology, 32 phytocompounds found effective in, 41f traditional Indian herbs beneficial, 38te40t Neurodiversity, 3, 4f

Neuroendocrine-hypothalamic-pituitaryadrenal (HPA) axis, 180e181 Neuro-inflammation, 426, 426f Neuroinflammatory disorders Centella asiatica, 318e320 cerebral ischemia, 319e320 drug/chemical neurotoxicity, 319 Neurological disorders BDNF role in, 205 Centella asiatica epilepsy, efficacy against, 314 neuropathy, efficacy against, 314e318 spinal cord injury, efficacy against, 314e318 Neuronal density, 22 Neuroprotective effects, 216e217 of curcumin, 170 of EGCG isolated from green tea, 171 of resveratrol, 170e171 Neuroprotectivity, 243, 243t Neuroscience, 281 Neurotransmitter modulators, 427, 427f Neurotransmitter release/transportation, 19 Neurotransmitters (NTs), 5e6, 181, 283 roles of, 204 synthesis of, 204 Neurotransmitter synthesis BH4 role in, 205 Niche, 233 NMDA receptors, 20 N-methyl-D-aspartate (NMDA), 216 Nonenzymatic antioxidants, 61t Nonflavonoid polyphenols, 71e74 Nonflonoid polyphenols, 73e74 NrF2-ARE signaling pathway, 165 Nutraceutical consumption, 429e430 Nutraceutical interventions aging population, 57e58 biological factors influencing cognitive aging, 58e59 carotenoids, 67e70 coenzyme Q10, 63e64 cognition via reducing oxidative stress, 63 cognitive aging, 58 oxidative stress, 60 in aging and disease, 60e61 antioxidant defenses, 60 and cognition, 61e63 reactive oxygen species, 59e60 polyphenols evidence for effects on cognition, 72e74 evidence for effects on oxidative stress, 71e72 flavonoids, 70e71 nonflavonoid polyphenols, 71 safety, 74 pycnogenol (PYC), 64 evidence for effects on cognition, 65 evidence for effects on oxidative stress, 65 safety, 66 vitamins E and C, 66e67 Nutraceuticals, 2, 232e233, 288 Acorus calamus, 416

Baccopa monnieri, 415 brain health, 411e421 African traditional medicine (ATM), 411e412 Chinese traditional medicine, 411 Indian traditional medicine, 411 Japanese traditional medicine, 411 Traditional Korean medicine (TKM), 412e413 traditional medicine, 413 Celastrus paniculatus, 416 Centella asiatica, 416 Clitoria ternatea, 417 cognitive performance, 18 Convolvulus pluricaulis, 416 Coriandrum sativum, 417 Curcumin, 417 definition, 410 dietary supplements, 417, 418te420t Asian diet, 421, 421t Mediterranean diet (MD), 420e421 traditional versus modern outlook, 417e421 eicosapentaenoic acid (EPA), 429 gastronomic evolutions, 429 Ginkgo biloba, 415 gut-brain axis, 428 healthy brain aging, 125 ascorbic acid in healthy brain aging, 130e131 brain aging and associated neurodegenerative diseases, 126e134 calorie restriction mimetic in healthy brain aging, 132e134 crocin in healthy brain aging, 131 curcumin in healthy brain aging, 126e127 ellagic acid in healthy brain aging, 131e132 epigallocatechin gallate (EGCG) in healthy brain aging, 132 gingerol in healthy brain aging, 127e128 Gingko biloba in healthy brain aging, 128e129 ginseng in healthy brain aging, 129 quercetin in healthy brain aging, 129e130 resveratrol in healthy brain aging, 130 a-tocopherol in healthy brain aging, 131 Hemidesmus indicus, 416 historical perspective, 409e410 Holy basil, 416 Lycium barbarum, 417 mechanistic insights, 422e427 misfolded protein aggregation, 424, 424f mitochondrial dysfunction, 422e424, 423f Nardostachys jatamansi, 417 neurodegenerative conditions, 414e417, 415t neuro-inflammation, 426, 426f neurotransmitter modulators, 427, 427f nutraceutical consumption, 429e430 origin, 410 oxidative stress, 424e426, 425f

Index

Panax ginseng, 417 potential benefits, 411f Resveratrol, 417 Semecarpus anacardium, 416e417 TBI, 49, 52 Trapa bispinosa, 416 Withania somnifera, 416 Nutrient-specific transport systems, 1 Nutrition active sports, 287e288 adulthood, 286 brain-derived neurotrophic factor (BDNF), 281e282 brain well-being, 283e285 carotenoids, 285 cognition, 282e283 cognitive enhancers, 287 cognitive health, 286 cognitive performance, 287e288 diet, 281, 286, 288 early growth stage, 286 energy metabolism, 281e282 epigenetics, 288 fatty acids, 284 host and microbiota, 205e206 management, 50e51 metabolic diseases, 285e286 neuroscience, 281 neurotransmitters, 283 nutraceuticals, 288 oxidative damage, 282e283 polyphenols, 284 psychiatric conditions, 285e286 synaptic plasticity, 281e282 trace elements, 285 vitamin B family, 284e285 Nuts, 301e302

O Ojokshaya, 83 Olive oil, 301 Omega-3 polyunsaturated fatty acids, 6e9, 51, 364 Oxidative damage, 282e283 Oxidative stress, 60, 338, 360, 424e426, 425f in aging and disease, 60e61 antioxidant defenses, 60 and cognition, 61e63 effects on, 66e67 reactive oxygen species, 59e60

P Panax ginseng, 417 Panax notoginseng saponins (PNS), 129 Paneth cells, 199 Parkinson disease (PD), 3e4, 8e9, 38te40t, 44f Ayurveda, 446e447 Indian herbs against, 42f neurodegenerative diseases, 256e259 anthocyanins, 259 caffeine, 259

catechins, 258e259 curcumin, 257e258 morin, 259 quercetin, 259 resveratrol, 258 taurine, 258 vitamin A, 259 vitamin C, 258 Sri Lankan medicinal herbs, 380e381 Patent, 233 Pathogenesis, 228e229 Pentylenetetrazole (PTZ)-induced convulsions, 217 Perinatal brain injury, 159 Phenolic compounds, 6 Phosphatidylcholine (PC), 349 Phyllanthus emblica L., 118 Physiological measures, 144e145 Phytochemicals, 398e401 PI3K/Akt signaling pathway, 20e21 Piper nigrum L., 118 Pishachgraha unmad, 85e86 Pitta dosha, 83, 85 Pittagrahayukta unmad, 85e86 Pittaj Unmad, 85 Placebo capsule profiles, 144 Placenta, 158e159 Plant-derived AD drugs, 233 Poly (lactide-co-glycolic acid) (PLGA), 349 Polycystic ovary syndrome in females (PCOS), 358 Polyherbal formulations and synergistic effects, 120 Polyphenols, 169, 284 evidence for effects on cognition, 72e74 evidence for effects on oxidative stress, 71e72 flavonoids, 70e71 human central nervous system functions, 171e172 nonflavonoid polyphenols, 71 safety, 74 Polyunsaturated fatty acids (PUFAs), 3, 6e7 Pomegranate, 142, 144 Pragyparadha (intellectual irreverence), 82 Prebiotics, 184e185 Primary lateral sclerosis, 381e382 Proapoptotic/anticancer, 162e163 Probiotics, 51, 184e185, 186t, 207 Proteasomal degradation, 59 Protein phosphorylation, 17 Psychiatric conditions, 285e286 Psychological disorders Centella asiatica antidepressant-like activity, 309 anxiety disorders, efficacy against, 309e310 chronic mild stress (CMS) model, 309 depressive disorders, efficacy against, 308e309 monoamine oxidase-A (MAO-A), 309 mood disorders, efficacy against, 308e309

461

stress-related disorders, efficacy against, 310e311 Psychopharmacology of saffron, 213 chemical constituents, 214 clinical applications, 217e222 effects of saffron beyond depression, 219te220t flowers except stigma, 214e215 mode of action, 216e217 anticonvulsant effect, 217 antidepressant effect, 216 neuroprotective effect, 216e217 stamen, 215 stigma, 214 tepal, 215 traditional and ethnomedicinal uses, 213e214 Punicalagins, 142 PycnogenolÒ, 64 aging brain, 336e337 cognitive enhancer, 337e339 cognitive skills, 335 evidence for effects on cognition, 65 evidence for effects on oxidative stress, 65 GLUT1 transporters: erythrocytes, 337 herbal medication, 336 insufficient oxygen, 335 mechanism, 337 metabolites, 339 oxidative stress, 338 polyphenols, 337 positive activities, 336 reactive oxygen species, 337 safety, 66 Pyridoxine, 369e370

Q Quercetin healthy brain aging, 129e130 liposomes, 350

R Rakshashgrahayukta unmad, 85e86 Rasayana herbs, 32 Reactive oxygen species (ROS), 59e60, 162e163 Redox-inflammation, 200 Redox signaling, 163 Reelin-dependent NMDAR-BDNF expression, 21 Resveratrol, 51, 71, 130 Road traffic accidents (RTA), 48

S Saffron, psychopharmacology of, 213 chemical constituents, 214 clinical applications, 217e222 effects of saffron beyond depression, 219te220t flowers except stigma, 214e215 mode of action, 216e217 anticonvulsant effect, 217

462 Index

Saffron, psychopharmacology of (Continued ) antidepressant effect, 216 neuroprotective effect, 216e217 stamen, 215 stigma, 214 tepal, 215 traditional and ethnomedicinal uses, 213e214 Salivary glucocorticoids, 144e145 Sannipataj Unmad, 85 Sarpagraphayukta unmad, 85e86 Saturated fatty acids (SFAs), 182e183 Schizophrenia, 161 Scientific data life cycle management (SDLM) model, 331 Second messengers, 17, 20e21 Selenium, 363e364 Semecarpus anacardium, 416e417 Serotonergic receptors, 19e20 Serotonin, 204 Serotonin transporter (SERT), 19 Severe acute respiratory syndromeeassociated coronavirus (SARS-COV), 273 SFA toxicity and protection, 165 Sharir evam Manobhighat karan dravya, 82 Short-chain fatty acids (SCFAs), 179e180 Signaling apoptosis through extrinsic pathway, 163 Signal transduction, factors influencing cerebral blood flow, 18 genes and their expression, 17e18 neurotransmitters, 16 receptors, 16e17 second messenger system, 17 structural factors and neuronal connections, 18 Silent information regulator 2 (SIRT2), 9 Sinapis nigra L., 114 SMYD3 genes, 164e165 Solid polymeric nanoparticles, 348e349 Sri Lankan medicinal herbs Alzheimer disease (AD), 380 Amukkara, 385e386 Amyotrophic lateral sclerosis (ALS), 382 Ayurveda system of medicine, 382 Centella asiatica, 383e384 chronic traumatic encephalopathy, 381 frontotemporal lobar degeneration, 381

Gotu kola, 383e384 Lunuvila, 384e385 Parkinson’s disease, 380e381 phenolic and polyphenolic substances, 383 primary lateral sclerosis, 381e382 therapeutic targets in, 382e383 traditional medicine, 382 Vishnukranti, 386e387 Wanduru Me, 386 Stamen, 215 Stigma, 214 Sulforaphane protection pathway (Nrf2/ ARE), 157e158 Superoxide dismutases (SOD), 59 Synaptic plasticity, 22, 281e282 Syzygium aromaticum (L.) Merrill & Perry, 119

T Tea (Camilla sinensis) leaves extract, 399 Tepal, 215 Terminallia chebula Retz, 119 Therapeutic agents, 229te232t Therapeutic emphasis, shifting, 197e201 Therapeutic interventions, 207 Thrombosis, 360 Thyroid function, 360e361 Tight junction, 200e201 Tinospora cordifolia (Guduchi), 105e106 a-Tocopherol in healthy brain aging, 131 Trace elements, 285 Traditional Korean medicine (TKM), 412e413 Traditional Persian Medicine (TPM), 113 for brain health, 115t for neuroprotective protection, 116t Transient 2 vessels occlusion (T2VO), 21 Trapa bispinosa, 416 Traumatic brain injury (TBI), 47e49 herbs and traditional medicines, 52 nutritional management in, 50e51 Treatment protocol, 143e144 Tumor suppressor genes, 164 Turmeric, 399e400

V Valeriana wallichii (Tagar), 107e108

Vascular endothelium, 360 Vata dosha, 83 Vataj Unmad, 85 Vatananatmaja Vikaras, 86 Vegan diet, 361 Vegetables, 302 Vegetarian diet, 361 Vishaada, 86 Vishnukranti, 386e387 Vitamin B6/ B9/B-12 Alzheimer’s disease (AD), 369, 373e374 application, 374 clinical recommendations, 374 cobalamin, 370 cognitive decline, 370e373 dementia, 370e373 FACIT trial, 372 folate, 370 homocysteine, 370 homocysteine hypothesis, 370e373 N-acetylaspartate (NAA), 372e373 pyridoxine, 369e370 Vitamins, 397e398 cardiometabolic disease folate, 362 vitamin B1, 362 vitamin B2, 362 vitamin B6, 362 vitamin B12, 362 vitamin C, 362 vitamin D, 362e363 vitamin E, 363 vitamin K2, 363 minerals, 51 vitamin B family, 284e285 vitamin E and C, 66e67

W Wanduru Me, 386 Water channel protein, 163 Western countries, 302e303 Westernized diet, 361 Withania somnifera, 103e105, 416

Z Zinc, 364 Zingiber officinale Roscoe, 119e120