Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities 9819968062, 9789819968060

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Awanish Mishra · Hitesh Kulhari   Editors

Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities

Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities

Awanish Mishra • Hitesh Kulhari Editors

Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities

Editors Awanish Mishra Department of Pharmacology and Toxicology National Institute of Pharmaceutical Education and Research (NIPER) Guwahati, Assam, India

Hitesh Kulhari School of Nano Sciences Central University of Gujarat Gandhinagar, Gujarat, India

ISBN 978-981-99-6806-0 ISBN 978-981-99-6807-7 https://doi.org/10.1007/978-981-99-6807-7

(eBook)

# The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore Paper in this product is recyclable.

Foreword

In the realm of modern healthcare, the convergence of biomedical science and technology has sparked unprecedented advancements, offering new hope and possibilities for addressing complex challenges in neurological disorders. The book entitled Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities, by Dr. Awanish Mishra and Dr. Hitesh Kulhari, stands as a testament to the collective efforts of researchers, scientists, and clinicians who are navigating the intricate landscapes of neuroscience and pharmaceutical innovation. Neurological disorders, ranging from Alzheimer’s disease and Parkinson’s disease to epilepsy and stroke, present a formidable challenge to both patients and healthcare professionals. The intricacies of the central nervous system and the bloodbrain barrier pose formidable obstacles to effective drug delivery. Yet, amid these challenges lie opportunities for groundbreaking solutions that can revolutionize the treatment landscape. This comprehensive book endeavors to explore the multifaceted dimensions of drug delivery strategies explicitly tailored for neurological disorders. The chapters within this book are crafted by leading experts and pioneers in the fields of neuropharmacology, nanotechnology, biotechnology, and clinical neurology. Their collective expertise brings forth a rich tapestry of knowledge, encompassing the latest advances in drug delivery systems, targeted therapies, and innovative approaches designed to overcome the hurdles of drug transportation across the blood-brain barrier. Readers will embark on a journey through the intricacies of drug formulation, nanomedicine, and emerging technologies that hold promise in optimizing drug delivery to the brain. Moreover, the book sheds light on the evolving landscape of personalized medicine, emphasizing the importance of tailoring drug delivery strategies to individual patient profiles. As we navigate the pages of this book, we are reminded that the pursuit of effective drug delivery in neurological disorders is not merely a scientific endeavor but a quest for improved patient outcomes and enhanced quality of life. This book is

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Foreword

an invaluable resource for researchers, clinicians, students, and anyone invested in advancing neurological therapeutics. May this book inspire collaboration, innovation, and a renewed sense of optimism in the quest to unlock the mysteries of the brain and deliver hope to those affected by neurological disorders. National Institute of Pharmaceutical Education and Research (NIPER) Guwahati, India

U. S. N. Murty

Foreword 1

Neurological disorders are a major cause of disability and a leading cause, alongside cardiovascular disease and cancer, of death worldwide. One of the primary reasons behind this is its poor and late recognition, and therefore patients with various neurological conditions remain majorly undiagnosed, especially in developing countries. Main neurological disorders include stroke, dementia (under which Alzheimer’s disease), Parkinson’s disease, epilepsy, and brain tumors. Pharmacotherapeutic approaches for managing neurological disorders today tend to be symptomatic rather than offering a cure or delaying the onset of the disease. In addition, these pharmaceutical agents have several potentially adverse effects that negatively affect morbidity and mortality and add to the socio-economic burden on the patient. Such challenges can be addressed using nanotechnology to enhance targeted brain delivery and reduce peripheral side effects. There are several challenges in the development of drugs for neurological disorders. Major limitations include the physicochemical characteristics of the agents, physiological barriers such as blood-brain and blood-cerebrospinal fluid barrier, transporter substances, and drug metabolism at these barriers. Using nanotechnology approaches, we may overcome these obstacles. Due to the various side effects of classical medicine drugs, the alternative therapies to treat neurological disorders safely and effectively are gaining more and more attention. Herbal bioactive molecules have gained broader attention of researchers. Limitations of bioactive herbal remedies include poor bioavailability and higher metabolism. These can be improved using nanoformulations. Important topics in this book are as follows: • What are the major challenges in drug discovery for neurological disorders? • A discussion of recent updates in pathophysiology and management of neurological disorders • What are the recent advancements in therapeutic approaches for neurological disorders using nanotechnology? • The possibilities of nanotechnology in the diagnosis of neurological disorders vii

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This book is divided into three parts. The first chapter of the three chapters of Part I Anatomy and Physiology of Human Nervous System introduces us into the world of the central nervous system and blood-brain barrier. Next, the reader is faced with the challenges in drug development for neurological disorders. In Chap. 3, the transporter systems and metabolism at the blood-brain barrier and blood-CSF barrier are detailed. Part II explores in depth the pathophysiology and management of different neurological disorders: Alzheimer’s disease, Parkinson’s disease, epilepsy, traumatic brain injury, multiple sclerosis, Huntington’s disease, and other neurodegenerative diseases. In the last chapter of Part III, alternative approaches for the management of neurological disorders are discussed. The seven chapters of Part III cover drug delivery strategies in neurological disorders. The first chapter of this part makes essential considerations on brain delivery of nanoformulations. The six following chapters cover these drug delivery strategies in depth. Chapter 16 has as its theme drug delivery strategies of herbal bioactives to the brain. A multitude of authors contributed to this work. Their efforts ensure that the content of this book provides relevant information about disease pathology, current management approaches, novel nanotechnology-based approaches, and clinical updates related to various neurological disorders. It provides basic information about the disease, recent advancements, and future prospectives. I like to congratulate both editors, Dr. Awanish Mishra and Dr. Hitesh Kulhari, for the development of such an interesting work. University College Ghent Ghent, Belgium

Leo M. L. Nollet

Preface

Neurological disorders are the leading cause of disability and the second leading cause of death worldwide after cardiovascular diseases. According to global burden data for neurological disorders, around 40% hike in the death toll has been observed in the past three decades. One of the primary reasons behind this is the poor prognosis, and therefore patients with various neurological conditions remain majorly undiagnosed, especially in developing countries. The primary neurological disorders include stroke, dementia (primarily due to Alzheimer’s disease), Parkinson’s disease, epilepsy, and brain tumors. Despite significant advances, the therapeutic efficacy of existing drugs is limited due to the presence of physiological barriers, poor bioavailability, and uncontrolled biodistribution of administered drugs. Therefore, a high amount of drug is required to achieve the desired therapeutic effects, and it leads to higher cost to the manufacturer and severe side effects in patients. In the past two decades, nanotechnology has emerged as a new approach to design better pharmaceutical formulations with improved delivery of drugs to the brain, which results in enhanced pharmacological effects and decrease in side effects. Nanoparticle-mediated delivery of drugs has shown significant achievements with respect to crossing of biological barriers, enhancing of bioavailability and permeability, localized and targeted drug delivery, and improvement in pharmacologically beneficiary effects. Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities has been designed to provide a complete compendium about neurological disorders and their treatment approaches to the readers. This book has three parts: Part I describes the anatomy and physiology of the human nervous system. This part has three chapters about central nervous system, biological barriers, challenges in drug development for neurological disorders, and various transporter systems present in brain. Part II, i.e., Pathophysiology and Management of Neurological Disorders, explains the pathophysiology and treatment approaches for curing the neurological issues like Alzheimer’s disease, Parkinson’s disease, epilepsy, traumatic brain injury, multiple sclerosis, and Huntington’s disease. One chapter is focused on the gene encoding ion channel neurotherapeutics. Due to several adverse effects of synthetic drugs, the current paradigm shifts toward alternative therapy to manage neurological disorders safely and effectively. In this regard, herbal bioactive molecules have gained the broader attention of researchers, and thus, a book chapter ix

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is dedicated to the herbal approaches which are used in the management of neurological disorders. Part III highlights the various drug delivery strategies (conventional to advanced) for the treatment of different neurological disorders. Nose-tobrain delivery is one of the most promising and challenging strategies for the delivery of drugs to brain and has been highlighted in a separate chapter. The last chapter describes the delivery strategies for the herbal drugs. Finally, editors thank the authors for their generous support and contribution of chapters. Guwahati, Assam, India Gandhinagar, Gujarat, India

Awanish Mishra Hitesh Kulhari

Contents

Part I 1

Anatomy and Physiology of Human Nervous System

Nanocarriers as an Emerging Tool for Drug Delivery to Combat Neurodegenerative Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pooja Sharma and Damanpreet Singh

2

Challenges in Drug Development for Neurological Disorders . . . . . Lahanya Guha, Nidhi Singh, and Hemant Kumar

3

Transporter Systems and Metabolism at the Blood–Brain Barrier and Blood–CSF Barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Kanika Verma, Devesh Kapoor, Smita Jain, Ritu Singh, and Swapnil Sharma

Part II 4

3 27

47

Pathophysiology and Management of Neurological Disorders

Pathophysiology and Management Approaches in Alzheimer’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Shreshta Jain, Divya Goel, Sheikh Sana Nazir, Vaishali Yadav, and Divya Vohora

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Pathophysiology and Management Approaches for Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Khan Sabiya Samim, Padmashri Naren, Poojitha Pinjala, Sainikil Uppala, Shashi Bala Singh, and Dharmendra Kumar Khatri

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Pathophysiology and Management Approaches for Epilepsy . . . . . . 155 Enes Akyuz and Betul Rana Celik

7

Pathophysiology and Management Approaches for Traumatic Brain Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173 Prachi Suman, Anupama Paul, and Awanish Mishra

8

Pathophysiology and Management Approaches for Huntington’s Disease, Multiple Sclerosis, and Other Neurological Disorder . . . . . 189 Chetana Ahire, Prachi Suman, and Awanish Mishra

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Contents

9

Genes Encoding Ion Channels in Neurotherapeutics: Opportunities and Challenges . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 201 Enes Akyuz and Habiba Eyvazova

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Herbal Approaches for the Management of Neurological Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 Vikas Yadav, Sandeep Guin, Sudipta Nayak, and Awanish Mishra

Part III

Drug Delivery Strategies in Neurological Disorders

11

Essential Considerations for Brain Delivery of Nanoformulations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 Sunaina Chaurasiya and Hitesh Kulhari

12

Drug Delivery Strategies in Alzheimer’s Disease . . . . . . . . . . . . . . . 271 Govind Hake, Akshada Mhaske, and Rahul Shukla

13

Drug Delivery Strategies in Parkinson’s Disease . . . . . . . . . . . . . . . 305 Gurpreet Singh, Anupama Sikder, Shashi Bala Singh, Saurabh Srivastava, and Dharmendra Kumar Khatri

14

Nanotechnological Drug Delivery Strategies in Epilepsy . . . . . . . . . 325 Gerard Esteruelas, Lorena Bonilla, Miren Ettcheto, Isabel Haro, María José Gómara, Eliana B. Souto, Marta Espina, Antonio Camins, Mª. Luisa García, Elena Sánchez-López, and Amanda Cano

15

Drug Delivery Strategies in Traumatic Brain Injury . . . . . . . . . . . . 351 Hinal Shah, Jitendra Kumar, Gajanan Paul, and Awesh Kumar Yadav

16

Drug Delivery Strategies in Multiple Sclerosis, Huntington’s Disease and Other Neurodegenerative Diseases . . . . . . . . . . . . . . . . 375 Sofiya Tarannum and Keerti Jain

17

Nose-to-Brain Drug Delivery Strategies for the Treatment of Neurological Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 405 Prabakaran A, Dhananjay Bhatane, and Amit Alexander

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Drug Delivery Strategies for the Administration of Natural Compounds to the Brain in Neurodegenerative Diseases . . . . . . . . . 429 Lorena Bonilla, Gerard Esteruelas, Miren Ettcheto, María José Gómara, Isabel Haro, Eliana B. Souto, Marta Espina, Antonio Camins, Mª. Luisa García, Amanda Cano, and Elena Sánchez-López

Editors and Contributors

About the Editors Awanish Mishra is an Assistant Professor in the Department of Pharmacology and Toxicology at the National Institute of Pharmaceutical Sciences and Drug Research, Guwahati. He has earlier served as an Assistant Professor in the Department of Pharmacology and Toxicology at the National Institute of Pharmaceutical Sciences and Drug Research, Raebareli (2013–2020). He is focused on understanding the molecular mechanisms for the development of neurological diseases (like epilepsy, Alzheimer’s disease, and Parkinson’s disease) and associated psychiatric comorbidities. He has added interest in how groundwater pollutants (arsenic, iron, copper, fluoride) and insecticides (especially organophosphates) are causing neurotoxicity and how natural bioactive molecules are useful in mitigating the same. In addition, he is also working on utilizing nanomedicine in neurological disorders and the evaluation of toxicological aspects of nanomedicine. He has more than 11 years of teaching experience in pharmacology, toxicology, drug metabolism, and pharmacological screening models of various diseases. He has contributed more than 55 peer-reviewed articles in international journals, authored 14 book chapters, and filed 3 patents. He is a member of many international scientific societies and organizations, importantly Indian Pharmacological Society, Indian Academy of Neurosciences, and Laboratory Animal Science Association of India, and editorial member to various prestigious journals like Metabolic Brain Disease (Springer Nature). Hitesh Kulhari is an Assistant Professor at the School of Nano Sciences, Central University of Gujarat, Gandhinagar. Previously, he worked as an Associate Professor at the Department of Pharmaceutical Technology (Formulations) at the National Institute of Pharmaceutical Sciences and Drug Research, Guwahati. Dr. Kulhari received his PhD degree from RMIT University, Melbourne, Australia, in the area of nanomedicines. His research focuses on designing targeted drug delivery systems and pharmaceutical nanotechnology. He has published 71 research articles in peerreviewed international journals and 14 book chapters and edited 1 book on pharmaceutical applications of dendrimers. Dr. Kulhari is a recipient of several awards and

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research grants including Prof. CNR Rao Research Excellence Award in material science in 2015; INSPIRE faculty award from DST, New Delhi in 2015; and appreciation award from Cancer Research Foundation, India, in 2020. He has more than 13 years of teaching and research experience in pharmaceutical technology, biopharmaceutics, and nanotechnology.

Contributors Chetana Ahire Department of Pharmacology and Toxicology, NIPER, Guwahati, Assam, India Enes Akyuz University of Health Sciences, International Faculty of Medicine, Istanbul, Turkey Amit Alexander Department of Pharmaceutics, NIPER, Guwahati, Assam, India Dhananjay Bhatane Department of Pharmaceutics, NIPER, Guwahati, Assam, India Lorena Bonilla Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain Antonio Camins Centre for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED), Carlos III Health Institute, Madrid, Spain Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain Institute of Neurosciences, University of Barcelona, Barcelona, Spain Amanda Cano Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain Centre for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED), Carlos III Health Institute, Madrid, Spain Ace Alzheimer Center Barcelona – Universitat Internacional de Catalunya, Barcelona, Spain Betul Rana Celik School of Medicine, Marmara University, Istanbul, Türkiye Sunaina Chaurasiya School of Nano Sciences, Central University of Gujarat, Gandhinagar, Gujarat, India

Editors and Contributors

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Marta Espina Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain Gerard Esteruelas Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, Barcelona, Spain Miren Ettcheto Centre for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED), Carlos III Health Institute, Madrid, Spain Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain Institute of Neurosciences, University of Barcelona, Barcelona, Spain Habiba Eyvazova University of Health Sciences, International School of Medicine, Istanbul, Türkiye Mª. Luisa García Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain Centre for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED), Carlos III Health Institute, Madrid, Spain Divya Goel School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India María José Gómara Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, Barcelona, Spain Lahanya Guha Department of Pharmacology and Toxicology, NIPER, Ahmedabad, Gujarat, India Sandeep Guin Department of Pharmacology and Toxicology, NIPER, Guwahati, Assam, India Govind Hake Department of Pharmaceutics, NIPER, Raebareli, Uttar Pradesh, India Isabel Haro Unit of Synthesis and Biomedical Applications of Peptides, IQACCSIC, Barcelona, Spain Keerti Jain Department of Pharmaceutics, NIPER, Raebareli, Uttar Pradesh, India

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Shreshta Jain School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India Smita Jain Department of Pharmacy, Banasthali Vidyapith, Jaipur, Rajasthan, India Devesh Kapoor Dr. Dayaram Patel Pharmacy College, Bardoli, Gujarat, India Dharmendra Kumar Khatri Department of Pharmacology and Toxicology, NIPER, Hyderabad, Telangana, India Hitesh Kulhari School of Nano Sciences, Central University of Gujarat, Gandhinagar, Gujarat, India Hemant Kumar Department of Pharmacology and Toxicology, NIPER, Ahmedabad, Gujarat, India Jitendra Kumar Department of Pharmaceutics, NIPER, Raebareli, Uttar Pradesh, India Akshada Mhaske Department of Pharmaceutics, NIPER, Raebareli, Uttar Pradesh, India Awanish Mishra Department of Pharmacology and Toxicology, NIPER, Guwahati, Assam, India Padmashri Naren Department of Pharmacology and Toxicology, NIPER, Hyderabad, Telangana, India Sudipta Nayak Department of Pharmacology and Toxicology, NIPER, Guwahati, Assam, India Sheikh Sana Nazir School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India Anupama Paul Department of Pharmacology and Toxicology, NIPER, Guwahati, Assam, India Gajanan Paul Department of Pharmaceutics, NIPER, Raebareli, Uttar Pradesh, India Poojitha Pinjala Department of Pharmacology and Toxicology, NIPER, Hyderabad, Telangana, India A. Prabakaran Department of Pharmaceutics, NIPER, Guwahati, Assam, India Khan Sabiya Samim Department of Pharmacology and Toxicology, NIPER, Hyderabad, Telangana, India Elena Sánchez-López Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain

Editors and Contributors

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Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, Barcelona, Spain Centre for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED), Carlos III Health Institute, Madrid, Spain Hinal Shah Department of Pharmaceutics, NIPER, Raebareli, Uttar Pradesh, India Pooja Sharma Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India Swapnil Sharma Department of Pharmacy, Banasthali Vidyapith, Jaipur, Rajasthan, India Rahul Shukla Department of Pharmaceutics, NIPER, Raebareli, Uttar Pradesh, India Anupama Sikder Department of Pharmaceutics, NIPER, Hyderabad, Telangana, India Damanpreet Singh Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India Gurpreet Singh Department of Pharmacology and Toxicology, NIPER, Hyderabad, Telangana, India Nidhi Singh Department of Pharmacology and Toxicology, NIPER, Ahmedabad, Gujarat, India Ritu Singh Department of Pharmacy, Banasthali Vidyapith, Jaipur, Rajasthan, India Shashi Bala Singh Department of Pharmacology and Toxicology, NIPER, Hyderabad, Telangana, India Eliana B. Souto Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Porto, Portugal REQUIMTE/UCIBIO, Faculty of Pharmacy, University of Porto, Porto, Portugal Saurabh Srivastava Department Telangana, India

of

Pharmaceutics,

NIPER,

Hyderabad,

Prachi Suman Department of Pharmacology and Toxicology, NIPER, Guwahati, Assam, India Sofiya Tarannum Department of Pharmaceutics, NIPER, Raebareli, Uttar Pradesh, India

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Editors and Contributors

Sainikil Uppala Department of Pharmacology and Toxicology, NIPER, Hyderabad, Telangana, India Kanika Verma Department of Pharmacy, Banasthali Vidyapith, Jaipur, Rajasthan, India Divya Vohora School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India Awesh Kumar Yadav Department of Pharmaceutics, NIPER, Raebareli, Uttar Pradesh, India Vaishali Yadav School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India Vikas Yadav Department of Pharmacology and Toxicology, NIPER, Guwahati, Assam, India

Part I Anatomy and Physiology of Human Nervous System

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Nanocarriers as an Emerging Tool for Drug Delivery to Combat Neurodegenerative Diseases Pooja Sharma and Damanpreet Singh

Abstract

The central nervous system (CNS)-related diseases pose a significant challenge due to the inherent blood–brain barrier (BBB) that hampers the drug delivery process. The BBB is a constituent of the neurovascular unit. It comprises neurons, astrocytes, microglia, a basement membrane, and a layer of microvascular endothelial cells around the brain that protect the same. It maintains the right ionic balance within the brain and blocks the substances that disrupt essential neuronal functions. Some examples of neurodegenerative conditions include Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. One of the most challenging problems faced in the therapy of neurodegeneration is the delivery of a therapeutic agent into the CNS. Nanostrategy is an inspiring and encouraging newer approach to managing neurological conditions. Recent advances in nanomedicines have contributed to developing novel and efficacious delivery strategies to improve CNS disorders. Nanomedicines enable the drug delivery to penetrate the BBB and bind to the target regions without drug degradation. In the present chapter, we discussed the importance of nanocarriers such as liposomes, solid lipid nanoparticles, dendrimers, micelles, and nanoemulsions for delivering neurotherapeutic agents. Furthermore, problems associated with conventional drugs and the significance of nanoparticle delivery have also been discussed.

P. Sharma · D. Singh (✉) Pharmacology and Toxicology Laboratory, Dietetics and Nutrition Technology Division, CSIRInstitute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh, India Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Mishra, H. Kulhari (eds.), Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities, https://doi.org/10.1007/978-981-99-6807-7_1

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Keywords

Central nervous system · Neurodegenerative diseases · Nanotechnology · Blood– brain barrier · Nanomedicines

Abbreviations AD ApoE ASNPs AuNPs Aβ BBB BCSFB CAG CNS DOX DOXIL DRV ePC i.v. I6P8-D-M MAG-NCs mPEG-PLGA MPTP NLCs o/w PAMAM PD PLGA PNPs SLNs Tf-NE TNF-α USFDA w/o

1.1

Alzheimer’s disease Apolipoprotein E AMD3100-conjugated, size-shrinkable nanoparticles of glyburide Gold nanoparticles Amyloid beta Blood–brain barrier Blood–cerebrospinal fluid barrier Cytosine, adenine, and guanine Central nervous system Doxorubicin PEGylated liposomal doxorubicin Darunavir Egg phosphatidylcholine Intravenous I6P8-conjugated DOX-loaded micelle Magnolol-nanocrystals Monomethoxy (polyethylene glycol) d,l-lactic-co-glycolic acid 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Nanostructured lipid carriers Oil in water Polyamidoamine Parkinson’s disease Poly(D,L-lactide-co-glycolic acid) Polymeric nanoparticles Solid lipid nanoparticles Transferrin-conjugated nanoemulsion system Tumor necrosis factor-alpha United States Food and Drug Administration Water in oil

Introduction

A report from the World Health Organization shows that neurological disorders affect up to one billion populations worldwide (WHO 2007). In the past two to three decades, neurological disorders have increased substantially (Luo et al. 2021).

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Nanocarriers as an Emerging Tool for Drug Delivery to. . .

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Globally millions of people are affected by Alzheimer’s disease (AD) and Parkinson’s disease (PD) (Han et al. 2018). Cholinesterase inhibitors (rivastigmine, galantamine, and donepezil) and NMDA receptor antagonists (memantine) are approved by the USFDA for managing AD. Currently, no therapeutic medication is available to stop disease progression (Herrmann et al. 2011). The USFDA approves safinamide for the management of PD and for patients experiencing “off” episodes. An “off” episode causes a return in PD symptoms such as tremors, stiffness, and staggering in the patient on carbidopa and levodopa therapy. However, the drugs used for symptomatic treatment fail to stop the disease procession (Ellis and Fell 2017). These obstacles give rise to the involvement of newer therapeutic perspectives. The upcoming nano strategies open a unique platform for diagnosing and treating neurological disorders. Other obstacles in the transport of drugs to the central nervous system (CNS) include penetration of the blood–brain barrier (BBB). The BBB is a highly selective semipermeable layer of endothelial cells that protects against the toxins and pathogens that could cause brain infections. Generally, only the fat-soluble molecules, small molecules, and some gases transit the endothelial tight junction into the brain tissue. Poor absorption from the target site, high first-pass metabolism, low bioavailability, premature excretion from the body, and high-dose dumping are the problems associated with conventional drug delivery. With conventional drug delivery systems, only a small portion of active pharmaceutical ingredients reaches the organ. The adverse effect could sometimes result when a drug reaches a nontargeted organ and cannot achieve sustained release (Prabhakar and Banerjee 2020). By facing these challenges, the nanotechnology-based approach is being widely assessed in developing neurotherapeutics. Nanomedicine effectiveness is based on the efficiency of crossing BBB and several other parameters, for example, shape, size, lipophilicity, permeability, and structure stability. Cell-mediated transport, absorption-mediated transcytosis, and receptor-mediated transcytosis are the main pathways facilitating BBB penetration (Hanif et al. 2020). Nanomedicine is a recent technology involving better delivery methods and drug formulations. The nanocarriers used in neurotherapeutics should be biodegradable, nontoxic, sitespecific, and biocompatible. Recently, nanocarrier-based drug delivery revolutionized the treatment of neurodegenerative diseases by more robust techniques; for example, nanogels, nanosuspension, nanotubes, nanoemulsions, and dendrimers are used in the delivery system (Bonferoni et al. 2019). Controlled drug release and selective targeting is the reason for the acceptance of nanocarriers. Hence, to manage neurodegenerative conditions by nanomedicine, there is a need to design and administer strategies capable of bypassing the BBB and blood–cerebrospinal fluid barrier (BCSFB). In the present chapter, we discussed the problems related to conventional drugs, specific challenges in designing nanocarriers, and drug delivery to the brain in neurodegenerative diseases. Furthermore, barriers in delivering a therapeutic agent to CNS and strategies to enhance drug delivery across the BBB are explored. We provided an overview of the hurdles across the effective delivery of drugs to CNS

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with the significance of nanomedicine in various neurological disorders and opportunities for future research.

1.2

Barriers in Delivery of Therapeutic Agent to CNS

The human brain comprises numerous innate barriers, including BBB and BCSFB that protect the brain from noxious and infectious agents. Drug delivery to the brain is challenging due to above-mentioned factors that hinder the direct entry of drug candidate.

1.2.1

BBB

The BBB acts as an anatomic and biochemical barrier that averts the passage of large and potentially poisonous molecules into the brain. It comprises microvasculature endothelial cells, basement membranes, astrocytes, pericytes, and microglia (Fig. 1.1a). The BBB is permeable to enter lipophilic substances (e.g., oxygen, carbon dioxide) and nutrients like blood, glucose, proteins, peptides, and related peptide drugs. It restricts the entry of hydrophilic substances (e.g., hydron, bicarbonate), drugs, therapeutics, and diagnostic agents used in the treatment of neurodegenerative disorders. The BBB acts as a selective semipermeable membrane that separates the peripheral blood vessel from the cerebrospinal fluid (CSF) and regulates the composition and volume of CSF to maintain the homeostatic environment within the CNS (Akhtar et al. 2021). The endothelial tight junction consists of claudin and occludin protein, which interact to produce an almost impenetrable barrier between the blood and brain. The luminal portion is separated from the basolateral region by the tight junction, which acts as a fence around the cell. P-glycoprotein is the mechanism by which the BBB excludes compounds from the brain. The BBB cells also contain a high level of the metabolizing enzyme, for example, cytochrome P450. A molecule needs to have a molecular weight of less than 400 Daltons, be unionized at physiological pH, and have high lipophilicity to cross through the BBB (Warren 2018). Pericytes are an essential component of the brain capillaries that play a crucial function in maintaining BBB integrity and microvascular stability. Pericytes are closely connected with endothelial cells that permit the exchange of ions, metabolites, ribonucleic acid, and secondary messengers between them. Pericytes help in the removal of toxic metabolites due to their phagocytic function. Astrocytes are a type of star-shaped glial cells considered the primary workhouse of the CNS. Astrocytes are the cell projections called astrocytic feet that surround the endothelial cells and are necessary to maintain BBB integrity. Astrocytes are responsible for maintaining ionic homeostasis, injury protection, pH regulation, and neurotransmitter uptake and processing by providing energy-rich substrate to the neurons. The two neighboring endothelial cells are connected by the highly tight three different junctions, i.e., tight junction, adherent junction, and gap junction. The tight junction consists of three transmembrane

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Fig. 1.1 Schematic illustration of the BBB and delivery of biotherapeutics across the BBB. (a) Anatomical structure of the BBB and other components of the brain. The tight junction in BBB are formed by endothelial cells. A network of astroglial foot processes and pericytes surrounds the endothelium. Neurons remain close to endothelial cells to regulate the blood flow and allow action potential generation and propagation. Perivascular macrophages provide structural and functional support for maintaining brain homeostasis. Microglias are the long-living resident immune cells. (b) Routes of transport across the BBB: (1) paracellular transport, (2) transcellular transport, (3) carriermediated transport, (4) efflux pumps, (5) receptor-mediated transcytosis, (6) adsorptive-mediated transcytosis, and (7) cell-mediated transcytosis

proteins: claudin, junction adhesion molecules, occludin, and various cytoplasmic proteins, i.e., cingulin, zonula occludens -1, -2, -3, and others. Adherent junctions are formed from a cadherin–catenin complex and its associated proteins, which are present at the basal side of the cell–cell junction in BBB endothelial cells. Gap junctions are present between the tight and adherens junction. Gap junctions are intracellular channels built up by two integral proteins, i.e., connexions and pannexins. Other components of BBB are microglia and basement membrane. The vesicular basement membrane can provide structural support for endothelial cells and is made from complex extracellular matrix proteins. The vesicular basement membrane separates the endothelial cells from neurons and glial cells and sheathes the smooth muscle and pericyte in CNS. Microglia are the kind of neuroglia cells

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situated throughout the brain and spinal cord. The primary function of microglia is immune defence and CNS maintenance (Ding et al. 2020; Kadry et al. 2020). Substances can cross the BBB by different transport routes (Fig. 1.1b). • Diffusion of substances involves two mechanisms, i.e., paracellular and transcellular. Paracellular transport is a transport that occurs between cells. Small water-soluble substances diffuse paracellularly. • Lipid soluble substances pass through transcellular by dissolving in the lipid plasma membrane, for example, alcohol. • Carrier-mediated transport involves the transport of substances from high to low concentration. Solute molecules cause a conformational change in the protein after binding with a protein transporter on one side of the membrane, resulting in the transport of substances to the other side of the membrane (Alam et al. 2010). • ATP binding cassette transporter (P-glycoprotein) is responsible for extruding drugs from the brain, and this transporter is majorly responsible for the accumulation of potent molecules in the brain. • In receptor-mediated transcytosis, a specific type of receptor presents on the luminal membrane, which involves selective uptake of high-molecular-weight molecules. Cellular receptors uptake different ligands, including enzymes, hormones, growth factors, and plasma proteins. It is widely studied for brain targeting. • Pinocytosis is another name for adsorptive-mediated transcytosis. It is activated by electrostatic interaction between a negatively charged plasma membrane surface (e.g., heparin sulfate proteoglycans) and a positively charged compound (e.g., charged fraction of peptide). • Cell-mediated transcytosis depends on immune cells, such as monocytes or macrophages, to cross the BBB. It can be used for any kind of molecule and particulate carrier system (e.g., HIV entry into the brain) (Chen and Liu 2012).

1.2.2

BCSFB

The BCSFB is formed by epithelial cells and located at the choroid plexus and the arachnoid membrane. The choroid plexus is located in the brain’s lateral, third, and fourth ventricles and secretes the CSF. The blood CSF barrier facilitates the exchange and removal of metabolites and averts the passage of blood-borne substances into the brain. In CNS homeostasis, the choroid plexus plays an essential role since it helps regulate the constituents of brain interstitial fluid and the CSF. The choroid plexus contains a fenestrated endothelium, which permits the rapid delivery of water to aid in CSF production. Drugs and other molecules are averted from entering the CSF due to the tight epithelial junction, although they quickly diffuse through these fenestrae. CSF has multiple functions, including overall drainage of brain metabolites, pH buffering for the brain’s extracellular fluid, and inorganic ion osmoregulation. The CSF has a specific characteristic that can impact the drug delivery into the CNS tissue and also has a crucial function in drug delivery throughout the leptomeninges. First, drugs administered into the CSF propagate

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nonhomogeneously, and the factors that can alter this circulation are gravity and the presence of increased proteins, such as leptomeningeal disease. Second, due to continuous CSF production, substances are “diluted out.” Lastly, the potency of some drugs can be reduced due to the transformation from the CSF into the bloodstream. The blood–CSF barrier is less notable obstacle to drug delivery as the BCSFB has 1000 times less surface area relative to the BBB (Warren 2018).

1.3

Problems Associated with Conventional Drug Delivery

Conventional drug delivery system contains several limitations and drawbacks. The conventional drug delivery system includes syrups, capsules, tablets, ointments, etc. In the conventional drug delivery system, only a small amount of drug reaches the organs. Occasionally, drugs also affect nontarget organs, resulting in adverse effects. The current problems associated with conventional drug delivery system includes the following: • Poor bioavailability: Due to incomplete absorption, drugs bioavailability decreases when administered through a route other than intravenously. Incomplete absorption is also due to low water solubility. • High first-pass metabolism/presystemic metabolism: First-pass metabolism occurs in the liver when an orally administered drug suffers immense biotransformation to the extent that bioavailability is reduced. Drugs that experience presystemic metabolism are imipramine, diazepam, morphine, propranolol, insulin, and cimetide (Prabhakar and Banerjee 2020). • High dose dumping: In the case of controlled release formulation, a large amount of drug is rapidly released, and a potentially toxic amount of drug reaches systemic circulation. • Premature excretion from the body: Early excretion of drug molecules makes it less effective, as the desired concentration still needs to be reached in the target organs (Kok-Yong et al. 2015). • Lack of selectivity: Oral drug needs better-targeted delivery due to their poor biodistribution. Toxicity can occur in detoxification organs, for example, the liver and kidney, as drug uptake could be high in those organs (Dang and Guan 2020).

1.4

Nano Strategies to Enhance Drug Delivery Across the BBB

The capability of nanocarriers to pass through the BBB is expected to set a new direction for the transport of drugs inside the brain. Due to the physiological properties of nanomedicine, such as strength, sensitivity, solubility, stability, reactivity, and surface area, the therapeutic agent can efficiently deliver into the CNS. Nanocarrier system utility for site-specific drug delivery improves the pharmacokinetic profile and biodistribution of the active drugs. Targeted drug delivery avoids any damage to the healthy tissue via the drug, for example, in cancer (Naqvi et al.

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Fig. 1.2 Schematic illustration of different types of nanocarriers used in the delivery of therapeutic agent. (a) Liposome, (b) solid lipid nanoparticles, (c) polymeric nanoparticles, (d) nanoemulsion, (e) dendrimers, (f) polymeric micelles, (g) nanocrystal, (h) nanotube, (i) gold nanoparticles, (j) quantum nanoparticles, and (k) natural polymer-based nanoparticles (chitosan nanoparticles)

2020). Currently, researchers mainly focus on targeted delivery systems and sustained release formulation. The targeted drug delivery system involves a therapeutic agent that is active in the target area of the body, and sustained release formulation includes the therapeutic agent being released from the formulation in a controlled manner over a while (Tharkar et al. 2019). A targeted drug delivery system leads to the reduction of dosage taken by the patient, reduction of side effects, and more homogeneous effect of the drug. A broad category of nanocarriers includes liposomes, polymeric nanoparticles (PNPs), solid lipid nanoparticles (SLNs), micelles, dendrimers, nanotubes, nanocrystals, etc. (Fig. 1.2).

1.4.1

Liposomes

Liposomes are small artificial vesicles consisting of either one or more phospholipid bilayers. Liposomes are mostly made up of phospholipids, particularly phosphatidylcholine, and cholesterol. They are divided into three groups based on their

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number of layers and size: multilamellar vesicle (with various lipid bilayers) (20–100 nm), the small unilamellar vesicle (with one lipid bilayer) (10–50 nm), and the large unilamellar vesicle (50–1000 nm). Liposomes can be used as an approach for drug delivery, proteins, peptides, and nutrients like lipid nanoparticles for vaccines (Wang et al. 2022). Liposome is the most researched nanocarrier system due to its simple preparation method, biodegradability, high efficacy, and low toxicity. One of the current applications of liposomes is the delivery of anticancer drugs. Liposomes can store drugs with different physical and chemical characteristics. It is good enough in drug delivery and cancer treatment. Moreover, conjugating the liposome with various polymers, ligands, and molecules enhances their pharmacological value and improves anticancer drug effectiveness (Rommasi and Esfandiari 2021). The first FDA-approved nanomedicine is DOXIL (PEGylated liposomal doxorubicin), in which doxorubicin (DOX) is loaded on PEGylated liposome that is used for the treatment of certain cancers. The delivery of PEGylated liposomes depends on passive targeting and enhanced permeability. DOXIL has a higher drug concentration in malignant effusions as compared to free DOX (Liu et al. 2021). DOX is used against glioma cells, but the BBB prevents its entry into the brain. R8PLP is a liposome formed from 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N[methoxy-(polyethylene glycol)-2000], 1,2-dioleoyl-3-trimethylammonium-propane chloride, cholesterol, and egg phosphatidylcholine (ePC). Moreover, R8PLP was modified by cell-penetrating peptide R8 conjugated with oleic acid as a novelty for delivering DOX. DOX was filled into R8PLP with more than 95% encapsulation efficiency, and the size of R8PLP was 95 nm. There was a 8.6-fold higher cellular uptake of R8PLP by U87-MG cells than unmodified liposomes. Compared to cholesterol-ePC-liposomes and free DOX, R8PLP reduced cell viability by 16.18% and 18.11% after 24 h treatment. This indicated that R8-conjugated oleic acid-modified liposomes are effective delivery vehicles with potential applications in glioma therapy (Yuan et al. 2019). Liposomal dispersion of rivastigmine is one of the highly potent therapy for AD. Electrostatic stealth liposomes are nearly neutral zeta potential that can avoid body identification as foreign, and prevent opsonization and phagocytic uptake. Moreover, they can flow in the bloodstream for a prolonged time. The incorporated PEGylated lipids (1,2-distearoyl-sn-glycero-3phosphoethanolamine-poly(ethylene glycol)) are attributed to the steric stabilization (Nageeb El-Helaly et al. 2017). Intravenous administration of liposomes in stroke-induced BBB disruption into mice exposed to cerebral artery occlusion demonstrates the capability of liposomes to maximize selective translocation into the brain. The advantage of BBB damage is to enhance drug delivery by evaluating the brain aggregation and localization of i.v. Liposomes are injected at different time points after stroke to cover the biphasic increase in BBB permeability (Al-Ahmady et al. 2019). For the treatment of neurodegenerative diseases such as AD and PD, liposomal drug delivery system of Aphanamixis polystachya leaf extract demonstrates notable enhancement of the behavioral characteristics in dementia-induced mice compared to per se leaf extract treatment (Jiang et al. 2017). Animal studies depicted that drug carriers

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(liposomes and lipid nanoparticles) targeted to vascular cell adhesion molecule-1 assemble in the inflamed brain more effectively than intracellular adhesion molecule and transferrin receptor-targeted counterparts (Marcos-Contreras et al. 2020).

1.4.2

Solid Lipid Nanoparticles (SLNs)

SLNs are suitable candidates for drug targeting the brain involving BBB penetration. SLNs are composed of lipids. A SLN is typically spherical with a size range of 50–1000 nm. SLNs consists of a solid lipid core that can solubilize lipophilic molecules, and surfactants stabilize this solid lipid core. They have low toxicity and excellent stability compared to polymeric and liposomal nanoparticles. SLNs are novel colloidal drug carriers for intravenous administration. SLNs have a small size, large surface area, high drug loading, drug solubility, controlled drug release, and better drug targeting. They can easily be administered through various routes: peroral, pulmonary, parenteral, and topical (Mukherjee et al. 2016). SLNs of β-elemene had a significantly higher concentration in the brain than β-elemene. β-elemene has anti-tumor activity but has some disadvantages, such as poor water solubility, low bioavailability, and volatility. An alternative colloidal drug carrier, SLNs were introduced to overcome these problems. Many studies have shown that SLN formulation enhances drug accumulation in the brain, even for the drugs with poor BBB penetration. SLNs loaded with β-elemene appeared to overcome the shortcomings of β-elemene (He et al. 2019). In vitro and in vivo studies proved that borneol-modified chemically solid lipid nanoparticles had better drug delivery systems for treating brain ailments as compared to the borneol-modified physically solid lipid nanoparticles and solid lipid nanoparticles (SLNs). Two borneol-modified SLNs had less cytotoxicity on human brain microvascular endothelial cells in comparison with SLNs, and the chemical modification of borneol had a higher targeting ability and BBB permeation (Song et al. 2018). Agomelatine-loaded SLNs effectively increased both the bioavailability and the brain delivery of agomelatine (antidepressant drug), seemingly due to the avoidance of the first-pass metabolism and the favored BBB uptake of the SLNs. Agomelatine-loaded SLNs are directly transported from the intranasal to the brain through the olfactory nerves (Fatouh et al. 2017). In accordance with some published reports, the researchers have developed the next generation of lipid carriers called NLCs (nanostructured lipid carriers) to increase the stability and incorporation capacity of SLNs. The solid and liquid lipids are combined under ambient temperature to prepare the lipid phase in NLCs (Amiri et al. 2021).

1.4.3

Polymeric Nanoparticles

Polymeric nanoparticles are 1 to 1000 nm in size, and mostly, they are solid and spherical structures prepared from natural and synthetic polymers. Commonly used polymers are poly(alkylcyanoacrylate), polyesters such as Poly-ε-caprolactone, poly

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(D,L-lactide-co-glycolic acid) (PLGA), and several others such as natural proteins and polysaccharides. Polymeric nanoparticles are formed by the entrapment of active compounds inside or absorbed on the surface of the polymeric core. Nanoparticles include nanosphere (matrix system) and nanocapsule (reservoir system). Polymeric nanoparticles have several advantages, such as control over drug release profile, tuneability, and stability to molecules that readily undergo change and breakdown. Nonetheless, they include tissue-specific ligands that facilitate targeted drug delivery to the brain (Zielińska et al. 2020; Peltonen et al. 2020). PEGylated nanoparticles were surface functionalized with an antibody directed against Aβ1–42 for treating AD in transgenic mice. A significant reduction of the Aβ soluble peptide was observed. Moreover, a substantial increase of the Aβ levels in plasma and complete correction of the memory defect in an experimental model of AD were reported (Carradori et al. 2018). An in vivo study demonstrated that the memory CD4+ helper T cells were used as a carrier for the delivery of polymeric nanoparticles (poly (ethylene glycol)-modified polystyrene nanoparticles) to cross the BBB. Nanoparticle-modified T cells are shown to enter the brain parenchyma in preclinical models (Ayer et al. 2021). The BBB prevents therapeutic macromolecules from passing across it in their free form. Apolipoprotein E (ApoE)-functionalized polymeric nanoparticles (NPs) are able to transport medicines over the BBB via low density lipoprotein (LDL) receptor-mediated transcytosis. This approach significantly increases brain uptake (Hartl et al. 2021).

1.4.4

Polymeric Micelle

Polymeric micelle is a novel drug carrier system to CNS made up of amphiphilic block copolymers that self-aggregate to form a single layer in a liquid solution. After reaching the critical micelle concentration, the copolymer undergoes micellar formation. Micelles aggregate commonly in aqueous forms, in which the hydrophilic head is in contact with the surrounding solvent and the hydrophilic tail toward the micelle center. The size ranges from 10 to 100 nm, and they can solubilize a number of poorly soluble active ingredients. The stability of polymeric micelle depends on the drug-to-copolymer ratio (Jhaveri and Torchilin 2014). Currently, camptothecin (an anticancer drug) conjugated with polyethylene glycol (PEG) and further modified with internalizing RGD peptide demonstrated a favorable ability to cross the BBB and target glioma cells. Ligand-mediated polymeric micelles have shown that they effectively reach the glioma site by crossing barriers and have great potential for enhancing the efficiency of glioma treatment with laser irradiation. Micelles exhibit better stability and control over drug release (Lu et al. 2020). A polymeric micelle proven to be a vehicle for long-term delivery of anticancer drugs, i.e., DOX, was modified by I6P8 peptide to overcome the BBB for glioma-targeted therapy. In vitro and in vivo results confirmed that I6P8-conjugated DOX-loaded micelle (I6P8-D-M) introduced highest apoptosis of glioma cells and prolonged survival of mice having glioma as compared to other groups (Shi et al. 2017). Paclitaxel is an anti-neoplastic agent mainly used in the treatment of breast, ovarian,

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lung, and head and neck cancers. A combination of paclitaxel and lapatinib targeted micellar drug delivery system was developed, and these micelles were modified with Angiopep-2. Experimental studies show that micelles modified with Angiopep-2 and loaded with paclitaxel and lapatinib had extended the life span of mice with metastatic brain tumors (Lu et al. 2022).

1.4.5

Dendrimers

Dendrimers are branched polymeric three-dimensional molecules with the core at the center composed of an atom and several repeated branches emerging from the core. Polyamidoamine (PAMAM) and poly(propyleneimine) are mainly used for biomedical applications. The amine groups present in these dendrimers are positively charged and cationic group, making them toxic and limiting their use in clinical application. PAMAM dendrimers have many advantages, including water solubility, biocompatibility, and nonimmunogenicity (Srinageshwar et al. 2017). PAMAM dendrimers are injected via tail-vein into healthy mice in multiple doses and taken up by neurons and glial cells as observed after the staining. More dendrimers are found in the brain and kidney than in other peripheral organs, such as the liver, lungs, and spleen. This prevents their accumulation and immediate excretion from the body. The study proved that dendrimers become safe after surface modifications and deliver the therapeutic cargo into the brain by crossing BBB (Srinageshwar et al. 2019). Dendrimers are mainly used as diagnostic imaging agents or nanocarriers in cancer treatment. In context to neurodegenerative diseases, dendrimers may decrease neuroinflammation and reduce protein aggregation. Some researchers demonstrate the potential application of this nanosystem as an antigen carrier for vaccines. Dendrimers are more stable than liposomes (Gauro et al. 2021).

1.4.6

Inorganic Nanoparticles

Inorganic nanoparticles, including silver, gold, iron oxide, carbon silica, silicon, and others, are used in brain drug delivery. Inorganic nanoparticles have many advantages over polymeric and lipid-based counterparts for brain drug delivery. Inorganic nanoparticles can be used as a vehicle, imaging agent, and theranostic agent (diagnostic agent and therapeutic agent) for CNS disorders. The stability of inorganic nanoparticles can be easily increased by modification in the surface of these nanoparticles with polymers, drugs, and ligands, which facilitate their brain permeation (Morales and Gaillard 2021). Metal nanoparticles are mostly for thermal heating and magnetic imaging. Mesoporous silica and silicon dioxide are used for targeted and controlled delivery of active ingredients (i.e., small drugs, proteins, and DNA) because of their size, shape, porosity, and surface properties (Persano et al. 2021).

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Quantum Dots

Quantum dots are very small metallic particles of semiconductor atoms like ZnS, ZnSe, ZnO, CdS, CdSe, CdTe, GaAs, InAs, or InP. Size ranges from 2 to 10 nm and has many advantages, like long-term photostability, narrow emission spectrum, and high brightness. Quantum dots can be used in therapy and diagnosis of CNS disorders since there is an option to incorporate therapeutic agents in the outer layer of quantum dots (Xu et al. 2013).

1.4.8

Nanocrystals

Nanocrystals are a kind of crystalline drug composed of 100% drug with no carrier and size below 100 nm. Nanocrystals in dispersion media are called nanosuspensions. Dispersion media includes water, aqueous and nonaqueous media, i.e., liquid polyethylene glycol. Surfactants and polymeric stabilizers are used to stabilize the dispersed particles from aggregation and crystal growth. Three principles can be used for the production of nanocrystals: first is milling, second is the precipitation method, and the third is homogenization. Industries used top-down and bottom-down approaches for production. Top-down includes breaking largesize drug particles into small ones, and bottom-down includes precipitation from a supersaturated solution (Junghanns and Müller 2008). Magnolol-nanocrystals (MAG-NCs) are complexed with the noninvasive thermosensitive poly (N-isopropylacrylamide), and a drug delivery platform hydrogel (MAG-NCs@Gel) was prepared. MAG-NCs@Gel shows that enhancement in the solubility of the drug, effective brain-targeted drug delivery, and continuous delivery facilitate magnolol to cross the BBB, thereby improving the symptoms of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-induced PD by entering dopaminergic neurons (Tan et al. 2021).

1.4.9

Nanotubes

Nanotubes are nanocarriers that have a tube-like structure. Nanotubes are made up of several materials, such as boron, carbon, silicon, etc. Carbon nanotubes have many advantages, such as high biocompatibility, less toxicity, small size, large surface area, and their capability to accommodate more than one component by conjugation. Due to these properties, they can supply various drugs to the brain by crossing BBB (Henna et al. 2020). Carbon nanotube drug delivery systems demonstrate the effectiveness and penetrability of drugs into the CNS. The role of ivermectin and its multi-walled carbon nanotube was evaluated in spinal cord injury. Ivermectin and its multi-walled carbon nanotube-treated animals indicated better results by decreasing oxidative stress than ivermectin-treated animals (Rahbar et al. 2021).

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1.4.10 Nanoemulsion Nanoemulsion is a submicron-sized colloidal dispersion system that acts as a drug carrier for delivering therapeutic agents. Nanoemulsion is a thermodynamically stable biphasic dispersion of oil in water (o/w) or water in oil (w/o) stabilized by a surfactant with droplet size in the range of 20–200 nm. Because of submicron size, they are used in the targeted delivery of various anticancer drugs, photosensitizers, and diagnostic agents. There are three types of nanoemulsion: oil in water, water in oil, and bi-continuous nanoemulsion (Jaiswal et al. 2014; Shah et al. 2010). Darunavir (DRV), an antiretroviral agent, was encapsulated into a transferrinconjugated nanoemulsion system (Tf-NE) to achieve brain delivery by efficiently crossing the BBB. In vitro and in vivo studies disclose that Tf-NE-DRV formulation is superior to a free drug and is a potential agent to cross the BBB for treating HIV-associated neurocognitive disorder (Si 2019).

1.4.11 Natural Polymer-Based Nanoparticles These include polysaccharides, proteins, and amino acids formed during the lifecycle of plants, animals, fungi, and bacteria. They are of two types: polysaccharide-based (chitosan, hyaluronic acid, agarose, dextral, and cyclodextrin) and protein-based (gelatin, albumin, and collagen). Functionalizing the polymers mentioned above helps develop a powerful drug delivery system (Idrees et al. 2020). Functionalized nanoparticles are used in many medical, biological, and pharmaceutical applications due to their biodegradability, attainability, and biocompatibility. Natural polymer-based hydrogels have the potential for remote control drug release of curcumin in cancer treatment. In an external magnetic field, the hydrogel can release a larger concentration of drugs from the hydrogel network (Paulino et al. 2012).

1.5

Application of Nanotechnology in Neurological Conditions

Nanotechnology has emerged as an emerging device for treating neurological disorders such as AD, PD, Huntington’s disease, stroke, and brain tumors. Nanomedicine has many advantages over conventional medicines due to its safety, efficacy, physicochemical properties, and targeted delivery to a specific site. Therapeutic agents are nano-engineered for the delivery of radiocontrast, imaging, and diagnostic agents due to their ability to pass through the BBB. Much of the evidence regarding the applications of nanotechnology in neurodegeneration is described in Table 1.1

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Table 1.1 Nanocarrier approaches to target neurodegenerative conditions Approach AD Unconjugated PLGA nanoparticles

Drug/extract

Model

Outcome

Reference

Not applicable

Inhibiting Aβ aggregation

Paul et al. (2022)

Lipid nanoparticles

Quercetin

Aβ-induced toxicity in neuronal cells isolated from BALB/c mice hCMEC/D3 cells

Pinheiro et al. (2020)

Gold nanoparticles

Not applicable

Okadaic acid (OA) induced AD rat model

Liposome

Rivastigmine

Biodistribution studies

Inhibiting fibril formation and also decreasing peptide aggregation Reducing TNF-α levels in the hippocampus, maintaining the phosphorylation state of tau Preventing opsonization and phagocytic uptake

PD Chitosan nanoparticles

Rotigotine

Haloperidolinduced PD rats

Bhattamisra et al. (2020)

Liposome

Aphanamixis polystachya

Olanzapine-induced dementia in mice

Chitosan nanoparticles

Selegiline

Rotenone-induced PD in rats

Enhanced brain targeting efficiency and drug bioavailability Improvement in memory function, locomotor activity, and ambulatory performance Increasing the brain bioavailability of selegiline by decreasing its pre-systemic metabolism

Transgenic mice model

Preventing cognitive decline and ameliorating motor defects

Birolini et al. (2021)

Glyburide

Middle cerebral artery occlusion models

High delivery efficiency and low toxicity

Guo et al. (2018)

Cisplastin

In vitro BBB model (HBEC-5i cells) Female CD-1 mice, female athymic

Inhibition of tumor growth Sustained drug supply for brain

Shen et al. (2018) Madala et al. (2018)

Huntington’s disease PLGA Cholesterol nanoparticles

Stroke Polymeric micellar nanoparticles Brain tumors Magnetic nanoparticles Polymeric nanoparticles

Disulfiram

dos Santos Tramontin et al. (2020)

Nageeb El-Helaly et al. (2017)

Jiang et al. (2017)

Sridhar et al. (2018)

(continued)

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Table 1.1 (continued) Approach

Drug/extract

Model

Outcome

nude (nu/nu) mice, and the triple immune-deficient NCG (NOD CRISPR Prkdc Il2r gamma) mice

cancer treatment through an enhanced permeability retention (EPR)

Reference

PLGA poly (D,L-lactide-co-glycolic acid), Aβ amyloid beta, OA okadaic acid, TNF-α tumor necrosis factor alpha, PD Parkinson’s disease, BBB blood–brain barrier, EPR enhanced permeability retention

1.5.1

AD

AD contributes to more than 80% of dementia cases worldwide, primarily affecting a person in the sixth decade of life. AD is associated with the accumulation of amyloid beta (Aβ) aggregates and neurofibrillary tangles consisting of hyperphosphorylation of tau protein and synaptic dysfunction. The formation of amyloid plaque is the primary factor in AD. β and γ secretase are involved in the cleavage of amyloid precursor protein and the formation of Aβ. Presenilin has a proteolytic action on amyloid precursor protein, leading to the aggregation of the Aβ peptide (Banerjee and Mukherjee 2018; Agraharam et al. 2022). A recent study reveals the significance of unconjugated PLGA particles by inhibiting Aβ aggregation and its capability in AD therapy. A rise in temperature from 27 to 40 °C leads to spontaneously increasing the rate of Aβ1–42 aggregations. Unconjugated PLGA particles potently inhibit Aβ aggregation at all temperatures and protect cultured neurons from degeneration (Paul et al. 2022). Quercetin was modified with lipid nanoparticles and functionalized with transferrin to enhance its bioavailability and targeted delivery into the brain. Lipid nanoparticles can improve brain permeability and protect quercetin from photodecomposition and degradation. It was demonstrated that transferrin-functionalized nanostructured lipid carriers could inhibit fibril formation and decrease peptide aggregation (Pinheiro et al. 2020). Gold nanoparticles (AuNPs) have antioxidant and anti-inflammatory properties, which can be used to treat neurological disorders. AuNPs are a scavenger for hydrogen peroxide (H2O2) and the superoxide anion (O2-). AuNPs decrease the TNF-α levels in the hippocampus and regulate oxidative stress by reducing the release of mitochondrial cytochrome C. AuNPs treatment is known to improve mitochondria function in the hippocampus and the cortex. It also maintains the phosphorylated state of Tau. AuNPs can be considered as safe and effective option to treat neurodegenerative diseases (dos Santos Tramontin et al. 2020).

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PD

PD is the second major neurodegenerative disease caused due to dopaminergic neuronal loss and degeneration. Reduction in dopamine level occurs since dopaminergic neurons die within the substantia nigra of the midbrain. Dopamine is the major centrally acting neurotransmitter and is essential in the function of dopaminergic neurons, leading to symptoms like tremors, rigidity, and bradykinesia (García-Pardo et al. 2021). Rotigotine, a dopamine agonist, has low aqueous solubility and low bioavailability. In a recent study, rotigotine-loaded chitosan nanoparticles can better treat PD through nose-to-brain delivery. Animal studies show an increase in drug bioavailability and brain-targeting efficiency (Bhattamisra et al. 2020). Selegiline gets highly metabolized in the liver and has poor oral bioavailability. Compared to oral, intranasal administration has a 12-fold higher plasma Cmax for selegiline nanoparticles. Brain bioavailability of selegiline increases due to a decrease in its pre-systemic metabolism after intranasal administration (Sridhar et al. 2018).

1.5.3

Huntington’s Disease

Huntington’s disease is a rare neurodegenerative genetic disorder that causes cell death in the brain. Huntington’s disease results in motor, cognitive, and psychiatric disorders. It occurred due to an expanded CAG (cytosine, adenine, and guanine) repeat in the Htt gene on chromosome 4. Aggregating mutant huntingtin protein may cause histone acetylation, which plays a crucial role in cognitive functions such as learning and memory. Mitochondrial dysfunction leads to excessive production of reactive oxygen species, further leading to oxidative stress and might play essential roles in neuronal death (Cong et al. 2019). The major drawback of current drug treatment is the low efficiency of crossing the BBB and reaching the CNS. Current nanoparticle drug delivery strategies involve encapsulating therapeutic agents to enhance bioavailability and slow release. Recently, nanoparticle targeting involves silencing of Htt gene, immunomodulation, inactivation, or modification of the huntingtin protein (Valadão et al. 2022). Inefficient brain cholesterol synthesis occurs in HD, and transferring cholesterol to the striatum is challenging due to the BBB. Birolini et al. modified the cholesterol with a heptapeptide (g7) and PLGA nanoparticles to cross BBB (hybrid-g7-NPs-chol). Hybrid-g7-NPs-chol releases cholesterol in a controlled manner and becomes available for neuronal function.

1.5.4

Stroke

Stroke is the primary cause of death and disablement globally. Stroke involves the rupture and blockage of blood vessels, either by clots or bursts, which prevents blood supply to the brain. It leads to hypoxia in brain tissues, disability, and death (Rana et al. 2022). Mechanical thrombectomy and tissue plasminogen activator are

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reperfusion methods to restore the blood flow in the brain in the case of ischemic stroke. Reperfusion generates reactive oxygen species, which leads to cellular damage. These changes initiate inflammatory reactions, including cytokine production and leukocyte infiltration. Conventional drug delivery systems have so many limitations in reperfusion-induced injury. First, it is inefficient to cross BBB. Second, drugs have poor stability and toxicity. Third, there is a trouble in choosing the right drug or dose due to the stroke severity and location (Dong et al. 2020). The major limitation of glyburide is its toxicity. AMD3100-conjugated, size-shrinkable nanoparticles (ASNPs) of glyburide have low toxicity and high efficiency for delivery. Significantly ASNPs increase the therapeutic potential of glyburide for stroke treatment (Guo et al. 2018).

1.5.5

Brain Tumors

These are intracranial tumors, where abnormal cell growth occurs in the brain. They are categorized into primary and metastatic tumors in the CNS. Therapy of brain tumors always remains a fearful challenge in the area of neurooncology. Hurdles behind the successful treatment of brain tumors involve an inadequate concentration of active molecules at the tumor site, the complexity of brain structure, the trespassing ability of brain tumors, and resistance to chemotherapy (Cheng et al. 2014). Cisplastin is modified with lactoferrin to target receptors and increase translocation. Cisplatin-loaded hybrid nanoparticles with lactoferrin and RGD dimer conjugated could pass through the BBB due to its small size and lactoferrin receptor-mediated transport. This led to cisplatin’s targeted delivery and tumor growth’s significant inhibition (Shen et al. 2018). Disulfiram is a rapidly metabolizing drug with low therapeutic efficacy. Disulfiram nanoformulation was prepared using a polymer named mPEG-PLGA (monomethoxy (polyethylene glycol) d,l-lactic-co-glycolic acid). Disulfiram effectively accumulates in the brain and provides sustained drug delivery through enhanced permeability retention (Madala et al. 2018).

1.6

Conclusion and Future Perspectives

The treatment for neurological disorders is hindered by several aspects like BBB complexity, intracranially delivered therapeutic agents must be able to resist the flow of CSF, and complexity of the brain impedes the targeted treatment of the specific site. Nanotechnology has found its way by improving drug delivery, site-specific treatment, and enhancing bioavailability. Furthermore, it improves the early diagnosis of CNS disorders based on detecting pre-inflammatory states and characterizing lesions or plaques. Combining the nanoscale treatment with cells increases the overall effect of nanoscale treatment. Nanotechnology enabled the targeted delivery of chemotherapeutics and potential inhibition of disease progression in models of

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brain tumors. In nanotechnology, nanocarriers can include numerous properties to provide site-specific delivery, gene delivery, and diagnostic potential. Several studies have shown that covalent and noncovalent methods communicate extra stability to nanoparticles via surface modification of nanoparticles by different functional groups. Potential future perspectives for nanoparticle drug delivery systems involve refining the particles to minimize toxicity and empower to increase targeted delivery. Time ahead, nanotechnology provides possible treatment for neurological disorders, and they can be applied for labeling, bioimaging, and drug delivery tracing for biomedical applications. Regardless of advancements in nanotechnology, there are a limited number of commercially available products. Very rarely, these animal studies are translated for clinical practice. There are a number of barriers to successful translation, such as difficulty in scaling up the production process, preliminary studies of nanomaterial toxicity, and immunological compatibility. It is easy to generate a small number of nanoparticles in the laboratory, but it is challenging to scale up the production process. Launching efficient scaling-up methodology and vast toxicology profiles is crucial to ensure the faith of patients and clinicians, which would precede the authentic use of nanoscale in clinics. Key Findings • Therapies for CNS disorders must be adequate to overcome obstacles such as multifactorial neurological diseases and complex cellular networks of the brain and BBB. • Nanotechnology is a promising approach to combat the hurdles and challenges in drug delivery to the brain. • Nanotechnology can incorporate multiple features into nanocarriers to provide site-specific targeting, gene delivery, and diagnosis capabilities. • The future of nanotechnology will depend on scaling up methodology and toxicology profiles of nanoparticles, as rarely any animal study has been translated for clinical practice. Acknowledgements The authors are thankful to the Director, CSIR-IHBT, Palampur (HP), India, for providing the essential facilities. Pooja Sharma is grateful to the ICMR, New Delhi, India for granting Senior Research Fellowship vide letter No. 3/1/2/225/2021-Nut. The institute manuscript communication number is 5281.

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Challenges in Drug Development for Neurological Disorders Lahanya Guha, Nidhi Singh, and Hemant Kumar

Abstract

Neurological disorders are the group of pathogen, trauma, or disease induced pathologies that mainly affects our central nervous system, impairing locomotion and cognition ability. It poses a significant problem to society due to the nonregenerative nature of neurons and the sensitive architecture of the brain and spinal cord, leading to the unmet need to develop a proper treatment strategy. Although the progress in neurosciences has decreased the disease burden, there are still significant hurdles in drug development for neurological disorders. The significant scientific challenges are connected to the complexity of the blood– brain and blood–spinal cord barrier system, difficulty in target identification and validation, an incomplete understanding of disease biology, imprecise clinical outcome measures, shortage of trial ready patients, variability in the clinical population, low reproducibility and predictive value of preclinical animal models, and lack of pharmacodynamic biomarkers and reliable target engagement. Targeting these factors will help us understand the potholes better to enhance the drug development process. Keywords

Central nervous system · Blood–brain barrier · Blood–spinal cord barrier · Clinical trial · Drug development L. Guha · H. Kumar (✉) Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India e-mail: [email protected] N. Singh Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, India # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Mishra, H. Kulhari (eds.), Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities, https://doi.org/10.1007/978-981-99-6807-7_2

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Introduction

The central nervous system (CNS) is an integral part comprising the brain and spinal cord. CNS serves as the processing center of our body, serving several functions, starting from receiving sensory signals from organs like eyes, ears, and skin through sensory neurons, processing of the sensory signals by the brain, and transmission of the motor signals to the motor organs by the spinal cord. It collects information from around the body and regulates activities throughout the whole system giving it the “central” terminology (Macejkovic et al. 2012). Being a key mediator of our normal bodily activities and owing to its organs’ highly sensitive and complex architecture, CNS is prone to many disorders. Neurological disorders are becoming more common over the globe as a result of variables such as the increased aging rate of the population due to poor diet and lifestyle and the increasing pollution rate in most nations (Feigin et al. 2019). Many neurological disorders, such as stroke, Alzheimer’s, and Parkinsons’ disease, have an age component in that their prevalence rises with age (Callixte et al. 2015). According to the European Commission’s aging report, the number of individuals over 65 is estimated to increase to over 51.2% by 2070. As a result, the prevalence of cerebrovascular disease is also expected to climb (Nerlich 2018). According to the global burden of disease research, neurological and psychiatric disorders accounted for more than 8.76% of total disability-adjusted life years (DALYs) worldwide (Kissimova-Skarbek 2016). The nonregenerative property of CNS neurons makes any damage to them irreversible. So, it poses an unmet need to develop effective drugs for the treatment. Drug discovery is the lengthy, costly, and complex process of discovering and developing new chemical entities (NCEs) for curative, symptomatic, or diagnostic therapeutic interventions for diseases. It covers a broad range of processes, from the synthesis of the lead pharmacophore compound to post-marketing surveillance of the drug (Zhou and Zhong 2017; Seidel et al. 2020). It is the perfect blend of chemistry, biotechnology, and pharmacology, ensuring better bioavailability, efficacy, and cost-effectiveness (Duelen et al. 2019). Unfortunately, the progress in drug development has been very slow in India. For example, no drug has effectively treated the core symptoms of autism spectrum disorders. The last one being given the green light was chlorpromazine, which was first released to the market over 60 years ago (Ban 2007). The development process of the potential new contender, a nondopamine (D2) receptor-blocking agent, for schizophrenia and autism spectrum disorders, has also been sluggish due to inadequate funding (Kaar et al. 2020; Howes et al. 2018). Some pharmaceutical companies have even stopped or significantly reduced their efforts to develop treatments for mental health issues (Kaar et al. 2020). Popular names like Glaxo Smith Kline (GSK) and Pfizer Smith Kline are in this group, as are psychiatry-focused companies like Eli Lilly (Howes and Mehta 2021). GSK even pulled out of drug discovery of a large number of screening of compounds in some aspects of neuroscience, including pain and psychiatric disorders, leaving many researchers in the field of neurology concerned (Craven 2011). CNS illnesses have bigger, more complicated clinical trials with tighter inclusion criteria, making drug research more expensive and time-consuming.

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Clinical studies take around 10 years to get regulatory approval. CNS drugs also have the lowest success rates. Sadly, only 8% of clinical trial products reach the market. The worst-case scenario for the industry is that fewer than half of substances that pass phase 3 testing get approval (Gribkoff and Kaczmarek 2017). The complexity of the blood–brain barrier (BBB) and blood–spinal cord barrier (BSCB) system, difficulty in target identification and validation, an incomplete understanding of disease biology, imprecise clinical outcome measures, shortage of trial-ready patients, variability in the clinical population, inferior reproducibility and predictive value of preclinical animal models, and lack of pharmacodynamic biomarkers and reliable target engagement are just some parameters to slow the progress of drug development in neurological disorders (Cha 2014; Pardridge 2005; Pankevich et al. 2014; Schein and Lynch 2022). Current treatment strategies are unsuccessful or inadequate for a sizable majority of patients. Even if they are successful, they often result in adverse pharmaceutical reactions (ADRs). Furthermore, 6–7% of hospitalizations are predicted to be caused or contributed by severe adverse medication reactions (Eichelbaum et al. 2006; Pirmohamed et al. 2004). ADRs are predicted to cost 706 million euros in the United Kingdom annually, while they are responsible for 100,000 deaths in the United States (Pirmohamed et al. 2004; Lazarou et al. 1998). Furthermore, around 4% of all new drugs must be withdrawn from the market due to ADRs alone (Depondt 2009). Overcoming these obstacles can pave the way toward more potential and safer drug development. Currently, extensive research is being made like to develop animal models specific for the disease, development of target-specific leads by improved pharmaco-informatics, development of nanotechnology to target the BBB and BSCB, and extensive studies related to pharmacogenomics. They can contribute to providing crucial information as to the ultimate likelihood of success of a novel treatment (Nguyen et al. 2021; Salman et al. 2021). Medicinal chemistry is crucial in reducing ADRs, but it presents unique challenges. For better translation from the lab to the clinic and phenotypic screening, hit discovery has adapted to incorporate target-based screening. The most recent advancements in microfluidics have been directed at developing organs on a chip to speed up this translation process (Thomford et al. 2018). Chemistry research and development have also been crucial to the success of CNS medication discovery. Deuterium or fluorine incorporation, as well as late-stage functionalization, have all been used by chemists to create new drugs (Lage et al. 2018). The development of pharmacodynamic biomarkers should be a high priority in Phase 1, 2, and 3 studies (O’Neill 2012).

2.2

Barriers to CNS Drug Development

CNS is a very complex system. So, the drug development process for neurological disorders has been a challenge that results in very few drugs reaching the market, leading investors and sponsors pulling out from their drug development process. Astonishingly high price to conduct the process and the lengthy duration of the development process also contribute to the delay. The barriers to CNS drug

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development can be classified broadly into two groups. Initial barriers are related to the biological aspect that involves the complexity of the BBB and BSCB, incomplete understanding of disease biology, low reproducibility and predictive value of preclinical animal models, and lack of pharmacodynamic biomarkers and reliable target engagement. The second type of barriers are related to drug development: difficulty in target identification and validation, imprecise clinical outcome measures, shortage of trial-ready patients, variability in the clinical population, and flawed regulatory approval process. Here, we will discuss each aspect in detail.

2.2.1

Barriers Related to the Biological Aspect

2.2.1.1 Complexity of Blood–Brain and Blood–Spinal Cord Barrier The brain and spinal cord are the two most important organs that make the foundation of CNS. Together, they control a plethora of functions to maintain normal homeostasis of the body (Snell 2010). For their importance and functions in our body and the nonregenerative nature of neurons of the brain and spinal cord and to ensure a stable microenvironment to provide appropriate circumstances for neuronal signaling, nature has developed protective measures to protect the brain and spinal cord from foreign proteins, toxins, and pathogens in the form of the BBB and BSCB, respectively (Redzic 2011; Sommonte et al. 2022; Jin et al. 2021). Glial cells make a barrier that keeps the nervous systems of invertebrates, which are much simpler than the nervous systems of mammals, safe from changes in body fluids. Some ancient vertebrates also had this kind of structure (Luisetto 2019). As the CNS developed and became more complex over time, it developed endothelial septum and eventually formed BBB and BSCB anatomy to help precisely control the entry of molecules through CNS (Mancuso et al. 2008). BBB is formed by brain endothelial cells (BECs), while BSCB is made of choroid plexus (CP) epithelial cells (Engelhardt and Sorokin 2009). Endothelial cells have many metabolic, transport, and physical characteristics that aid in the coordination of the BBB and BSCB with various brain, vascular, immune, and other types of cells (Profaci et al. 2020). In addition to acting as physical barriers, they are dynamic tissues expressing many enzymes, receptors, and transporters (Allt and Lawrenson 2000). The neurovascular unit (NVU) formed by microglia, pericytes, and perivascular astrocytic endfeet is responsible for regulating the permeability of the BBB and BSCB, preventing the unrestricted transport of ions, metabolic waste products, and essential nutrients between the two fluids (Blanchette and Daneman 2015). There are tight junctions (TJs) made of zonula occludens and claudin-associated proteins, and the presence of several efflux transporters like glucose transporter 1 (GLUT-1), ABC efflux transporter P-glycoprotein (Pgp), and ATP-binding cassette subfamily G member 2 (ABCG2) that control the entry of the molecules in CNS (Lochhead et al. 2020; Löscher and Potschka 2005). The complex architecture meant to exclude the toxic molecules from the brain, and spinal cord can also prevent the entry of drug molecules into them, making BBB and BSCB a double-edged sword. They exclude 100% of large-molecule

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neurotherapeutics and more than 98% of all small-molecule drugs, which is a concerning statistic (Pardridge 2005). The TJs present in them make the entry of the drug molecule difficult, and the efflux transporters pump out the drug molecules from the brain and spinal cord (Di and Kerns 2015). Drug molecules binding to blood and brain tissue reduces brain drug exposure. This reduces medication binding to therapeutic target protein molecules (Pardridge 2012). Drugs found in brain tissue were thought to bind to the brain target at their total concentration. In recent years, the free drug hypothesis—that only unbound drug molecules may attach to the target and produce efficacy—has gained popularity. Structure and physicochemical factors may impact binding (Chen et al. 2020). This explains many problems translating in vitro and in vivo lab results to the clinic (Fig. 2.1).

2.2.1.2 Incomplete Understanding of Disease Biology CNS diseases include a number of them, such as stroke, Alzheimer’s and Parkinson’s disease, spinal muscular atrophy (SMA), multiple sclerosis, Huntington’s disease, amyotrophic lateral sclerosis (ALS), and glioblastoma (Ormerod 1892). Several risk factors, including aging, genetic endocrine conditions, hypertension, inflammation, depression, infection, diabetes, polymorphism, vitamin deficiencies, metabolic conditions, dietary supplements, chemical exposure, and oxidative stress, have been identified as potential contributors to the pathogenesis of these disorders (Brown et al. 2005; Büeler 2009; Kieper et al. 2010). Due to our CNS’s complexity, some versatile factors are involved in their pathology, like apoptosis, immunological factors, inflammation, and other spontaneous factors (Honig and Rosenberg 2000; Gendelman 2002; Lucas et al. 2006). Due to the involvement and crosstalk of many pathways and their associated proteins, most of the cause for CNS pathology remains unclear (Jha et al. 2022). More study links CNS defects to various disorders. Neuroplastic changes stimulate adaptive neurophysiological processes that respond to altered afferent stimuli like neuropathic and nociceptive transmission to cortical, subcortical, and spinal areas (Pelletier et al. 2015a). These processes might be helpful at first, but in a chronic state, they contribute to be a part of the pathophysiology, and be involved in the maintenance and development of chronic signs and symptoms (Pelletier et al. 2015b). The other issue in exploring disease biology is the involvement of many orphan and even unexplored receptors that have a major role in their pathology and our limited efforts to explore them (Shi 2007). Brain biopsy is also inaccessible due to its nature and our primitive instruments to map the brain. Despite advances in genetics and clinical biology, most nervous system illnesses lack established molecular targets. Those deorphanized address depression, anxiety, and psychosis, and they date back decades (Saikia et al. 2019). Only a few novel targets have been properly researched in recent times, making it challenging to design cutting-edge medications. The scarcity of appealing biomarkers and creative disease models hinders researchers’ capacity to examine the pharmacology of potential medicines in proof-of-concept studies (functional, behavioral, electrophysiological) (Hanson et al. 2010).

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Fig. 2.1 Barriers related to biological aspect of drug development for neurological disorders. Biological barriers consist of the factors related to species, disease, or other biological factors hindering drug development. It consists of the (i) complexity of blood–brain and blood–spinal cord barriers due to the presence of blood endothelium septum at BBB and choroid plexus epithelial cells at BSCB along with the formation of the neurovascular unit, tight junctions, and efflux transporters at blood–brain and blood–spinal cord junctions, (ii) incomplete understanding of disease biology due to lack of technological advancement in detection methods and involvement of orphan receptors at their pathology, (iii) inferior reproducibility and predictive value of preclinical animal models due to poor predictive value and reproducibility and high mortality rate and their inability to mimic the disease pathology, and (iv) lack of pharmacodynamic biomarkers and reliable target engagement owing to improper infrastructure, funding delays. BBB: blood–brain barrier, BSCB: blood–spinal cord barrier, NVU: neurovascular unit, TJs: tight junctions, CNS: central nervous system

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2.2.1.3 Inferior Reproducibility and Predictive Value of Preclinical Animal Models Foreseeing how therapeutic medications would perform in humans is what preclinical research in drug development is all about. The pharmaceutical industry invests much in identifying the most promising drugs by studying their efficacy, toxicity, and dosage requirements (Atkins et al. 2020). Many preclinical and clinical investigations of potential treatments, as well as a basic scientific study into disease mechanisms and their causes, depend primarily on animal models of human pathologies (Chesselet and Carmichael 2012). Many diseases of the CNS, including Parkinson’s disease (both its nonmotor and motor pathologies), stroke (cell repair and apoptosis), optic nerve injury (axonal regeneration), and peripheral nerve injury (axonal regeneration), have benefited greatly from the rapid development of animal models (Carmichael 2005; Murphy and Corbett 2009; Dunnett and Lelos 2010; Chesselet and Richter 2011; Limb and Martin 2011). In a perfect world, research conducted using animal models should lead to new insights into human health problems and the preclinical testing of ground-breaking treatments, but the real picture is quite contrasting. First of all, even though these animals are close to humans in mimicking pathological conditions, they are not perfect for being different species having different alimentary, circulatory, and nervous system anatomy as compared to a human. Their pathological signs also vary as compared to a human (Jucker 2010). This often leads to harm to a human for a molecule in a clinical trial, previously deemed safe by preclinical animal studies (Van Norman 2019). Significant recent evolutionary changes in the human brain are poorly imitated in animals, making the human brain a formidable obstacle to the study of biology (Miller et al. 2019). Using animal models to predict human trials for neurological diseases has been ineffective. Trialists, study participants, and pharmaceutical manufacturers’ multiple responsibilities in clinical trials for neurological disorders result in enormous expenses. It may be helpful to determine whether the flaws lie with the models themselves, the methodology for applying the models to uncover the underlying treatment notion, the execution of clinical investigations, preclinical effectiveness trials, or all of the above (Ransohoff 2018). According to 221 animal experiments, human studies only agree 50% of the time (Perel et al. 2007). A 2006 meta-analysis of 76 animal trials found that only 37% were reproduced in humans, and 20% were directly challenged by human evidence (Hackam and Redelmeier 2006). A 2366-drug review reveals that, when it comes to forecasting harmful human reactions, animal research (particularly mouse, rabbit, and rat models) is imprecise and no better than chance (Bailey et al. 2014). US study of 37 substances by a national toxicology program found no indication of noncarcinogenic transferring toxicity from rats to humans. Short-term mouse-to-rat positive predictive value (PPV) was 44.8%, and long-term was 55.3%, with no significant differences between sexes or historical control animals. PPV between mice and rats was 50% when sex and organ exposure length were considered (Wang and Gray 2015). MORE studies confirmed that dogs and chimpanzees have similar outcomes (Bailey et al. 2015). High drug development failure rates raise worries about animal research’s ability to predict human toxicity. Only 1 in 20 medicines pass preclinical

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testing for human clinical trials (Thorpe et al. 2018). Only 60% passed the first phase, with half of the innovative medications that fail human clinical trials due to toxicity alone (Van Norman 2016). These problems contribute to a great amount of drug development in neurological disorders. The reliability of many animal models for CNS illnesses must be addressed if the private sector is to reinvest in these areas. Many companies believe that animal-based drug action testing and existing putative brain disease models filter out potentially useful medications and screen in pharmaceuticals that won’t demonstrate benefit in human trials. There are no adequate animal models that capture the pathophysiology of schizophrenia and depression. Attention to the evolutionary conservation of important human systems may make disease models feasible in the future. Animal-based pain tests that don’t match human conditions may explain the difficulties of finding analgesics with new modes of action (anticonvulsants, nonsteroidal anti-inflammatory drugs, and some opiates) (Mogil 2009). Antipsychotic and antidepressant medications were discovered by accident. Assays using these pharmaceuticals, such as tail suspension and forced swim test for antidepressants and amphetamine-induced hyperlocomotion test for antipsychotics, have only revealed molecules with the same mechanism as 1950s prototypes and have not boosted efficacy. IOM neuroscience forum sessions have focused on methods for creating more accurate prediction models based on humans, animals, or cellular biology (Hyman 2012).

2.2.1.4 Lack of Pharmacodynamic Biomarkers and Reliable Target Engagement Biomarkers are molecules in tissues, blood, or other bodily fluids that indicate an average or aberrant process, condition, or illness. Biomarkers measure how effectively the body reacts to a disease or condition therapy (Califf 2018). Owing to the intricacy of neural circuit function and structure, the wide variety of synaptic connections present in the brain, and the vast number of different cell types, it remains challenging to understand disease causes. Identifying and assessing promising molecular biomarkers in treating brain diseases is difficult because of the limited understanding of their pathogenesis (Pankevich et al. 2014; Byrne 2013). Furthermore, the sluggish pace of treatment development is correlated with the lack of reliable biomarkers (Altevogt et al. 2008). The use of biomarkers may enhance efficacy determination and target validation; nevertheless, the technique and resources needed to transform potential biomarkers into reliable tools are out of reach for academic researchers. The industry invests much in the research and development of biomarkers, but the difficulty has been that the creation and confirmation of these indicators often lags behind the creation of the therapeutic chemical. Despite the potential for biomarkers to speed drug discovery, commercial, university, government, and research projects, there is a lack of emphasis on biomarker development owing to inadequate funding and improper biomarker development processes. Target engagement of pharmacodynamic biomarkers is crucial for showing whether the targeted route has been functionally modulated in the right human compartment, as shown in landmark research that reviewed a retrospective review of Pfizer’ s early development programs (Colburn 2003). It is more likely that

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a good proof-of-concept could be achieved in the clinic when proper data regarding target engagement and pharmacodynamics biomarkers are available and have been demonstrated to be responsive to pharmacological treatment. Similar findings were subsequently confirmed by a detailed analysis of Astrazeneca’s early development programs, which found that projects with efficacy biomarkers available at the commencement of clinical testing have a higher likelihood of progressing to the next phase of testing (Cook et al. 2014).

2.2.2

Barriers Related to the Drug Development Aspect

2.2.2.1 Difficulty in Target Identification and Validation Target identification identifies the target protein or nucleic acid of small molecules/ entities. Target identification in clinical pharmacology determines a medication or other xenobiotic’s most probable target organ or system (Schenone et al. 2013). Methods might be based on biophysics, biochemistry, chemical biology, genetics, and others (Wang et al. 2004). After that comes target validation, which predicts the drug molecule’s molecular target (Williams 2003). The strategy takes 2–6 months and employs several techniques to demonstrate that pharmacological actions on the target may provide therapeutic benefit within an acceptable safety window (Hutson et al. 2017). Most companies keep their approach to validating and identifying innovative targets for developing new therapies a top secret. They determine the strongest lines of evidence, the modality (biologics/small molecule), and the most persuasive facts. This may be entirely based on human genetics for companies interested in rare diseases caused by single-gene mutations. The project will succeed if the mutation can be treated (Hutson et al. 2017). This approach discovered Huntington’s disease’s gene huntingtin decades ago (MacDonald et al. 1993). Despite this mutant gene being a proven therapeutic target, no effective therapy has been found. Even with a legitimate objective, a treatment strategy may not be possible (Davis 2020). CNS is a complex part of our body that does not serve an individual function like other major organs but coordinates all functions between them (Brodal 2004). Many receptors, proteins, and ion channels are involved in its functioning, leading to difficulty in drug designing for CNS. The first major drawback is the rise of adverse or unwanted side effects. It can be because of the nonspecific nature of the CNS drug, target, and mechanism-based side effects (Morofuji and Nakagawa 2020). Molecules that are not very selective may have unintended effects called off-target effects. Before the development of molecular pharmacology, drugs looked like this (Lynch III et al. 2017). For example, the atypical antipsychotic class has a wide range of pharmacology, some related to efficacy and others related to side effects (activity of cardiac ion channels such as Cav1.2, Nav1.5, and hERG, which regulate heart rate and elongation and QT interval) (Mauri et al. 2014). When calculating the appropriate therapeutic index (the ratio of the dose required for safety or toxicity to the dose required for maximal efficacy), it may be difficult to distinguish adverse effects from efficacy (significant changes in blood pressure). Depending on the

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severity of side effects, a therapeutic index of 10 or more is recommended, although lower numbers may be acceptable (Tamargo et al. 2015; Kang and Lee 2009). Heart rate and blood pressure may increase when adrenergic-blocking drugs used to treat attention-deficit hyperactivity disorder (ADHD) are stopped. Despite its risks, d-amphetamine has helped many patients with ADHD (Castells et al. 2018). Among mechanism-based side effects, side effects may occur when the target of interest is expressed in central or adjacent tissues as well as in functionally important CNS regions (Hughes et al. 2011). For example, dopamine D2 receptor antagonists often cause extrapyramidal side effects when used to treat positive symptoms. Schizophrenia or prolactinoma is caused by blocking dopamine D2 receptors in the striatum or pituitary (Sykes et al. 2017). If the distribution of target receptors is known, side effects can be predicted or at least studied. Another problem in target design is the lack of methods and assays to confirm target drug entanglement. The choice of approach depends on several factors, including target molecule intrinsic modality and efficacy and target receptor distribution and density in the brain and spinal cord (Schenone et al. 2013; Davis 2020; Talevi 2015). One difficulty in using new genetic discoveries to further our knowledge of disease processes and identify potential therapeutic targets is that practically all risk alleles have little penetrance. Rare variations that have originated more recently in the history of the human population and therefore have been exposed to less evolutionary pressure than older more frequent variants seldom exhibit mendelian or near-mendelian behavior. This suggests that systems biology techniques, which usually need novel molecular knowledge that is cell-type specific, are crucial for target identification and validation (Claussnitzer et al. 2020) (Fig. 2.2).

2.2.2.2 Imprecise Clinical Outcome Measures Clinical trials are research studies that use human subjects to address specific questions about the potential benefits and risks of a potential therapy, such as a new drug vaccination, drug treatment modality, or repurposing of an existing treatment (Berger and Alperson 2009). Various factors can affect the trial of neurological disorders. The most prominent one is the insufficient sharing of expertise, knowledge, and data. Despite pronouncements from numerous sectors in favor of data sharing for serious neurological disorders, industrial and academic scientists continue to avoid sharing their data (Committee on Strategies for Responsible Sharing of Clinical Trial D, Board on Health Sciences P, Institute of M 2015; Taichman et al. 2016). Furthermore, the antiquated and regressive structure of the Health Insurance Portability and Accountability Act (HIPAA) continues to hinder research (Nosowsky and Giordano 2006). Another problem is the high expenses and failure rates of conducting these trials. The cost of a single molecule clinical trial hovers around 944–2826 million dollars in the USA (Simoens and Huys 2021). If we include the cost of failure, this value skyrockets to 2.6 billion dollars (Kuppuswamy et al. 2021). All costs associated with medication development are increasing. From the early 1960s, spending on research and development exceeded production in all therapeutic categories. These increased costs may be partially attributed to the scope and complexity of clinical studies, which include a growing number of stakeholders

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Fig. 2.2 Barriers related to drug development aspect of drug development for neurological disorders. Drug development barriers consist of the factors that can arise at the time of drug development and clinical trial. It consists of (i) difficulty in target identification and validation due to genetic polymorphism and nonspecific nature of CNS drugs leading to adverse effects, (ii) imprecise clinical outcome measures due to high cost, shortage of trial-ready patients, long duration and tediousness of the clinical trial process, and variability in a clinical population, and (iii) faulty regulatory approval process due to nonclarity in regulatory approval pathway, complexity in registration and application process, conflict among agencies regarding requirements, and inconsistent IP regulations. CNS: central nervous system, IP: intellectual property

(Scherer 2001). Drug discovery operations at various stages of the drug development pipeline for neurological diseases assess thousands of compounds, with hundreds making it to the preclinical stage. Only around 10% of all chemicals that make it to human trials end up on the market. On average, this process takes 10–15 years (DiMasi and Grabowski 2007). A more significant percentage of clinical trials fail at each successive step of development, which harms R&D output (Pammolli et al. 2011). There is often a lack of clarity on regulatory requirements that also decrease outcome measures. Data on nonserious adverse measures or events obtained as part of routine clinical care on every patient registered in a large crucial trial are useless to regulators and expensive to collect, but sponsors collect them out of fear that regulators will reject their applications if these data are not included (Johnson 2004). It may be challenging to finish research on time and implement the results

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of clinical trials into clinical practice. It takes an average of 17 years and 14% of research breakthroughs to improve patient therapy (Balas et al. 2000).

2.2.2.3 Shortage of Trial-Ready Patients Trial volunteers are the foundation of good clinical research as they increase the drug’s statistical evaluation and help researchers make critical observations for any events that cannot be observed in preclinical trials. Despite a general willingness of patients to participate in clinical trials, only a subset of patients enrolled in them. Factors like patients not being adequately educated about the process, fear of the adverse effects of the drug, or simply being nonchalant about enrolling in the process contribute to this scarcity (Vaswani et al. 2020). People with previous medical histories, elderly patients, and minorities are all underrepresented in research. This impacts impeding our capacity to generalize research outcomes, worsening inequities, and delaying trial completion in clinical trials (Epstein 2008). For example, in the anti-amyloid treatment in an asymptomatic Alzheimer’s disease trial (the first phase III trial in preclinical AD), it took 3.5 years and over 5900 screenings to enroll and randomize 1169 patients, which is a shockingly low number (Aisen et al. 2022). Even though patients become ready to participate, the complex legal framework to register, the minuscule amount of compensation given to the patients, and the lack of support and guidance from the participating organization lead to them pulling out from the trial altogether or not being able to participate (Tanushka et al. 2018). Patients with ALS also don’t get enough opportunities to participate, and those who are often pulled out due to painful procedures have to endure minimal compensation (Kiernan et al. 2021). 2.2.2.4 Variability in the Clinical Population Neuropsychiatric disorders are characterized by a high degree of variability in clinical presentation and functional organization, brain morphometry, and cognitive ability. Demographic disparities may generate an interstate variance in the burden of neurological illnesses caused by ethnicity, age, gender, and service location (King et al. 2009). Despite a large body of literature describing various changes across patient profiles, the origins of such inter-individual heterogeneity remain largely unknown and understudied. As we know, the genetic makeup of each individual is different, so the pathophysiology of a disease or the mode of action and metabolism of a drug also varies, creating variations in the clinical trial results. Chance variation produced a varied array of predicted geographical effects. Marschner discovered, in a research including five areas and 80% power, that the predicted regional treatment effects varied from no difference to double the actual difference, with a likelihood of seeing a region favoring the control of around 50%. With 10 locations, this probability neared 85%, and the anticipated range of regional consequences was greater than 85% (Marschner 2010). This variability increases even further when we compare the effects between different races around the globe. This is the reason all cannot use a single drug molecule. This genetic polymorphism and difference can also give rise to idiosyncratic or tachyphylaxis effects on a molecule in a partial population, making drug discovery more difficult (Kesavan et al. 2011). Apart from

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this, the timeliness of clinical research, especially preventative ones, is another major issue for neurological and mental disorders. For instance, Alzheimer’s disease is a degenerative disorder that takes decades to build up to the point when clinical symptoms develop. The need to weigh the benefits of investing in preventative clinical trials against the risks involved is a major obstacle. So, because of these issues, the translation of preclinical medications into the clinical domain is slow (Choi et al. 2014).

2.2.2.5 Faulty Regulatory Approval Process The present regulatory processes may sometimes stymie the medicine development pipeline. If more training and clarification were given about the prerequisites for getting approval for investigational new drug application (INDA), such as thorough testing for absorption, distribution, metabolism, excretion, toxicity testing, and safety pharmacology, regulatory approvals might be achieved more swiftly and readily. There is also a need for surrogate indicator validation, especially for those that may be used in large-scale, long-term preventive research (Holbein 2009). The inconsistent intellectual property (IP) regulations also aggravate the regulatory process (Brindley and Giordano 2014). The use of expedited and conditional approval routes is another important strategy for speeding up the drug development pipeline; however, greater information and eagerness to utilize these pathways for drugs addressing neurological disorders is required. Due to the wide variety and complexity of the underlying pathophysiology of neurological disorders, it is highly unlikely that a single drug would be equally effective in treating all of them (Pankevich et al. 2014; Choi et al. 2014). To effectively treat some disorders, it may be required to mix pharmacological treatment, behavioral and psychotherapy therapies, and technology interventions. However, there has been little research into these possibilities yet. Even in the few areas where clinical data exist, the regulatory procedures for these combination drugs are not clearly defined, and payment policy is unclear (Altevogt et al. 2014).

2.3

Conclusion

An emphasis on the capacity to foresee results and define which steps in the development pipeline are or are not informative would likely be advantageous, given the challenges involved with present therapy development methods for nervous system disorders. Research, target validation and selection, clinical trials, regulatory procedure, and repeatability all have limitations that must be understood to reduce risk. New technologies, techniques, and processes are being developed that may 1 day improve the drug development process; however, more research is needed as clinical outcomes cannot be predicted. Animal and nonanimal models of mechanism, as well as further research into potentially common disease processes, may also aid in advancing early-stage pharmaceutical research and development. In addition to a centralized database for preclinical trials, other potential solutions include patient identification and stratification using human data, open data sharing

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among researchers, improved regulatory guidance, decreased replication, increased collaborative efforts, and systematic evaluations of failed clinical trials. New methods and improved infrastructure in the drug development pipeline may improve the quality of research and speed up the process. Numerous options exist to improve the drug development pipeline for neurological disorders, including improvements in methodological methods, adjustments in present procedures, and alterations to drug development infrastructure.

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Transporter Systems and Metabolism at the Blood–Brain Barrier and Blood–CSF Barrier Kanika Verma, Devesh Kapoor, Smita Jain, Ritu Singh, and Swapnil Sharma

Abstract

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), are a leading cause of morbidity and mortality. The presence of blood–cerebrospinal fluid (B-CSF) and blood– brain barrier (BBB) causes attenuation of site-specific delivery of therapeutic agents in neurodegenerative disorders. Since last decade, nanocarriers such as liposomes, nanoparticles (NPs), nano emulsions, dendrimers, and exosomes have appeared as reliable drug delivery systems that provide site-specific drug release in the central nervous system and have overcome the limitations associated with these barriers to improve therapeutic outcome in neurodegenerative disorders. Thus, in the present chapter, we have highlighted physicochemical aspects of barriers and various drug transporting mechanisms across the BBB and B-CSF barriers.Besides, recent developments and future prospects of transporter systems in combating neurodegenerative diseases have also been discussed. Keywords

Neurodegenerative disorders · BBB/B-CSF · Nanoparticles · Liposomes · Dendrimers · Exosomes · Carbon dots

K. Verma · S. Jain · R. Singh · S. Sharma (✉) Department of Pharmacy, Banasthali Vidyapith, Banasthali, Rajasthan, India D. Kapoor Dr. Dayaram Patel Pharmacy College, SardarBaug, Bardoli, Gujarat, India # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Mishra, H. Kulhari (eds.), Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities, https://doi.org/10.1007/978-981-99-6807-7_3

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K. Verma et al.

Introduction

Neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), are considered significant challenges to human health (Niu et al. 2019). According to statistical reports given by the United Nations, the world population of elderly individuals aged above 65 years in 2019 is projected to double in 2050. Neurodegenerative disorders are rapidly prevailing with the increasing global population. Notably, the number of cases of neurodegenerative patients is expected to increase from 13.5 million in 2000 to 36.7 million in 2050 (Zheng and Chen 2022). Various therapeutic agents e.g., antisense drugs, proteins, polypeptides, and nucleic acids, have been evidenced as neuroprotective, but the majority of these agents are unable to noninvasively enter the brain parenchyma. Diagnosis and targeted drug therapy are the major challenges due to the presence of two barriers: blood–cerebrospinal fluid (B-CSF) and blood– brain barrier (BBB). In fact, the existence of these barriers restricts the transportation of imaging probes and drugs into the brain. In order to treat neurological disorders, several investigators have attempted to efficiently develop novel treatment approaches using multiple strategies, such as increasing the lipid nature of watersoluble drugs, the alterations in BBB permeability, disruption of BBB, or the development of multifunctional nanocarriers for targeted drug delivery. Nanotechnology is one of the novel approaches for overcoming barriers and includes a diverse spectrum of proteins whose unique chemical and physical properties allow sitespecific drug delivery in the brain. Nanocarriers for the treatment and diagnosis of neurodegenerative diseases mainly include nanogels, hydrogels, liposomes, nanoparticles, and exosomes. Here, in the present chapter, we have reviewed the structure of barriers and their physiological transport mechanisms. In addition, the recent developments in different types of nanocarriers for targeted drug delivery across barriers are discussed. Furthermore, different transport mechanisms (carrier-mediated transcytosis, adsorptive-mediated, and receptor-mediated) are reviewed. Finally, the nanocarrier-associated limitations and future prospects in combating neurodegenerative diseases have been discussed.

3.1.1

Barrier to CNS Drug Delivery

3.1.1.1 The Blood–Brain Barrier (BBB) Central nervous system (CNS) homeostasis is strictly maintained by two biochemical barriers, termed B-CSF and BBB, which govern various metabolic and transportation processes to the brain. The BBB is an exclusive and selective barrier composed of endothelial cells and other structures, including basement membrane, astrocytes, capillaries, and pericytes (Fig. 3.1). These structures provide the brain with essential nutrients, such as oxygen and glucose, but prevent the entry of neurotoxins into the neural cavity. The BBB separates blood circulation from the neural environment in the brain due to the presence of the least permeable capillary

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Fig. 3.1 Structure of the BBB and B-CSF barrier

barriers in the entire body. The unique biological properties and complexities associated with BBB separated them from other peripheral endothelial cells. These cerebral endothelia have special characteristics that allow revascularization by maintaining angiogenic capability, transendothelial transportation, and integrity of BBB. In addition, brain endothelial cells express proteins like adherens junctions and tight junctions to reinforce the cohesiveness of the barrier. Tight junctions are composed of cytoplasmic and transmembrane proteins that include zona occludens, junction adhesion molecules, occludins, claudins, and accessory proteins. Despite the cohesive force that binds endothelial cells intact, the BBB allows the passage of selective molecules and cells to the brain. Such cells found in the BBB are astrocytes, microglia, pericytes, and adjacent neurons. However, the adherens junction holds tissue together by providing structural support. Anatomically, multifunctional pericytes surround the endothelial cells and allow transcytosis across tight junctions, adjacent cells, and BBB. In addition, being a member of the vascular smooth muscle cell lineages, these cells regulate the blood flow in the brain capillaries via relaxation and contraction of brain capillaries. Contrarily, astrocytes are glial cells that maintain redox potential, remove waste from cerebrospinal fluid, and help neurons in maintaining homeostasis. Furthermore, microglia being immune cells in the brain are stimulated in response to trauma or inflammation. On the other hand, the basement membrane consists of endothelial cells and pericytes, which embody >99% of capillaries found in the CNS. Notably, the electrical resistance within other endothelial cells is much lower than endothelium in the brain, which presents as a limitation during paracellular transportation. Moreover, due to such structure-based limitations, several substances even lose the potential to cross BBB via transcellular transport (Song et al. 2021; Ahlawat et al. 2020; Sweeney et al.

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2018; Saraiva et al. 2016; Nguyen et al. 2021; Seko et al. 2020; Mulvihill et al. 2020).

3.1.1.2 The Blood–Cerebrospinal Fluid (B-CSF) Barrier The CSF is synthesized from the choroid plexus, which lines four ventricular cavities, two midlines, and two lateral ventricles. The CSF flows from these ventricles and is then absorbed into the superior sagittal sinus via the arachnoid villi. The electrical signaling and neurotransmission depend on the extracellular fluid of the specialized composition (Fig. 3.1). The blood–CSF barrier in choroid epithelial divides the CSF compartment from systemic circulation. Despite the existence of two barriers, the research focusing on BBB seems to be rather unbalanced. However, this is not entirely surprising since a larger surface area and intimate contact of BBB with neuronal constituents justify its consideration in the development of neuroprotective drugs. Nonetheless, the insufficient attempts to evidence blood– CSF as another critical barrier of choice in maintaining brain homeostasis have finally come to an end in the face of research pieces of evidence. Choroid plexus actively participates in various aspects, including neuroendocrine regulation, immune functions, neuronal functional maturation, and early brain development, in addition to its role in understanding the transfer of material between CSF and systemic circulation (Pardridge 2016; Zheng and Chodobski 2005; Johanson and Johanson 2018). Recently, great research efforts have been made to better understand the role of blood–CSF in neurological disorders (Naessens et al. 2018). The blood–CSF and BBB are usually coordinated, secrete cytokines in the brain and CSF, and contain the elements of the innate immune system. Both barriers act as guardians to prevent the diffusion of potentially toxic molecules. Thus, the dual blood–CSF and BBB interfaces display dynamic transport physiology as a cardinal feature. However, an in-depth insight into the disruption of barriers would present new insight into transportation across membranes and will allow the development of novel drug carrier systems.

3.2

Transport Mechanisms of Drug-Loaded Nanocarriers Across the Barriers

Nanocarriers ease the penetration of the drug to the target site without causing any problems to a patient during the administration of a molecule. It has the ability to target tumor cells and permeate the BBB and blood–CSF barriers. Nanocarriers could act intranasally, intravascularly, by means of intraparenchymal injections, or intraventricular administration. However, all these routes possess certain drawbacks that prevent nanocarriers from being used more frequently. For instance, via intranasally, ciliary movement inhibits the drug’s clearance, and methods like intraventricular or intraparenchymal injections require surgical procedures that also seek difficulty to incorporate a nanoparticle-loaded drug into an individual. It is essential to note that the molecule must reach barriers to show its therapeutic activity by following certain transport pathways such as carrier transport, passive diffusion,

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Fig. 3.2 Transport mechanisms across the barriers

adsorptive mediated, and receptor-mediated transcytosis (Ceña and Játiva 2018; Fowler et al. 2020; Shyam et al. 2015; Chaichana et al. 2015; Mignani et al. 2021; Elder et al. 2006). In this section, we will be focusing on three main transport mechanisms of nanocarriers, viz. receptor-mediated transcytosis, adsorptivemediated, and carrier-mediated (Fig. 3.2).

3.2.1

Receptor-Mediated Transcytosis (RMT)

This type of transport includes the binding of a nanoparticle to a particular receptor located on the outer lining of endothelial cells. The process is mediated by certain ligands that promote endocytosis. RMT is involved in commuting nutrients such as iron, leptin, insulin, and nanoparticles via ligands (either natural or artificial). RMT, also referred to as clathrin-dependent endocytosis, is target-specific and energymediated. It is also referred to as “Trojan horses” because of its promising approach to penetrating brain cells (Qiao et al. 2012). Receptors such as lectins, mannose, macroglobulin, galactose, transferrins, epidermal growth factor (EGF), insulin, platelet-derived growth factor (PDGF), and vasculature receptors are involved in endocytosis after binding to a specific ligand (Yu et al. 2010). After binding to a specific receptor, ligand-bound nanoparticles muster at targeted sites of cell membrane termed as “coated pits.” These pits further develop into coated vesicles after invagination and later proteins, and clathrin dissociates from the vesicles after endocytosis. These further form new coated pits at the plasma membrane. At the end of the process, the vesicles get acidified, which dissociates ligand-bound nanoparticles from the receptor and releases the drug to the cell (as the nanoparticle degrades) (Tabernero et al. 2002). With emerging research in developing target-specific ligands, many proteins are designed, such as small proteins acting as antibodies termed avimers (Silverman et al. 2005), heavy chains extracted from antibodies known as nanobody (Cortez-Retamozo et al. 2004), and small protein domain, affibody (Wikman et al. 2004). This type of endocytosis is a prominent way to target neuronal tissues. For example, a chelator-nanoparticle system was developed by Liu et al. (2006a,b) that binds with iron and targets neurological diseases such as AD. The nanosystem

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facilitates the treatment of dyshomeostasis caused by an abnormal increase of iron content in the brain. Another example is vincristine sulfate conjugated LDL particles. It was observed that after binding with the LDL receptor, the specificity to target glioma cells was increased in mice (Liang et al. 2018). Kratzer et al. (2007) also designed a protamine-oligonucleotide nanoparticle bound with apolipoprotein A-I (apoA-I) that easily penetrated BBB in vitro. The antitumor effect of doxorubicin was evaluated by Petri et al. (2007) when they developed poloxamer 188 coated poly(butyl cyanoacrylate) nanoparticle loaded with doxorubicin. The nanoparticle showed a significant effect in intracranial glioblastoma in rats. Demeule et al. (2008) designed Angiopep-2 (Kunitz domain-derived peptides) that exhibited maximal transcytosis capacity and deposition in parenchymatous cells. The effect of this peptide was more prominent than avidin, transferrin, and lactoferrin.

3.2.2

Carrier-Mediated Transcytosis (CMT)

CMT involves transport from blood to the brain in a unidirectional way. CMT or carrier-mediated influx mainly transports polar substances into the brain using certain carrier systems. These transporters include cationic amino acid transporter (CAT1), nucleoside transporter (CNT2), glucose transporter (GLUT1), large neutral amino acid transporter (LAT1), and monocarboxylic acid transporter (MCT1) that penetrates into the brain. The transport system mainly transports small polar substances such as amino acids, ions, and energy sources. It transports drugs noninvasively after binding them to natural substrates. A major limitation of this transport mechanism is that due to the small pore size of the carriers, it is not possible to transport larger molecules via this pathway (Jones and Shusta 2007). Some carriers such as GLUT1, transport glucose, and LAT1 transports phenylalanine through BBB. LAT1 is also used to transport L-DOPA to treat PD (Peura et al. 2013).

3.2.3

Adsorptive-Mediated Transcytosis (AMT)

The mechanism has gained a lot of attention from researchers as it involves both positively charged as well as negatively charged substances. This results in an electrostatic interaction that causes invagination of the cell membrane. Positively charged substances such as albumin or other cationized peptides form vesicles by attaching to negatively charged molecules such as glycoprotein present at the sites of brain endothelial cells. The caveolae or clathrin-coated pits form a vesicle when combined with positively charged substances. The interaction is observed between the plasma endothelial membrane and the outer surface of nanoparticles (Pulgar 2019). Afergan et al. (2008) reported the adsorptive-mediated transport of drugs that are loaded on either monocytes or neutrophils that carry the negatively charged surface of nanoparticles to the endothelial surface of the brain to transport serotonin. This showed that monocytes possess a better effect to transport serotonin across

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BBB. Liu et al. (2006a,b) also exploited this mode of transport to understand the transport of endomorphin (endogenous opioid receptor agonist). The research suggested that Gly-containing pentapeptide had a significant effect on CNS, resulting in a better analgesic effect (permeation of large peptide chain). Lu et al. (2006) exploited AMT to target brain tumors by adding cationic albumin-conjugated PEGylated nanoparticles into pORF-hTRAIL (pDNA) to analyze activity against gliomas when incorporated in gene therapy. It was reported that after the incorporation of nanoparticles bound with glycoproteins, apoptotic brain tumor cells were noted, suggesting that adsorptive-mediated transcytosis is a promising route to deliver drugs across BBB and hence can be used to target CNS-related ailments.

3.3

Nanocarriers for Drug Delivery Across Barriers: Special Emphasis on Neurodegenerative Disease

3.3.1

Liposomes

Delivering medications across the BBB is a significant obstacle in the treatment of neurogenerative illnesses. The development of a liposome-based drug delivery system with improved penetration in BBB is effective for medication delivery to the brain. Liposomes have drawn a lot of attention as drug delivery vehicles due to their biocompatibility, lack of toxicity, ability to prevent their degradation by plasma enzymes, and ability to deliver lipophilic and hydrophilic drugs across BBB and other biological membranes. The undesired properties of small hydrophobic molecules (SHMs) can be overcome by the formulation of liposomes. The SHMs loaded in liposomes are very beneficial to treat neurodegenerative diseases (NDs). The different nanocarriers employed to treat neurodegenerative diseases are shown in Fig. 3.3.

3.3.1.1 Transferrin-Modified Liposomes Kong et al. fabricated transferrin liposomes (Tf-LIPs) modified with osthole (OST); a possible medication for the treatment of AD is osthole (Ost), a coumarin molecule that protects hippocampus neural stem cells and neurons against oligomer-induced neurotoxicity in AD mice. The researchers fabricated Tf-LIPs of OST because of limited bioavailability and solubility and poor permeability through BBB. The thinfilm hydration method was employed to fabricate the LIPs. Using an in vitro BBB model, the capacity of liposomal formulations to translocate across BBB was examined. The Tf-LIPs-OST protective effect was evaluated against the APP-SHSY5Y cells. The neuroprotective effect of Tf-LIPs-OST was also observed by the researchers in APP/PS-1 mice. The in vitro studies demonstrated that Tf-LIPs-OST could enhance the intracellular uptake of APP-SH-SY5Y and hCMEC/D3 cells and surge the drug concentration across the BBB. In addition, Tf-LIPs-OST showed significant protection against APP-SH-SY5Y cells. In vivo investigation of pharmacokinetics of OST in brain tissue exhibited that Tf-LIPs-OST enhanced OST

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Fig. 3.3 Different nanocarriers employed for ND treatment

accumulation in the brain and prolonged the cycle time in mice. Moreover, it was revealed that Tf-LIPs-OST improved OST’s ability to reduce pathology linked to AD. The administration of OST via Tf-LIPs has enormous potential for treating ADs.

3.3.1.2 Glutathione-Modified Liposomes The GSH-coupled liposomes exhibit a promising method for functionalizing nanocarriers to cross the BBB. The liposomes anchored with GSH and apolipoproteins E facilitate the permeation through BBB. The liposomes also regulated the mitogen-activated protein kinase in ADs. The GSH-modified liposomes decorated with PEG considerably enhance the penetration of doxorubicin through the BBB (Kuo et al. 2021;. Mehrabian et al. 2022). 3.3.1.3 PEG-Modified Liposomes The 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy-(polyethylene glycol)-2000] (PEG-DSPE) modified liposomes loaded with doxorubicin along with cholesterol, egg phosphatidylcholine (ePC), and 1,2-dioleoyl-3trimethylammonium-propane chloride (DOTAP) effectively cross the BBB and delivered DOX to glioma cells in the brain. The developed liposomes significantly declined the U87-MG cells’ viability in the brain (Yuan et al. 2019). The PEGylated bifunctional liposomes were developed by combining poly-L-arginine (PR) and transferrin (Tf). The Tf was employed to facilitate the cell penetration and poly-L-

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arginine (PR) used for receptor targeting. The developed liposomes exhibited noteworthy cellular uptake by brain endothelial cells (Sharma et al. 2012). The Coumarin 6 loaded phospholipid and glucose-modified liposomes were prepared by using the thin-film dispersion ultrasound method. The formulated liposomes effectively transport the drugs into the brain parenchyma via BBB (Xie et al. 2012). Recently, PEGylated liposomes conjugated with glutathione (GTH) ligands were prepared and evaluated for transcellular transport and payload through the BBB. The GTH presence increased the liposome’s transcellular transport efficiency through the BBB and also enhanced the delivery of drugs by increasing cellular uptake and vesicular exocytosis route of brain endothelial cells (Reginald-Opara et al. 2022).

3.3.1.4 Multifunctional Liposomes Multifunctional nanoliposomes exhibit a viable and promising approach to cross the BBB and blood–CSF barrier. They are extremely flexible and biocompatible and have the capacity to carry different types of therapeutic moieties across the blood– CSF and BBB. They can be modified to enhance the blood circulation time and can be employed against single or multiple pathological targets. Li et al. formulated liposomes of artemether loaded with paclitaxel and evaluated the efficacy of these liposomes in treating invasive brain gliomas. The researchers examined the potential of fabricated liposomes to cross the BBB, destroy vasculogenic mimicry (VM) channels, and eliminate cancer stem cells and brain cancer cells. The researchers observed that VM channel destruction occurred due to the regulation of VM indicators. The activation of apoptotic enzymes, pro-apoptotic proteins, and inhibition of anti-apoptotic proteins cause apoptosis in CSCs and brain cancer cells. The outcome revealed that invasive brain glioma treatment, functional targeting artemether liposomes combined with paclitaxel, may offer a new approach (Li et al. 2014). Papadia et al. also studied the multifunctional liposomes loaded with curcumin lipid ligands together with two other ligands to target the amyloids, low-density apolipoprotein, and transferrin receptor of BBB as a potential therapeutic system for AD (Papadia et al. 2017).

3.3.2

Nanoparticles (NPs)

Most NPs are made to be able to traverse the BBB by transcytosis in order to boost their BBB penetration capabilities. Their surfaces must be altered to accomplish this, either noncovalently with a coating or covalently with functionalization. One of the techniques to improve NPs’ BBB penetration capabilities was coating them with a surfactant. Treatment for cerebral illnesses using NP-mediated medication delivery is becoming a popular noninvasive method. The NP-based drug delivery includes different mechanisms to cross the BBB, such as receptor-mediated endocytosis, adsorption-mediated endocytosis, carrier-mediated transport, and diffusion of lipophilic molecules via endothelial cells. The NPs that are developed to cross the BBB and blood–CSF include gold NPs, silver NPs, cerium oxide and molybdenum NPs, silica NPs, and organic NPs (Zhou et al. 2018).

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3.3.2.1 Gold Nanoparticles (Gold NPs) A promising choice in the biomedical domains, gold NPs exhibit the qualities of good biocompatibility, flexible surface modification, distinctive optical properties, and changeable size. Research has evidenced the therapeutic potential and possible benefits of gold NPs in medication delivery. These advantageous benefits of gold NPs offer assistance for fresh investigations to comprehend the mechanism of neurodegenerative disorders (de Bem Silveira et al. 2021). Cheng et al. fabricated gold NPs modified with transactivator of transcription (TaT) peptide to cross the BBB and deliver the contrast agents (GD + 3) and doxorubicin (DOX), an anticancer drug to brain tumor tissues. The TaT gold NPs significantly delivered the GD + 3 with increased retention time for brain tumor targeting as compared to free Gd + 3. The intravenous administration of fabricated NPs exhibited the survival benefit of mice having intracranial glioma xenografts (Cheng et al. 2014). Another study carried out by Ruff et al. demonstrated that gold NPs modified with β-amyloid specific peptides impede the BBB passage significantly (Ruff et al. 2017). The gold NPs chemically conjugated with agglutinin horse radish peroxidase can be considerably transported to the brain stem and spinal cord. The NPs have the ability to deliver the drug at very low doses as compared to unconjugated drugs (Zhang et al. 2016). The neuron-targeted exosome is employed to coat the surface of gold NPs to enhance the BBB penetration (Khongkow et al. 2019). The gold NPs coated with 8D3 anti-transferring receptor antibody effectively cross the mouse BBB (Cabezón et al. 2015). Etame et al. successfully delivered the gold NPs into the central nervous system of the rat model by using magnetic resonance imaging-guided focused ultrasound technique (Etame et al. 2012). The multibranched gold NPs functionalized with levodopa significantly cross the BBB without inducing any inflammation (Gonzalez-Carter et al. 2019). 3.3.2.2 Iron Oxide Nanoparticles (IONPs) In the CNS, superparamagnetic iron oxide NPs offer a variety of prophylactic, diagnostic, and possibly therapeutic applications. They can be used as MRI contrast agents to assess areas of BBB dysfunction, in vivo cellular tracking in CNS disease, and cerebrovasculature using perfusion-weighted MRI sequences associated with tumors and other neuroinflammatory disorders (Weinstein et al. 2010). Shi et al. demonstrated that iron NPs coated with collagen, polyvinyl alcohol (PVA), and bovine serum albumin exhibited better cellular uptake as compared to IONPs coated with glycine, glutamic acid, and PVA. The researchers concluded that IONPs have the potential to deliver the drugs to the brain effectively and can be employed to treat various neurological disorders (Shi et al. 2016). The hyperthermia induced by alternating magnetic fields (AMFs) enhances the cell uptake of IONPs in BBB models. The hyperthermia induced by AMF significantly increased the paracellular pathway flux (Dan et al. 2015). The supramagnetic IONPs coated with Tween 80, polyethylene glycol, and polyethylene imine effectively cross the BBB of rats under the implementation of a magnetic field (Huang et al. 2016). The IONPs equipped with PLGA and L-carnosine peptide loaded with dexamethasone effectively deliver drugs through BBB and are employed to treat ischemic

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stroke (Lu et al. 2021). The IONPs decorated with phosphorylcholine and PEG significantly cross the BBB confirmed by quantitative analysis such as fluorescence spectrometry (Ivask et al. 2018). The IONPs conjugated with angiopep 2-pluronic F127 exhibited little cell cytotoxicity, significant permeability across the BBB, and superior cellular uptake in U87 cells (Chen et al. 2016). The IONPs decorated with trimethoxysilylpropylethylenediamine triacetic acid effectively delivered doxorubicin in human U251 glioblastoma multiforme (GBM) cells. The fabricated NPs enhanced the uptake of DOX in GBM cells (U251) and considerably attenuated the GBM cell (U251) proliferation (Norouzi et al. 2020). Shen et al. also demonstrated that hydrophobic IONPs were coated with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N[methoxy(polyethylene glycol)-2000] and loaded with DOX function as a nanoprobe for magnetic resonance and fluorescence bimodal imaging. These NPs also serve as a carrier to deliver the anticancer drug DOX effectively in the rats bearing C6 glioma. The researchers revealed that IONPs could be beneficial for theranostic treatment of glioma (Shen et al. 2019).

3.3.2.3 Cerium Oxide Nanoparticles (CEONPs) CEONPs are now receiving more attention as an effective nanomedicine for neurodegenerative disease (NDGs) due to their capacity to modify signaling pathways, antioxidant capabilities, a tiny diameter that allows passage through the BBB, and scavenging of ROS. The CEONPs are employed to treat various NDGs, which include PDs, ALS, multiple sclerosis, AD, and ischemic stroke (Naz et al. 2017). Heckman et al. demonstrated that the CEONPs have the potential to penetrate the brain significantly, decline reactive oxygen species (ROS) considerably, and attenuate motor deficits and clinical symptoms in mice murine models of multiple sclerosis. The researchers revealed that CEONPs could be beneficial in alleviating tissue damage brought on by the buildup of free radicals in biological systems (Heckman et al. 2013). The CEONPS formulated with Caccinia macranthera leaf extract, a reducer agent and stabilizer loaded with temozolomide, exhibited significant antiproliferative activities against glioblastoma cells (U87), apoptosis, and cell cycle arrest. The researchers concluded that fabricated NPs have noteworthy potential to cross the BBB and deliver the anticancer drug at the tumor site (Foroutan et al. 2022). The CEONPs loaded with a polymer matrix of PLGA/PEG showed significant results in alleviating the focal ischemia by 60% and declining brain edema by 80%. The researchers revealed that PLGA/PEG had surged the neuroprotective efficiency of CEONPs by protecting the areas of the brain cortex from ischemic damage (Gao et al. 2018). 3.3.2.4 Molybdenum Nanoparticles Liu et al. investigated the effect of molybdenum sulfide nanosystems (MbS2) decorated with gold NPs on aggregation of amyloid β40 (Aβ40). The researchers revealed that low concentrations of MbS2-gold NPs enhance the aggregation of Aβ40 fibrils; conversely, Aβ40 fibril aggregation is inhibited with a high concentration of

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MbS2-gold NPs. The researchers concluded that nanocomposites based on MbS2 have good potential to treat amyloid-related disorders (Liu et al. 2020). Han and his colleagues also reported that MbS2NPs exhibited significant inhibitory effects against Aβ aggregation. The investigators formulated MbS2NPs functionalized with polyvinylpyrrolidone by using the laser ablation method. The researchers found that MbS2NPs showed multifunctional effects on Aβ peptides, including inhibition of Aβ aggregation, alleviation of the oxidative stress induced by Aβ and Aβ-induced cell toxicity, and destabilization of Aβ fibrils. These NPs also have the potential to block the Aβ-induced Ca2+ channel in the cell membrane. The researchers recapitulated that fabricated NPs could be a good candidate or amyloidrelated disease treatment (Han et al. 2017a).

3.3.2.5 Silica Nanoparticles (SiNPs) Mesoporous silica nanoparticles (MSiNPs) have drawn a lot of interest because of their use in biomedicine and as drug delivery systems. Their simple functionalization, excellent biocompatibility, high surface area, and structural tunability provide important advantages over traditional materials. The SiNPs functionalized with PEG effectively cross the BBB, and significant uptake was exhibited by cerebral endothelial cells (bEnd.3) of mice confirmed by in vitro and in vivo investigations performed by Liu et al. (Liu et al. 2014). Tamba et al. formulated SiNPs functionalized with PEG methyl ether amine and glucose by employing the microemulsion method and examined the potential of fabricated NPs to cross the BBB of rodent brains. The researchers showed that PEG-glucose SiNPs reached endothelial cells effectively by infiltrating the BBB (Tamba et al. 2018). Mo et al. demonstrated that SiNPs functionalized with cancer-targeting polymer (PEI-cRGD) and loaded with anticancer drug doxorubicin (DOX) penetrate the BBB and disrupt the cells of glioblastoma multiforme (GBM) significantly (Mo et al. 2016). The SiNPs decorated with arginine–glycine–aspartate (RGD) peptide effectively permeate the BBB and antagonize the human brain glioma cells (You et al. 2016). Yang et al. investigated the potential of SiNPs for crossing the BBB by attaching the lactoferrin (LF). The surface of NPs was modified with PEG to diminish the adsorption of protein. The three different in vitro BBB models such as endocytes, astrocytes, and pericytes were employed to investigate the efficiency of SiNPs. The outcome indicated that LF-SiNPs demonstrated increased transport efficiency across the BBB with size dependence compared to plain SiNPs. The maximum transport efficiency of LF-SiNPs was seen for 25-nm diameter particles (Song et al. 2017). 3.3.2.6 Organic Nanoparticles In recent times, the development of organic NPs has allowed the targeted delivery of drugs into CNS via BBB. After surface alteration of these NPs, one can enhance the lipophilicity, brain targeting ability, biocompatibility, and surface charge. These organic NPs can greatly boost the concentration of medicines in the brain by avoiding RET phagocytosis. For instance, PEG decoration can increase the retention period of liposomes in blood. Targeting ligands enable NPs to cross the BBB using a

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variety of transport methods and achieve active targeting, which encourages the carriers to continue accumulating in the brain. Furthermore, by changing the surface charge and enhancing electrostatic contact, surfactant modification can promote BBB crossing (Tan et al. 2022). Barbara et al. fabricated PLGA (polylactide-coglycolic-acid) NPs encapsulating curcumin as the chief ingredient, altered with g7 ligand to penetrate the BBB. The researchers’ findings indicate that the designed NPs do not exhibit any toxicity in any discernible way, but that curcumin-loaded NPs significantly reduce the amount of Aβ aggregates. Thus, investigators draw the conclusion that delivering curcumin to the brain via BBB-crossing NPs is a potential strategy for the future of AD treatment (Barbara et al. 2017). Grosso et al. fabricated PLGA NPs encapsulated with cross-linked enzyme aggregates (CLEA) decorated with brain-targeting peptides such as Tf2, Ang2, and g7 to treat Krabbe disorder, a neurodegenerative disorder caused by deficiency of galactosylceramidase. The Twitcher mouse is used to successfully test the prepared formulations by the researchers. The investigators investigate the enzymatic activity following intraperitoneal injections in the nervous system and in accumulation regions, showing activity recovery in the brain up to the level of unaffected animals. These findings bring up fresh therapeutic options for any lysosomal storage disorders that significantly affect the CNS (Del Grosso et al. 2019). Chowdhury et al. formulated NPs of polyfluorene (PF), having chitosan (CH) as an additive for effective penetration of BBB. The PF-CH-NPs exhibit no toxicity in the MTT assay and prevent Aβ1–40 and human cerebrospinal fluid oligomers from self-aggregating to form fibrils (Roy Chowdhury et al. 2018). In a recent study, chitosan NPs increase the nasal absorption and brain targeting of sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, for the treatment of AD (Wilson et al. 2021). The chitosan NPs coated with polysorbate 80 enhanced the brain uptake of ropinirole hydrochloride (Ray et al. 2018). A DPP-4 inhibitor, saxagliptin effectively penetrates the BBB by employing chitosan NPs conjugated with amino acids (Fernandes et al. 2018).

3.3.2.7 Nanoemulsion (NE) and Nanosuspension (NS) The NS composed of a drug and little amount of stabilizer has been evidenced as a novel delivery system for insoluble drugs. They are dispersed in an aqueous solution that has a large specific surface area, high dispersion, small particle size, and high drug loading. It can considerably increase the bioavailability, effectiveness, and solubility of insoluble drugs. Fan et al. fabricated NS of paclitaxel (PTX), an anticancer drug, to treat the glioma by penetrating the BBB and BBTB. The results exhibited that PTX-NS effectively cross the BBB and selectively target the tumor tissues of glioma confirmed by in vivo imaging and cell uptake examination. This study shows the intriguing potential of biomimetic NS suited to tumor therapy and offers an integrated strategy for optimizing the targeting of NS (Fan et al. 2021). The chitosan nanosuspension loaded with hesperidin along with tripolyphosphate prepared by the ionic gelation approach exhibited significant penetration against the BBB for parkinsonism treatment (Somasundaram et al. 2018). The BBB penetration of Tanshinone I-NE modified with coumarin-6 and lactoferrin, a brain

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targeting ligand, was much better than the coumarin-6 solution. The lactoferrinmodified NE has noteworthy potential to deliver the Tanshinone I effectively across the BBB (Wu et al. 2019).

3.3.2.8 Dendrimers The adaptable nanopolymers known as dendrimers have homogeneous and precisely specified particle sizes and shapes. Due to its capacity to traverse cell membranes, dendrimers are of prime interest for biomedical applications. The BBB is crossed by this possible drug delivery route, along with other crucial target sites. Dendrimers are excellent drug delivery vehicles for the brain because of their high degree of control over the dendritic architecture (surface functioning, branching density, and size). Dendrimers with the highest relevance are polyether-copolyester (PEPE), poly(propylene imine) (PPI), and poly(amidoamine) (PAMAM), as well as pH dendrimers and glyco and PEGylated peptides. While these dendrimers carry drug molecules through chemical bonding or encapsulation, the pH-sensitive dendrimers transport drug molecules by modulating the ionic balance within the brain environment at the tumor site. Santos et al. investigated the effect of PAMAM dendrimers functionalized with PEG for BBB transport and uptake of neurons after focal brain ischemia. The researchers exhibited that PEGylation significantly improved the biocompatibility of PAMAM as a function of dendrimer production and functionalization level. The integrity of an in vitro BBB model was unaffected by the PEGylated RITC-modified dendrimers. Additionally, even after coming into contact with bEnd.3 cells, the functionalized dendrimers remained secure. The suggested formulation has the potential to be an effective therapeutic application delivery vector to the stroke-damaged brain, reaching the ischemia neurons (Santos et al. 2018). Shrinageshwar et al. examined the function of novel mixed surface dendrimers, exhibiting reduced toxicity administered to mice through their carotid arteries, which can cross the BBB. The G4–90/10 can be injected through the carotid artery, can cross the BBB, and is located in neurons and glial cells, according to in vivo experiments. One week after intracranial injection, the dendrimers were discovered to move via the corpus callosum. The glial cells that are moving are dendrimer-infected, according to immunohistochemistry. Overall, the use of PAMAM dendrimers is a minimally invasive method of delivering drugs for the treatment of neurodegenerative diseases or disorders (Srinageshwar et al. 2017). 3.3.2.9 Nanogels (NGs) The NGs are crosslinked 3-D polymers with nanoscale dimensions that have a lot of potential for usage in the biomedical industry. Their usage as a drug delivery system to reduce severe adverse effects and raise the therapeutic index of medications is of particular attention. They have recently gained attention due to their ability to modulate their structure by incorporating responsive modalities, which further allow them to immediately exhibit a therapeutic effect. In comparison to non-crosslinked polymers, their larger sizes and regulated architecture and functionality make them particularly intriguing to investigate novel modalities to cross biological barriers.

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The NGs labeled with poly(N-isopropylmethacrylamide) exhibited significant uptake by polarized brain endothelial cells (Ribovski et al. 2021). The NGs with dual targeting function include thermosensitive targeted nanogel delivery systems (DPPC) with cell-penetrating peptides (CPP) that efficiently penetrate the BBB, enhance the accumulation of drugs at the tumor site, and improve the killing of tumor cells (Liu et al. 2021). The ultra-small gadolinium (GD)-conjugated gelatin NGs effectively cross the BBB and blood–CSF and are suitable for use as MRI contrast agents. In vivo investigation revealed that prepared nanogels exhibited no toxicity and effective relativity as MRI contrast agents (Kimura et al. 2021).

3.3.3

Nanomicelles

Micelles are amphiphilic molecules encompassing the tail with hydrophobic and the head with hydrophilic properties. Typically, micelles range between 5 and 25 nm in diameter. Micelles are effective drug carriers for targeted brain delivery because of their small diameters and capacity to solubilize drugs in their cores. Wear et al. revealed that nanomicellar (Ubisol-Q10) with the water-dispersible formulation of coenzyme-Q10 showed significant neuroprotection in in vitro and in vivo models of ADs against neurotoxin (Wear et al. 2021). Drug transport across the BBB was considerably improved by pluronic micelles. The Pluronic P85 enhanced the micellar permeability through the BBB, demonstrated by employing the bovine brain microvessel endothelial cell monolayer model. The research revealed a 19-fold increase in the drug’s permeability (Batrakova et al. 2003). By controlling the autophagy pathway, PEG-ceramide nanomicelles increased the autophagic flux and reduced overexpressed human tau proteins in N2a cells. PEG-ceramide nanomicelles have considerable promise as AD therapy agents that can activate autophagy and destroy tau proteins (Gao et al. 2020). The dual-sensitive nanomicelle system effectively delivered the 3D6 antibody fragments into the brain parenchyma of mice models of ADs to attenuate the aggregation of Aβ (Xie et al. 2020). The mixed micelles of galantamine formulated with the help of the QbD approach showed significant enhancement of cellular permeability and enhanced uptake of the drug in the brain. The results from preclinical studies of the fabricated nanocarrier systems efficaciously show the noteworthy effects of improved patient compliance, prolonged duration of action, and increased drug efficacy (Lohan et al. 2021). The curcumin-loaded nanomicelles exhibited promising results in mitigating the progression of ADs by inhibiting amyloidogenesis by using the glycation process. The nanomicelles release the curcumin in a sustained manner and prevent the development and accumulation of amyloid fibrils (Mirzaie et al. 2019). The intranasal administration of siRNA through the nanomicelle equipped with hyaluronic acid and CPP (DPC-7) prevented tumor growth and considerably enhanced the survival time and diminished the tumor volume (GL261). The developed nanomicelles could be an alternative to deliver siRNA through the intranasal route for glioma therapy (Yang et al. 2022). The glycolipid nanomicelles decorated with peptides also have the potential to deliver the drug across the BBB for glioma

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therapy (Vasudevan et al. 2019). The doxorubicin (DOX)/Borneol (BRL) nanomicelles considerably increased the DOX transport efficiency across the BBB and also showed fast deposition in the brain tissues. The DOX/BRL nanomicelles considerably attenuated the proliferation of glioblastoma cells, demonstrated by in vitro anti-proliferation assay. The developed nanomicelles strongly declined the tumor growth and also the metastasis of glioblastoma (Meng et al. 2019).

3.3.4

Exosomes

Exosomes are lipid bilayer-membraned cell-derived vesicles that are crucial for intercellular communication. Due to their capacity to alter the functions of recipient cells, stability, biocompatibility, low toxicity, and low immunogenicity, they offer unprecedented possibilities for the development of drug delivery nanoplatforms. Exosomes are able to cross the BBB, where they can then target and aggregate in specific brain regions that are relevant for pathologies. The development of new BBB-penetrating exosome-based contrast agents is essential for precise neuroimaging. Chen et al. reported through in vitro investigation that cell-derived exosomes have the potential to cross the BBB barrier under stroke-like conditions (Chen et al. 2016). The prepared exosomes augmented the cytotoxicity of antitumor drugs and fluorescent marker uptake via receptor-mediated endocytosis in cancer cells. The zebrafish images exhibited that anticancer drugs delivered by exosomes effectively crossed the BBB and reached the brain (Yang et al. 2015).

3.3.5

Carbon Dots (CDs)

A large category of CD nanomaterials includes graphene quantum dots (GQDs), polymer dots, carbon nanodots, and carbon nitride dots, among others (CNDs). CDs possess noteworthy properties including a size of less than 10 nm, excellent photoluminescence, tunable optical properties, biocompatibility, BBB penetration, and photostability, allowing them to be employed for different biomedical applications. The different types of CDs and CD ligands conjugates have the potential to penetrate the BBB effectively, which exhibit the excellent progress of CD-based drug delivery system to treat disease related to CNS (Zhang et al. 2021). Han et al. demonstrated that carbon dots (CDs) were biocompatible and permeable to BBB, inhibiting Aβ fibrillation and toxicity (Han et al. 2017b). The amphiphilic yellow emissive CDs were formulated using ultrasonication-mediated methodology along with o-phenylenediamine and citric acid. These CDs cross the BBB significantly and attenuate the β-amyloid (Aβ) and human amyloid precursor protein (APP), mainly responsible for the pathology of ADs (Zhou et al. 2019). The CDs loaded with metformin (METF) exhibited noteworthy biocompatibility against tumor and nontumor cells. Without the aid of another ligand on their surface, METF-CDs are able to cross the blood–brain barrier. METF-CDs are able to cross the cell membrane and spread throughout the entire cell, including the mitochondria

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and nucleus (Cilingir et al. 2021). The CDs conjugated with transferrin (TF) effectively delivered the anticancer drug DOX to pediatric brain tumor cells. The investigation exhibited that TF-DOX-CDs (10 nm) were considerably more toxic than DOX alone and diminished the viability of multiple pediatric brain tumor cell lines by 15–45% (Li et al. 2016). Lu et al. employed a one-pot hydrothermal method in the presence of polyethyleneimine (PEI) for the synthesis of nitrogenbased CDs (NCDs). They also investigated their ability to permeate the BBB using an in vitro model of rat astrocytes and microvascular endothelial cells. NCDs were translocated through the BBB in a concentration-dependent manner, demonstrated by the blue photoluminescence of NCDs under UV irradiation (Lu et al. 2016). Mintz et al. fabricated CDs by employing tryptophan (TP) as a precursor. The TP-CDs significantly crossed the BBB via LAT-1 mediated transport. The CDs show promising outcome in treating the disorders and disease of CNS (Mintz et al. 2019).

3.4

Nanocarriers in Clinical Trials

The ubiquitous properties of these nanocarriers allow the development of suitable drug carriers for drug delivery through the most complicated organ system, such as the brain. The developed nanomaterials possess the ability to efficiently move across the BBB and CSF barriers. The associated advantages include reduced therapeutic dose, increased therapeutic efficacy, decreased systemic side effects, encapsulation and delivery of hydrophobic drugs, and controlled and sustained release of therapeutic drugs at targeted sites. Various nanocarrier-based drug delivery systems are studied as a potential treatment for neurodegenerative diseases (Table 3.1). Liposomes, among other nanocarriers, hold potential as a therapeutic and diagnostic tool to treat neurodegenerative disease symptoms (Montesinos 2017). However, among several liposomal formulations in clinical trials, brain-targeting liposomal carriers in clinical practice are limited (Hernandez and Shukla 2022). Amphotericin B (AmBisome®) is an FDA-approved drug used to treat cryptococcal meningitis (Loyse et al. 2013), while in another study commenced in 2021, the safety of Talineuren as a neuroprotective agent in combination with a proprietary liposomal formulation is being assessed in phase I trial (Clinical trial, NCT04976127). Notably, liposomes as diagnostic tools have also been employed in a phase I trial to establish proof of concept and safety of ADx-001 in Alzheimer’s disease patients. ADx-001 is a novel macrocyclic gadolinium (Gd)-containing molecularly targeted liposomal preparation developed for use in contrast-enabled MR imaging of amyloid plaques (Clinical trial, NCT05453539). Nanoparticles are another theranostic approach to medicine with a principal role in overcoming challenges faced by conventionally used drugs, such as reduced plasma half-life, solubility, potential immunogenicity, and poor stability. Some of the approved strategies for treating neurodegenerative disease and related conditions include selegiline (Emsam®) for treating depression, while transdermal patches using rotigotine (Neupro®) treat the restless leg syndrome symptoms of PD (Jagaran and Singh 2022). However, in the

Parkinson disease

Exosome

Alzheimer disease

Parkinson disease-associated depression Alzheimer disease

Alzheimer disease

Neurodegenerative disease Parkinson disease

Nanoparticle

Type of nanocarrier Liposome

40–150

1–100

Size of the carrier (nm) 50–450

Exosomes derived from allogenic adipose MSCs

Exosome-proteomes as a biomarker

APH-1105

Drug/application Talineuren (GM1 (monosialotetrahexosylganglioside)) ADx-001 (DSPE-DOTA-Gd liposomal injection) Selegiline (Emsam®)

Table 3.1 Nanocarriers as a diagnostic and therapeutic agent in clinical trials for brain drug delivery Ref. Clinical trial, NCT04976127 Clinical trial, NCT05453539 Jagaran and Singh (2022) Clinical trial, NCT03806478 Clinical trial, NCT01860118 Clinical trial, NCT04388982

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latest search of the last 10 years of the NIH library for clinical trials, it was revealed that the potential of NPs is yet to be exploited as therapeutic nanocarriers. A phase 2 study analyzing the potential of NP was commenced in 2019 and is scheduled to be completed in 2024. The study focuses on assessing the efficacy, safety, and tolerability of APH-1105 via the intranasal route for the treatment of AD (Clinical trial, NCT03806478). However, some studies using lipid nanoparticles in transthyretinmediated amyloidosis patients (Clinical trial, NCT01960348) and gold nanocrystals in PD patients have been completed (Clinical trial, NCT03815916). Similarly, the use of nanomaterial-based sensors as a diagnostic biomarker of PD from exhaled breath may help in the diagnosis and differentiation of diseased and healthy individuals (Clinical trial, NCT01246336). The results are awaited and could provide novel insights for nanoparticle-based therapeutic and diagnostic nanocarriers. The application of nanoparticles needs to be further investigated to explore their potential in the formulation of novel targeted delivery systems for neurodegenerative diseases. Exosomes are efficient intercellular transporting lipid nanovesicles capable of offering novel drug delivery of molecules like miRNA and mRNA to cells. Exosomes with such inherent ability act as therapeutic agents for pathological conditions like cancer, neurodegenerative diseases, and cardiovascular disease, as well as in prognosis and diagnosis (Bhatti et al. 2019). In recent years, two types of exosomes were explored in clinical trials, specifically, exosomes of plants and human cell samples. Given that exosomes delivered intravenously can cross the BBB, a study was initiated in 2019 and is scheduled to be completed in 2024. The study was designed to evaluate the efficacy and safety of exosomes in patients with anxiety, depression, and neurodegenerative dementia (Clinical trial, NCT04202770). In another study conducted by Rujin Hospital, a phase I/II clinical trial was initiated to explore the efficacy and safety of exosomes derived from allogeneic adipose tissue-derived-mesenchymal stem cells (MSCs) for the treatment of dementia due to AD. They strategized to administer exosomes at three varied dose levels biweekly for 12 weeks (Clinical trial, NCT04388982). Furthermore, a study by the University of Alabama at Birmingham determined whether exosomeproteomes derived from Parkinson’s disease patients can be considered as a biomarker (Clinical trial, NCT01860118). The application of such nanocarriers proliferates for therapeutic and diagnostic purposes, following their development as imperative players in pathology and physiology. Numerous strategies to optimize and validate the therapeutic potential of exosomes are being explored. In addition, improved scaling-up strategies and regulatory frameworks are emerging in order to allow safe clinical trials and overcome manufacturing processes. Hence, while in its infancy stage, the development of exosomes is evolving frequently for the benefit of patients.

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Potential Risk of Nanocarriers

The nervous system possesses the ability to protect itself from xenobiotics (foreign bodies, toxins, and pathogens) through strict barriers, viz. BBB and CSF barrier. Nanocarriers can successfully circumvent these barriers and efficiently deliver drugs in a nonuniform manner to the brain parenchyma. However, this delivery might result in overexposure to these nanocarriers, allowing nanocarriers for CNS therapy to be regarded as a dual-edged sword. Thus, it’s imperative to determine systemically the toxicity of administered nanocarriers, which is again a challenge for the clinical translation of nanocarrier systems (Lee et al. 2021; Hersh et al. 2022; Zhang et al. 2022). Nanomaterials can also allow changes in the route of drug administration, from the oral to the parenteral route, which is not a common route. In general, nanoformulations exist in parenteral form, while general pharmaceutical preparations are given in oral dosage forms. Moreover, oral dosages are easier to use and more acceptable than injectables in patients with neurodegenerative diseases (Niu et al. 2019). Neurotoxicity caused by nanocarriers can also be associated with inflammatory mechanisms. For instance, exposure of nanogels to the brain stimulates glial cells, leading to a strong inflammatory response of vital organelles (Trompetero et al. 2018). In addition, exposure to nanomaterial may also induce neurodegenerative disorders characterized by the accumulation of misfolded amyloid proteins and fibrin aggregates. Plausible interaction between nanocarriers and the brain may exacerbate these pathological mechanisms of neurodegenerative diseases. Furthermore, the physical properties, such as composition, charge, and size of nanocarriers, all affect blood circulation time and must be investigated peculiarly. Nanocarriers exist as a potential means of ameliorating uptake of the drug across the barriers, allowing for the development of promising therapeutic and diagnostic tools in neuronal cancers (Hersh et al. 2022; Zhang et al. 2022). However, still observed failures are testaments of the challenges that exist with the advancement in the development of an effective drug delivery system targeting the brain. Current data on nanocarrier-associated neurotoxicity suggests that intensive in vivo, in vitro, and clinical toxicity studies are required before translating them onto a clinical platform. Emphasized in-depth toxicity study of nanocarrier is crucial to provide detailed insight into risks associated with these promising drug delivery systems.

3.6

Future Perspectives and Conclusions

Nanocarriers have emerged as a promising opportunity for the treatment of neurological diseases. Nanocarriers such as exosomes, carbon dots, nano micelles, nanoparticles, and liposomes were modified in the brain surface in order to overcome the barriers and enhance brain targeting activity. However, several issues need to be resolved before bringing a nanomedicine used to treat neurodegenerative diseases into the clinical setting. The first obstacle is the low targeting efficiency, which interferes with the beneficial effect and causes impairment to other organs. Despite

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much research on drug delivery systems, drugs, or macromolecular drugs, a very low transition rate of these studies into clinical trials is recorded and one main reason is barriers. Transient disruption of barriers, modification of drug delivery systems, and their combination are the main approaches to overcome this problem; for example, modified nanoparticles combined with FUS are given in Alzheimer’s disease to transiently disrupt BBB. Recently, FUS as a tool has been keenly explored to increase the transportation of nanomaterials through barriers with minor or without side effects. Thus, in the near future, FUS technology can be inexpensive and more reachable since it has the potential and scope to overcome barriers. Second, to achieve accurate targeting in the brain, the distribution and specific targeting in the brain deserve attention. Even after many years of research in this field, researchers have poorly acquired quantitative and qualitative data supporting relative doses delivered in brain parenchyma. More oriented and mechanistic studies focusing on the amount of drug distributed and intracellular mechanisms involved after the uptake of nanocarriers in endothelial cells should be performed. Third, the nanocarrier-induced long-term neurotoxicity should never be overlooked. Fourth, the influence of characterization and physical parameters like zeta potential, charge, shape, size, and particle dispersity index influencing brain targeting system must be fully understood. Thus, the development of efficient nanocarrier-based formulations overcoming barriers can be a promising breakthrough in the near future for the treatment of neurodegenerative disease and other related disorders.

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Part II Pathophysiology and Management of Neurological Disorders

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Pathophysiology and Management Approaches in Alzheimer’s Disease Shreshta Jain, Divya Goel, Sheikh Sana Nazir, Vaishali Yadav, and Divya Vohora

Abstract

Alzheimer’s disease is recognized as a progressive multifarious neurodegenerative disorder that is pathologically characterized by the deposition of amyloid-β plaques and neurofibrillary tangles of pathologic tau. Over the years, researchers have made advances in investigating the pathophysiology of Alzheimer’s disease progression and identifying novel therapeutic targets. Currently, available therapeutic armory is, however, restricted in terms of single target approach and deceleration of disease progression while mostly providing symptomatic relief only. The present-day treatment is based on various hypotheses governing the pathogenesis, such as amyloid deposition, tau phosphorylation, cholinergic dysregulation, mitochondrial dysfunction, oxidative stress, and neuroinflammation. The current surge in the incidence of people with Alzheimer’s disease (PwAD) coerces the investigators to define the intricacies of the mechanism to facilitate the development of innovative strategies to tackle the progression of this disease. This chapter is orchestrated to elucidate the different aspects of the neuropathophysiological mechanisms underlying the development of Alzheimer’s disease and its management, exercising the conventional as well as contemporary therapeutic strategies. Keywords

Alzheimer’s disease · Amyloidosis · Tau phosphorylation · Neuroinflammation · Acetylcholinesterase inhibitors · Mitochondrial dysfunction

S. Jain · D. Goel · S. S. Nazir · V. Yadav · D. Vohora (✉) Department of Pharmacology, School of Pharmaceutical Education and Research, Jamia Hamdard, New Delhi, India e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Mishra, H. Kulhari (eds.), Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities, https://doi.org/10.1007/978-981-99-6807-7_4

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Introduction

In 1907, the German physician Dr. Alois Alzheimer was the first one ever to describe an unusual mental illness that was associated with profound memory loss and microscopic brain changes—a disease that is now known as Alzheimer’s (Stelzmann et al. 1995). Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases and is the most common cause for dementia, which accounts for more than 80% of dementia cases worldwide in elderly people. It leads to the progressive loss of mental, behavioral, and functional decline and ability to learn (Jack Jr. et al. 2018). The number of Alzheimer’s disease cases in Americans of age 65 or older may rise from estimated 6.5 million in 2021 to 12.7 million by 2050, according to Alzheimer’s association report 2022. From the estimated 6.5 million cases that have been reported, 4 million are observed to be female and 2.5 million are male. Alzheimer’s disease had been listed as the sixth leading cause of death in United States in 2019 before COVID-19 entered in the list of leading causes of deaths as the third in the United States, thereby rendering it the seventh leading cause in 2021, according to the latest data provided by Alzheimer’s association (2022 Alzheimer’s disease facts and figures 2022). According to the data provided by the Centre for disease control and prevention (CDC), an estimated 121,499 people died of AD in the year 2019 (U.S. Department of Health and Human Services, Centers for Disease Control and Prevention 1999–2019). Since the discovery of Alzheimer’s disease, several neuropathologists have tried to identify the pathophysiology of the disease. The most common diagnosis has been the incidence of extracellular senile plaques of insoluble β-amyloid peptide (Aβ) and neurofibrillary tangles composed of phosphorylated tau protein (P-tau) in the autopsied brains of people with AD (Kang et al. 2017). Amyloid plaques are extracellular deposits of amyloid beta protein (Aβ) in the brain parenchyma and in the cerebral blood vessels and are known as cerebral amyloid angiopathy (CAA). Subsequently, NFTs are composed of largely paired helical filaments with hyperphosphorylated tau proteins and neuronal and synaptic loss (Anand et al. 2014). The US Food and Drug Administration (FDA) has approved six drugs for the treatment of Alzheimer’s disease, including the five drugs that are used to treat the cognitive manifestations of AD: rivastigmine, galantamine, tacrine, donepezil, and memantine. Except memantine, which acts as an antagonist on the NMDA receptor, the other mentioned drugs inhibit the neurotransmitter acetyl cholinesterase; however, the approved drugs only provide temporary symptom relief and do not provide any changes in the brain physiology of persons with AD (Alzheimer’s and Dementia 2017). The sixth drug is known as the aducanumab, which was approved by US FDA in 2021, and is the first drug that acts on the pathophysiology of Alzheimer’s disease (Padda and Parmar 2022). Aducanumab is a human monoclonal antibody directed against the amyloid β proteins and was tested to be found promising in clinical trials in the subset of subjects with mild cognitive impairment or mild dementia stage of AD (Walsh et al. 2021). However, the safety and efficacy of the

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drug remain a controversial topic as aducanumab has also been associated with a risk of a severe condition known as amyloid-related imaging abnormalities (ARIA) that can be identified by swelling of brain tissue (Salloway et al. 2022). Hence, there lies a strong need for further research in the management of Alzheimer’s disease that can only be achieved by an advanced understanding of the pathophysiology behind the disease. In this chapter, we have presented the various hypotheses related to the biophysical mechanism that leads to the progression of Alzheimer’s disease and review all the therapeutic treatments that are available for the prevention of the development of Alzheimer’s disease by targeting each pathological pathway.

4.2

Pathophysiology of Alzheimer’s Disease

4.2.1

Ab in Alzheimer’s Disease

β-amyloid (Aβ) is a pathogenetic peptide, and associated neurotoxicity in the hallmark of Alzheimer’s disease (AD) results in memory impairment and cognitive dysfunction (O’Brien and Wong 2011). The type I transmembrane amyloid precursor protein (APP), an integral protein found on the plasma membrane, is cleaved by a protease to produce β-amyloid protein, which is the main component of AD-associated amyloid plaques. Alternative transcriptional splicing of APP can result in anywhere between 8 and 11 APP isoforms, and the three most common splice isoforms are the 695 amino acid form (APP695), which is primarily expressed in neurons, and the 751 and 770 amino acid forms (APP751, APP770), which are both expressed in neurons and glial cells (Tiantian Guo et al. 2020; Matsui et al. 2007). Numerous physiological functions for APP have been proposed; for example, cell-to-cell adhesion is mediated by the extracellular domain of the APP and supports synaptic connections. By activating calcium channels, APP homodimers may serve as cell-surface G-protein coupled receptors that bind Aβ and influence neuronal signaling and neurotransmitter release (Guo et al. 2020; O’Brien and Wong 2011). The enzymes α-secretase (ADAM9, 10 and 17), β-secretase (BACE1), and γ-secretase [presenilins (PS1 and PS2), niacstrin, PEN2, and APH1] play a major role in the processing of APP. Processing of APP can be classified as either nonamyloidogenic or amyloidogenic based on the cleavage products. In nonamyloidogenic processing, full-length APP is broken down by α-secretase, releasing the sAPP ectodomain outside the cell membrane while keeping the C-terminal fragment of APP of 83 amino acid C-terminal APP fragment (α-CTF or C83) inside the plasma membrane. The p3 fragment is released into the extracellular area when C83 is further broken down by γ-secretase, while the intracellular domain of the remaining APP is kept in the cytoplasm. sAPPα has been shown to be neuroprotective against Aβ-induced toxicity and plays a significant role in neuronal plasticity and survival (O’Brien and Wong 2011). Furthermore, it can also regulate early developmental events in the CNS and proliferation of neural stem cells (Tiwari et al. 2019). On the other hand, APP is cleaved sequentially by β-secretase and the γ-secretase complex in the amyloidogenic pathway. The sAPPβ ectodomain is

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released after β-cleavage, and a 99 amino acid APP carboxy-terminal fragment (β-CTF or C99) can be further cleaved by γ-secretase at several sites to produce amyloid peptides such as A37, 38, 39, 40, 42, and 43. Amyloid peptides with chain lengths of 40 and 42 amino acids are the main species having a high tendency to form aggregates due to hydrophobicity within their two terminal residues. In addition, the N-terminal fragment of APP resulting from sAPPβ can promote axonal pruning and neuronal cell death by binding to the death receptor 6. Indeed, Aβ42 has been found to be neurotoxic and is the primary component of amyloid plaques (Tiwari et al. 2019). The assembly of Aβ aggregates from Aβ monomers into a range of unstable oligomeric forms, which then continues to aggregate to form small, flexible, and irregular protofibrils. The protofibrils lengthen into insoluble fibrillar assemblies made up of β-strand repetitions positioned perpendicular to the fiber axis (Aleksis et al. 2017). Oligomerized Aβ diffuses into synaptic clefts and interferes with synaptic signaling. Ion channel blockade, altered calcium homeostasis, increased mitochondrial oxidative stress, impaired energy metabolism, and impaired glucose regulation are all consequences of Aβ40/Aβ42 aggregation, which ultimately leads to neuronal cell death (Masters et al. 2015). All of these effects deteriorate the health of neurons. Along with the classical APP processing pathways, other types of APP cleavage may exist. Recent studies demonstrated APP cleavage by potential membrane-bound matrix-metalloproteinase η-secretase, such as MT5-MMP, which colocalizes with amyloid plaques in AD brain (Dzwonek et al. 2004). Cleavage of APP by η-secretase releases a soluble APPη ectodomain and retains a membrane-bound η-CTF product (Willem et al. 2015).

4.2.2

Cholinergic Dysregulation

One of the key characteristics of AD is the loss of cholinergic neurons. The cerebral cortex, hippocampus, and amygdala receive their cholinergic innervations mainly from cholinergic neurons, which are believed to be important in cognition and attention (Hampel et al. 2018). These are the main areas affected in the brain of AD. The hypothesis of cholinergic dysregulation is based on three major studies: the identification of decreased presynaptic cholinergic markers in the cerebral cortex, finding that Alzheimer’s disease causes extensive neurodegeneration of cortical cholinergic innervation that originates in the nucleus basalis of Meynert (NBM) in the basal forebrain (Mesulam 1976; Whitehouse et al. 1981); and studies showing that cholinergic antagonists impair memory whereas cholinergic agonists have the opposite effect. Cholinergic dysfunction is characterized by a decrease in acetylcholine (Ach) synthesis as a result of decreased choline acetyltransferase (ChAT) and choline uptake, cholinergic neuronal and axonal abnormalities, and cholinergic neuron degeneration (Hampel et al. 2018). As a result, the cholinergic hypothesis proposes that ACh-containing neuron dysfunction contributes significantly to the cognitive and behavioral deficits observed in AD patients, prompting the development of treatment strategies aimed at restoring cholinergic function via the use of acetylcholinesterase inhibitors and cholinergic muscarinic receptor agonists.

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Previous postmortem investigations have indicated that neurofibrillary tangles in the NBM are related and likely induce loss of cortical cholinergic innervation. According to animal studies, cholinergic depletion facilitates β amyloid-deposition and tau pathology in ways that contribute to cognitive impairment. Also, stimulation of cholinergic receptors with either muscarinic agonists or cholinesterase inhibitor therapy shifted the processing of APP toward nonamiloidogenic pathways (Hampel et al. 2018). Another mouse model with AD, APP SweDI, which overexpresses APP with Swedish K670N/M671L, Dutch E693Q and Iowa D694N mutations, has been used to study cholinergic dysfunction. It was discovered that the transgenic mouse model had significantly less cholinergic neurons than the wild-type mice. This was demonstrated by immunohistochemistry against ChAT and p75NTR as well as by in situ hybridization. Furthermore, transgenic mice had much less cortical cholinergic fibers than wild-type animals. Swollen cholinergic varicosities were observed in the cerebral cortex of APP SweDI mice around Ab plaques (Foidl et al. 2016).

4.2.3

Metal Ion Toxicity

The accumulation of metal ions such as copper, iron, and zinc beyond levels seen in normal brains is shown by postmortem examination in AD patients, suggesting a direct relationship between AD and dysregulation of redox metals (Liu et al. 2019). Additionally, these metals are crucial for the metabolism and aggregation of tau and Aβ. Therefore, targeting metal interactions with Aβ may be beneficial in preventing AD, according to studies. Upregulation of CUTA (the mammalian CutA divalent cation tolerance homolog of Escherichia coli), a BACE1 trafficking regulator, alters Aβ production without changing APP expression, while copper overload enhances APP expression and Aβ formation (Huat et al. 2019; Lin et al. 2017). Cu2+ chelators can cure episodic memory impairment in nontransgenic AD mice by preventing ROS generation induced by Cu-Aβ (Liu et al. 2019). In vitro hyperphosphorylated tau aggregation has been linked to a lack of magnesium. Furthermore, magnesium-lthreonate supplements lower levels of enzyme β-secretase (BACE1), which lowers levels of free APP and C-terminal fragments of APP and lowers synaptic loss and cognitive decline related to AD. Magnesium sulfate treatment lowers hyperphosphorylated tau levels by decreasing glycogen synthase kinase 3 (GSK3) levels and inhibiting its phosphorylation, while increasing phosphatidylinositol three kinase (PI3K) and protein kinase B (PKB) activity (Islam et al. 2022). Through interactions with iron-dependent oxidases such as lipoxygenase, iron can alter lipid peroxidation, promoting ferroptosis and accelerating AD development (Takano et al. 2007). Aluminum has also been found to accumulate with Aβ peptide in the brains of patients with dialysis-associated encephalopathy (Ogunlade et al. 2022). Of note, the higher concentrations of zinc released into the synaptic cleft can produce neurotoxicity via inhibition of NMDAR and AMPAR (Watt et al. 2011). Furthermore, lead has been associated with several signs of AD, including Aβ accumulation, tau pathology, and inflammation. Early exposure to lead generated an addiction-like illness in young rats, increasing APP and BACE1 expression and promoting Aβ

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accumulation and plaque formation in the hippocampus and cortex, respectively. Its exposure also leads to enhanced microglial activation and deprived long-term potentiation (Islam et al. 2022). Together, re-establishing the appropriate metal ion balance in the brain may improve AD.

4.2.4

Neuroinflammation

There is mounting evidence that the development of AD interacts extensively with immunological processes in the brain and extends beyond the neuronal compartment. Instead of being only a passenger activated by developing senile plaques and neurofibrillar tangles, neuroinflammation plays an equal or greater role in the pathogenesis of AD (Heneka et al. 2015; Leng and Edison 2021). In addition to being able to directly activate the classical complement pathway in vitro, b-pleated aggregates, fibrillar Ab, and NFTs may also indirectly induce the formation of reactive oxygen species (ROS). Microglia and astrocytes, two of the brain’s main glial cell types, proliferate and become activated when AD takes the form of gliosis and neuroinflammation. They are the main source of cytokines in AD. It is assumed that the ability of microglia to attach to soluble amyloid (Aβ) oligomers and fibrils in AD is a result of receptors such as class A scavenger receptor A1, CD36, CD14, 6β1 integrin, CD47, and toll-like receptors (TLR2, TLR4, TLR6, and TLR9). Additionally, TNF-, IL-6, IL-1, and granulocyte macrophage-colony stimulating factor (M-CSF) are among the pro-inflammatory cytokines that are found in greater amounts in aged TgAPPsw and PSAPP transgenic mice (GM-CSF). After stimulation with Aβ, active microglia release IL-1 in vitro. Inhibition of long-term potentiation (LTP) of synaptic transmission provides evidence that IL-1β, TNF-α, and other cytokines may damage neuronal function even before causing structural alterations (Guo et al. 2020; Heneka et al. 2015; Leng and Edison 2021). Multiple interactions, increased expression of various cytokines/chemokines, and innate immune receptors all contribute to AD’s propensity for an M1-like activation state. A crucial enzyme in the synthesis of neurons Ab, b-secretase mRNA protein and enzymatic activity (BACE1), can also be upregulated by cytokines (Sastre et al. 2006). In contrast, activating a few pro-inflammatory signaling pathways appears to be a successful strategy in AD mouse models. AAV-mediated production of IFN-γ in the brains of the TgCRND8 mouse model exhibited the potential of this pro-inflammatory cytokine to accelerate clearance of amyloid plaques, as well as a general rise in astrogliosis and microgliosis (Heneka et al. 2015).

4.2.5

Tau Hyperphosphorylation

Aggregation of hyperphosphorylated or abnormally phosphorylated tau protein into intraneuronal neurofibrillary tangles (NFTs) is one of the major hallmarks of AD. The NFTs were first described by Alois Alzheimer, who discovered the accumulation of argyrophilic material in the soma of the neurons after the

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Bielschowsky silver stain (Perl 2000). Both amyloid plaques, particularly cored neuritic plaques, and neurofibrillary tangles made of filamentous tau proteins are necessary for a neuropathologic diagnosis of AD. Evidence further suggests that the latter lesions, rather than amyloid deposits, correlate more strongly with cognitive decline. Tau is a microtubule-associated protein (MAP), which is frequently present in the cytosol and axons of neurons (Tong Guo et al. 2017; Tiwari et al. 2019). The classically described function of tau is, as a neuronal microtubule-associated protein, mainly found in axons. Recent studies further confirm the additional role of tau; for example, through stabilizing ß-catenin, tau phosphorylation allows neurons to evade an abrupt apoptotic death. Besides, by regulating the anterograde transport by kinesin and the retrograde transport driven by dynein, tau also plays a crucial part in maintaining the equilibrium of microtubule-dependent axonal transport of organelles and biomolecules (Muralidar et al. 2020). Under physiological conditions, tau exists as a highly soluble and natively unfolded protein that interacts with tubulin and promotes its assembly into microtubules, which helps stabilize their structure. The most prevalent clinical signs of many neurodegenerative illnesses are abnormal protein buildup and aggregation around neurons. In such a situation, tau proteins’ ability to form intraneuronal filaments is thought to be a key factor in a variety of neurodegenerative disorders. Furthermore, this accumulation or deposition of tau filaments within neurons was not only discovered in AD but also found in other neurodegenerative diseases, which are collectively termed tauopathies (DeTure and Dickson 2019; Duyckaerts et al. 2009; Kolarova et al. 2012). This microtubule-associated protein undergoes hyperphosphorylation, which leads to NFTs. In the cell cytoplasm of neurons as well as in their processes, NFTs are pieces of paired and helically wound protein filaments (Ashrafian et al. 2021). The tau protein has a microtubule-binding domain and co-assembles with tubulin to form matured and stable microtubules. It has the capacity to stabilize microtubules and create connecting bridges between adjacent microtubules in order to properly assemble and maintain a stable network of microtubules. Due to the excess of amyloid beta in the environment, kinases are produced, which interact with the tau protein and cause its hyperphosphorylation. Tau becomes oligomerized as a result of its hyperphosphorylation. The tubule gets unstable due to the dissociation of tubule subunits, which fall apart and then convert into big chunks of tau filaments, which further aggregate into NFTs (Otero-Garcia et al. 2022). These NFTs are liner, fibrillary, and highly insoluble patches in the neuronal cytoplasm and processes, leading to abnormal loss of communication between neurons and signal processing and finally apoptosis in neurons (Chong et al. 2018; Muralidar et al. 2020; Wegmann et al. 2021). Studies suggest that tau phosphorylation is also regulated by several kinases, including glycogen synthase kinase 3 (GSK3β) and cyclin-dependent kinase 5 (CDK5), like protein kinase C, protein kinase A, ERK2, a serine/threonine kinase, caspase 3, and caspase 9, which may be activated by amyloid beta (Plattner et al. 2006). Numerous studies link the deposition of neurofibrillary tangles as opposed to amyloid beta to the severity of AD. However, the presence of tau and amyloid beta in

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most AD brains indicates a pathogenic relationship between these two proteins (Blennow et al. 2001). A transgenic mouse model, in which animals are engineered to express mutant tau and APP, lends credence to this theory. The limbic cortex of these mice exhibits significantly more neurofibrillary tangle disease, which suggests a synergistic neurodegenerative effect between these two proteins (O’Neill et al. 2001).

4.2.6

Oxidative Stress

The brain is predominantly susceptible to oxidative damage due to the high consumption of inspired oxygen, the high concentration of readily oxidizable polyunsaturated fatty acids, the quantity of redox-active transition metal ions, and the relative paucity of antioxidant defense mechanisms make the brain particularly vulnerable to oxidative injury (Praticò and Delanty 2000). Numerous processes, including enzymatic, mitochondrial, and redox metal ion-derived sources, result in the production of free radicals. The brains of patients with AD present a significant extent of oxidative damage associated with the abnormal marked accumulation of Aβ and the deposition of neurofibrillary tangles (Moreira et al. 2005). The intricate balancing act between the rate of ROS (reactive oxygen species) formation and the pace of their clearance by antioxidants and associated enzymes preserves their levels relatively low under normal circumstances. As a result, either increased ROS generation or a compromised antioxidant system will push the cellular redox balance toward oxidative imbalance and result in excessive ROS production. Since ROS are typically unstable and highly reactive and have a very short half-life, it is challenging to directly quantify them. Oxidized biomolecule products generated by ROS are much more stable and commonly used as ROS markers (Christen 2000; Markesbery 1997). Furthermore, by monitoring antioxidant levels or antioxidant enzyme activity, ROS can also be indirectly measured. Studies have provided evidence that lipid peroxidation products (such as 4-hydroxynonal, malondialdehyde, acrolein), oxidative modification of proteins (such as protein carbonyls and 3-nitrotyrosine), and oxidative DNA/RNA (8-hydroxydeoxyguanosine) are major oxidative products, which are significantly increased in AD (Wang et al. 2014). The reactive products are generated either from direct ROS attack through a free radical chain reaction to lipids or from the reaction with glycation, glycoxidation, and lipid peroxidation product binding. Levels of these products are evidently raised in various regions of brains (hippocampus, cortex, cerebellum) and biological fluids (cerebrospinal fluid, urine, and plasma) of AD patients (Agostinho et al. 2010). Furthermore, genetic factors have also been proposed to understand the role of oxidative stress in AD. According to some researchers, increased presenilin 2 expression causes apoptotic alterations and DNA fragmentation, both of which are significant impacts of oxidative damage. Apolipoprotein E protein has been found to confer increased susceptibility when the ApoE4 allele is present. ApoE has been shown to be adducted with the highly reactive lipid peroxidation product, hydroxynonenal, in

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AD brains and cerebrospinal fluid. Moreover, ApoE is a strong chelator of copper and iron, which are significant redox-active transition metals (Cioffi et al. 2019). Thus, excessive ROS generation that causes oxidative stress has a negative effect and is a key mediator of cell structure destruction, which in turn leads to aggravation of disease state and aging.

4.2.7

Mitochondrial Dysfunction

Many theories have been put out to account for the origins of AD. One of the most highly contested theories at the moment links oxidative stress and mitochondrial dysfunction to the earliest stages of AD development as well as possible therapeutic research. There is mounting evidence that aging and age-related neurodegenerative diseases are accompanied by mitochondrial malfunction. Defects in mitochondrial function have been linked to the onset of AD in numerous studies (Mancuso et al. 2009). In the brains, fibroblasts, and blood cells of AD patients as well as in AD transgenic animal models and cell lines expressing mutant amyloid precursor protein (APP) or treated with amyloid beta, mitochondrial dysfunction has been documented. At all stages of the illness, mitochondrial dysfunction exists and gets worse as AD develops. Additionally, it is not only found in the brain, which raises the possibility that AD is a systemic condition (Swerdlow 2020). A number of mitochondrial processes have been linked to AD. Reduced glucose metabolism, mitochondrial enzymatic dysfunction, and increased ROS generation are a few of them (before amyloid beta and tau tangles have begun forming) (Reddy and Beal 2005). Early-stage AD also exhibits dysfunction in a number of aspects of mitochondrial dynamics, including a disturbance in the equilibrium between mitochondrial fusion and fission, which represents mitochondria dividing and binding with one another, a reduction in the amount of mitochondria transported along axons, a reduction in the proportion of mitochondria within a cell, and a change in size, with mitochondria in AD maintaining much shorter and wider shapes. There are also disruptions in the glycolytic processes, abnormalities in the antioxidant enzyme activity, and impairments in the enzymatic activity of the protein complexes of the ETC. Complex IV activity has also been extensively studied in relation to AD dysfunction since it is frequently shown to be deficient in the early stages of the disease (Maruszak and Żekanowski 2011; Moreira et al. 2006). Nevertheless, the mitochondrial cascade hypothesis was put up as a replacement for the amyloid cascade concept (which has been the dominant theory since 1922) by Swerdlow and Khan (2004, 2009) and Swerdlow et al. (2010). A comprehensive explanation for the clinical, biochemical, and histologic characteristics of AD is attempted by the mitochondrial cascade hypothesis (Swerdlow and Khan 2004). Numerous conceptual leaps are made by the mitochondrial cascade hypothesis. It’s assumed that brain aging and AD are caused by comparable physiological mechanisms. It asserts that since mitochondrial dysfunction in AD affects the entire body, it cannot be the result of neurodegeneration alone. The non-Mendelian genetic cascade hypothesis contends that nonautosomal dominant AD is caused by

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non-Mendelian genetic variables. Finally, it suggests that mitochondrial malfunction drives amyloidosis, tau phosphorylation, and cell cycle re-entry in AD brains. This theory has a lot of support as it has been shown through several in vitro, in vivo, and human studies that mitochondrial abnormalities are a prevalent pathogenic occurrence in AD (Swerdlow et al. 2010, 2014; Swerdlow and Khan 2004, 2009).

4.2.8

Miscellaneous

Epigenetic regulation: Epigenetics describes the dynamic control of different genomic functions that occur independently of DNA sequence and are mostly mediated by changes in DNA methylation and chromatin structure. The most frequently studied epigenetic mechanisms related to AD are DNA methylation and histone modification (Nikolac Perkovic et al. 2021). DNA methylation of several specific genes has been examined in some candidate gene approaches, such as APOE, brainderived neurotrophic factor (BDNF), glycogen synthase kinase 3 beta (GSK3β), triggering receptor expressed on myeloid cells 2 (TREM2), and ankyrin 1 (ANK1) gene (Chouliaras et al. 2010; Qazi et al. 2018). The research implies that no single gene can be identified as the exclusive carrier of AD disease and that the risk of AD is instead increased by a confluence of many genetic variations and nongenetic variables. Histone modifications are crucial in neuronal development, aging brain, and AD pathogenesis. It has been postulated that extensive degradation of heterochromatin in AD may facilitate tau-mediated neurodegeneration and aberrant gene expression. This loss of heterochromatin has been shown in tau transgenic Drosophila, mice, and human AD patients. Also, transgenic tau expression and heterochromatin relaxation have been linked mechanistically through oxidative stress and consequent DNA damage. Epigenetic changes are successfully detected in the CNS and CSF and on the periphery, according to the available evidence, which increases their potential as biomarkers for AD (Esposito and Sherr 2019; Fischer 2014; Wood 2018). α-Synuclein: α-Synuclein is a ubiquitous presynaptic molecule, which belongs to a synuclein protein family comprising of β- and γ-syn and is crucial to regulate vesicular synaptic release. α-Synuclein belongs to a class of so-called naturally unfolded proteins and contains a highly amyloidogenic hydrophobic domain in the N-terminus region (Bendor et al. 2013). It has been demonstrated that α-syn builds up in the limbic system in cases of AD, Down’s syndrome, and familial AD. Under pathological circumstances, amyloid beta and α-syn may directly interact, resulting in the production of toxic oligomers and nanopores that elevate intracellular calcium. Amyloid beta and α-syn interactions may also cause mitochondrial malfunction, oxidative stress, and lysosomal leakage (Twohig and Nielsen 2019). Studies have confirmed that it is prevalent in the majority of autopsied AD brains, and higher levels of α-syn are observed in the CSF of patients with mild cognitive impairment (MCI). Additionally, recent research suggests that subjects with autosomal dominant AD mutations and at risk for sporadic AD have higher amounts of α-syn in their CSF when amyloid beta plaques are accumulating asymptomatically (Hamilton 2000).

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Experimental evidence has further linked α-syn mainly to tau hyperphosphorylation, but also to the pathological actions of Aβ and the APOEε4 allele (Kim et al. 2004). Gut microbiome imbalance: The complex bacteria that live in the human gut have a direct impact on our health. Recent research has revealed that AD may be influenced by the human gut flora. It is known that symbiotic gut microbiomes regulate the host’s metabolic process, immunological response, neurological system, and endocrine function to preserve brain health. Furthermore, in the case of gut dysbiosis and barrier disruption, gut pathobionts interfere with the immunological, neural, metabolic, and endocrine systems’ ability to maintain homeostasis, which worsens brain processes and consequently encourages the onset of AD (Seo et al. 2019; Sochocka et al. 2019). The most notable changes in the gut microbiome flora seen in AD are a decrease in the enormous amount of anti-inflammatory bacterial species like Bifidobacterium breve strain A1 and an increase in the ample supply of pro-inflammatory bacterial species like Firmicutes and Bacteroidetes, which can increase inflammation levels in the plasma and ultimately in the CNS (Vogt et al. 2017). Studies support the idea that the pathophysiology of AD and gut microbiomes are closely related and that a reduction in microbial diversity can lead to a number of diseases in the brain, including inflammation, cerebrovascular disease, amyloid beta aggregation, and tau pathology (Doifode et al. 2021). Insulin resistance: A critical role of insulin resistance in Alzheimer’s disease includes beta-amyloid production and accumulation, the formation of neurofibrillary tangles, failure of synaptic transmission, and neuronal degeneration (de la Monte 2009). Amyloid beta is successively amended from APP by β-secretase and γ-secretase (which are proteolytic enzymes). Insulin resistance could control betaamyloid synthesis via improving β- and γ-secretase activity (Cai et al. 2015). Betaamyloid and tau disease are exacerbated by insulin resistance, which causes oxidative stress and inflammation in the brain. Amyloid beta depositions can improve insulin resistance through beta-amyloid-mediated inflammation and oxidative insults. Furthermore, insulin resistance could disrupt acetylcholine activity and accelerate its axon degeneration, which consequently results in cognitive impairment in AD (Gasparini et al. 2002; de la Monte 2012). Clinical and preclinical studies also revealed that the liver–brain axis, through which toxic lipids, such as ceramides, cross the blood–brain barrier and cause brain oxidative strain, insulin resistance, neuro-inflammation, and cell death, is the expected mechanism by which neurodegeneration associated with peripheral insulin resistance occurs (Watson and Craft 2003; Yan and Vassar 2014) .

4.3

Management Approaches in Alzheimer’s Disease

4.3.1

Targeting Amyloid-Beta (Ab) Protein

Amyloid beta accumulation in the brain (mainly in the hippocampus and entorhinal cortex) marks the initial event in the progression of AD. Anti-amyloid drugs that possess the potential to modify AD progression and are currently in Phase 3 trials

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Table 4.1 Immunotherapies targeting Aβ Target name Full length targeted

Drug AN1792

N-terminal targeted

Amilomotide Aducanumab

C-terminal targeted Central domain targeted N-terminal and central domain targeted

Donanemab Lecanemab ABvac40 Crenezumab Solanezumab Gantenerumab

Status Terminated/ withdrawn Terminated/ withdrawn FDA approved Phase 3 Phase 3 Phase 2 Phase 3 Phase 3 Phase 3

Sponsors Janssen/Pfizer

Immunotherapy type Active

Novartis

Active

Biogen

Passive

Eli Lilly Biogen/Eisai Araclonbiotech Roche Eli Lilly Roche

Passive Passive Active Passive Passive Passive

include anti-Aβ immunotherapies and BACE inhibitors, which trigger Aβ clearance and decrease Aβ production, respectively. Anti-amyloid beta immunotherapies: Use of immunotherapies to clear Aβ seems a rational approach for treating AD. Monoclonal antibodies (mAbs) are a part of several clinical trials that target Aβ. Therefore, active immunization with vaccines or passive immunization with specific antibodies may promote Aβ clearance and thus restrict the progression of AD. In active immunization, Aβ or its fragments are administered to induce an immune response and to produce antibodies against Aβ, whereas in passive immunization specific antibodies (monoclonal or polyclonal) that promote clearance of Aβ are administered (Song et al. 2022). Active immunotherapy is more advantageous than passive as it involves short-term drug administration with a persistent level of antibodies, but challenges in the prediction of adverse reactions add to the limitation of this therapy (Song et al. 2022). Some active immunotherapies include AN1792, which was the first clinically tested anti-Aβ vaccine, amilomotide, and UB-311. Passive immunotherapies include aducanumab, (a human IgG1monoclonal antibody that targets Aβ aggregates), donanemab, lecanemab, solanezumab, crenezumab, and gantenerumab (Song et al. 2022) (Table 4.1).

4.3.1.1 Targeting Secretase Beta-secretase (BACE) inhibitors: The first step in the generation of Aβ begins with the cleavage of APP by β-secretase (BACE-1). Several BACE inhibitors developed were withdrawn due to their toxicities, particularly in humans, and a few are in Phase 3 trials (Panza et al. 2019) (Table 4.2). Verubecestat: It is an oral BACE-1 inhibitor. In animal models of AD and Alzheimer’s disease patients, it reduced the brain concentrations of Aβ40 and Aβ42 in plasma and cerebrospinal fluid (CSF) (Kennedy et al. 2016). Lanabecestat: It is an oral, long-acting BACE-1 inhibitor with nanomolar affinity for BACE-1 (Panza et al. 2019).

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Table 4.2 Beta-secretase inhibitors Drug Verubecestat Lanabecestat Atabecestat Elenbecestat

Sponsor Merck Astra Zeneca, Eli Lilly & Co. Janssen research and development Eisai, Biogen

Status Terminated Terminated Terminated Terminated

Trial Phase 3 Phase 3 Phase 3 Phase 3

Atabecestat: It is a nonselective oral BACE-1 inhibitor (Panza et al. 2019). Elenbecestat: A BACE-1 inhibitor known to lower Aβ concentrations in the brain and CSF of rats, guinea pigs, and nonhuman primates (Panza et al. 2019). CNP520: It is an oral, long-acting, and selective BACE-1 inhibitor with good brain penetration (Panza et al. 2019). Gamma-secretase (γ) inhibitors: Inhibiting gamma-secretase may also prove a useful strategy for the treatment of AD by preventing the production of Aβ. Gammasecretase inhibitors such as semagacestat and avagacestat reduced Aβ production in transgenic mice model (Hur 2022). Alpha-secretase stimulators: Activation of alpha-secretase may cause a reduction of Aβ.

4.3.2

Targeting Tau-Hyperphosphorylation

Another indication of AD is the neurofibrillary tangles (NFTs) that are produced as a result of hyperphosphorylated tau protein. Thus, accumulation of tau may trigger neurodegenerative condition known as “tauopathy,” which is one of the consequences of Alzheimer’s disease (Das and Yan 2019). Targeting tau protein aggregation: The aggregation of tau protein and the presence of NFTs are more significantly associated with severity of symptoms and neuronal loss than the Aβ lesions (Congdon and Sigurdsson 2018). Methylthioninium chloride was found to prevent the aggregation of tau protein in vitro and in preclinical models. In addition, a double-blind clinical trial was conducted on patients with Alzheimer’s disease, and a 6-month methylthioninium monotherapy resulted in promising signs of benefit in moderate cases of the disease (Wischik et al. 2015). ACI-3024 (Tau MorphomerTM) is another small molecular inhibitor of tau aggregation that disrupts the β-sheet structure and prevents tau toxicity by reducing intracellular misfolding of tau protein (Kroth et al. 2012). In addition, other natural compounds such as curcumin, purpurin, and ginseng are also being investigated for their therapeutic potential against the development of AD (Soeda and Takashima 2020). Inhibition of post-translational tau phosphorylation: The presence of hyperphosphorylated tau protein is one of the earliest events in the progression of AD, and the degree of phosphorylation is regulated by the abnormal activity of protein kinases. One of the kinases that is targeted is the glycogen synthase kinase 3 (GSK3), one of the primary enzymes involved in tau phosphorylation (Medina and

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Avila 2014). Recently, tideglusib (NP031112, NP-12), an irreversible inhibitor of GSK3b, was invested in a clinical trial after it exhibited positive results in preclinical trials by reducing tau phosphorylation, Aβ plaque burden, memory deficits, cell death, and astrocytosis (DaRocha-Souto et al. 2012; US National Library of Medicine 2012). Another protein kinase that is gradually being studied as a potential therapeutic target is the Fyn tyrosine kinase, which is known to be involved in the phosphorylation of tau protein at the N-terminal domain and also affects the amyloid signaling pathway (Nygaard et al. 2014). Saracatinib (AZD0530) is a Fyn inhibitor that has been observed to improve memory impairment in preclinical studies and was also considered safe based on a phase I clinical trial (Nygaard et al. 2015). Targeting tau acetylation and glycosylation: Lysine residues are more highly acetylated in the brains of AD and other tauopathy patients than in healthy brains (Irwin et al. 2012). Salsalate is a salicylate derivative and is a nonsteroidal antiinflammatory drug that inhibits the acetylation of tau by blocking the activity of acetyltransferase p300 (Min et al. 2015). Furthermore, another post-translational modification is the modulation of tau phosphorylation and aggregation due to O-β-linked N-acetylglucosaminylation (O-GlcNAcylation), which is regulated by two antagonist enzymes, O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (OGA) (Cantrelle et al. 2021). Pathological increase in the level of O-GlcNAc modification by an OGA inhibitor such as LY3372689 indirectly reduces the phosphorylation level of tau protein, as well as prevents tau aggregation (Paul et al. 2019). Targeting microtubule destabilization: Microtubule stabilizers are being considered to prevent tauopathies by preventing axonal or dendritic degeneration (Khanna et al. 2016). Epothilone D is a microtubule-stabilizing compound, previously classified as an antifungal agent, which can cross the blood–brain barrier and has been reported to improve cognitive function by showing a significant increase in microtubule density (Brunden et al. 2010). Davunetide (NAP, AL-108), derived from a growth factor called activity-dependent neurotrophic protein, is a neuroprotective peptide that can modulate the pool of microtubules in neurons and glial cells (Ivashko-Pachima et al. 2017). Tau-based immunotherapy: Current therapies that target tau revolve around immunotherapy where both active and passive immunization are being designed to promote immunological clearance of tau, thereby reducing neuronal loss and ameliorating clinical symptoms (Sandusky-Beltran and Sigurdsson 2020; Soeda and Takashima 2020). Active immunization therapy includes the first anti-tau vaccine that underwent clinical trials, AADvac1, a synthetic peptide consisting of residues 294–305 derived from a fragment of a misfolded tau protein (Novak et al. 2017). The antibodies produced on the administration of the AADvac1 vaccine are capable of differentiating between pathological and physiological tau; ensuring the specificity against pathological tau protein, it significantly delays the formation of tau pathological lesions along with the decline of cognitive behavior (Kontsekova et al. 2014). Other active immunotherapies, such as the ACI-35 vaccine and intravenous immunoglobulin IVIg Flebogamma®, are also being investigated under clinical

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Table 4.3 Various passive immunotherapies under clinical trials Clinical phase Phase II

Clinical trial no. NCT03352557

Phase II

NCT03518073

Phase II

NCT02820896

IgG1

Phase I

LuAF87908

IgG1

Phase I

NCT03375697 NCT03689153 NCT04149860

Tilavonemab ABBV-8E12 Bepranemab UCB0107

IgG4

Phase II

NCT02985879

IgG4

Phase I

NCT04185415

Vaccine Gosuranemab (BIB092) Zagotenemab (LY3303560) Semorinemab (RO7105705) JNJ-63733657

Isotype IgG4 Monoclonal antimouse MC1 IgG4

Reference Qureshi et al. (2018) Luo et al. (2015) Kerchner et al. (2017) Galpern et al. (2019) Guo et al. (2022) Höglinger et al. (2021) Albert et al. (2019)

trials. In addition to this, strategies for passive immunization using various antibodies against the tau protein are also under investigation (Table 4.3).

4.3.3

Targeting Intracellular Signaling Cascades

The regulation of certain intracellular signaling pathways that are activated by the Aβ oligomers is also being targeted as a therapeutic intervention in AD. Phosphodiesterase (PDE) inhibitors have been investigated in Alzheimer’s disease as they modulate neurodegenerative conditions by regulating cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) (Tibbo et al. 2019). The selective PDE3 inhibitor cilostazol has been found to improve cognition, in particular in MCI/mild AD patients (Ihara et al. 2014). Nonselective PDE-4 inhibitors such as rolipram and roflumilast, along with selective PDE4 inhibitors like MK-0952 and BPN14770, are also being investigated in clinical trials for their potential in reducing cognitive impairment in healthy subjects and AD patients (Prickaerts et al. 2017). Clinical investigations involving a PDE9 inhibitor (BI409) are also ongoing in patients with AD (Wu et al. 2018). Even sildenafil, which is a PDE-5 inhibitor, also exhibited potential against cognitive deficit (Shim et al. 2014).

4.3.4

Targeting the Neurotransmitters

The modulation of the levels of neurotransmitters in the brain remains the only therapeutic approach approved for the management of AD. However, these

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approved drugs only provide symptomatic relief and do not act on the progression of the disease. Acetylcholinesterase inhibitors (AChEIs): The AChEIs that have been approved by the US FDA for the treatment of AD, including donepezil, rivastigmine, and galantamine (Alzheimer’s and Dementia 2017). In the past couple of years, the novel AChEI molecule memogain (GLN-1062), a pro-drug of galantamine, has been developed with enhanced efficacy and reduced adverse effects (Maelicke et al. 2010). Novel compounds such as huperzine A, a potent reversible inhibitor of AChE that is derived from a Chinese shrub and its pro-drug ZT-1, have shown admirable therapeutic potential in AD patients by regulating the metabolism of APP and protecting against Aβ-mediated oxidative stress and apoptosis (Zhang et al. 2008). Furthermore, it has also been observed that M1 agonists are more beneficial as they play a role in APP processing and also control hyperphosphorylation of tau protein (Reid et al. 2011). Some of the M1 partial agonists include AF102B, AF150(S), AF267B, and AF292. The mixed muscarinic agonist, ANAVEX 2–73, has also exhibited regression in Aβ-induced toxicity, memory deficits, and tau phosphorylation (Lahmy et al. 2013). The neuroprotective activity of cotinine, a metabolite of nicotine on α7 ACh receptors, also yielded improved memory deficits associated with AD (Echeverria and Zeitlin 2012).

4.3.4.1 Modulation of GABAergic Neurons GABA is a neuroinhibitory neurotransmitter that is said to be downregulated in the presence of Aβ that leads to diminished synaptic inhibition (Ulrich 2015). However, GABA transmission shifts from inhibitory to excitatory due to chronic nerve growth factor deprivation (Lagostena et al. 2010). SGS742 is a GABA(B) receptor antagonist that has been investigated in the treatment of patients with mild to moderate AD (Froestl et al. 2004). In another clinical trial, a GABA (A) receptor modulator, known as EHT0202 (etazolate hydrochloride), was investigated primarily for its clinical safety and tolerability (Vellas et al. 2011). NMDA receptor antagonism: Glutamatergic neurotransmission plays an important role in cognition, learning, and memory that is dysregulated in AD patients, whereby excess glutamate production leads to the activation of NMDA receptors (Revett et al. 2013). Memantine is an uncompetitive NMDA antagonist that is widely used in the treatment of patients with moderate to severe AD in the USA and Europe (Hellweg et al. 2012). Further clinical trials are being conducted with a combination of memantine with anticholinergic drugs such as donepezil for the treatment of AD (Molino et al. 2013). Another clinical investigation involving SUVN-502 with donepezil and memantine for the treatment of moderate AD is also underway (NCT02580305) (Nirogi et al. 2022).

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4.3.5

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Targeting Mitochondrial Dysfunction

Mitochondrial dysfunction due to the accumulation of Aβ occurs due to the inhibition of mitochondrial import channels followed by a decrease in the action of complex IV, thereby increasing the production of reactive oxygen species (ROS) (Misrani et al. 2021). Coenzyme Q10 is a co-factor of mitochondrial uncoupling proteins that suppresses the mitochondrial ROS production and decreases the mitochondrial transmembrane potential, thereby reducing the deposition of Aβ (Lanzillotta et al. 2019). A novel mitochondria-targeted antioxidant known as MitoQ is mitoquinone mesylate, which was found to mitigate β-amyloid (Aβ)induced neurotoxicity in preclinical models (McManus et al. 2011). The combined formulation of α-lipoic acid (LA) with vitamin E and C was found to delay cognitive decline in AD patients (Hager et al. 2010). Idebenone is an analog of ubiquinone that has shown potential to improve cognitive impairment (Gutzmann and Hadler 1998). Szeto-Schiller peptide (SS-31) is also a small molecule with antioxidant potency and has exhibited beneficial effects against the mitochondrial alterations in the pathogenesis of AD (Manczak et al. 2010).

4.3.6

Targeting Oxidative Stress

Reactive oxygen species (ROS) that occur majorly due to metal-induced oxidative stress play an important role in the pathology of Alzheimer’s disease (Butterfield and Halliwell 2019). As AD is pathogenetically multifactorial, compounds that target oxidative stress act either individually or as an active part of a multifunctional drug. Natural oxidants such as vitamin E, vitamin C, and carotenoids provide neuroprotection against AD. Antioxidants such as melatonin and coumarin reduce the level of oxidative stress via ROS-scavenging mechanisms as well as via chelation of redox-active Cu and Fe. Most of the antioxidants act as a hybrid drug in combination with a cholinergic antagonist such as vitamin E with memantine, tacrine with coumarin, tacrine with melatonin, tacrine with Trolox, and other related drugs (Simunkova et al. 2019). Trolox is a synthetic, water-soluble, and cellpermeable derivative of vitamin E (C. Guo et al. 2012).

4.3.7

Targeting Neuroinflammation

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used against neuroinflammation associated with AD, which work mainly by inhibiting cyclooxygenase (COX) enzyme activity, maintaining mitochondrial Ca2+ homeostasis, and targeting g-secretase, Rho-GTPases (guanosine triphosphate), and peroxisome proliferator-activated receptors (PPARs), all of which play a role in the pathogenesis of AD (Ali et al. 2019; Kumar et al. 2015). Certain NSAIDs, such as Sulindac, Ketorolac, Ibuprofen, and Naproxen, act as inhibitors of Aβ aggregation by inhibiting the binding affinity of Aβ fibrils (Azam et al. 2018).

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In addition to this, other anti-neuroinflammatory agents, such as AD-4833 (Pioglitazone), which acts as an insulin sensitizer for peroxisome-proliferatoractivated receptor gamma (PPARγ) agonists, are involved in the regulation of Aβ phagocytosis and decrease cytokine release, neuroinflammation, and Aβ levels (Galimberti and Scarpini 2017). Furthermore, antagonists of the receptor for advanced glycation end products (RAGE), such as azeliragon, also play a regulatory role in the transport of circulating plasma Aβ to the brain, inflammatory process, oxidation stress, and cerebral blood flow (Huang et al. 2020). Furthermore, apart from the above mentioned therapeutics, there are several other potential drug agents that are currently under clinical trials to investigate their effects for the management of Alzheimer’s disease (Table 4.4).

4.4

Conclusion

In this chapter, we discussed the pathogenesis and the progression of Alzheimer’s disease along with an insight into the management of AD with the currently available potential therapeutic targets. AD is a complex multifactorial neurodegenerative disease, and even though we have a better understanding of the pathophysiology of AD at the molecular level, there is still no permanent cure to terminate, inhibit, or even decelerate the progression of this neurodegenerative disease. Currently approved drugs include inhibitors of the cholinergic and glutamatergic transmission, which mainly provide symptomatic treatment. Other pharmacological therapeutic strategies that have been targeted and are under investigation include drugs focusing on the control of Aβ aggregation and tau hyperphosphorylation and nonpharmacological treatments such as occupational therapy or psychological help that provide symptomatic relief or for the prevention of the development of the disease. Aducanumab (Aduhelm) is the only other novel monoclonal antibody that has been approved by the FDA for people with mild symptoms of Alzheimer’s disease; however, there lies residual uncertainties regarding the clinical benefits of the drug, according to the FDA. There is still a lack of in-depth knowledge of the pathophysiological of the disease with regard to the diagnosis and therapeutic management that justifies the need to investigate further for potential biomarkers that can determine the early stages of the disease, as well as novel pharmacological and nonpharmacological treatments that would facilitate the prevention of the disease progression, thereby improving the quality of life of persons with Alzheimer’s disease.

Therapy Semaglutide

Simufilam

Seltorexant

Gantenerumab

Donanemab

Remternetug

Lecanemab

Senicapoc

Blarcamesine

Guanfacine

Metformin

Brexpiprazole

S. No. 1.

2.

3.

4.

5.

6.

7.

8.

9.

10.

11.

12.

Selective alpha-2A adrenergic receptor agonist Biguanide, anti-hyperglycemic drug Atypical anti-psychotics

Intracellular sigma 1 receptor agonist

Gardos channel blocker

Monoclonal antibody

Monoclonal antibody

Monoclonal antibody

Selective Orexin-2 receptor (OX2R) antagonist Monoclonal antibody

Small molecule drug

Category GLP-1 receptor agonist

Table 4.4 Current drugs undergoing clinical trials Status Recruiting (Phase 3) Recruiting (Phase 3) Recruiting (Phase 2) Recruiting (Phase 3) Recruiting (Phase 3) Recruiting (Phase 3) Recruiting (Phase 3) Recruiting (Phase 2) Recruiting (Phase 2) (Phase 3) Recruiting (Phase 3) Recruiting (Phase 3) Recruiting (Phase 2) Otsuka Pharmaceutical Co., Ltd.

Columbia University, NIA

Imperial College London

University of California, Davis Anavex Life Sciences Corp.

Eisai Inc.

Eli Lilly and Company

Eli Lilly and Company

Janssen Research & Development, LLC Hoffmann-La Roche

Cassava Sciences, Inc.

Sponsor Novo Nordisk A/S

January 4, 2019 March 22, 2021 August 20, 2018

March 18, 2022 October 10, 2019

February 1, 2021 August 27, 2021 August 1, 2022 July 14, 2020

November 18, 2021 May 19, 2022

Start date May 18, 2021

December 31, 2022 April 30, 2026 March 2023

July 31, 2024

April 19, 2023 December 25, 2026 November 8, 2027 March 27, 2025 October 25, 2027 June, 2025

Estimated end date April 26,2026 June,2024

Clinical trial.gov Clinical trial.gov Clinical trial.gov

Reference Clinical trial.gov Clinical trial.gov Clinical trial.gov Clinical trial.gov Clinical trial.gov Clinical trial.gov Clinical trial.gov Clinical trial.gov Clinical trial.gov

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Pathophysiology and Management Approaches for Parkinson’s Disease Khan Sabiya Samim, Padmashri Naren, Poojitha Pinjala, Sainikil Uppala, Shashi Bala Singh, and Dharmendra Kumar Khatri

Abstract

Parkinson’s disease (PD), a most common face of neurodegenerative disorders, affects the aged population worldwide. The disease affects neurological functions causing motor and nonmotor symptoms. The pathophysiology for such a debilitating disorder remains elusive due to the involvement of complex pathological cascades and proteins. The key molecular players remain to be α-synuclein (α-Syn), organelle dysfunction (mitochondria, ER, lysosomes), autophagic failure, and oxidative stress. The conventional therapy has been targeting symptomatic management by replenishing the dopamine levels, but as the pathological markers were explored, the management paradigm has now shifted toward disease-modifying agents. Even nonpharmacological interventions like deep brain stimulation, mitochondrial transplantation, stem cell therapy, etc., have now come into the picture. Besides such interventions, developing alternative drug delivery systems like the nanotechnological approach has grabbed attention in past decades to overcome the limitations of the existing conventional therapy. The major challenge in PD management still remains to be targeted therapy for treatment-resistant patients at later stages of the treatment regime. The pathological marker refinement and appropriation for selecting a best-fit treatment regime for PD patients may be a promising approach for PD management. Keywords

Parkinson’s disease · Pathophysiology · Therapeutics approaches · Pharmacological and nonpharmacological interventions K. S. Samim · P. Naren · P. Pinjala · S. Uppala · S. B. Singh · D. K. Khatri (✉) Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)- Hyderabad, Balanagar, Hyderabad, Telangana, India # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Mishra, H. Kulhari (eds.), Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities, https://doi.org/10.1007/978-981-99-6807-7_5

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Introduction

Being an extremely complex molecular-linked neurodegenerative condition, Parkinson’s disease (PD) has an archetypal characterization of dopaminergic (DA) neurodegeneration in the substantia nigra pars compacta (SNpc) accompanied by cytoplasmic inclusions of Lewy bodies (LB) (Mezey et al. 1998; Emin et al. 2022). The cardinal clinical presentations of PD encompass tremors, postural instability, bradykinesia, and rigor. However, the symptomology has been broadly classified into two categories, namely, motor and nonmotor. Anosmia, constipation, depression, and REM sleep behavior disorder are a few of the nonmotor symptoms that potentially surface years before the motor deficits during the clinical diagnosis of PD. Motor features such as slowly progressing asymmetric resting tremors, cogwheel rigidity, and bradykinesia are also evaluated while performing the clinical diagnosis of PD (Simon et al. 2020; Moriyasu et al. 2022). To date, there are no disease-modifying therapies that tone down the ongoing neurodegeneration. Most of the current therapeutic strategies only aim at alleviating the symptoms of the disease rather than altering the molecular pathogenesis. Several consistent advances in the discovery of novel or repurposed moieties, as highlighted later in this chapter, possess promising potential in altering the pathological course of the disease, which would most likely cease the sufferings of the fateful population afflicted with PD.

5.2

Epidemiology

PD is still comparatively rare, despite being the second most prevalent neurodegenerative disease after Alzheimer’s. However, the number of PD patients is anticipated to double by 2030 due to the population’s general aging. Aging incidence of PD is differently reported in different studies due to the use of variable methodologies and diagnostic criteria. The disease onset occurs mostly at the age above the 50’s and is considered a risk factor. Global PD prevalence data showed that around 9.4 million PD patients exist according to sources in 2020, where the USA ranks first in PD cases. Prevalence went up from less than 1% of men and women aged 45–54 years to 4% of men and 2% of women aged 85 or older in a meta-analysis of four North American populations (Marras et al. 2018). Incidence, prevalence, and years lived with disability were analyzed using annual percentage change and age-standardized incidence rate (ASIR) from 1990 to 2019. Males have a higher tendency to be exposed to factors like higher stress, poor lifestyle choices, and occupational links to environmental factors, increasing the tendency to have higher ASIR rates compared to females (Ou et al. 2021). Chronic and nonfatal PD is characterized by an increasing prevalence trend among the aging population. From 1990 to 2016, the ASIR of PD prevalence increased by nearly 22%. Low- and middle-income nations have a high prevalence of PD-related disabilities, but growing awareness and education about PD can improve disease management and resource access (Patel et al. 2016). The striking rise in later-life disability and related comorbidities like

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depression, anxiety, and stroke are likely related to the substantial growing trends in years lived with disability (YLD) in several high-income nations, including Norway, Canada, and Germany (Spiers et al. 2021). According to the World Health Organization (WHO) ranking, India stands at the 65 position all over the world with a prevalence rate of 4.57%. According to 2018 data, no comprehensive and extensive epidemiological data on PD are available from India. According to WHO, a population of 63,645 from rural Kashmir had a crude prevalence rate of 14.1 per 100,000. There were 247 people per 100,000 over the age of 60. In Bangalore, there was a low prevalence rate of 27/100,000, and in rural Bengal, it was 16.1/100,000. A population of 14,010 Parsis living in colonies in Mumbai, Western India, was found to have a high crude prevalence rate of 328.3/100,000 (Radhakrishnan and Goyal 2018). The data suggest that the aging population is on the rise in countries like USA and India, which complies with the projection of a doubling of PD cases by 2030 globally. To rectify such drastic surge in PD prevalence, the diagnostic and therapeutic approaches are modified as more and more research is being carried out in the pathological and therapeutic exploration of PD.

5.3

Transition of the Brain: Biology to Pathology

The brain is a complex structure of the body and also a principal biological control unit. It is a highly functional unit demanding maximum utilization of the body’s available resources, including ATP. This high demand is fulfilled by coordinating organ systems, like the cardiovascular system and digestive system, using cellular modalities like mitochondrial, endoplasmic reticulum (ER), and lysosomal functioning for vital activities like protein synthesis and ATP production. Upon homeostatic balanced state, under physiological conditions, the cellular activities are strictly regulated, but when high energy demand arises or there is an occurrence of physiologically unrectifiable imbalance, it leads to pathological conditions in the brain. Talking of the PD brain, clinical reports suggest extreme dysfunctionality of the dopaminergic neurons in the SNpc region of the brain and pyramidal neurons of the basal ganglia (DeMaagd and Philip 2015). The anatomical and pathogenic changes are elaborated below.

5.3.1

Neuroanatomical Changes in PD

Macroscopically, the idiopathic PD brain does not have any remarkable features that stand apart. Mild atrophy of the frontal cortex and ventricular dilation are a few changes that have been observed in some cases. There are no such hallmark neuroanatomical changes that universally hold true for all cases of PD, and it ideally varies with the accompanying nonmotor manifestations such as cognitive decline, depression, psychosis, hyposmia, and sleep disturbances. Advanced MRI methods such as voxel-based morphometry (VBM; measuring the volume changes in grey and white matter), diffusion tensor imaging (DTI; visualizes microstructural changes

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in white matter), and susceptibility weighted imaging (SWI; records hemorrhage, iron and calcium level alterations) are being implemented to study the structural changes. Mild cognitive impairment in PD (PD-MCI) was found to be characterized by decreased connectivity between the dorsal attention network and right anterior insula and increased connectivity between the posterior corticular area and default mode network (DMN). DTI results show degeneration of central white matter tracts in early PD and link the axonal damage as one of the reasons for cognitive dysfunction in PD-MCI (Duncan et al. 2016). PD dementia (PDD) is characterized by a bilateral decline in gray matter in the hippocampus, parahippocampal gyrus, frontal, occipital, and parietal lobes, and certain subcortical regions (Melzer et al. 2012). Widespread cortical thinning has also been reported in PDD patients (Zhu et al. 2022). Psychosis in PD patients characterized by visual hallucinations showed a marked hypoperfusion in the right fusiform gyrus (visual recognition) and hyperperfusion of the right superior and temporal gyri (generates complex visual images) (Oishi et al. 2005). PD-ICB (impulse control disorder) is characterized by precentral and superior frontal cortical thinning and motor and extramotor white matter damage (Prell 2018). Recent longitudinal diffusion tensor imaging of before and after prodromal motor PD development showed higher fractional anisotropy in the motor cortex and corticospinal tract compared to control patients (Fu et al. 2022).

5.3.2

Neuronal Circuitry Changes in PD

Defective striatal signaling in PD contributes to the malfunctioning of the tightly knit motor network, precipitating abnormal oscillatory activity and plasticity within it. There exists a rich dopaminergic projection to the M1 region via the mesocortical system arising in the ventral tegmental area and the medial substantia nigra. Human M1 contains both D1 and D2 receptors, and its plasticity is significantly altered by glutamatergic striato-thalamo-cortical pathway functioning. This pathway is compromised in PD, and exposure to dopaminergic drugs has been shown to rescue it (Prell 2018). Indulging in phases of movement or locomotion seemed to increase the functional connectivity between SNpc and regions falling in the supplementary motor area (SMA), premotor cortex (PMC), putamen, globus pallidus externa and interna (GPe, GPi), subthalamic nuclei (STN), thalamus, and brainstem. Thus, prolonged maintenance of movement requires intense dopaminergic influence when compared to resting state. Under normal physiological resting state, SNpc has a positive effect on SMA and a negative effect on M1, and during movement, it has a positive effect on both SMA and M1. However, in the case of PD, it has a negative effect on SMA in the resting state. The influence of SNpc on both SMA and M1 drastically weakens during PD. A reciprocal connectivity between the cerebellum and SNpc is observed normally, and the causal effect from SNpc to the cerebellum is decreased in PD, maybe due to the arising of abnormal signals from the BG. Weakening of cerebellar-striatal connectivity can result in the manifestation of ample clinical problems in PD.

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Neuropathology

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LB Formation and Neuronal Loss

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The transverse sections of the brain stem of PD patients show a remarkable loss or reduction in the brown pigmentation in the areas of SNpc and locus coeruleus due to the respective loss of neuromelanin-containing dopaminergic and nonadrenergic neurons. The neurodegeneration found in PD is highly specific to the set of dopaminergic neurons; namely, the A9 neurons and the other types of neuronal and glial cells are relatively spared. Apart from the SNpc, immense neuronal loss in locus coeruleus, the nucleus basalis of Meynert, the dorsal motor nucleus of the vagus nerve, the pedunculopontine nucleus, the raphe nuclei, the hypothalamus, and the olfactory bulb is also observed (Giguère et al. 2018). Studies stipulate that the nerve cell death observed in SNpc (Kordower et al. 2013) is long preceded by the loss of axon terminals projecting into the striatum. Another outstanding hallmark of PD pathology is the inclusion of aberrant cytoplasmic deposits of α-syn, called LBs in the neuronal cells. The size of an LB ranges from 5 to 30 μm in diameter, and many such intracytoplasmic inclusions can be observed inside a single neuron. Each LB has a granular or fibrillar core with a halo surrounding it. LBs are of two distinct types: classical brainstem LBs and cortical LBs. Cortical LBs are generally smaller in size and often lack the outer halo. LBs are typically made of abnormally phosphorylated and aggregated filamentous α-syn, and apart from α-syn, the halo comprises moieties such as tau, parkin, heat shock proteins (HSPs), ubiquitin, oxidized/nitrated proteinaceous species, proteasomal and lysosomal elements and cytoskeletal proteins like neurofilaments, MAPs, and tubulin (Spillantini et al. 1997; Xia et al. 2008). Lewy body pathology first manifests in the ventrolateral part of the brain and subsequently spreads to the paranigral nucleus, then later to the medial part, and finally to the dorsal part. The spatiotemporal pattern of neuronal loss observed in PD is intricately parallel to the LB deposition pattern and neuromelanin depletion (Wakabayashi et al. 2006). Braak and colleagues proposed that the spread of LB pathology in PD happens in a rostrocaudal sequence in the brain (Braak et al. 2003). In the initial Braak stages 1 and 2, LB lesions are observed at the regions of the lower brain stem, like the medulla oblongata and the anterior olfactory nucleus. Such clinical subjects are considered asymptomatic or presymptomatic and display nonmotor symptoms such as constipation and sleep-related concerns. LB sequestration in the melanincontaining dopaminergic neurons of the SNpc occurs at Braak stage 3 (Khoo et al. 2013). During the stages 3 and 4, clinical motor symptoms begin to manifest. The entire neocortex and other high-yield areas of the brain, such as prefrontal cortex and primary sensory and motor areas, begin to experience LB deposition and worsen during the further stages, 5 and 6, ultimately resulting in immense cognitive decline. The contributing pathological factors are explained further, which are reasoned for the disease’s pathological progression.

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Genetics at the Interplay

Weighing around 14.5 kDa, SNCA is a 140 amino acid long protein encoded by 5 exons. SNCA structurally contains a highly acidic C terminal domain, a NAC domain, and an N terminal domain comprising incomplete KXKEGV motifs (Hashimoto and Masliah 1999). Under normal physiological conditions, SNCA exists as a predominantly disordered monomer or in a helically folded tetramer conformation. Though the normal physiological functions of SNCA majorly remain ambiguous, well-known neuroprotective functions include the regulation of dopamine release, stabilization of microtubules by acting as a microtubule-associated protein (MAP), promoting the fibrillation of another MAP, tau, and also the regulation of caspase-3 levels by suppressing the expression of p53 (Leveille et al. 2021). Misfolded forms of the protein are rendered extremely neurotoxic and fatal, but its chaperone behavior and tetrameric conformation are hypothesized to protect against such toxic oligomeric aggregations. The evolution of the SNCA protein with respect to its sequence and structural mechanisms and implications within the sarcopterygian lineage, along with its pathogenicity, were deduced in a recent study. So far, five point mutations in SNCA are reported as one of the causative factors of autosomal dominant PD (Siddiqui et al. 2016). SNCA mutations, including missense variants and multiplications, are deemed as causes for the manifestation of PD and/or dementia with Lewy bodies (DLB). The SNCA mutation p.Ala53Thr was identified as the cause of PD in an Italian family presenting early-onset autosomal dominant disease. As of now, there are four pathogenic missense mutations classified in the Myelodysplastic syndrome (MDS) gene database: p.Ala30Pro, p. Gly51Asp, p.Ala53Glu, and p.Ala53Thr. Not so strongly PD-affiliated mutations such as SNCA p.Glu46Lys, p.His50Gln, p.Glu46Lys, p.His50Gln, and p.Ala53Val are also reported as pathogenic contributors to PD in the MDS gene database. Multiplication of SNCA is much more common than missense mutations. Duplications (three SNCA copies) are more common in familial PD than triplications (four SNCA copies) (Brás et al. 2021). Mutations of the LRRK2 gene have been long associated with PD and account for 5–13% of familial PD and 1–5% of sporadic PD. The pathogenic missense LRRK2 mutations include R1441G, R1441C, R1441H, Y1699C, G2019S, R1628P, G2385R, and I2020T located in different functional domains of LRRK2. It is hypothesized that LRRK2 facilitates the microglia-mediated neuroprotective clearance of misfolded α-syn, and its inherited mutations would alter this process leading to compromised neuronal health. Apart from this, hindered autophagy, endolysosomal signaling, and Golgi functioning have also been recorded in mutants. LRRK2 also interacts with microtubules and functions as a roadblock for motor proteins such as kinesin-1 and cytoplasmic dynein-1, which drive the transport of different organelles and proteins across the neuronal axons (Deniston et al. 2020). The development of potent, ultra-selective, and brain-penetrating LRRK2 inhibitors has continued to show promising therapeutic results in the disease-modifying aspects of PD. BIIB122 (NCT05348785), DNL 201 (NCT03710707), and

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BIIB094/Ion-849 (NCT03976349) are a few such agents currently being scrutinized in clinical trials. Mutations in DJ-1 result in autosomal recessive forms of early-onset familial PD. DJ1 has potential oxidative stress sensing property, and its overexpression blocks oxidative-damage-induced cell death in PD (Ariga et al. 2013). Mutations in the GBA1 gene (encoding for lysosomal enzyme glucocerebrosidase) have recently emerged as the most common genetic abnormality linked with PD. Heterozygous or homozygous mutations of GBA1 increase the risk of PD by 20–30 folds, and 5% of the PD patients carry a GBA1 mutation. Located on chromosome 16, the vacuolar protein sorting 35 (VPS35) gene has lately been linked with late-onset familial PD. Mutations of VPS35 have been linked with altered lysosomal autophagy as well as mitochondrial dysfunction. VPS5 D620N mutations essentially impair the activity of Wnt/β-catenin signaling pathway and cause abnormal morphology and dysfunction of the mitochondria and thereby lead to the collapse of dopaminergic neurons of the SNpc (Chiu et al. 2020). Whole exome sequencing studies have shown mutations in SYNJ1, DNAJC6, VPS13C, ATP13A2, PLA2G6, FBXO7 and PTRHD1 to cause a rarer yet severe form of PD with atypical features and a poorer response to levodopa (Lesage et al. 2021).

5.4.3

Microtubule Malfunctioning

Amid the various PD-related genes enlisted above, SNCA, PINK1, LRRK2, and DJ1 have been evidenced to bind directly or indirectly with α and β tubulin heterodimers of the microtubules and thereby modulate its stability and dynamics. Microtubules function as transporting highways in the neuronal cells and regulate the shuttling of various cargos such as organelles, vesicles, proteins, lipids, and miRNAs effectively within a neuron. The transport of organelles such as the mitochondria is integrally invaluable to the neuronal cells for their energy-dependent meticulous functioning. Microtubules are the delivery lanes for intra-mitochondrial commute, and its perishing would inevitably result in neuronal collapse. The loss of this tightly regulated intracellular cargo trafficking ultimately results in abnormal microtubule dynamics, which is implicated as a key insult in the pathogenesis of several neurodegenerative conditions, including PD (Naren et al. 2023). Microtubule dynamics are highly interdependent on microtubule-associated proteins (MAPs) such as SNCA, Tau, TPPP/p25, and their post-translational modifications (PTMs). The increased dysregulation of these very same MAPs in PD is hypothesized to be not a mere coincidence, though its cause and correlation have not been established yet (Li and Götz 2017; Lehotzky et al. 2021; Oláh et al. 2020). The successful preclinical studies of tubulin-based therapies in PD improve mitochondrial dynamics, thereby rescuing the dopaminergic neuronal health and further strengthening the possibility of microtubule malfunctioning as a key factor in PD pathology (Brunden et al. 2017; Eira et al. 2016).

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Mitochondrial Dysfunction and Oxidative Stress

Mitochondrial dysfunction has been tightly knit with neurodegeneration in PD for nearly three decades. The etiopathogenesis of sporadic PD is highly complex and is influenced by environmental and genetic factors. These factors also influence the overall mitochondrial health by interfering with its quality control, dynamics, bioenergetics, and biogenesis. Aberrant mitochondrial structural forms with malfunctioning properties have been long reported in PD patients (Henchcliffe and Beal 2008). Moreover, recent findings reveal altered specific topological patterns of mitochondria interaction networks (MINs) in the midbrain dopaminergic neurons of PD patients (Zanin et al. 2020). The manifestation of PD due to various toxins inhibiting the mitochondrial complex 1 (MPTP, Paraquat, rotenone, etc.) indicates that its dysfunction lies at the heart of PD. The phenomena of mitochondrial dysfunction and oxidative stress are complexly intertwined with each other. Striatal oxidative stress in the PD population increases and worsens with the progression in disease severity (Ikawa et al. 2011). In general, mitochondrial dysfunction is widely characterized by the generation of reactive oxygen species (ROS), complex 1 dysfunction, reduced ATP synthesis, cytochrome c release, and caspase 3 activation. Off-track functioning of the mitochondria in the nigral region would most definitely generate additional ROS, leading to the collapse in the integrity of the dopaminergic neuronal network through the activation of several signaling pathways responsible for cell death (Asemi-Rad et al. 2022). PINK1/Parkin mutation-induced impaired mitophagy also putatively remains as one of the causative factors behind PD pathology. The mutations in these genes are responsible for early-onset autosomal recessive PD phenotype. Recent data indicate the function of Parkin in mitophagy, mitochondrial biogenesis, and mtDNA maintenance pathways, thereby offering neuroprotection to the midbrain dopaminergic neurons. Several mitophagy inducers are consistently tried and tested for PD and have shown immense promising results (Asemi-Rad et al. 2022). Finally, monomeric α-syn is converted into two distinct oligomeric forms at the mitochondrial membrane and compromises the membrane integrity by interacting with membrane components and accumulating inside it, precipitating the dysfunction of complex 1 (Choi et al. 2022). α-syn oligomers interact with TOM20 and impair the mitochondrial protein import machinery, reducing respiration and ultimately leading to the excessive production of ROS (Di Maio et al. 2016; De Miranda et al. 2020).

5.4.5

ER Stress/UPR

A key cellular dysfunction linked with the pathogenesis of PD is the unfolded protein response (UPR), which transpires as a result of altered calcium levels, increased oxidative stress, accumulation of misfolded protein, and impaired protein N-glycosylation. UPR is activated by three membrane sensors: IRE1 (inositolrequiring enzyme-1), PERK (protein kinase RNA-like endoplasmic reticulum kinase), and ATF6 (activating transcription factor 6). Hoozemans et al. observed

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the fluctuated levels of these UPR modulators for the very first time in PD brains (Hoozemans et al. 2007). Conn et al. observed the accumulation of ER chaperons in LBs as well (Conn et al. 2004). UPR ultimately aims to restore the proper functioning of ER by triggering a massive transcriptional upregulation of ER chaperones for its effective quality control. IRE1, PERK, and ATF6 have the potential to sense misfolded proteins through the BiP/grp78 chaperone and abolish them. In cases where the initial response of UPR fails to promote ER homeostasis, the overwhelming pile up of misfolded proteins triggers the switch from an adaptive response toward neuronal apoptosis. Cellular apoptosis is majorly triggered by PERK- or ATF6-mediated stimulation of CHOP, a pro-apoptotic moiety. Apart from this, IRE-1 mediated activation of TRAF2 and ASK-1, which in turn activates JNK and inhibits Bcl-2, and Bcl-XL also functions as a pro-apoptotic pathway. Genetic models of PD have been ceaselessly exploring the relationship that exists between ER stress and α-syn for a long time. Pathogenic α-syn triggers ER dysfunction and subsequently ER stress-mediated cell death, both of which were rescued by L-DOPA treatment (Patel and Jimenez-Shahed 2018). Future pharmacological approaches designed for tackling ER stress would prove to be an excellent disease-modifying treatment option.

5.4.6

Neuroinflammation

Though, for a prolonged time, the concept of neuroinflammation and dopaminergic neuronal loss remained a chicken and the egg paradox, recent research findings incline toward neuroinflammation as the first manifestation before dopaminergic cell death. The innate immune system is triggered when plasticity alteration and striatal neuronal degeneration of dopaminergic neurons occur long before the death of SNpc neurons. The immune system keeps the brain health in check by regulating the activity of the microglia. Microglia activates pro-inflammatory responses upon sensing the ill health of the central nervous system, especially in neurodegenerative conditions such as PD. The microglia are chronically activated and hence produce detrimental effects that lead the neuronal cells to their demise (Sood et al. 2021). Apart from microglial activation, complement activation, T-lymphocyte infiltration, and enhanced levels of pro-inflammatory cytokines are observed in the striatum and SNpc of PD patients. Inflammatory mediators such as NO, iNOS, and COX-2 that transpire as a result of aging, pollution, oxidative stress, and infection trigger the activation of NF-κB, MAPK (mitogen-activated protein kinase), and PI3K/AKT pathways, which further induce neuroinflammation. Overwhelming evidence shows that α-syn can trigger direct microglial activation; e.g., in primary cultures, a dosedependent increase in microglial activation is observed and can increase the already existing inflammatory response (Bido et al. 2021). In a recent paraquat model of PD, microglial activation was characterized as a mixed M1/M2 population in the early stage and wide M1 polarization in the late stages (Seneff et al. 2022). Due to the enlisted extravagant findings and evidence in PD, neuroinflammation is considered a legitimate hallmark of PD.

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Autophagy Impairment

The dysregulation of autophagy remains a cardinal feature of many synucleopathies including PD. Nigral neurons of PD brains showed increased levels of the autophagosome marker LC3-II, indicating the accumulation of autophagosomal vacuoles. The clearance of α-syn occurs via macroautophagy, wherein proteins are degraded in the interior of vacuolar structures called autophagosomes upon their fusion with the lysosomes and chaperone-mediated autophagy (CMA), where chaperone proteins direct the soluble proteins to lysosomes for direct degradation. Interestingly, point mutations in the gene of the lysosomal protein ATP13A2 (PARK9) precipitate Kufor–Rakeb syndrome, a type of atypical recessive autosomal parkinsonian condition. Additionally, the mutations involved in GBA1 resulting in the dysfunction of the lysosomal-autophagy system and its strong link with PD also that autophagy plays a part in PD pathogenesis. Fluctuations in the levels of DEF8, belonging to the Rubicon family of proteins, have been shown to dysregulate autophagy in LB diseases (Tanaka et al. 2022). The end result of dysregulated autophagy is the increased active accumulation of the misfolded proteins, the genetic level inhibition of transcription and translation of encoded proteins, and the subsequent downregulation of their downstream pathway. Altered autophagy and aggravated PD pathological progression form a bidirectional pathogenic loop. PD-associated SNCA, LRRK2, PINK1, PRKN, DJ1, GBA, and VPS35 mutations also display impaired macroautophagy or CMA. Interestingly, there exists a relationship between autophagic dysfunction and synaptic homeostasis (Soukup et al. 2018). The discovery of molecules modulating autophagy in a positive as well as negative way would fetch a grounded stability that the dying neuronal cells lack and would render a ground-breaking disease-modifying approach for PD.

5.5

Symptomatic Targeting: A Conventional Approach

5.5.1

Symptomatic Dopaminergic Agents

5.5.1.1 Levodopa Though many treatment options have been developed over the past 30 years, levodopa is considered to be the most effective drug for treating the symptoms of PD. However, levodopa has many limitations that must be addressed to improve its efficacy. Although levodopa is considered the gold standard in PD treatment, it is ineffective in treating nonmotor symptoms like sleep disturbances, orthostatic hypotension, constipation, erectile dysfunction, urinary disorders, and thermoregulatory impairment (Kaufmann et al. 2004). Nocturnal treatment with levodopa may improve sleep in a few patients, but it is more probable to increase the risk of diurnal drowsiness (Arnulf et al. 2002). Long-term levodopa treatment is linked with complications like motor fluctuations and dyskinesia. Motor fluctuations occur due to the delayed onset of levodopa’s pharmacological effect or on–off mechanism between the doses characterized by painful muscle spasms and nonmotor symptoms

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like mood changes, anxiety, diaphoresis, etc. Dyskinesia is thought to occur due to excessive stimulation of the dopaminergic neurons when the dopamine levels are temporarily increased by levodopa administration (Lewitt 2008). These problems are considered to be solved by developing strategies that improve the pharmacokinetic profile of levodopa. It has been found that amantadine can be utilized to remediate levodopa-induced dyskinesia (Moriyasu et al. 2022), especially when H. pylori infection is involved in motor fluctuations (Pierantozzi et al. 2006). Various approaches are being designed to ensure a steady supply of levodopa to the striatum, which involves administering the drug through different routes: i) oncedaily oral formulation, which slows down the transit time of levodopa and increases absorption, ii) transdermal patch to deliver low concentrations of levodopa and avoid skin irritation, iii) continuous infusion by intraduodenal route to decrease off periods and dyskinesias in advanced cases of PD, iv) utilizing nasal puff/aerosol to bypass BBB and enable preferential absorption, and v) transferring dopamine-producing cells into the affected brain to improve motor fluctuations, restore DA, and increase the survival of nigrostriatal fetal cells. The main aim is to continue this quest for novel formulations that facilitate stable and controlled levodopa release and reduce side effects (Pezzoli and Zini 2010).

5.5.1.2 Dopamine Agonists (DAAs) US-FDA-approved DAAs include bromocriptine, pramipexole, ropinirole, and injectable apomorphine, of which pramipexole and ropinirole are most frequently used. Other drugs like pergolide and rotigotine were withdrawn due to an increased risk of cardiac valvopathy and drug dissolution issues in the transdermal patch, respectively (Wood 2010). DAAs are considered in managing early PD cases individually and moderate or advanced cases of PD in combination with levodopa. Also, they can delay levodopa-induced motor complications and provide symptomatic control of motor and nonmotor complications (Perez-lloret and Rascol 2010). Like any other drug, DAAs are also responsible for causing adverse drug reactions related or unrelated to dopaminergic hyperactivation and drug withdrawal. If a patient is not responding to one agonist, switching to another agonist is suggested, considering the current regimen to avoid drug interactions, concomitant medical conditions, and hepatic and renal dysfunction. Combination therapy of two agonists can be viewed as an option, though its safety and efficacy have not been established yet (Junghanns et al. 2004). Compared to levodopa, the intensity of adverse events shown by DAAs is greater; dopaminergic adverse effects include peripheral (nausea, vomiting, orthostatic hypotension, leg edema) or central (psychotic or behavioral syndromes, sedative reactions), whereas nondopaminergic complications include fibrosis, daytime somnolence, and impulse-control disorders (Perez-lloret and Rascol 2010). It is necessary to educate the patient before beginning therapy with DAAs regarding the possible side effects and discuss with the healthcare team to seek and implement strategies for their management when they occur.

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5.5.1.3 Monoamine Oxidase-B Inhibitors (MAO-BIs) MAO-BIs show neuroprotective action by reducing the oxidative stress induced by free radicals from dopamine metabolism, increasing neurotrophic factors in neurons and glia, or upregulating anti-apoptotic factors (Boll et al. 2011; Tatton et al. 2003; Wu et al. 2000). Though they are less efficient than levodopa and DAAs, clinical trials indicate that MAO-BIs are safe, well tolerated, and effective as monotherapy in early PD and used in combination with levodopa in advanced stages of PD, favoring their usage in elderly patients. They can be used to delay the need for levodopa by reducing off-time, enhancing on-time, and acting as a possible add-on to DAAs (Robakis and Fahn 2015). Apart from the already available drugs, namely selegiline and rasagiline, a newer compound named safinamide was discovered. It exhibits higher selectivity toward MAO-B than the former two compounds, and the inhibition caused is reversible due to noncovalent binding to the enzyme. It provides an additional benefit of being an anti-glutamatergic agent showing neuroprotective and neuro-rescuing properties (Dezsi and Vecsei 2017). Two potentially severe complications with high doses of MAO-BIs are the hypertensive cheese effect and serotonin syndrome. Administering MAO-BIs within recommended doses of up to 30 mg/day and 0.5–1 mg/day, respectively, for selegiline and rasagiline is an approach to avoid cheese reaction. Though restriction of tyramine consumption was considered earlier, it is no longer related to the onset of cheese reaction. When there is a loss of selectivity toward MAO-B in MAO-BIs and a serotonergic medication is concomitantly administered, it can lead to a fatal condition called a serotonin syndrome, characterized by the toxic build-up of serotonin (Robakis and Fahn 2015). It is recommended to terminate MAO-BIs if there is a necessity to use serotonergic-based anti-depressants only when the affected patient requires a dose more significant than the recommended concentration. 5.5.1.4 Catechol-O-Methyltransferase Inhibitors (COMTIs) Because of rapid changes in the levels of levodopa and dopamine-related to chronic administration of levodopa, COMTIs were implemented as an adjunctive therapy to levodopa to provide essential clinical benefits (Kurth and Adler 1998). COMTIs, including entacapone, tolcapone, and opicapone, have been developed to protect levodopa from its major peripheral metabolic pathway, COMT. Tolcapone and entacapone have been used in advanced cases of PD with chronic motor fluctuations. Tolcapone shows hepatotoxicity, while entacapone has a short plasma half-life, requiring frequent dosing with every dose of levodopa. Thus, a novel thirdgeneration COMTI termed opicapone was designed rationally to reduce the toxic effects and enhance the inhibitory capacity. It allows once-daily treatment, allowing levodopa to be administered in any desired regimen and frequency throughout the day (Jenner et al. 2021). COMTIs prolong the duration of action of levodopa compared to the levodopa–carbidopa combination and extend on time in patients with motor fluctuations. They have a faster onset of action than DAAs but are more likely to induce adverse CNS effects (psychosis, hallucinations) and orthostatic hypotension. To prevent the dopaminergic side effects, reducing the daily dosage

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of levodopa by about 25% is suggested to increase the efficiency of COMTIs (Rivest et al. 1999).

5.5.2

Symptomatic Nondopaminergic Agents

5.5.2.1 Acetylcholine (ACh)-Based Therapeutics To restore the balance between DA and ACh, which is impaired in PD pathology, anticholinergics like trihexyphenidyl, benztropine, biperiden, orphenadrine, and procyclidine are utilized to antagonize the hyperactive cholinergic system by blocking postsynaptic muscarinic receptors. As an adjunct to levodopa, they are more effective in managing the mild symptoms of tremor and rigidity without altering bradykinesia (Yuan et al. 2010). However, they display many side effects like dry mouth, blurred vision, urinary retention, and inhibition of sweating (Lieberman 3rd. 2004). Though cholinesterase inhibitors like rivastigmine and donepezil are clinically used in PD-based cognitive impairment and dementia, they show mixed reactions on motor function; it has been suggested that a combination of anticholinergics with anticholinesterases would correct the ACh deficits (Schapira et al. 2006). Nicotine was found to be neuroprotective in various PD models by acting on nicotinic receptors present in the cortex and thalamus (Costa et al. 2001; Jeyarasasingam et al. 2002). 5.5.2.2 5-HT-Based Therapeutics 5-HT receptors, especially 5-HT1A, 5-HT1B, 5-HT2A, and 5-HT2C, are important for motor functioning and are involved in levodopa-induced dyskinesia (LID). 5-HT1A agonists sarizotan (Grégoire et al. 2009) and 8-hydroxy-2-di-n-propylamino-tetralin (8-OH-DPAT) (Carta et al. 2007) significantly reduced LID in MPTP-induced parkinsonian monkeys, whereas, in clinical trials, sarizotan along with another 5-HT1A agonist, buspirone (Vegas-Suárez et al. 2020), increased the duration of action of levodopa. It was found that higher doses of sarizotan worsened PD condition, which could be possibly due to the involvement of the D2 receptor. In preclinical studies, 5-HT2A and 5-HT2C receptor antagonists, i.e., methylsergide, quetiapine, and clozapine, can reduce LID either directly or indirectly by enabling the reduction in levodopa dosage without exacerbations (Fox et al. 2011). While clozapine was effective in decreasing LID in clinical studies, quetiapine failed to show any therapeutic action on dyskinesia. Certain studies concluded that 5-HT1B agonists and partial agonists with a similar pharmacokinetics of levodopa are capable of crossing the BBB and act as an excellent novel anti-dyskinetic agent in PD (Schapira et al. 2006). The diversity of 5-HT receptors raises a question on the specificity and effectiveness of molecules targeting these receptors, but efforts are being made to develop therapeutic agents combining two or more of the specific agonist and antagonist properties. It was successful through the development of mirtazapine, a molecule with 5-HT1A agonist and 5-HT2A antagonist properties, which minimized LID in marmosets (Hamadjida et al. 2017), and MDMA (3,4-methyl enedioxy methamphetamine) or “ecstasy” lowered the dyskinesia and

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extended the duration of on time by stimulating both 5-HT1A and 5-HT1B receptors (Huot et al. 2011).

5.5.2.3 Glutamate and GABA-Based Therapeutics Since glutamate and GABA act as excitatory and inhibitory neurotransmitters in the basal ganglia, respectively, they are obvious drug targets, but targeting them is full of complications like lack of specificity due to the ubiquity of the receptors and increased possibility of altering the normal basal ganglia function. Thus, it is essential to have a detailed understanding of the site and mechanism of action of the potential drug candidates to increase the efficacy and decrease the possible side effects (Schapira et al. 2006). NMDA receptor antagonists, like remacemide, amantadine, and dextromethorphan, were found to reduce the motor disturbances related to levodopa therapy. Memantine, also an NMDA receptor antagonist but specific in nature, has low-affinity and is highly voltage-dependent, which helps in avoiding unnecessary NMDA receptor activation, thereby preventing the intense transient activation through glutamate release (Emre et al. 2010). It was used in PD-induced dementia with or without Lewy bodies to treat cognitive impairment (Emre et al. 2010). NR2D, a subtype of NMDA receptor, is found abundantly in SNpc neurons, making them an interesting target to develop lead molecules that led to the discovery of CP-101 and CP-606, which were found to provide mild synergism to the antiparkinsonian effect of levodopa in MPTP-induced PD marmosets (Nash et al. 2004). Allosteric potentiators of group III mGluRs, namely N-phenyl-7-(hydroxylimino) cyclopropa [b]chromen-1a-carboxamide(Nickols and Conn 2014), were used to reverse reserpine-induced akinesia because certain evidence stated the involvement of metabotropic glutamate (mGlu) receptors in dyskinesia by intense alteration in depotentiation. Similarly, AMPA receptor antagonists such as E-2007 (NCT00368108), GYKI-47261(Bibbiani et al. 2005), and noncompetitive inhibitor talampanel (NCT00108667) were found to be potential neuroprotective agents in PD as they displayed positive results. Though GABA is the principal inhibitory neurotransmitter in the striatum and plays an important role in voluntary movements, not many therapeutics have been developed owing to their lack of specificity in the basal ganglia (Gonzalez-Latapi et al. 2020). GABA receptor agonists are required to manage nonmotor symptoms like decreased sense of smell, depression, and various gastrointestinal and systemic features that occur due to a lack of required GABA levels (Pellicano et al. 2007). Clinical trials on Zolpidem, a GABAA receptor agonist (NCT03621046), and Zuranolone (SAGE-217), a positive allosteric modulator of GABAA receptor, were performed to test their efficacy on developing motor functions (NCT03000569), but the results remain undisclosed. In a small study, nabilone, a cannabinoid receptor agonist, showed a remarkable improvement in total rush dyskinesia rating scale (assess the severity of overall dyskinesia based on interference in activities of daily life) scores, and the authors stated that it occurred through a decrease in LID due to enhanced GABA transmission in the GPi (Sieradzan et al. 2001). Levetiracetam, an anti-epileptic drug that alters the release of glutamate and GABA through its action on synaptic vesicle glycoprotein (SV2A), potentially

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reduced LID in preclinical studies, but the results in clinical trials were differing (Du et al. 2015). Pridopidine is a σ1R receptor agonist with a secondary affinity toward adrenergic and serotonergic receptors, which displayed an anti-dyskinetic effect and reduction in LID in animal models (Johnston et al. 2019).

5.5.2.4 NA (Noradrenaline)-Based Therapeutics Recent evidence has stated that Lewy pathology in the locus coeruleus (LC), main source of NA in the brain, is majorly involved in initiating the first etiological events of PD. NA-based neurons directly innervate the SNpc and LC lesioning to further exacerbate the dopaminergic loss and motor dysfunction and are also linked to the vulnerable LC-NA system, which is linked to the cognitive pathophysiology of dementia (Vermeiren and Deyn 2017). Thus, targeting NA-based neurons in PD can be considered an important pharmacological target. To restore NA neurotransmission, the following strategies are executed: (i) administering NE precursors to increase NA levels, (ii) intensifying NA release by antagonizing pre-synaptic α2receptors, and (iii) enhancing NE (Norepinephrine) synthesis (Espay et al. 2014). A double-blind RCT of droxidopa, a precursor of NA, was conducted using a dose of 600 mg/day in 240 moderate to severe PD patients. A significant improvement in UPDRS II & III scores was observed after 8 weeks (Zhao et al. 2015). Fipamezole, a selective α2-receptor antagonist, improved LID in PD patients in the MPTP-lesioned primate model of PD (Savola et al. 2003) and improved the quality of levodopa action in PD primates (Johnston et al. 2010). It acts by binding to α2receptor and stimulates NA activity, and an anti-dyskinetic effect occurs due to the expression of α2-receptors in several parts of the brain. To increase the synthesis of NA, the employment of MAO inhibitors is recommended as an adjunct therapy to levodopa in early PD. It delays the need for other anti-parkinsonian drugs and increases the UPDRS score (Vermeiren and Deyn 2017). 5.5.2.5 Adenosine-Based Therapeutics A2A receptors can be considered potential nondopaminergic targets as they regulate GABAergic transmission at striatopallidal synapses and modulate both glutamatergic and GABAergic transmission in the striatum. Blocking overactive A2A receptors in the striatopallidal GABAergic synapse or at corticostriatal glutamatergic synapses ameliorates the motor symptoms of PD (Schwarzschild et al. 2006). Istradefylline, an A2A receptor blocker that reduces off time, improves motor function, and increases duration of action without problematic dyskinesia, was the first nondopaminergic agent approved by the FDA for PD (Paton 2020). Other drugs being explored for their efficacy from the same family include Preladenant, Tozadenant, Vipadenant, and KW-6356. After decreasing off time in Phase II, preladenant exhibited no significant clinical efficacy in Phase III, either in monotherapy or in combination (Ntetsika et al. 2021). Tozadenant showed similar results in Phase II, but Phase III trials were discontinued due to safety issues (Hauser et al. 2014). At the lowest dose of 2.5 mg and saturation at 100 mg, vipadenant attained a binding capacity of 74–94% with A2A receptors in the human brain when an open-label PET study was performed (Brooks et al. 2010). KW-6356 is a

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Fig. 5.1 Pathological targeting through emerging therapeutic targeting

second-generation A2A antagonist (Chen and Cunha 2020), which showed positive results with respect to motor functioning in combination with levodopa (NCT03703570) and as monotherapy (NCT02939391). Therapeutically targeting agents and pathological alterations observed in PD are presented in Fig. 5.1 and explained in the following sections.

5.6

Pathological Targeting: Disease-Modifying Approach

PD is a progressive neurodegenerative disease and diagnosed post-pathological alteration nearly after 10–15 years; symptomatology-based management does not remain promising anymore. However, surely, targeting pathological hallmarks at an early stage offers a better avenue to hinder the disease progression and even might, in future, prove to cure the disease with suitable technological advancement in disease diagnosis at a preliminary stage.

5.6.1

Agents Targeting Specific PD Pathological Hallmark

5.6.1.1 Proteinopathy in PD Proteinopathy in PD is linked to α-syn, a 140-amino acid protein comprising the N-terminal domain, NAC domain, and C-terminal domain. The point mutations in

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the N-terminal domain are responsible for the ability of α-syn to interact with vesicles and membranes, and the central NAC domain and polar C-terminal domain are responsible for the misfolding of β-sheet-rich amyloid aggregates and phosphorylation of α-syn to induce aggregation and toxicity respectively (Bendor et al. 2013). Though the native monomeric form of α-syn helps in maintaining presynaptic function and regulates neurotransmitter release, misfolded α-syn aggregates impair neuronal homeostasis, including vesicular trafficking dysfunction, autophagylysosomal pathway imbalance, oxidative and endoplasmic reticulum stress, and mitochondrial dysfunction (Dehay et al. 2015). Therapeutic approaches targeting α-syn aim to either decelerate or halt the progression of the disease. The following methods have been used to target α-syn aggregation. Reducing the expression of α-syn: A decrease in the levels of the pathogenic protein α-syn can be attained by minimizing transcription of the SNCA gene by epigenetic modifications/small molecules/biologics or by reducing the translation of SNCA mRNA utilizing nucleic acid-based therapeutics/small molecules. Among the pre-existing drugs, β2-adrenergic receptor agonists metaproterenol, clenbuterol, and salbutamol were found to decline the α-syn levels through histone acetylation at the promoter and enhancer regions of SNCA. In the cortical neurons of rats, metaproterenol and clenbuterol brought down α-syn mRNA and protein levels in the substantia nigra (Mittal et al. 2017). Two novel compounds SLS-004 and ST-502 are being studied for their potential of decreasing transcription of the SNCA gene. SLS-004 is an LV vector containing DNA-methyltransferase 3A (DNMT3A) that targets the intron 1 of the SNCA gene; ST-502 is a zinc-finger transcription factor delivered through AAV to repress the SNCA expression. Treating PD patient-derived induced pluripotent stem cells expressing SNCA triplication with SLS-004 exhibited reduced α-syn mRNA and protein levels (Grosso Jasutkar et al. 2022). Several studies have been performed to generate siRNA that could target the α-syn mRNA and produce therapeutic efficacy. siRNA and shRNA targeting nucleotides 288–309 of α-syn mRNA diminished α-syn translation in HeLa cells and SH-SY5Y cells transfected with α-syn, respectively (Sapru et al. 2006). Similar results were generated with an additional benefit of no adverse effects in terms of inflammation, the number of dopaminergic cells, or levels of dopamine and its metabolites when a siRNA duplex was administered into the SNpc targeting the SNCA transcript (McCormack et al. 2010). RNAi-mediated α-syn silencing is also considered a perspective to reduce nigrostriatal degeneration. The potency was found to be limited by the inability of RNAi to cross BBB; thus, a newer approach of intranasal treatment was tried. IND-499-siRNA, targeting monoamine neurons, was administered intranasally, and the α-syn levels were cut down by 70% in PD-induced monoaminergic neurons when compared to the control (Alarcón-Arís et al. 2018). Antisense oligonucleotides (ASOs) have recently grabbed a lot of attention because of their success in other neurological disorders like muscular atrophy, Duchenne muscular dystrophy, and transthyretin-mediated amyloidosis. Its efficacy was demonstrated in nonhuman primates but has not reached clinical trials. ASO enabling ribonuclease H-mediated degradation of SNCA mRNA and α-syn protein levels promoted neuroprotection in the PD animal model (Cole et al.

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2021). Ribozymes are antisense RNAs with enzymatic activity when injected intranigrally using AAV, which led to decreased α-syn levels in the MPTP-induced PD model (Hayashita-Kinoh et al. 2006). Though nucleic acid-based therapeutics are gaining popularity, small molecules targeting RNA are being acknowledged as a better strategy for dealing with PD when compared to nucleic acids. Iron responsive element (IRE) present in 50% of SNCA mRNA isoforms was targeted to reduce α-syn expression without reducing it entirely. Synucleozid, a novel molecule, was identified to act on IRE and lower the α-syn protein levels in SH-SY5Y cells (Zhang et al. 2020). Prevention of α-syn aggregation: This can be attained by using α-syn disaggregators (agents that interfere with the production of higher-order structures, further forming α-syn aggregates) and targeting α-syn pro-aggregation factors like post-translational modifications, lipid homeostasis disruption, oxidative stress, exposure to iron, and interaction with other proteins that promote α-syn oligomerization. Anle138b, a disaggregator identified through high-throughput screening, was found to inhibit α-syn oligomer formation and protect A30P α-syn transgenic mice against MPTP and rotenone-induced motor deficits. The neuroprotective effect was found to be extended in the MI2 mouse model of PD as well (Wagner et al. 2013). Recently, the first-in-human, placebo-controlled, double-blind, randomized trial using Anle138b was performed to analyze safety, tolerability, and pharmacokinetics (NCT04208152). NPT200-11 was developed to prevent α-syn aggregation and safeguard against pathologic changes observed in α-syn transgenic mice (Price et al. 2018), and phase 1 clinical trials were completed in early 2016, but results remain unpublished (NCT02606682). Another molecule falling into the category of disaggregators is a fusion protein, NPT088, which has the ability to bind to α-syn and disrupt its amyloid confirmation. Though its efficacy and safety were demonstrated through its intravenous administration in AD (NCT03008161), studies in PD are still undetermined. A group of peptides, specifically S62 and S71, belonging to the SLS-007 family, were designed using computational modeling to prevent α-syn aggregation preclinically utilizing AAV vectors for delivery (Sangwan et al. 2020). Targeting post-translational modifications, especially phosphorylation, appears to be a promising approach. S129 phosphorylated form of α-syn exhibited greater protein fibrillation in vitro than its nonphosphorylated form; hence, molecules targeting this aspect can give rise to novel therapy (Hasegawa et al. 2002). Additionally, α-syn phosphorylation can also be reduced by activating PP2A, a protein responsible for dephosphorylating S129-p-synuclein and ameliorating PD symptoms in α-syn transgenic mice (Park et al. 2016). Disturbed lipid homeostasis also promotes oligomerization because of the interaction between α-syn and lipid membrane. Inhibitors of Ole1, the yeast homolog of human stearoyl-CoA desaturase (SCD), were found to inhibit lipid-based activation of α-syn expression by reducing the synthesis of oleic acid involved in the generation of SCD (Fanning et al. 2019). While SCD inhibitor 5b acted as a neuroprotective against motor impairment in triple-mutated α-syn transgenic mice, clinical trials were performed to understand the safety and tolerance of YTX-7739, a small molecule inhibitor of SCD in the Netherlands (Grosso Jasutkar et al. 2022).

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Transglutaminase 2 (TG2) is an enzyme involved in the formation of highmolecular-weight aggregates of α-syn in association with loss of calcium homeostasis, ROS formation, and energy deficiency. In a study, an increase of TG2 mRNA was correlated with increased α-syn protein expression in the substantia nigra of PD patients (Wilhelmus et al. 2011). TG2 inhibitors, cystamine, and its active reduced form cysteamine were effective in exhibiting neuroprotection in MPTP and 6-OHDA lesioned mouse models of PD (Sun et al. 2010; Tremblay et al. 2006). Immunotherapies targeting α-syn: Immunization enables the clearance of intracellular α-syn aggregates by binding antibodies with α-syn pathogenic protein. While active immunization utilizes immunogenic epitopes within the C- and N-termini of α-syn within amino acids 89–140, passive immunization uses MAbs developed against these epitopes (Wang et al. 2019; Mandler et al. 2014). Clinical trials are being conducted for vaccines AFFITOPE PD01A (synthetic peptide based on C-terminal amino acids 110–130 of α-syn administered 15 μg/75 μg as required for 4 weeks, exhibited remarkable humoral response and good safety and tolerance), AFFITOPE PD03A (similar technology used for development, identical dosing and results as that of AFFITOPE PD01A in clinical trials), and UB312 (peptide-based vaccine targeting 12-amino acid sequence in C-terminus of α-syn with no preclinical studies performed) (Mandler et al. 2014). A number of MAbs are being investigated for the purpose of facilitating passive immunization. Prasinezumab, a humanized IgG1 Mab, which recognizes amino acids 118–126 near the C-terminus of α-syn, exhibited a protective effect with respect to α-syn accumulation, synapse loss, and improved performance in rotarod, water maze, and pole test (Masliah et al. 2011). A single ascending dose study of prasinezumab was conducted, which showed its good safety profile and dose-dependent lowering of α-syn with maximal effect at a dose of 30 mg/kg (Schenk et al. 2017). Cinpanemab, fully human IgG1 MAb targeting epitope near N-terminus, demonstrated high specificity toward aggregated α-syn and delayed the onset of paralysis and neuronal loss (Weihofen et al. 2019). Dose up to 45 mg/kg was tolerated in the phase 1 trial, but the phase 2 trial was discontinued due to a lack of proper primary and secondary endpoints (NCT03318523). MEDI1341, another MAb aimed at the C-terminus of α-syn within amino acids 103–129, reduced α-syn levels by 81.5% at peak and 45% even after 4 days of its intravenous administration in PD rats and inhibited the spread of α-syn to the contralateral hippocampus via intraperitoneal treatment (Schofield et al. 2019). At present, two phase 1-trials, i.e., a single ascending dose study in healthy volunteers and a multiple ascending-dose study in PD patients, are being conducted (NCT03272165, NCT04449484). BAN0805 is a humanized MAb considered to target both α-syn oligomers and protofibrils. Though this aspect has not been established in preclinical trials, the phase 1 clinical trial was registered but was terminated before candidates were enrolled (NCT04127695). Though immunotherapy is showing good tolerability, its application is limited because of low levels in CSF, thus requiring further investigations.

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5.6.1.2 Targeting LRRK-2 After α-syn, another vital protein that is involved in the pathogenesis of PD is LRRK2, whose mutations contribute to 1% of patients with sporadic PD and 4% of familial cases worldwide (Healy et al. 2008). LRRK2 contains many domains indicating its role in autophagy, vesicle trafficking, retromer complex modulation, and cellular signaling, especially the kinase domain. Upon interaction with other key proteins like α-syn, it synergizes the disease pathogenesis (Daher 2017). It has been suggested through a hypothesis that increased kinase activity by LRRK2 mutation is accountable for parkinsonism. LRRK2 induced Ser/Thr phosphorylation and G2019S mutation increased LRRK2 kinase activity; in addition, overphosphorylation of the downstream MAPK kinase leads to neuronal death signal pathway (Rui et al. 2018). Therefore, LRRK2 kinase inhibitors are being considered a therapeutic strategy at various preclinical stages of PD. Several efforts are being made to establish potent pharmacological agents targeting LRRK2. A healthy volunteer phase 1 study was conducted by Denali Therapeutics using DNL201, exhibiting 90% inhibition of LRRK2 kinase activity at peak and 50% inhibition at the trough. Initially, the FDA imposed an exposure limit to achieve 50% inhibition. After this hold was lifted, the company continued the studies to find that DNL201 exhibited sufficient CNS penetration ability and is actively recruiting healthy volunteers to perform a second dosing (Jennings et al. 2022). Certain studies stated that reversible lung morphological changes were induced by LRRK2 kinase inhibitors; hence, alternatives termed GNE-7915, MLi-2, and PFE-360 cause no or mild pathological changes in the lungs (Baptista et al. 2020). Since BIIB094 showed neuroprotective action against phosphorylated α-synuclein aggregates in primary hippocampal cell cultures preclinically (Zhao et al. 2017), Phase 1 clinical trials are currently being performed to determine the safety and tolerability (NCT03976349). Other potential therapeutics inhibiting LRRK2 kinase tested in preclinical models but have not reached clinical trials include MLi-2(Scott et al. 2017), LRRK-IN-1 (Deng et al. 2011), PF-06447475 (Daher et al. 2015), JH-II-127 (Hatcher et al. 2015), and microRNA-205 (Cho et al. 2012). 5.6.1.3 Targeting Glucosylceramide Beta 1 (GBA) GBA is a lysosomal hydrolase that converts glucosylceramide to ceramide and glucose. While homozygous mutations in the GBA gene cause Gaucher disease, heterozygous mutations increase the risk of developing PD and synucleinopathy. It has been postulated that loss-of-function mutations induced in GBA lead to an abnormal glycosphingolipid environment, leading to proteinopathy and neuronal dysfunction (Beavan and Schapira 2013). To develop an efficient GBA-based gene therapy, it is essential to select the optimal serotype, route of delivery, and brain distribution. Therapeutic intervention of PD can be performed by either enhancing GCase activity or modulating GBA-associated glycosphingolipids (i.e., substrate reduction therapy). Decreased glucocerebrosidase (GCase) is associated with increased α-synuclein aggregates and motor function abnormalities. Thus, to restore the glycosphingolipid balance, it is necessary to mediate the overexpression of exogenous GCase in CNS through AAV (Sardi et al. 2018). It was found that

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AAV1 reverses the cognitive loss in the mouse model of Gaucher-concerned synucleinopathy and decreased α-synuclein in the A53T-SNCA mouse model (Sardi et al. 2011). Additionally, small molecules able to cross the BBB to enhance the lysosomal GCase activity are designed and investigated for their efficacy in PD. Ambroxol, a mucolytic with chaperone activity, capable of bringing down α-synuclein protein levels, is in clinical trials, and it is being evaluated for its safety, tolerability, and efficacy in PD (Migdalska-Richards et al. 2016). Inhibitory chaperones are compounds that increase the activity of GCase by binding to the active site. However, isofagomine from this category failed to show any clinical efficacy; thus, its clinical trial was ceased (Boyd et al. 2013). A new class of noninhibitory GCase chaperones, namely NCGC758 and NCGC607, were developed to overcome the disadvantages of inhibitory GCase chaperones. Instead of binding to the active site, these compounds exert a confirmational change and either increase the activity of GCase or prolong the half-life, reduce α-synuclein aggregation, and enhance the lysosomal activity (Aflaki et al. 2016; Mazzulli et al. 2016). To modulate the glycosphingolipid turnover, a novel GBA inhibitor, GZ/SAR402671 (Venglustat), is being tested for improving the behavioral outcomes in Gaucherrelated synucleinopathy through a double-blind, placebo-controlled study.

5.6.1.4 Targeting PINK-1/Parkin PINK1/Parkin activates the mitochondrial quality control pathways, especially mitophagy, in response to any mitochondrial damage. Parkin is an E3 ubiquitous ligase protein, expressed in large amounts in CNS, responsible for tagging the degraded proteins with ubiquitin, enabling their degradation. PINK1 activates Parkin and increases the damage detection signal, facilitating the formation of more ubiquitin chains and recruiting more Parkin in the mitochondria. Mutations in Parkin encoded by the PARK2 gene and PINK1 gene cause recessive, early-onset PD associated with Lewy body formation (Ge et al. 2020). Different aspects that can be considered to stimulate the PINK1/Parkin pathway include PINK1 activation, Parkin activation, and Ubiquitin-specific protease (USP) 30 inhibitors (Miller and Muqit 2019). PINK1 activation: Three approaches can be used to enable PINK1 activation. Almost 30 missense and nonsense human PINK1 mutations are responsible for PD pathology. Upon mitochondrial depolarization, PINK1 accumulates on the outer membrane and forms a large 700 kDa multimeric complex with translocase, which prompts autophosphorylation and activates PINK1 (Lazarou et al. 2012). i) Autophosphorylation can happen at three sites of hPINK1: Thr257, Ser228, and Ser402, out of which the latter two are involved in Parkin and ubiquitin phosphorylation. While Ser402 preserves the activation loop of hPINK1, maximizes the kinase activity, and increases Parkin recruitment, Ser228 increases substrate phosphorylation and initiates mitophagy (Sim et al. 2012). ii) Small molecules like ubiquitin conformational modulators are used to increase ubiquitin phosphorylation levels or increase dimerization, which triggers PINK1 activation (Miller and Muqit 2019). iii) ATP analog kinetin triphosphate, a neo-substrate in vitro, is used (Orr et al. 2017).

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Parkin activation: Parkin contains five domains, namely Ubl, RING0, RING1, IBR, and RING2. Parkin exists in an autoinhibited conformation in the following conditions: RING0 partially blocks the catalytic cysteine, repressor element of parkin along with Ubl, which blocks the predicted E2 binding site on RING1, and the distance between RING2 catalytic cysteine and predicted E2 catalytic cysteine is greater than the optimal 30 Å. New structures are required to be designed, which can disrupt these autoinhibitory mechanisms and activate catalytic activity (Trempe et al. 2013; Kumar et al. 2015; Chaugule et al. 2011). Ubiquitin-specific protease (USP) 30 inhibitors: To modulate the action of Parkin, deubiquitinating enzymes (DUBs), which equip the elimination of ubiquitin from substrates, are required. Three DUBs named USP15 (Cornelissen et al. 2014) and USP30 (Bingol et al. 2014) (inhibits parkin-mediated mitochondrial ubiquitination and mitophagy in vitro and in Drosophila, stating molecules interfering with this enzymatic activity needs to be developed), and USP8 (Durcan et al. 2014) (triggers mitophagy by removing ubiquitin residues from Parkin and prevents auto-inhibition, thus requiring therapeutics further promoting this mechanism) have been considered as attractive therapeutic options, out of which research is being performed to a greater extent on developing molecules targeting USP30. It is because mounting evidence has suggested increased mitophagy overexpressing Parkin in USP30 KO human cell lines and Drosophila, suggesting that USP30 may act as an upstream of PINK1 (Bingol et al. 2014). Currently, USP 30 small molecule inhibitors are being developed by Mission Therapeutics and Mito Bridge LLC (Gui et al. 2015).

5.6.2

Agents Rescuing Neurons

5.6.2.1 Calcium Targeting Therapies Though calcium plays a vital role in the normal functioning of neurons, its involvement in other cellular processes like oxidative stress, proteasomal abnormality, excitotoxicity, mitochondrial dysfunction, neuroinflammation, and apoptosis can prove detrimental to neuronal health because they ultimately lead to neurodegeneration, a key characteristic of PD (Witte et al. 2010; Hurley and Dexter 2012; Büeler 2010; Berridge et al. 2000). The Ca2+ hypothesis of PD states that dopaminergic neurons in substantia nigra use Cav 1.3 L-type Ca2+ channels to initiate pace-making activity in the 2–4 Hz range. The excessive influx of Ca2+ ions has a deleterious effect on mitochondrial functioning (Chan et al. 2007). Therefore, Cav 1.3 L-type Ca2+ channel blockers, especially dihydropyridine derivatives, can be considered to facilitate neuroprotection in PD patients. Several studies have claimed that these pharmacological agents have reduced the risk of PD in patients receiving them. Among them, isradipine was demonstrated for its neuroprotective activity in experimental models of PD (Ilijic et al. 2011). Upon conducting clinical trials, it was concluded that no significant clinical effect of ivabradine was observed in early-stage PD (NCT02168842). Thus, identification of in vivo markers of disease progression and measurement of target measurement is

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required for further studies to be continued (Maiti and Perlmutter 2020). An antihistaminic drug named dimebon exhibited neuroprotective action in in vitro studies. It protects the neurons from MPTP-induced neurotoxicity in mitochondrial preparations extracted from C57BL/6 mouse brains against the decrease of mitochondrial membrane potential by blocking the opening of mitochondrial transition pore due to elevated calcium levels (Staal et al. 2009) and decreases α-syn overexpression in rotenone-induced PD expressing SH-SY5Y cells (Delgado et al. 2011). Certain mitochondrial stabilizers and energizers like Ketasyn, creatine, CoQ10, and MitoQ are being tested for their ability to alleviate PD symptoms by targeting the link between Ca2+ imbalance and mitochondrial dysfunction (Chaturvedi and Beal 2008).

5.6.2.2 Iron Targeting Therapies Iron is an important constituent of TH-dependent dopamine synthesis and other enzymatic and nonenzymatic reactions engaged in dopamine metabolism. Ferroptosis, a novel iron-dependent cell death pathway, is responsible for various pathological alterations like glutathione depletion, lipid peroxidation, mitochondriopathy, increase in nigral iron, elevated ROS production, upregulation of α-syn, and oxidation of dopamine, leading to PD (Weinreb et al. 2013). Iron chelators are promising chemical entities, their efficacy was tested using various genetic and pharmacological methods, and it was evident that they reduced iron levels and prevented toxic effects in MPTP-induced PD. They cross the blood–brain barrier and inhibit ferroptosis by either of the mechanisms, including complexing free reactive iron, or stabilizing and transcriptionally activating iron-dependent HIF-1 or inhibiting α-syn aggregation, resulting in increased neuronal viability and normalized dopamine metabolism (Moreau et al. 2018; Dexter et al. 2011). Deferiprone (DFP) has shown a significant decline in SNpc siderosis and 3-point improvement in the unified Parkinson’s disease rating scale, implicating a diseasemodifying effect in an early-stage PD patient pilot study. It is currently being tested in phase 3 clinical trials after showing a positive result in the double-blind, randomized, placebo-controlled clinical trial of early-stage PD patients over 12 months treated with deferiprone (30 mg/kg/day) by successfully reducing the iron deposits (Devos et al. 2014). Other compounds with iron scavenging ability, including clioquinol, VK28, M30, and certain natural plant-based polyphenol flavonoids, have been studied but have not reached clinical trials (Moreau et al. 2018). Clioquinol and its new derivative, PBT434, were found to restore the nigral neurodegeneration in A53T α-syn transgenic mice, as well as in 6-OHDA and MPTP animal models of PD (Kaur et al. 2003; Finkelstein et al. 2017). VK28 can enter the mitochondrial membrane and inhibit lipid peroxidation; a neuroprotective activity of 68% was observed against 6-OHDA-induced oxidative damage (Ben et al. 2004). M30 exhibits a dual role of iron chelator and an MAO-B inhibitor; it acts as a neuroprotectant in MPTP-induced neurodegeneration and simultaneously elevates the concentration of dopamine (Perez et al. 2008). Polyphenol flavonoids like green tea extract containing (-)-epigallocatechin 3-gallate (EGCG) was found to reverse striatal DA depletion in mouse and SN dopaminergic neuronal loss in SH-SY5Y

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cells and PC-12 cells, respectively (Levites et al. 2001; Kim et al. 2010). All these studies prove that iron chelation can be used as a strategy to overcome PD pathology.

5.6.2.3 Neuroinflammation Targeting Agents Sufficient evidence has been generated claiming that inflammation-derived oxidative stress due to activated microglia, NF-κB pathway, and cytokine-dependent toxicity leads to nigrostriatal degeneration and accelerated pathological mechanisms of PD. Irrespective of the origin of the neuroinflammatory mechanism of PD, utilizing pharmacological interventions that would either delay or stop the pathological processes involved in neuroinflammation could be of great use (Tansey and Goldberg 2010). NSAIDs, preferentially COX2 inhibitors, are being experimentally and epidemiologically studied for their effective ROS, reactive nitrite scavenging activity, and peroxisome proliferator-activated receptor γ (PPARγ) pathway activation because they have been confirmed to show protective action against other neurodegenerative disorders like Alzheimer’s disease (Hirsch and Hunot 2009). Additionally, broad-spectrum anti-inflammatory agents regulating glial-associated innate immunity have been tested in many animal models. Among them, PPARγ agonists were found as promising candidates for PD intervention. An important advantage of these agents is that they act through multiple mechanisms beyond their immunoregulatory properties to reduce the inflammatory burden and restore mitochondrial function (Randy and Guoying 2007). Pioglitazone, a potent PPARγ agonist, shows mitigation of the pathogenic PD phenotypes by reducing neuroinflammation in a novel PD mouse model (Pinto et al. 2016). Another drug, minocycline, a tetracycline derivative, exerts its neuroprotective activity by modulating microglia activation and inflammatory mediators like cytokines and chemokines, inhibiting apoptosis, and suppressing ROS production (Cankaya et al. 2019). Apart from glial-associated innate immunity, adaptive immune response initiated by T-cells is also involved in neurodegeneration. Antigen-based immune intervention is facilitated by the administration of glatiramer acetate, a copolymer consisting of glutamine, lysine, alanine, and tyrosine. Glatiramer acetate-specific T cells reach the affected brain areas and inhibit the activation of microglial cells in MPTP-induced dopaminergic neuronal death (Tsai 2007). A synthetic triterpenoid CDDO-Me, an activator of Nrf2 anti-oxidant pathway and inhibitor of NF-κB pathway, reduces the neurotoxicity of microglia in dopaminergic neurons by declining the TNF production and glial-derived inflammatory mechanisms (Tran et al. 2008). 5.6.2.4 Mitochondria Targeting Agents Various studies suggest the significant role played by mitochondria in the onset of PD. Targeting mitochondria can alleviate the PD phenotype by either restoring the nonfunctional neurons or delaying the mortality of the neurons. Several compounds have been developed by considering novel mitochondrial targets with the intention of altering the mitochondrial pool to maintain biogenesis and mitophagy (Henry and Schapira 2012). Coenzyme Q10, an antioxidant and an electron carrier, when administered through the intra-striatal route, increased the dopaminergic neurons

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and caused lesser inflammation and greater expression of neurogenetic and angiogenetic factors (Park et al. 2020). It was also tested in early PD patients at a dose of 1200 mg/day and claimed to decelerate the progression of PD (Shults et al. 2002). Creatine, a naturally occurring nitrogenous compound associated with energy supply, acts as a neuroprotectant against neurotoxins like 3-NP, MPP+, and 6-OHDA. Additive neuroprotective action is observed upon co-administration with CoQ10, nicotinamide, and minocycline (Chaturvedi and Beal 2013). Supplementing creatine (20 g/day) enhanced muscle endurance with resistance training and upper body strength in PD patients (Hass et al. 2007). Mito-Q is the most studied and widely used mitochondria targeting agent that possesses direct antioxidant action due to its ability to scavenge various ions like peroxyl, peroxynitrite, and superoxide and protects the mitochondria against lipid peroxidation. The therapeutic efficacy of MitoQ was demonstrated in both in vitro and in vivo studies by utilizing MPP+-induced cellular and mouse disease models (Jin et al. 2014). Selegiline, apart from being an MAO-B inhibitor, inhibits the neurotoxin and trophic factor-induced neuronal cell death by increasing the anti-apoptotic molecules like Bcl-2, glutathione, SOD-1, and SOD-2. It also ensures the closure of the mitochondrial permeability transition pore, whose opening is a key factor responsible for apoptosis. Resveratrol and its derivatives are naturally occurring polyphenolic compounds enhancing PGC-1α, an important regulator of mitochondrial activity, which in combination with SIRT1 promotes mitochondrial biogenesis (Henry and Schapira 2012). Resveratrol was found to alleviate MPTP-induced neurodegeneration in diseased PD mice in synergism with low doses of L-DOPA (Liu et al. 2019). Though these drugs have shown their efficacy in preclinical studies, their potency is yet to be tested in clinical trials.

5.6.3

Gene Therapy

Gene therapy acts as a therapeutic strategy to supply a functional gene to the patients expressing either a mutated functional gene or an under-expressed gene. The delivery of the desired gene is facilitated by viral vectors or through plasmid transfection (Pinjala et al. 2023) (Coune et al. 2012). Gene therapy has been employed in the treatment of PD via three approaches: increasing dopamine synthesis, enhancing the expression of tropic factors, and enabling neuromodulation (Hitti et al. 2019). A number of clinical trials are being performed to treat PD. Glutamic acid decarboxylase (GAD) is an enzyme involved in the production of GABA. GAD gene therapy aims to increase the presence of GABA by injecting the gene encoding for GAD with the help of a vector into the subthalamic nucleus of PD patients and ameliorate the pathophysiology (Lewitt et al. 2011) (NCT00195143). Aromatic amino acid decarboxylase (AADC) is involved in the conversion of levodopa to dopamine to moderate changes in long-term levodopa treatment. By introducing a gene for AADC into the putamen, it is expected to increase the concentration of AADC present and thereby make the levodopa treatment more effective (Wood 2020) (NCT01973543, NCT03065192). Similarly, studies are being performed to induce neurturin (Marks et al. 2010) (NCT00985517), glial-derived neurotrophic

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factor (Behl et al. 2020) (NCT01621581), and tyrosine hydroxylase (Pardridge 2005) into diseased animals to prevent nigrostriatal neurodegeneration, promote survival of neurons, and increase dopamine synthesis, respectively.

5.6.4

miRNAs as a Novel Therapeutic Approach

miRNAs are small double-stranded RNAs that induce a calibrated sequence-specific regulation of the cell transcriptome (Titze-De-almeida et al. 2020). They play an important role in maintaining the optimal mRNA levels in the healthy brain, and when expressed in abnormal concentrations, they contribute to PD disease pathology (Uppala et al. 2023) and miRNAs are able to perform targeted-mRNA degradation or translational inhibition via sequence complementarity to 3′UTR of mRNAs (Brodersen and Voinnet 2009). MPTP-induced neurodegeneration in the PD cellular model was attenuated by miR-7 by inhibiting neuronal apoptosis, reducing the mitochondrial permeability potential, caspase-3 activity, and nucleosomal enrichment factor by downregulating Bax and Sirt2 expression, suggesting miR-7 as an effective disease-modifying strategy (Li et al. 2016). It was found that the PD cell model, i.e., 6-OHDA-treated PC12 phaeochromocytoma cells, exhibited decreased expression of miR-221 when compared to the normal cells. By mimicking miR-221, enhanced cell viability and proliferation of 6-OHDA-treated PC12 cells, apart from promoting the phosphorylation of AKT by targeting PTEN, was achieved, and the mechanism was derived through gain and loss of function analysis (Li et al. 2018). After establishing PD-modeled rats showing increased neuroinflammatory response, oxidative stress, decreased dopamine levels, and aggregated neurobehavioral changes, they were treated with miR-375. The treatment reversed all the disease symptoms by inhibiting SP1 (Cai et al. 2020). miR-135b ameliorates MPTP-induced PD in the in vitro model by suppressing FOXO1-mediated NLRP3 inflammasome and pyroptosis, a unique inflammatory programmed cell death (Zeng et al. 2019).

5.7

Alternative Approaches for PD Management

PD is a multifactorial disease of dynamic pathology. At present, accessible traditional treatment approaches for PD have limitations of their own and has low consistency and fulfilments. Current contemporary treatment motives just give symptomatic alleviation and provide limited control to anticipate progression. In addition, these come up with adverse outcomes and do not offer long-term efficacy. Numerous rising pharmacotherapies for PD are in various phases of medical improvement, such as cellular therapy involving stem cell transplantation and replacement of degenerative dopaminergic neurons, nanoformulations, and brain stimulation methods; however, a combination of conventional and alternative therapies might provide better efficacy in terms of disease progression.

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Cellular Therapy

Cellular transplantation therapy was experimented in the late nineteenth century itself, where adrenal cells were transplanted into region of degenerated dopaminergic neurons to enhance the catecholamine levels but this did not show promising efficacy and so was abandoned. However, emerging strategies in this area gave a new hope for hindering the disease progression. In this, we discussed a few of the strategies such as transplantation with mesencephalic tissue of fetus and stem cell therapies along with the studies performed in order to assess their efficacy in PD.

5.7.1.1 Fetal Ventral Mesencephalic Tissue Various cell sources were found to be useful in managing PD, of which fetal ventral mesencephalic tissue, which contains developing dopaminergic neurons, was found to be successful in studies providing evidence of long-term survival of dopaminergic neurons in transplanted tissues by producing dopamine (Farrell and Barker 2012). Fetal ventral mesencephalic cells mainly target to physiologically replace the striatal dopaminergic input. Studies in animal PD models showed an improvement in dopaminergic transmission upon neural transplantation. Mesencephalic dopaminergic neurons obtained from 8–9 weeks of fetus showed survival in the brain upon transplantation (Lindvall 2015). Grafts upon unilateral implantation in putamen resulted in restoration in the grafted region upon examination by positron emission tomography using 6-L[18F] fluro dopamine (Lindvall et al. 1990). Two patients with idiopathic PD were followed for 3 years upon transplantation, where results showed that the functional effects of transplant were sustained for up to 3 years (Lindvall et al. 1994). Unilateral putamen transplantation, however, showed improvement in the unified Parkinson’s disease rating scale (UDPRS), but there was an incidence of graft-induced dyskinesia even after stopping levodopa therapy (Freed et al. 2001). These differential effects of transplant depend on various factors such as patient, site of transplantation, and type and duration of immune suppression. 5.7.1.2 Stem Cell Therapy Different stem cell lines, such as mesenchymal, human embryonic stem cells (hESC), and induced pluripotent stem cells (iPSC), were studied for PD management in animal models. Mostly preferred is the mesenchymal stem cells, which isolated from bone marrow mesenchymal stem cells (BM-MSCs) and umbilical cord MSCs (UC-MSCs) have been used in neuronal repair due to their ease of isolation and proliferation (Han and Hu 2020). BM-MSC transplantation into 6-OHDA-induced rats and MPTP-induced mice showed survival in striatum, and motor defects were ameliorated. Upregulation of dopaminergic neuron differentiating transcription factors such as LMX1a in BM-MSC showed increased expression of TH and dopaminergic neurons (Barzilay et al. 2009). One another strategy involved a combination of growth factors and hUC-MSC into 6-OHDA lesioned mice midbrain, where results showed improved motor functions and high efficiency in dopaminergic neuronal conversion (Matsuse et al. 2010). Embryonic stem cells are pluripotent and are found to derive dopaminergic neurons. Newer protocols were

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developed in order to avoid the use of feeders and Xander-free medium growth where these processes help in regulating midbrain development and TH-positive dopaminergic neurons started expressing in 3–4 weeks (Nakagawa et al. 2014). In 6-OHDA-lesioned rats, hESC-derived neuronal precursor cells relieved the motor dysfunctions. Specific neuronal patterning can be achieved by employing growth factors such as sonic hedgehog (SHH) and fibroblast growth factor (FGF8a), which showed a midbrain projection of neurons with large cell bodies (Ma et al. 2011). In addition, conversion of somatic cells to pluripotent stem cells by overexpression of oct4, klf4, c-myc, and sox-2 was reported. Two major possible approaches for the use of iPSC for neurodegenerative diseases include in vitro disease models for elucidation of pathological processes and evaluating potential drug therapies and generating cells for transplantation (Takahashi et al. 2007).

5.7.2

Nanotechnology

Advancements in medical nanotechnology showed a new path of delivering drugs with precision and better efficacy. Because some compounds have serious limitations, including instability and low bioavailability, they frequently fall short of therapeutic expectations. To overcome such limitations, the nanoformulation approach has been utilized for designing a drug delivery system for the therapeutic molecule’s targeted delivery with no to minimal compromise in desired biological action. Many nanomaterial substances, such as black phosphorous nanoclusters, carboxy fullerenes, and copper-based nanoclusters, showed better efficacy in controlling pathological effects such as excess ROS in PD. Most of the available drugs, such as dopaminergic agonists, anti-glutaminergic drugs, and anti-muscarinic drugs, help only in relieving dyskinesia but do not majorly have a role in stopping the disease progression. Hence, novel approaches such as nano therapy-mediated delivery provide advantages over the free form of drugs (Cheng et al. 2022). Basically, the nanocarriers are of three types, namely, organic nanocarriers that are largely biocompatible, inorganic carriers that show light absorption and also exhibit magnetic properties, and finally hybrid nanocarriers that have the advantage of easy manipulation (Tsou et al. 2017). The drug delivery capacity from nanocarriers depends on many factors, such as drug loading capacity, which depends on the properties of nanoplatforms and also its interaction with the drug being loaded. Higher specific surface areas offer better loading capacity. In addition, the size of the nano platform determines the BBB permeability; the lower the size (5–200 nm), the better the permeability. Higher zeta potential offers better BBB permeability, and this also aids in bypassing the lysosomal degradation in endothelial cells (Cheng et al. 2022). Targeting ROS: Under normal physiological conditions, the toxic oxidative molecules such as hydrogen peroxide, singlet oxygen, and superoxide anions get eliminated, but excessive production can induce oxidative stress. Metal nanoparticles are majorly employed, which upon valence conversion show better BBB crossing ability. A study conducted in the PD mice model using ceria

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nanoparticles showed to inhibit intracellular and mitochondrial ROS along with protection of TH in the striatal region (Kwon et al. 2018). Another approach of combining materials with zero valency and adjustable catalytic activity led to the preparation of Pt-Cu nano alloys, which prevented the neuronal loss in α-Syn preformed fibrils and was also found to reduce the H2O2 and superoxide levels. Nonetheless, nonmetal nanomaterials also possess similar properties; one such is graphene oxide quantum dots (GOQD), which have redox properties. MPP-treated PC12 cell lines showed efficiency in reducing the ROS and H2O2 along with neuroprotective effects in the neuronal cell model by ameliorating apoptosis and α-Syn upon GOQD treatment. Similarly, an improvement in locomotor activity and Nissl bodies in the brain of the MPP-treated zebrafish model was noted by GOQD pre-treatment (Ren et al. 2018). Recently, carbon-based nanoparticles’ carboxy fullerane and black phosphorous showed ROS scavenging activity, but these also come with adverse effects such as increased Cu+2 and Cu+ content as a result of nanomaterial degradation, which may further increase the ROS generation. Inhibition of α-Syn aggregation: It is a well-known pathological event that leads to the formation of oligomers, fibrils, and Lewy bodies in the brain leading to PD. Metal-derived gold nanoclusters prevented α-synuclein fibrillation and exerted neuroprotective effects in PD cell models and also diminished the behavioral alterations of sick mice (Gao et al. 2019). GOQD nanoparticles were also found to show negative effects on α-Syn fibrillization and also trigger their disaggregation. They also cross the BBB and inhibit the neuronal loss induced by α-Syn aggregation. The hypothesized mechanism for this action is the binding of negatively charged groups of nanoparticles with a positively charged group of protein via electrostatic forces, further inhibiting the monomer formation (Kim et al. 2018). Dopaminergic neuron regeneration: Regeneration of the lost dopaminergic neurons is the most promising approach for regulating the decreased dopamine levels and related symptoms in PD. Nanomaterials, for the first time, were used to induce the differentiation of neuronal stem cells using nanohelices and nanozigzags. Incubation of neuronal stem cells in these nanoparticles exhibited differentiation along with increased tyrosine hydroxylase (TH) expression and glutaminergic acid decarboxylase (GAD) biomarkers in dopaminergic neurons (Zhang et al. 2019). A combination of the electromagnetic field and gold nanoparticles was found to have better inducing capacity of dopaminergic neurons in fibroblasts with transcription factors, and also, somatic fibroblasts showed increased content of cellular biomarkers of dopaminergic neurons (Tuj1 and map2), suggesting their differentiation into dopaminergic neurons. This combination therapy also improved behavioral parameters in PD mice upon increased DA neurons in the striatum (Zhang et al. 2019). The nanotherapeutic approach has been tested by following routes of drug delivery, showing an overall positive response for PD management. Intranasal nose-to-brain delivery: Nose-to-brain delivery has a potential advantage to avoid the involvement of blood–brain barrier, but the precise mechanism is unclear. The olfactory nerve that connects the nasal passages with the brain and spinal cord plays a significant role. This approach comes with the added advantage

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of bypassing the involvement of chemical degradation (metabolism), extracellular transport (biodistribution), or cellular resistance (p-glycoprotein efflux), which increases CNS availability of drugs. Designing such an approach definitely raises a concern regarding the effective delivery of drug compounds to the brain. This can be resolved by recording the pharmacokinetic distribution of the drug in the blood versus the brain by keeping track of the brain–blood ratio of the drug (Kulkarni et al. 2015). This is supported by studies where the effects of chitosan nanoparticles loaded with bromocriptine in attenuating PD symptoms were observed in haloperidol-induced PD symptoms in mice (Md et al. 2013). Poly(ethylene glycol)– poly(lactide-co-glycolide) nanoparticles (PEG–PLGA) are also used in drug delivery, such as urocortin, where studies in rats showed an improved brain uptake and neuroprotection along with therapeutic efficacy (Wen et al. 2011). Many other studies have also proved the efficacy of nanoparticle-formulated drugs such as levodopa (Arisoy et al. 2020), rotigotine (Arisoy et al. 2020), selegiline (Rukmangathen et al. 2019), and curcumin (Liu et al. 2020). Local delivery of nanoparticles: Delivery of nanoparticles to the site of action can be achieved by stereotaxic delivery of therapeutic agents. It also avoids many limitations like BBB, peripheral inactivation of drugs, carrier, and prevention of systemic side effects (Garbayo et al. 2012). Implantation of supermagnetic iron oxide nanoparticles into the striatum provided neuroprotection in 6-OHDA PD rats (Umarao et al. 2016). Fe+2 and Fe+3 on the surface of nanoparticles provided free radical scavenging properties and also improved cytochrome c levels (Pal et al. 2013). Nanoparticle-mediated delivery is not only limited to drug compounds, but even biological agents like miRNA can be delivered through this means. miR-124 delivery upon coating with perfluoro 1,5 crown ether through intracerebral administration in 6-OHDA-treated mice resulted in an induction of neuronal migration into lesioned striatum, ameliorated motor symptoms, and also boosted endogenous brain repair mechanisms (Saraiva et al. 2016). DNA-compacted nanoparticles carrying the GDNF gene were administered through intracerebral injection, which improved the survival of dopaminergic neurons, DA fiber density, and motor function recovery (Yurek et al. 2017). In addition to these, conventional routes such as oral routes and intravenous routes are also widely explored for nanotechnology application as drug delivery systems. Oral administration of rod-shaped schisantherin-A nanocrystal showed an improved drug concentration than Schisantherin A suspension and also reversed MPTP-induced dopaminergic neuronal loss and locomotion in zebrafish (Chen et al. 2016). Curcumin- and piperine-coloaded glyceryl monooleate nanoparticles coated with surfactants enhanced penetration of brain tissue and also reduced rotenoneinduced oxidative stress and apoptosis (Kundu et al. 2016). The intravenous nanoparticle approach has also been reported to hamper the disease progression; one prominent example is iron chelating nanoparticles protected through zwitterionic PMPC (poly(2-methacryloyloxyethyl phosphorylcholine)) found to sequester the iron in the brain, thus reducing its accumulation, which otherwise causes dopaminergic cell death (Wang et al. 2017). Angiopep-conjugated dendrigraft poly-L-lysine nanoparticles were designed to facilitate gene delivery and showed a higher cellular

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uptake and gene expression and also improved locomotor activity in the rotenoneinduced chronic PD animal model (Huang et al. 2013). Mitochondria targeted drug delivery: As neurons depend majorly on oxidative phosphorylation for ATP generation, any dysfunction in this mechanism may impair neuronal function. In PD, α-Syn interacts with the cytochrome c oxidase, which leads to ROS production and apoptosis. So, the nanoplatforms employed for targeting mitochondria aim to reduce superoxide production and increase mitochondrial biogenesis. ROS scavengers aid in producing these effects. Triphenyl phosphonium (TPP) conjugated to ceria nanoparticles showed a pronounced effect in reducing neuroinflammation and mitochondrial cristae restoration, acting as an antioxidant in AD models. The free radical generation and ROS formation contribute majorly to dopaminergic neurodegeneration. Deferoxamine, which chelates iron in neurons, and curcumin, which is an antioxidant, were tested in combination for their antioxidant effect. Normally, when they are given in combination, they cause a toxic effect on cells and show limited efficacy due to decreased brain penetration, bioavailability, and stability. Nanocarrier formation with amphiphilic p68 polymer aids in overcoming these drawbacks with an additional approach of use of dequilinium, a mitochondrial targeting agent, to assess the mitochondrial antioxidant activity. Surface charge is maintained between -1 and - 15, which is required for penetrating BBB and also allows the particles to stay in the bloodstream for longer durations. The results showed better antioxidant activity and cell viability in drugs combined with nanocarrier-treated SHSY5Y cells (Mursaleen et al. 2020). Gene therapy with the neurotropic factor encoding genes (NF genes) has been shown to be effective in gene-mediated dysfunctions in PD (Singh et al. 2023). Adeno-associated virus (AAV)-mediated gene delivery was a conventional method but has limited benefits and unwanted effects such as immunogenicity. NF genes can be delivered using nanotechnologies such as liposomes, plasmid DNA, and chitosan nanoparticles. Recently, delivery of brain penetrating nanoparticles with the help of FUS (focused ultrasound stimulation), which helps them cross the BBB easily, was reported. Studies conducted in 6-OHDA-treated mice upon FUS BPN-mediated targeted delivery of GDNF into the striatum with MRI showed a significant increase in the levels of GDNF (Mead et al. 2017).

5.7.3

Invasive Brain Stimulation

5.7.3.1 Deep Brain Stimulation (DBS) In Parkinson’s disease, motor and nonmotor symptoms appear majorly due to dysfunction of thalamocortical loops in parallel and segregated basal ganglia, which results in alterations in neuronal firing rate, firing patterns, and oscillations in the brain (Alexander et al. 1986)). Many pharmacotherapeutic agents aid in the regulation of symptomatic control, but they come with drawbacks such as on–off effects and also do not provide benefits upon prolonged use. So, there is a need to find an alternative approach for drug therapy where deep brain stimulation comes into light. Deep brain stimulation (DBS) is a technique that works on the principle of

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delivering electrical stimuli using the implanted microelectrodes into specific regions of the brain. In Parkinson’s disease, major degenerative changes occur in two nuclei of basal ganglia, namely subthalamic nuclei (STN) and internal global pallidus (GPi), so these serve as the major targets for stimulation in DBS (Okun 2012). DBS methodology involves the creation of burr holes for implanting microelectrodes in the targeted region of the brain, and these are further connected to an impulse generator. The position of the implanted electrodes is confirmed using techniques such as computed tomography (CT) and magnetic resonance imaging (MRI). Brain edema is allowed to recover at the site of implantation for a few weeks, after which stimulation is given. The settings of the pulse generator, such as pulse widths and frequencies used, vary for each patient. DBS provides advantageous effects on the brain, which might provide possible hope as a long-term therapy for PD. In the brain, it produces an inhibitory effect on cells and exciting fibers, changes the firing rate and pattern of neurons in basal ganglia, and also acts on astrocytes to release calcium and thus aid in neurotransmitter release (Wichmann et al. 2011). Several reports from clinical studies also showed the effectiveness of DBS in PD. A study performed on 156 Parkinson’s patients from Germany and Austria undergoing medication therapy assigned for DBS for 6 months showed a better unified Parkinson’s disease rating scale (UDPRS) rate than a group taking only medication (Deuschl et al. 2006). In another randomized controlled study in the USA, 255 patients who underwent DBS for 6 months were assessed. The results also showed an improved on-time (time for which PD motor symptoms were under control) along with improvement in neurocognitive function (Weaver et al. 2009). Adaptive deep brain stimulation (aDBS) is a modification of conventional DBS,. In cDBS, a high frequency current that continuously stimulates the brain leads to adverse effects, but in aDBS, the stimulation is not continuous. Adaptive DBS works on a principle of applying stimulation based on feedback signal upon detection of certain events, such as when a certain marker crosses the threshold (Popovych and Tass 2019). Local field potential (LFP), a central biomarker, and tremor data, a peripheral biomarker, are used for the feedback response. Studies in nonhuman primate models showed beta oscillations across the basal ganglia through STN in PD conditions, suggesting its role as a potential biomarker (Deffains and Bergman 2019). Short LFP is correlated with motor impairment (Priori et al. 2021). LFP feedback in the beta frequency range has been the focus of adaptive DBS in PD as a correlate of bradykinesia and rigidity, while gamma activity picked up from a cortical strip electrode as a marker of dyskinesia (Little et al. 2013). The amplitude of STN beta activity increases with burst duration, i.e., shorter duration of bursts indicates more imposed motor impairments and upper limb rigidity. Studies were performed to analyze the efficacy of aDBS, where eight patients were subjected to alternative stimulation with aDBS and cDBS (conventional DBS), which resulted in low UPDRS scores with aDBS and also the total electrical energy delivered to tissue is more with cDBS. In contrast, another study performed with cDBS and aDBS reported improved bradykinesia and speech-related side effects in aDBS patients (Bocci et al. 2021).

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Brain Connectomic Studies

A connectome describes the neural connections that functionally links different regions of the brain. The application of brain connectome study in PD aids in determining the disease pathology and progression and helps in tracking the treatment response. Unlike invasive methods such as DBS, connectomic approaches involve noninvasive methods that help bypass the drawbacks of invasive methods used. Noninvasive brain stimulation has the advantage of personalized stimulation and cost-effectiveness with better efficiency than conventional invasive methods. These approaches undoubtedly have the ability to modulate brain plasticity, and thus methods such as tCDS and tACS are used in neurorehabilitation (Madrid and Benninger 2021).

5.7.4.1 Repetitive Transcranial Magnetic Stimulation (rTMS) TMS can be used to assess cortical excitability, where it creates a shifting magnetic field by passing an insulated coil over the scalp with a short, high-intensity electrical current of around 5000 amperes and a 100-s rise time. This magnetic field fluctuation generates electrical currents in the cortex beneath it, which trigger action potentials in the neurons. There are numerous research studies looking at intra-cortical circuits in PD utilizing single or paired pulse TMS (Chen and Chen 2019). Motor threshold (MT) is the lowest output from a simulator to induce small motor-evoked potentials (MEP). A sigmoidal increase of MEP amplitude with increasing TMS intensity until a steady level is referred to as the recruitment curve; this assesses that the excitability of corticospinal neurons that are less excitable in the primary motor cortex is found to increase in PD patients (Bologna et al. 2018). TMS induces motor cortical plasticity by various approaches, such as paired associative stimulation (PAS) involving repetitive peripheral nerve stimulation preceding TMS at the primary motor cortex (M1) to increase cortical excitability. Theta burst stimulation (TBS) is another approach that involves intermittent TBS, which increases the cortical excitation and continuous TBS, which reduces the excitation; another method is repetitive TBS, which at 5 Hz or higher aids in increasing the cortical stimulation. In PD patients, PAS-induced cortical excitation was found to decrease; however, this was further found to be restored by medications and STN DBS in levodopa-induced dyskinesia patients (LID) (Cunic et al. 2002). Motor symptoms of PD are treated with the aid of potential therapies such as rTMS. The combination of DBS and TMS explained the possible interaction between the cortex and basal ganglia. Cortical stimulation with TMS and local field potential assessment from basal ganglia elucidates functional connectivity in motor circuits (Chen and Chen 2019). 5.7.4.2 Transcranial Direct Current Stimulation (tDCS) and Transcranial Alternating Current Stimulation (tACS) in PD Both cathodal and anodal transcranial direct current stimulation (tDCS) are possible. Anodal tDCS often increases cortical excitability, whereas cathodal tDCS decreases it. With a stimulation strength of 2 mA or below, one tDCS session typically lasts no

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longer than 30 min and takes around 20 min on average. For tACS, it is intended to entrain the endogenous oscillations of neuronal populations to external rhythms by applying biphasic and sinusoidal currents. Although the strength of this sort of transcranial electric stimulation is insufficient to induce MEP, TMS can be used to quantify the effects on cortical excitability. The polarity of the stimulation determines how tDCS works on healthy subjects’ motor cortex. In PD patients, a single session of anodal tDCS at M1 dramatically increased MEP amplitude, whereas a session of cathodal tDCS lowered them. This is evidenced by increased MEP amplitude to TMS after anodal tDCS and decreased MEP after cathodal tDCS (Lefaucheur et al. 2017). A study performed by applying tDCS to both motor and prefrontal cortex in PD patients improved gait and bradykinesia but no difference in UDPRS part III scores compared to sham stimulation groups (Benninger et al. 2010). Cathodal, anodal, and sham stimulations were applied to both M1 in random order. Results showed improved finger tapping rates when anodal tDCS was applied to more affected M1 and no effect with cathodal tDCS. In a recent report, a combination therapy involving tDCS and cognitive therapy was used, and the results dominated in the aspect of verbal fluency more than the single therapy result (Cosentino et al. 2017). The stimulation polarity of transcranial alternating current stimulation (tACS) is changed at the frequency of interest. It aims to alter the cortical waveform’s frequency and amplitude background oscillations in the direction of the applied oscillations from outside. A study involved tACS application to the motor cortex for phase cancellation of rest tremor rhythm, which was recorded from a peripheral accelerometer in a single PD patient. When tACS was aligned with specific phases, rest tremor was suppressed (Brittain et al. 2013).

5.7.4.3 Transcranial Random Noise Stimulation (tRNS) The effects of noise on the human nervous system can range from cellular to systemic levels on signal processing. Noise can be applied to cortical circuits using transcranial stimulation to modulate neuronal activity in both healthy brains and in neurological patients, improving its function. tRNS is a technique that seems promising but is less explored than other noninvasive neuromodulatory techniques. tRNS is a noninvasive electrical stimulation of the brain where a pair of electrodes are used to oscillate current at random frequencies through the scalp. Mild cognitive impairment is one of the common nonmotor symptoms of Parkinson’s disease. tRNS is found to induce cortical excitability and was found to have effects on PD MCI patients in enhancing motor and cognitive functions. tRNS applied over M1 of PD patients was found to excite cortical regions and induce motor-evoked potentials (Moliadze et al. 2014). The tRNS effects rely on various parameters such as targeted area, intensity, duration, and type of stimulation. The results showed an improved motor performance and reduced UDPRS, but no significant difference was found in motor function, including bradykinesia and walking ability (Monastero et al. 2020). The increased cortical excitability of cortical areas by tRNS was found to be a result of a phenomenon called “stochastic resonance (SR),” where the subthreshold that are not sufficient to cause activation are increased by adding a noise such that these

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thresholds can be amplified leading to nerve stimuli synchronization (Antal and Herrmann 2016). Ample evidence suggests the role of tRNS in cortical excitability, but there was no proper evidence for its effect on synaptic plasticity; it seems to act via voltage-gated sodium channels, which may facilitate neuroplastic changes. These sodium channels were also found to be more responsive to lower signals when noise is applied. The tRNS alone cannot be effective in inducing neuroplastic changes; when used in combination with other brain stimulation methods, it could provide better results (Potok et al. 2022). The level of noise applied to the system needs to be optimized based on anatomy and task type to improve performance, which is based on SR theory (van der Groen et al. 2019).

5.7.4.4 Transcranial Pulsed Current Stimulation (tPCS) tPCS works based on two parameters, which are pulse duration (Pd) and inter-pulse interval (IPI). In contrast to the continuous flow of current in anodal tDCS, tPCS allows the flow of positive pulses separated by predetermined IPI. Based on the amplitude of pulses, duration, and IPI, this aids in the production of different ranges of net direct current components (NDCCs). Similar to tDCS, the current is applied over the scalp, and the current is tolerated by normal individuals, but due to discontinuous nature of current flow, the individual feels light flashes in eyes, known as retinal phosphene, which can be observed upon application of current (Jaberzadeh et al. 2014). Currently, the optimum parameters for tPCS to induce cortical spinal excitation (CSE) is unknown, but a study showed that identical Pd and shorter IPIs induce major changes in CSE. tDCS and tPCS on M1 induce changes in CSE. In addition, the static and dynamic nature of tPCS allows for larger changes in CSE (Jaberzadeh et al. 2015). A study was performed to compare the CSE of different stimulation techniques, such as tDCS and tPCS with short inter-pulse interval (SIPI) and tPCS with long inter-pulse interval (LIPI). CSE of the primary motor cortex was assessed before and after applying various methods, which showed an enhanced CSE in the M1 region upon tPCS (SIPI), but no major changes were observed with other methods, which explains the promising role of tPCS as a neuromodulator tool (Jaberzadeh et al. 2014). 5.7.4.5 Focused Ultrasound (FUS)-Based Gene Therapy MR image-guided focused ultrasound is a current approach that has the capability of noninvasively opening the BBB for spatially targeted delivery into the brain. This involves the use of microbubbles, which upon activation exert various mechanical forces on the walls and disrupt the tight junctions temporarily, thus facilitating the active transport processes. This opened barrier is restored within 6 h, thus ensuring safety (Vlachos et al. 2011). With this special combination of FUS-targeted BBB opening and brain-penetrating nanoparticle (BPN)-mediated brain distribution, GDNF plasmid delivery offers a single therapeutic strategy with improved spatial specificity, increased GDNF expression, and improved functional therapeutic results. Locomotor functions in 6-OHDA-treated mice were restored over the course

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of the 12-week experiment when FUS in combination with GDNF-BPN was applied (Mead et al. 2017).

5.8

Key Roadblocks and Pitfalls in PD Management

The identification of PD-related dopamine deficiency and the levodopa’s introduction revolutionized the way PD patients were therapeutically managed. Nevertheless, motor jerks and dyskinesias are noted in most patients’ under levodopa treatment (>90%) between 5 and 10 years after the start of treatment (Ahlskog and Muenter 2001). Many other therapies, including surgical procedures like deep brain stimulation, have been tested for the management of these motor problems with extensive success. However, none of these alternative therapies have been successful to date in order to substantially surpass the best response of levodopa. Consequently, the PD’s clinical profile has changed, and it is now typical to observe patients who have had their disease for at least 15–20 years. Functional issues like motor imbalance, dysfunctional gait, difficulties speaking and swallowing, and urinary dysfunction, in addition to nocturnal sleep disorders and severe constipation, are becoming more common (Ondo et al. 2001). L-DOPA is still the preferred medication for the treatment of PD due to its remarkable effectiveness on motor parkinsonian symptoms, and given that it is a relatively affordable therapy (Salat and Tolosa 2013). Despite these significant benefits, L-DOPA has no effect on many of the difficult issues of PD patients. Several motor functions, such as speech, gait, and posture imbalance, do not react to L-DOPA treatment; symptoms tend to deteriorate over time. Additionally, L-DOPA does not lessen nonmotor parkinsonian symptoms like hallucination, cognitive impairment, and orthostatic hypotension. Dopamine replacement therapy initially significantly enhances the motor PD patient’s symptoms and quality of life. Nevertheless, in a few years, treatment with levodopa induces the genesis of unwanted, debilitating, involuntary movements known as “levodopa-induced dyskinesia” (LID). With longer treatment periods, this LID, characterized by atypical combinations of dystonia and chorea, gets progressively worse. LID can show several patterns of expression, being most severe at the peak anti-parkinsonian effect of levodopa, at the beginning and end of the dose, or when off-treatment (Brotchie et al. 2005). In addition, dopaminergic agonists also come with side effects such as confusion, hallucinations, and psychosis. Standard pharmaceutical treatment for Parkinson’s disease (PD) has a poor therapeutic efficacy, providing only symptomatic relief and failing to address the underlying causes of the disease or slow its progression. Nonetheless, these pharmacotherapy approaches come with drawbacks such as restricted access across barrier layers, poor in vivo stability, low activity time, and premature drug release (Khatri et al. 2023). The low concentration of drugs that these treatments achieve in the central nervous system after systemic administration is one of their main drawbacks. Indeed, the blood–brain barrier (BBB) in particular prevents drugs from being delivered to the brain effectively, which lowers the

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potential benefit from taking the medication (Tonda-Turo et al. 2018). A few of these limitations were overcome by cellular therapy and DBS, but even these alternatives are ineffective in stopping the disease progression. Also, patients may find it difficult to undergo DBS due to various factors, one of which is its high cost and adverse events such as infection and intracranial hemorrhage due to electrode implantation (Fenoy and Simpson 2012). In addition, some patients exhibit postoperative behavioral changes such as depression and neurological side effects such as cognitive impairment, decreased verbal fluency, and also emotional and psychological side effects. However, one should consider the risks versus benefits of undergoing the therapy (Temel 2010).

5.9

Conclusion

Although efficacious at the initial stages of therapy, conventional therapy fails to offer disease-modifying ability besides causing severe side effects and therapeutic resistance over a period of time. Hence, therapeutic tailoring was done by designing pathology-targeted therapeutic agents that have the ability to overcome existing therapeutic failure causes. A detailed description is provided in the text for the newer approaches with their mode of action in disease modification. Besides pathological alterations in neuroanatomy, neurocircuitry of PD complexly linking dopaminergic projections to different brain parts ranging from the prefrontal motor cortex to the brainstem is altered. This was also targeted as a therapeutic approach through the brain stimulation technique. Despite such advances in scientific understanding of disease pathology, the diagnostic and therapeutic approaches still revolve around protein dysregulation and dopaminergic neuron degradation. The progress in the pathological science of PD reflects a need to retrospect the current understanding of PD pathology, which might instigate redirection of diagnostic and therapeutic methods to something more associable with disease progression like organellar dysfunction or post-translational protein dysregulation. The challenge with advancing techniques is missing guidelines for therapeutic intervention, cost-effectiveness, and applicability of the alternative therapy based on the disease progression stage. Therefore, a regulated guideline is required for forming a foundation for a welldefined regime for disease management combining the conventional and newer alternative approaches based on the disease nature and progression rate. Another major hurdle faced by clinicians in the current setting is that disease cure still remains missing from the management option. Further research in these fields might help in early disease diagnosis and an effective management.

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Pathophysiology and Management Approaches for Epilepsy Enes Akyuz and Betul Rana Celik

Abstract

Epilepsy is a neurological disease occurring as a result of disruption of the ion concentration balance in neurons. Another problem that accompanies this imbalance is the alteration of excitatory and inhibitory neurotransmitter settings. In particular, the inhibition of GABA neurotransmitters during seizures does not occur, which is expected to occur in a healthy state of neurons. Another situation is that excitatory glutamate neurotransmitters change in quantity and receptor type during seizures. Ionic and neurotransmitter disorders are one of the leading conditions in the pathophysiology of epilepsy. These disorders can be treated with antiepileptic drugs, but in drug-resistant cases, vagus nerve stimulation and surgical operations are performed. In this chapter, drug management of ionic and neurotransmitter imbalances in epileptic seizures, the effect of vagus nerve stimulation on epileptic seizures, and the role of surgical operations in damping seizures will be discussed. Keywords

Vagus nerve stimulation · Surgery · Antiepileptic drugs · Epilepsy

E. Akyuz (✉) Department of Biophysics, International School of Medicine, University of Health Sciences, Istanbul, Türkiye B. R. Celik School of Medicine, Marmara University, Istanbul, Türkiye # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Mishra, H. Kulhari (eds.), Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities, https://doi.org/10.1007/978-981-99-6807-7_6

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E. Akyuz and B. R. Celik

Introduction

Epilepsy occurs as a result of abnormal neural activity in the brain. The prominent feature of this disease is recurrent seizures (Akyuz et al. 2021). Epileptic seizures occur when the concentration of K+, Na+, Cl-, and H+ ions changes intra- and extracellular. As a result of this ion concentration change, deterioration in neural activity occurs (Raimondo et al. 2015). During seizures of epilepsy patients, an imbalance of neurotransmitters in the brain to be observed. Imbalances between glutamate, an excitatory neurotransmitter, and gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter, are neurotransmitter imbalances that cause epileptic seizures. However, dysregulation of catecholaminergic neurotransmitters and opioid peptides may also be effective in epileptogenesis (Engelborghs et al. 2000). Medications, surgical interventions, neuromodulatory devices, diets, and immunotherapy are available to control seizures (Fig. 6.1) (Sirven 2015).

Antiepileptic Drugs

Epilepsy Surgery

Management Approaches for Epilepsy Deep Brain Stimulation

Immunotherapy

Vagus Nerve Stimulation

Ketogenic Diet

Fig. 6.1 Management approaches for epilepsy. To control epileptic seizures, antiepileptic drugs, epilepsy surgery, neuromodulatory devices such as deep brain stimulation and vagus nerve stimulation, ketogenic diet, and immunotherapy are available

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The aim of the treatment of epilepsy is to enable anti-seizure drugs (ASDs) to stop epileptic seizures with minimal side effects. There are 26 drugs approved by the US Food and Drug Administration (FDA) for the treatment of epilepsy (Kanner and Bicchi 2022). Although ASD treatment is applied to epilepsy patients, seizures continue in approximately one-third of the patients. Patients with epilepsy who continue to have seizure activity despite receiving ASD are patients with medically resistant epilepsy. Since drug treatment is not beneficial for these patients, non-pharmacological surgical methods can be treated to control epileptic seizures (Wang et al. 2020). Seizure focus may not be found in patients with drug-resistant epilepsy. Surgical methods cannot be applied to epilepsy patients whose seizure focus cannot be found. The non-pharmacological and nonsurgical alternative treatment of these patients is neuromodulation (Rincon et al. 2021). Another non-pharmacological treatment method in epilepsy is the ketogenic diet (KD), which is a high-fat, low-protein, and carbohydrate diet (D’Andrea Meira et al. 2019). In addition to these methods, early immunotherapy is effective in patients with autoantibody-related epilepsy (Bakpa et al. 2016). Idiopathic generalized epilepsy (IGE) study performed that the effect of mono and combination ASM therapy on seizure control was investigated. Instead of monotherapy with levetiracetam, valproateti, or lemotrigine ASDs, combination therapy with these drugs was effective in HDI (Pipek et al. 2022). Ineffective monotherapy of valproate given in utero may be effective in combination with other ASMs. Improving the prediction of outcomes of epilepsy surgery by electroencephalography (EEG) study showed that EEG findings from patients with epilepsy were important for predicting the outcome of epilepsy surgery (Fitzgerald et al. 2021). The nomogram can be used to evaluate the relevance of findings before and after epilepsy surgery. Clinical epilepsy study used invasive and noninvasive vagus nerve stimulation (VNS) and improved the verbal memory performance. According to the results of the study, invasive VNS improved the verbal performance of memory positively (Mertens et al. 2022). Longer stimulation of the vagal pathway may be more effective in improving the memory of patients with epilepsy. For the treatment of patients with epilepsy, antiepileptic drugs, epilepsy surgery, neuromodulatory devices, diets, and immunotherapy are used to control epileptic seizures. In this chapter, epilepsy management approaches applied to control seizures of patients with epilepsy are explained. It is important to know the approaches used to manage the disease of epilepsy patients, to improve existing treatment methods, and to develop new treatment methods.

6.2

Antiepileptic Drugs

Antiepileptic drugs, or commonly called anti-seizure drugs (ASDs), are the basis for the treatment of epilepsy. There are about 30 ASDs for the challenging treatment of patients with epilepsy. In addition to these drugs, about 30 compounds have the potential to be antiepileptic drugs (Löscher and Klein 2021). Examples of new ASDs are cannabidiol, brivaracetam, and stiripentol. Also, pregabalin, lacosamide,

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oxcarbazepine, lamotrigine, topiramate, levetiracetam, zonisamide (Abou-Khalil 2019), phenytoin (Patocka et al. 2020), and gabapentin (Goa and Sorkin 1993) are some of the ASDs for seizure prevention. ASDs control the excitability of nerve cells using molecular targets. Thanks to this control, seizures are stopped before nonepileptic neural activity is impaired. For example, seizures can be controlled by targeting GABAA receptors, a receptor for the GABA neurotransmitter (Rogawski and Löscher 2004a,b). ASDs regulate the repression of voltage-gated cation channels and GABA. T-type voltage-gated calcium channels, α2-δ voltage-gated calcium channel subunits, SV2A synaptic vesicle protein, and alpha subunits of voltage-gated sodium channels are the primary molecular units that these drugs act on. Potential molecular targets for ASDs are ionotropic glutamate receptors, a subunit of voltage-gated calcium channels, and voltage-gated potassium channels of type M or A. Increasing knowledge about ion channels lead to the development of new targets for ASDs (Meldrum and Rogawski 2007). Alternative pathological channels are available for targeting ASDs. Related to this, gabapentin is an ASD that regulates subunits of the alpha2delta voltageactivated calcium channel (Rogawski and Löscher 2004a,b). The relationship between the administration of polytherapy with antiepileptic drugs that inhibit voltage-gated sodium channels in patients with epilepsy and the arrhythmionic ST-T abnormality in EKG that can be seen in these patients was investigated. As a result of the study, ST-T abnormalities were frequently observed in patients using antiepileptic drugs (Ishizue et al. 2016). Accordingly, the use of antiepileptic drugs that inhibit voltage-gated sodium channels may be associated with Brugada-type ST elevation in EKG. Clinical study, patients with drug-resistant epilepsy, investigated the relationship between the antiepileptic drug dose and the long-term response to the drug. The best response of the patient to ASDs used for monotherapy was obtained as a result of low-dose administration of the drug (Poolos et al. 2017). Accordingly, the doses of ASD routinely exposed to epileptic patients may be unnecessary. Mesial temporal lobe epilepsy (MTLE) from hippocampal sclerosis including clinical phenotypes were observed in patient responses to antiepileptic drugs. Patients with drug-resistant MTLE who did not undergo surgery did not have a long-term seizure with antiepileptic drug administration. However, seizure recurrences occurred in these patients in the following period (Gomez-Ibañez et al. 2013). Left or bilateral lesion in patients with MTLE may cause a worse course of epilepsy. Patients with MTLE with hippocampal sclerosis study for post-surgical antiepileptic drugs, disease management and long-term seizure status were investigated. According to this study, the need for antiepileptic drug use decreased in patients with MTLE with hippocampal sclerosis who underwent surgery (Pimentel et al. 2012). Untimely reduction of antiepileptic drugs may result in recurrence of seizures in one out of every three patients. Pediatric epilepsy study examined the efficacy of the first antiepileptic drug given to the patients. 66.2% of the pediatric patients included in the study recovered from their seizures with the first antiepileptic drug, which is usually at a moderate dose (Ma et al. 2009). Tolerability and efficacy can be used when determining the overall efficacy of antiepileptic drugs (Table 6.1).

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Table 6.1 Summaries of findings reporting the role of antiepileptic drugs in epilepsy S. N. 1

Study types Human study

Epilepsy model Epilepsy patients (n = 120)

2

Human study

Epilepsy patients (n = 164)

3

Human study

Patients with MTLE (n = 68)

4

Human study

Epilepsy patients (n = 164)

5

Human study

Epilepsy patients (n = 520)

Observation ST-T abnormalities in EKG are common in patients using antiepileptic drugs

The best response of the patient to ASMs used for monotherapy was obtained as a result of low-dose administration of the drug Patients with drugresistant MTLE who did not undergo surgery did not have a longterm seizure with antiepileptic drug administration The need for antiepileptic drug use decreased in patients with MTLE with hippocampal sclerosis who underwent surgery 66.2% of the pediatric patients included in the study recovered from their seizures with the first antiepileptic drug, which is usually at a moderate dose

Remarks The use of antiepileptic drugs that inhibit NaV channels may be associated with Brugada-type and ST elevation in EKG The doses of ASM routinely exposed to patients with epilepsy may be unnecessary

References Ishizue et al. (2016)

Poolos et al. (2017)

Left or bilateral lesion in patients with MTLE may cause a worse course of epilepsy

GomezIbañez et al. (2013)

Untimely reduction of antiepileptic drugs may result in recurrence of seizures in one out of every three patients

Pimentel et al. (2012)

Tolerability and efficacy can be used when determining the overall efficacy of antiepileptic drugs

Ma et al. (2009)

ASM anti-seizure medication, MTLE mesial temporal lobe epilepsy, NaV voltage-gated sodium channel

6.3

Epilepsy Surgery

Despite taking medication, approximately one-third of patients with epilepsy continue to have seizures. Epilepsy surgery to be applied to reduce the frequency of seizures in these patients. The operation-related mortality rate in this surgery is 0.1%. However, surgery is an effective and safe treatment for drug-resistant epilepsy patients (Health Quality Ontario 2012). Although neurosurgery is a powerful and effective technique in the treatment of epilepsy, this has not used enough. Preoperative reports are important to identify patients who will undergo this surgery and to

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make the surgery safer. The use of neuroimaging is necessary to make epilepsy surgery safe. In this direction, invasive EEG is used to make the decision for surgery in patients with epilepsy (Vakharia et al. 2018). Invasive EEG enables to find the epileptogenic region in patients with drug-resistant focal epilepsy. Imaging with electrodes placed inside the head provides higher-resolution information, better definition of epileptogenic regions, and recording of wide-frequency electrical activity compared to electrodes used outside the head. Stereo-EEG applied with intracranial electrodes is used in the invasive evaluations of epileptic patients before surgery. Although invasive evaluation has risks, it has more benefits in epilepsy surgery (Enatsu and Mikuni 2016). There are barriers in this surgery that prejudices against surgery in patients and misinformation about the risks of surgery, knowledge gaps in some physicians, insufficient access to information among the public, and socioeconomic biases can be given as examples (Samanta et al. 2021). Clinical focal epilepsy study examined that the molecular and genetic characteristics of patients’ seizure-free periods after resective surgery showing the ABCB1 gene is closely related to epileptogenesis and surgical outcomes (Louis et al. 2022). The ABCB1 gene may be a marker for the patient’s condition after surgery. The frequency of genetic testing applied to patients considered for epilepsy surgery was investigated in a cohort study. As a result of the study, the use of genetic testing in patients with focal epilepsy who are candidates for epilepsy surgery has increased over time (Sanders et al. 2019). The result of genetic testing may be useful for the selection of patients who are scheduled for resective surgery. The results of epilepsy surgery in lesional epilepsy were investigated in a longitudinal perspective study. As a result of the study, most patients with drug-resistant lesional epilepsy were positively affected by epilepsy surgery (Mehvari Habibabadi et al. 2021). Resective surgery may be an important method for the treatment of epilepsy, especially in developing countries. Complications of epilepsy surgery were examined in a retrospective study with invasive monitoring. According to the results of the study, epilepsy surgery was found to be safe and a low rate of postoperative morbidity occurred in developed centers (Bsat et al. 2022). Multidimensional monitoring of complications in epilepsy surgery may help identify risk factors. Examining the effect of epilepsy surgery on patients’ cognition observed that patients had errors in executive function tasks and weakened working memory after surgery (Partanen et al. 2022). According to this study, cognitive performance deficits may be observed after epilepsy surgery (Table 6.2).

6.4

Neuromodulatory Devices

Patients with drug-resistant epilepsy who are not amenable to epilepsy surgery can be treated with neuromodulation. This neuromodulation alternatives are VNS, deep brain stimulation (DBS), and sensitive neurostimulation (RNS). Thanks to these neuromodulation options, there has been an improvement in the control of epileptic seizures (Abouelleil et al. 2022).

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Table 6.2 Summaries of findings reporting the role of surgery in epilepsy S. N. 1

Study types Human study

2

Human study

3

Human study

4

Human study

Epilepsy patients

5

Human study

Adult epilepsy patients (n = 46)

6.4.1

Epilepsy model Epilepsy patients (n = 201)

Adult epilepsy patients (n = 1363) and children epilepsy patients (n = 1022) Adult epilepsy patients (n = 148)

Observation The ABCB1 gene may be closely associated with epileptogenesis and surgical outcomes The use of genetic testing in patients with focal epilepsy who are candidates for epilepsy surgery has increased over time Most patients with drug-resistant lesional epilepsy are positively affected by epilepsy surgery

After epilepsy surgery, a low rate of postoperative morbidity has occurred in developed centers Patients have errors in executive function tasks and weakening in working memory after surgery

Remarks The ABCB1 gene may be a marker for the patient’s condition after surgery The result of genetic testing may be useful for the selection of patients scheduled for resective surgery Resective surgery may be an important method for the treatment of epilepsy, especially in developing countries Multidimensional monitoring of complications in epilepsy surgery may help identify risk factors Cognitive performance deficits can be seen after epilepsy surgery

References Louis et al. (2022)

Sanders et al. (2019)

Mehvari Habibabadi et al. (2021)

Bsat et al. (2022)

Partanen et al. (2022)

Vagus Nerve Stimulation

VNS is a treatment method applied by stimulation of the left vagus nerve with implanted electrodes. The mechanism of action of this stimulation is not fully known. However, the effectiveness of VNS is safe. Approximately one-third of patients with this neuromodulation treatment experience a reduction in half of their seizures after 3 months of treatment. After 18 months of VNS application, half of the patients experience a reduction in their seizures, thanks to this treatment. Besides the positive effects of VNS, there are also side effects. These side effects are cough, shortness of breath, and hoarseness (Binnie 2000). Long-term outcome of VNS was observed in a study of patients with drugresistant epilepsy. Half of the patients who received VNS treatment in the study were positively affected by the treatment. Response remained stable in most patients who were positively affected by VNS treatment (Polkey et al. 2022). Patient data

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Table 6.3 Summaries of findings reporting the role of vagus nerve stimulation in epilepsy S. N. 1

Study types Human study

Epilepsy model Epilepsy patients (n = 464)

2

Human study

Children epilepsy patients (n = 29)

3

Human study

Epilepsy patients (n = 37)

4

Human study

Epilepsy patients (n = 46)

5

In vivo

Beagle dogs (n = 8)

Observation Half of the patients who received VNS treatment were positively affected by the treatment VSS significantly reduced the frequency of seizures in children with drug-resistant epilepsy Patients who did not respond to epilepsy surgery experienced only marginal improvement in seizures as a result of VSS treatment In patients with genetic generalized epilepsy, generalized tonic-clonic seizures were decreased as a result of VNS VNS increased the NE neurotransmitter in the brains of dogs with seizures

Remarks Patient data recorded in the clinic can provide retrospective information VNS therapy can be an effective and safe method in children with drug-resistant epilepsy Since VNS application has no surgical risk, it can provide the best seizure treatment if its side effects are minimized

References Polkey et al. (2022) Bodin et al. (2016)

Vale et al. (2011)

VNS may be a treatment alternative in patients with genetic generalized epilepsy

Suller Marti et al. (2020)

Research may continue to fully understand the effect of VNS on brain NE levels

Martlé et al. (2015)

NE norepinephrine, VNS vagus nerve stimulation

recorded in the clinic can provide retrospective information. The effect of VNS on children with drug-resistant epilepsy examined that VNS significantly reduced the frequency of seizures in children with drug-resistant epilepsy (Bodin et al. 2016). Accordingly, VNS treatment may be an effective and safe method in children with drug-resistant epilepsy. The effect of VNS treatment on patients who have had unsuccessful epilepsy surgery has been investigated. According to the results of this study, patients who did not respond to epilepsy surgery experienced only marginal improvement in seizures as a result of VNS treatment (Vale et al. 2011). Since VNS application has no surgical risk, it can provide the best seizure treatment whether the side effects are minimized. PTZ-induced seizures in dog study investigated the effect of VNS on CSF monoamines and VNS increased the neurotransmitter norepinephrine (NE) in the brain of dogs with seizures (Martlé et al. 2015). Research may continue to fully understand the effect of VNS on brain NE levels. Patients with drug-resistant generalized epilepsy study revealed the effect of VNS on patients and generalized tonic-clonic seizures were decreased (Suller Marti et al. 2020). In conclusion, VNS counted as an integrated treatment for patients with genetic generalized epilepsy (Table 6.3).

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163

Deep Brain Stimulation

DBS can invasively measure the pathological activity of the brain. However, this method can provide stimulation to correct abnormally functioning brain networks in neurological disorders (Lozano et al. 2019). Stimulation of the anterior thalamus (ANT) and hippocampus with DBS reduces the frequency of seizures in patients with resistant epilepsy (Li and Cook 2018). The stimulation of DBS in ANT and its effect on seizures in patients with drugresistant epilepsy investigated that DBS gave important information in the noninvasive measurement of therapeutic impedances (Möttönen et al. 2022). Therapeutic impedance measurements can be used to select active sites in the stimulation of ANT with DBS. Patients with drug-resistant epilepsy to investigate the effect of using 1.5 T magnetic resonance imaging (MRI) targeted ANT in DBS. To target ANT with DBS, visualization of ANT could be achieved with 1.5 T MRI preoperatively (Jiltsova et al. 2016). Thanks to imaging with MRI method, the deficiencies of other imaging methods can be eliminated. Power spectra examining in patients with drug-resistant epilepsy showed that ANT-DBS caused a decrease in the power of gamma and beta bands in the left frontal lobe and left temporal lobe (Tong et al. 2022). Therefore, beta and gamma bands may be a marker for the results of ANT stimulation in DBS. DBS has been administered to patients who have been living with drug-resistant epilepsy for a long time. As a result of DBS applied to the ANT of these patients, the severity of their seizures decreased (Passamonti et al. 2021). DBS can reduce the seizure frequency of patients with epilepsy. Patients with drug-resistant generalized epilepsy study conducted the effect of coadministration of DBS and VNS on patients was investigated. In the study, the number of patients with epilepsy who responded to VNS-DBS combined therapy was twice the number of patients who responded to VNS therapy alone (Cukiert et al. 2022). Finally, combined neuromodulation may be useful for the treatment of patients with epilepsy (Table 6.4).

6.4.3

Responsive Neurostimulation

RNS can be used to control seizures in patients with drug-resistant epilepsy. Thanks to this treatment method, seizures of patients with epilepsy are reduced. Neurostimulation is provided by closed-loop electrocorticography in the treatment of RNS. It is important to be careful in the use of RNS to eliminate the risks (Kusyk et al. 2022). The acute effects of RNS in patients with drug-resistant epilepsy were investigated in a retrospective study. In patients with drug-resistant epilepsy treated with RNS showed decrease in seizures (Rønborg et al. 2021). Intracranial EEG can be used in the treatment of RNS and the safety and efficacy of RNS were investigated in patients with autoimmune epilepsy. After the RNS treatment applied to the patients with drug-resistant epilepsy in this study, the seizures decreased (Chen et al. 2022). RNS treatment may be a safe option in patients with autoimmune

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Table 6.4 Summaries of findings reporting the role of deep brain stimulation in epilepsy S. N. 1

Study types Human study

2

Human study

3

Human study

ANT in nonepileptic subjects (n = 2), patients with VSS (n = 3), stereotactic MRI (n = 3), patients with ANT-DBS (n = 7). Epilepsy patients (n = 20)

4

Human study

Epilepsy patients (n = 6)

5

Human study

Male epilepsy patients (n = 11)

Epilepsy model Epilepsy patients (n = 16)

Observation DBS has provided important information in the noninvasive measurement of therapeutic impedances To target ANT with DBS, visualization of ANT could be achieved with 1.5 T MRI preoperatively

Remarks Therapeutic impedance measurements can be used to select active sites in the stimulation of ANT with DBS The deficiencies of other imaging methods can be eliminated with MRI imaging

References Möttönen et al. (2022)

ANT DBS caused a decrease in the power of the gamma and beta bands in the left frontal lobe and left temporal lobe As a result of DBS applied to the ANT of patients with drug-resistant epilepsy, the severity of the patients’ seizures decreased The number of patients with epilepsy who responded to VNS-DBS combined therapy was twice that of those who responded to VNS therapy alone

Beta and gamma bands may be a marker for the results of ANT stimulation in DBS

Tong et al. (2022)

DBS can reduce the frequency of seizures in patients with epilepsy

Passamonti et al. (2021)

Combined neuromodulation may be useful for the treatment of patients with epilepsy

Cukiert et al. (2022)

Jiltsova et al. (2016)

ANT anterior nucleus of the thalamus, DBS Deep brain stimulation, MRI magnetic resonance imaging, VNS vagus nerve stimulation

epilepsy. The relationship of RNS treatment with the condition of the patient with epilepsy in seizure control was examined. The effect of RNS treatment on seizure frequency depended on the disease status of the epileptic patient (Chiang et al. 2021). In the treatment of patients with epilepsy with RNS, the patient’s condition

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Table 6.5 Summaries of findings reporting the role of responsive neurostimulation in epilepsy S. N. 1

Study types Human study

Epilepsy model Epilepsy patients (n = 256)

2

Human study

Epilepsy patients (n = 85)

3

Human study

Adult epilepsy patients (n = 25)

4

Human study

5

Human study

Subjects (n = 10) and pregnant epilepsy patients (n = 14) Epilepsy patients

Observation In patients with drugresistant epilepsy treated with RNS, seizures were reduced After RNS treatment in patients with drugresistant epilepsy, seizures decreased The effect of RNS treatment on seizure frequency depended on the disease state of the patient with epilepsy No malformation occurred in pregnant patients with epilepsy

Side effects caused by RNS were less than those caused by VNS

Remarks Intracranial EEG can be used in the treatment of RNS

References Rønborg et al. (2021)

RNS treatment may be a safe option in patients with autoimmune epilepsy In the treatment of patients with epilepsy with RNS, the patient’s condition may be an important parameter New research may be conducted to prove the safety of RNS in pregnant patients with epilepsy

Chen et al. (2022)

VNS and RNS therapy can be safely administered simultaneously

Chiang et al. (2021)

Li et al. (2021)

Brown et al. (2022)

EEG electroencephalography, RNS responsive neurostimulation, VNS vagus nerve stimulation

is an important parameter. Pregnant patients with drug-resistant epilepsy study investigated the effect of RNS. As a result of the study, no malformation occurred in pregnant patients with epilepsy (Li et al. 2021). New research needed to prove the safety of RNS in pregnant patients with epilepsy. The effect of VNS and RNS treatments on patients with drug-resistant focal epilepsy has been observed and side effects caused by RNS were less than those caused by VNS (Brown et al. 2022). According to these studies, VNS and RNS treatment are safely administered simultaneously (Table 6.5).

6.5

Diets

KD is a dietary therapy used to control seizures in patients with drug-resistant epilepsy. More than half of the seizure frequency is reduced in children and adolescents with epilepsy who are treated with this treatment. KD treatment is administered as a high-fat diet for 2 years. Although the effect of KD on reducing the frequency of seizures is not fully known, ketone bodies produced as a result of KD modulate neurotransmitters in the brain (Lima et al. 2014). This treatment is a high-fat, low-carb diet and fat is used as the main energy source through ketone

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bodies instead of glucose in KD (Ko et al. 2022). There are four KD treatments including classic KD (cKD), medium-chain triglyceride KD (MCTKD), modified Atkins diet (MAD), and low glycemic index therapy (LGIT). The difference between the qualities of the four KDs is poorly known (Wells et al. 2020). KD treatment in epilepsy is effective in reducing the frequency of seizures and eliminating the negativities in cognition and behavior related to epilepsy. Although the effects of KD are not completely known, treatment of KD is safe. However, KD treatment has side effects. The prominent ones among these side effects are weight loss, glycemic index, and metabolic disorders (Ruan et al. 2022). Calorie restriction and a gluten-free diet may also be useful dietary treatments for drug-resistant epilepsy (Verrotti et al. 2020). Cerebrospinal fluid (CSF) samples of KD children with epilepsy examined that KD changed dopamine and serotonin levels in CSF samples of children with epilepsy (Dahlin et al. 2012). This shift is important for understanding the mechanism of KD in epilepsy. The association of high tumor necrosis factor (TNF) with seizure-freeness as a result of KD was investigated in children with drug-resistant epilepsy. According to the study, the rate of benefiting from KD increased with TNF elevation in children with drug-resistant epilepsy (Dahlin et al. 2022). Parts of the immune system may be a marker of disease progression in patients with epilepsy receiving KD therapy. Cholecystokinin-8 (CCK-8) and leptin levels were investigated in blood samples of patients with drug-resistant epilepsy receiving KD therapy. CCK-8 levels were significantly increased in the serum of patients with epilepsy who responded to KD treatment (Lambrechts et al. 2016). Due to the increase in CCK-8 as a result of KD treatment, this treatment may have a reducing effect on epileptic seizures. The effect of KD treatment on amino acid and neurotransmitter levels in CSF levels of children with epilepsy was observed. As a result of KD, the levels of lysine and arginine amino acids were altered in the CSF of children with epilepsy. However, biogenic amines did not change as a result of KD in the CSF of children with epilepsy (Sariego-Jamardo et al. 2015). Some amino acids may be associated with KD treatment in epilepsy. The effect of KD in adults and children with epilepsy has been studied. As a result of KD treatment, seizure severity decreased in 68.4% of adults with epilepsy. However, seizure severity was reduced in 63.6% of children with drug-resistant epilepsy (He et al. 2022). As a result, KD treatment can be an effective treatment in adults as well as children with epilepsy (Table 6.6).

6.6

Immunotherapy

Immunotherapy, which targets the immune system in epilepsy, is a rapid treatment method and the immune system works actively in patients with drug-resistant epilepsy. Immunotherapy is administered with medication to control epileptic seizures. Some of these drugs are azathioprine, corticosteroids, plasmapheresis, and immunoglobulins. Drugs used in immunotherapy function as steroid preservatives (Melvin and Huntley Hardison 2014).

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Table 6.6 Summaries of findings reporting the role of diets in epilepsy S. N. 1

Study types Human study

Epilepsy model Epilepsy patients

2

Human study

Children epilepsy patients (n = 28)

In children with drug-resistant epilepsy, the rate of benefiting from KD increased with TNF elevation

3

Human study

Epilepsy patients (n = 54)

4

Human study

Epilepsy patients (n = 60)

5

Human study

Adult epilepsy patients (n = 19), children epilepsy patients (n = 29)

CCK-8 levels were significantly increased in the serum of patients with epilepsy who responded to KD treatment Biogenic amines were not altered as a result of KD in the CSF of children with epilepsy As a result of KD treatment, seizure severity decreased in 68.4% of adults with epilepsy. However, seizure severity decreased in 63.6% of children with drug-resistant epilepsy

Observation KD altered dopamine and serotonin levels in CSF samples of children with epilepsy

Remarks Knowing the neurotransmitter change in CSF is important to understand the mechanism of KD in epilepsy Parts of the immune system may be a marker of disease progression in patients with epilepsy receiving KD therapy Due to the increase in CCK-8 as a result of KD treatment, this treatment may have a reducing effect on epileptic seizures Several amino acids may be associated with KD treatment in epilepsy KD treatment can be an effective treatment for adults as well as children with epilepsy

References Dahlin et al. (2012)

Dahlin et al. (2022)

Lambrechts et al. (2016)

SariegoJamardo et al. (2015)

He et al. (2022)

BOS cerebrospinal fluid, CCK-8 cholecystokinin-8, KD ketogenic diet, TNF tumor necrosis factor

6.7

Conclusion

Epilepsy is a neurological disease in which abnormal neural activity occurs in the brain as a result of an imbalance of neurotransmitters and changes in ion concentration in the brain of patients. Although patients have side effects, antiepileptic drugs are used to control epileptic seizures occurring as a result of abnormal nervous activity in epilepsy patients. These drugs regulate the impaired neurotransmitter

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balance in patients with epilepsy. If the seizure onset focus of patients with drugresistant epilepsy who do not respond to antiepileptic drugs can be detected by neuroimaging, the seizures of these patients can be controlled by epilepsy surgery. Patients with drug-resistant epilepsy who cannot undergo epilepsy surgery are treated with VNS, DBS, and RNS neuromodulator devices. These devices inhibit epileptic seizures by providing neuronal electrical stimulation. In addition, seizures are reduced by applying KD treatment, especially to patients with pediatric epilepsy. Immunotherapy with drug therapy is preferred to control seizures of patients with immune-mediated epilepsy. It is applied in order to control the seizures of patients with epilepsy, to increase the quality of life of patients, and to eliminate their diseases. Reliability and effectiveness of the approaches used for epilepsy management are the features to be considered. Knowing the approaches to manage epilepsy is important for improving existing epilepsy treatments and developing new treatment methods.

References Abou-Khalil BW (2019) Update on Antiepileptic Drugs. Continuum (Minneap Minn) 25(2): 508–536 Abouelleil M, Deshpande N, Ali R (2022) Emerging trends in neuromodulation for treatment of drug-resistant epilepsy. Front Pain Res (Lausanne) 3:839463 Akyuz E, Polat AK, Eroglu E et al (2021) Revisiting the role of neurotransmitters in epilepsy: an updated review. Life Sci 265:118826 Bakpa OD, Reuber M, Irani SR (2016) Antibody-associated epilepsies: clinical features, evidence for immunotherapies and future research questions. Seizure 41:26–41 Binnie CD (2000) Vagus nerve stimulation for epilepsy: a review. Seizure 9(3):161–169 Bodin E, Le Moing AG, Bourel-Ponchel E et al (2016) Vagus nerve stimulation in the treatment of drug-resistant epilepsy in 29 children. Eur J Paediatr Neurol 20(3):346–351 Brown MG, Sillau S, McDermott D et al (2022) Concurrent brain-responsive and vagus nerve stimulation for treatment of drug-resistant focal epilepsy. Epilepsy Behav 129:108653 Bsat S, Najjar M, Nawfal O et al (2022) Standardized reporting of complications of epilepsy surgery and invasive monitoring: a single-center retrospective study. Epilepsy Behav 134:108844 Chen B, Lundstrom BN, Crepeau AZ et al (2022) Brain responsive neurostimulation device safety and effectiveness in patients with drug-resistant autoimmune-associated epilepsy. Epilepsy Res 184:106974 Chiang S, Khambhati AN, Wang ET et al (2021) Evidence of state-dependence in the effectiveness of responsive neurostimulation for seizure modulation. Brain Stimul 14(2):366–375 Cukiert A, Cukiert CM, Burattini JA et al (2022) Combined neuromodulation (vagus nerve stimulation and deep brain stimulation) in patients with refractory generalized epilepsy: an observational study. Neuromodulation S1094-7159(22):01224–01227 Dahlin M, Månsson JE, Åmark P (2012) CSF levels of dopamine and serotonin, but not norepinephrine, metabolites are influenced by the ketogenic diet in children with epilepsy. Epilepsy Res 99(1–2):132–138 Dahlin M, Singleton SS, David JA et al (2022) Higher levels of Bifidobacteria and tumor necrosis factor in children with drug-resistant epilepsy are associated with anti-seizure response to the ketogenic diet. EBioMedicine 80:104061 D’Andrea Meira I, Romão TT, Pires do Prado HJ et al (2019) Ketogenic diet and epilepsy: what we know so far. Front Neurosci 13:5

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Pathophysiology and Management Approaches for Traumatic Brain Injury Prachi Suman, Anupama Paul, and Awanish Mishra

Abstract

Traumatic brain injury (TBI) encompasses a complex cascade of cellular, biochemical, and physiological events, resulting in immediate and delayed damage. This review outlines key mechanisms, including excitotoxicity, inflammation, oxidative stress, and disrupted blood-brain barrier integrity. Furthermore, it underscores the importance of tailored management approaches that encompass acute medical interventions, and various neuroprotective agents. The evolving landscape of TBI management integrates personalized strategies that target specific aspects of the pathophysiology, fostering neuroprotection, functional recovery, and improved outcomes. Through this comprehensive analysis, the chapter navigates the intricate journey from TBI’s molecular mechanisms to contemporary management paradigms, illuminating the multifaceted nature of addressing this critical neurological challenge. Keywords

Traumatic brain injury · Neuroinflammation · Antiplatelet agents · Thrombolytics · Neuroprotectants · Antioxidant

Prachi Suman and Anupama Paul contributed equally with all other contributors. P. Suman · A. Paul · A. Mishra (✉) Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)—Guwahati, Changsari, Kamrup, Assam, India e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Mishra, H. Kulhari (eds.), Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities, https://doi.org/10.1007/978-981-99-6807-7_7

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Introduction

Traumatic brain injury (TBI) has been a great cause of morbidity, disability, and mortality across all age group people. According to the Centres for Disease Control and Prevention (CDC), TBI results from an external force that depletes the brain’s normal functioning (Capizzi et al. 2020). The cause of the TBI largely depends on the age of the individual; for instance, falls account for one-third of head trauma in the United States and are a major cause of TBI in older people, but automobile crashes are the most frequent cause of TBI in those between the ages of 15 and 25 (Dixon 2017). TBI consists of two stages of injury, namely, the primary injury that results in mechanical damage and the secondary injury that results from primary damage and involves biochemical cascades including neuroinflammation (due to extravasation of immune cells), apoptosis, oxidative stress, and other pathophysiological abnormalities that eventually leads to neurodegenerative disorders (Bailes and Borlongan 2020). Secondary injury entails an imbalance in ionic homeostasis excitotoxicity due to the excess release of the neurotransmitter glutamate, mitochondrial dysfunction, and production of ROS that causes oxidative damage, which eventually contributes to additional neuronal cell damage. TBI can exacerbate neurological conditions like epilepsy, seizures, AD, and PD (Taylor et al. 2017), further enhancing neurological dysfunctions. Traumatic brain injury (TBI) is a crucial contributor to global health and socioeconomic issues. It affects people of all ages and is common in both high- and low-income nations. Additionally, TBI disability rates are even higher in low- and middle-income nations. According to estimates, there are 50 million TBI instances worldwide each year, meaning that over half of all people will experience a TBI episode at some point in their lives. It is the leading cause of death and disability in the United Kingdom for people under the age of 40. There are over 53,000 TBI-related deaths and more than 5.3 million TBI-related disabilities per year in the United States. Older adults (ages 65 years and above) are most likely to assist with a TBI (Georges and Das 2023). Approximately US$400 billion, or 0.5% of the world’s gross domestic product, are lost to TBI each year (Khellaf et al. 2019). Three broad variations of traumatic brain injury can be distinguished: (a) closed head (non-penetrating), (b) penetrating, and (c) explosive blast TBI. Headache, nausea, coma, seizures, forgetfulness, and behavioral impairments like agitation and nervousness are some of the clinical manifestations of TBI that can arise seconds to minutes after the injury (Ng et al. 2019).

7.2

Pathophysiology

Damage to brain tissue, blood vessels, and occasionally nerve fibers result from either direct or indirect mechanical stress on the brain. This condition is known as traumatic brain injury (TBI). Traumatic injuries lead to the disruption in the normal cellular functions of the brain. The frontal and temporal areas of the brain are the main areas involved (Georges and Das 2023). The pathophysiology involved behind

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Fig. 7.1 A comprehensive description of both the primary and secondary effects caused by a traumatic brain injury insult. “Created with BioRender.Com”

TBI is complex and involved several mechanisms of injury. Diffuse axonal damage can result from rotational stress halting the axons in the brain’s white matter pathway (Capizzi et al. 2020). Axonal damage also generates localized edema, further slowing down the signal transmission inside the brain. Traumatic injuries are also linked to changes in cerebral blood flow, which cause an initial drop in blood flow followed by an unresponsive vasodilation that is caused by the production of nitric oxide in the tissue. In rodent research, cases of mild traumatic brain injury provide the finest documentation of this vascular phenomenon (Capizzi et al. 2020). Damages associated with TBI are mainly categorized under two major classes (illustrated in Fig. 7.1): (a) Primary injury, which is caused because of any direct mechanical stress at the time of initial insult; and (b) secondary injury, which involves further damage to the cells or tissues after the primary insult.

7.2.1

Primary Brain Injuries

The mechanical cerebral insults that fall under the primary injuries might be either localized or diffuse. Also, both these types of injuries can exist simultaneously in a patient who is suffering from mild-severe forms of traumatic injuries. As a result of ripping, compression, jolt, and tearing of the tissue, both closed head and penetrating TBI exhibit focal brain injury with an indication of skull fracture and localized lesion at the active site of damage (Schmidt et al. 2004). Hematomas, epidural, subdural, and intracerebral hemorrhages are caused by necrosis, which develops because of

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insufficient blood supply to the neurons and glial cells that reside at certain layers of the brain. Additionally, there may be secondary bruising about the coup, contrecoup, or just across from it (Schmidt et al. 2004). Contrary to focal injury, diffuse brain injury is caused by noncontact stress from fast deceleration and/or acceleration, which causes shearing and stretching damage to the brain tissues. These powerful forces harm the blood vessels, myelin sheath, and axons, eventually causing illnesses including ischemic head injury and brain edema. Diffuse brain injury due to trauma is characterized by massive axonal deterioration, mainly affecting subcortical and deep white matter tissue (which includes the brain stem and corpus callosum) (Saatman et al. 2008). This involves disruption of axonal transport and degradation of the axonal cytoskeleton. The severity of the injury provoked will depend on the level of axonal transduction damage.

7.2.2

Secondary Brain Injuries

The prolonged damage at the cellular or biochemical level during the primary event will lead to more persistent secondary injury which can last from a few months to years. According to several studies, a variety of variables, including excitotoxicity, faulty mitochondria, oxidative stress, lipid peroxidation, neuroinflammation, axon degeneration, and apoptotic cell death, contribute to the emergence of secondary brain injury (Ladak et al. 2019).

7.2.2.1 Excitotoxicity After suffering from a traumatic brain injury (TBI), the blood-brain barrier (BBB) is disrupted because of forceful injury and neuronal cell death, which causes a massive release of stimulating amino acids like glutamate and aspartate from presynaptic nerve terminals (Thapa et al. 2021; Ng et al. 2019). Additionally, there is a collapse in the glutamate transporters, which further impairs glutamate uptake and leads to a rise in glutamate levels. Studies show that within the first day following a traumatic brain injury, the expression of the astrocytic sodium-dependent glutamate transporters GLAST (EAAT1) and GLT-1 (EAAT2) drops by about 40%, which results in a fast reduction in the resorption of excitatory neurotransmitters (Lee et al. 2019). Glutamate activates both its ionotropic receptors (iGluRs) as well as metabotropic receptors (mGluRs). Members of iGluRs like the NMDA receptor and AMPA receptor are ligand-gated ion channels that facilitate the entry of certain ions such as Na+, K+, and Ca2+ after the binding of glutamate, leading to depolarization. Overactivation by glutamate leads to alteration in the homeostasis in postsynaptic neuronal cells by an influx of extracellular Ca2+ and Na+ ions. Numerous subsequent signaling mechanisms are activated by NMDA-induced calcium within cells, including Ca2+/calmodulin-dependent protein kinase II (Folkerts et al. 2007), mitogen-activated protein kinases (Lu et al. 2008), and protein phosphatases (Bales et al. 2009). Protein kinase C is also activated, thereby enhancing more Ca2+ influx into postsynaptic neurons. This abundance of intracellular Ca2+ further involves an array of catabolic enzymes which includes phospholipases, proteases, and

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endonucleases. Excess cytosolic Ca2+ also activates various proteins, such as calcineurin, calpain, and caspases that are involved in apoptotic cell death. This calcium load also affects the structure and functioning of mitochondria, resisting mitochondria to generate ATP, thereby accelerating the breakdown of ROS and Ca2+ homeostasis. Some studies also elucidate that ATP synthase starts utilizing the cellular ATP, thus disrupting the metabolic supply-demand balance. Due to the increasing porosity of the mitochondria, increased enzyme loss is occurring, shifting to apoptosis and enhanced production of ROS (Ladak et al. 2019).

7.2.2.2 Mitochondrial Dysfunction A key feature of TBI is mitochondrial malfunction, which results in cell demise (Khatri et al. 2018). The creation of ROS, depolarization of the mitochondrial membrane, and restriction in ATP synthesis are all caused by the influx of Ca2+. Such circumstances lead to the breakdown of ETC and impaired oxidative phosphorylation, which impair Ca2+ expression and metabolic activity. The mitochondrial permeability is also enhanced by activating the “mitochondrial permeability transition pore (mPTP)” (Bauer and Murphy 2020; Toman and Fiskum 2011). Notable structural damages, such as damage to the cristae membrane, substantial swelling, and the loss of membrane potential, were discovered. The release of mitochondrial proteins into the cytosol, such as cytochrome c and apoptosisinducing factor (AIF), further contributes to apoptosis-induced cell death. 7.2.2.3 Neuroinflammation Neuroinflammation occurs post-TBI and involves penetration of several inflammatory mediators such as cytokines due to disruption of BBB which leads to distortion of normal restorative processes in the brain, thereby worsening neuronal cell death (illustrated in Fig. 7.2). Interferons, chemokines, and interleukins are examples of cytokines, which are protein-based inflammatory mediators generated by the body’s immune system and potentially affect other cells as well. Following damage, neuroinflammation essentially results from the stimulation of the complement, which is in charge of the repair process and offers protection from the invasive pathogen. Additionally, weakened BBB permits neutrophil, monocyte, and lymphocyte infiltration, ultimately releasing prostaglandins, chemokines, and cell-adhesion molecules. Additionally, plasma protein efflux into the extracellular space is seen, which activates TGF-b to cause neuroinflammation and the development of astrocytic scars. Neuroinflammation is further worsened by the activation of microglial cells because of inflammatory responses which leads to the weakening of BBB and the generation of ROS and some neurotoxins, which eventually leads to some secondary mechanism to cause cell death. Additionally, major histocompatibility complex (MHC) class II becomes elevated as a result of the persistent activation of microglial cells, resulting in the degeneration of neurons (Kovács-Öller et al. 2023). 7.2.2.4 Cell Death Process Following TBI Necrosis and apoptosis are the two primary mechanisms involved in the demise of brain cells. A sort of intentional cell death termed apoptosis causes the cytoplasm

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Fig. 7.2 Schematic representation of traumatic brain injury. Various inflammatory mediators enter the body through BBB leakage brought on by a TBI injury. ROS and inflammatory chemicals, including chemokines and cytokines, are produced by activated microglial cells, astrocytes, and leukocytes. These elements damage the axonal cytoskeleton, impairing signal transduction, and neuronal activity. On the other hand, excessive neurotransmitter buildup driven by defective reuptake activates the NMDAR and AMPAR receptors found on postsynaptic membranes, which causes an influx of Ca2+ ions. Additionally, the calcium ion’s release from the ER causes the creation of ROS. As a result of all these occurrences, mitochondrial malfunction, and an energy production crisis expand, which ultimately results in the death of neuronal cells. BBB blood-brain barrier, ROS reactive oxygen species, AMPAR α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, NMDA N-methyl-D-aspartate receptor, ER endoplasmic reticulum. "Created with BioRender.Com"

and nucleus to condense and fragment without harming the structure of the organelle. Other instances of programmed cell death comprise autophagy, paraptosis, calcium-dependent death, oncosis, caspases, and proapoptotic proteins such as Bcl2, JNK and ATG analogues, ERK2, cathepsins, and JNK. Cell cycle activities are induced by programmed cell death, which can also occur in adult forms of neurons, as in many neurodegenerative diseases. Various cell cycle activators, including cyclins and c-myc, can be upregulated as a result of trauma, whereas other cell cycle suppressors can be lowered (Ladak et al. 2019). Caspase 3 and 12 are significantly activated after TBI, resulting in an imbalance between molecules that encourage cell death (Bax and Bad) and those that oppose it (Blc-2 and Bcl-xl). Some caspase-independent pathways are also involved in causing cell death in which enhanced permeability of mitochondrial membrane plays a role. Proteins like DIABLO, HtrA2, apoptosis-inducing factor (AIF), and endonuclease G are

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released into the cytosol, initiating cell death. This AIF is involved in the condensation of chromatin fibers in the nucleus along with the fragments of DNA. Studies have elucidated that AIF causes wastage of NAD+, leading to mitochondrial failure via PARP-1 dependent pathway (Aungst et al. 2014). Dying cells frequently exhibit autophagic programmed cell death, which is marked by the lysosomal degradation of cellular organelles and proteins. An adaptive approach to inhibiting apoptosis is thought to be autophagy. In contrast, dying neurons is a far more intricate process that, in the absence of caspase activity, is governed by genes.

7.2.2.5 Long-Term Consequence Post-TBI damage damages an electrical pathway in the gray-matter section of the brain. Epilepsy is being seen as a result, primarily because TNF-a levels are elevated. An aberrant, uncontrolled, and synchronized electrical discharge in the brain cells known as neurons that results in abnormal motor, sensory, and psychological responses is the clinical manifestation of an epileptic seizure. Being a proinflammatory mediator that is produced at significant levels in neutrophils and microglia during an inflammatory response, TNF-a overexpression results in hyperexcitability and epileptic reactions. AD which is characterized by an increase in amyloid-beta plaque levels in the brain may also manifest as chronic TBI. However, the precise mechanism producing AD in post-traumatic dementia is still unknown (Griffin et al. 2019). Studies suggest the critical roles that neuroinflammation and oxidative stress play. Direct damage to lipids boosts the risk of oxidative stress by producing lipid peroxidation, followed by an increase in protein and DNA oxidation. The SOD-1 enzyme, which encourages antioxidant activity, becomes more active in response to this. An in-vitro study conducted on animals showed the promising effects of antioxidants in preventing neurodegeneration following TBI, suggesting the strong relation between oxidative stress and the progression of AD. As a response to oxidative imbalance, there is upregulation of some inflammatory processes to restore normal healthy cellular condition. Accumulation of Ab is recognized by astroglia and microglial cells, leading to stimulation of immune response which promotes clearance of the plaques formed at the initial phase of AD. But at a later stage, these inflammatory processes are downregulating Ab clearance, leading to the accumulation of Ab. Furthermore, glutamate levels are raised contributing to excitotoxicity and neurodegeneration. Other neurological deterioration such as CTE may also occur because of continuous blunt attacks on the brain which leads to a shift in personality, which is associated with Parkinsonism and dementia. In the cortical region, elevated phosphorylation of proteins called tau builds up as neurofibrillary tangled structures (NFTs), astrocytic tangles, and neurites encircling tiny blood vessels, which is what gives CTE its name (Mckee and Daneshvar 2015). This tau protein accumulation is more prominent in CTE rather than in AD.

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Management Approaches for Traumatic Brain Injury

There is mounting evidence that certain drugs can speed up recovery from brain injuries. The following class of drugs can be used for the treatment of TBI.

7.3.1

Antithrombotics and Thrombolytics

The possible risk of intracranial hemorrhage (ICH) from trauma must be carefully considered when deciding whether to use antithrombotics, antiplatelets, and/or anticoagulants, to prevent thromboembolic events in the elderly. Anticoagulants and antiplatelet drugs are the two categories of antithrombotic medications. Thrombolytics (also known as fibrinolytic medicines) are “clot-busting” medications that disintegrate and disperse blood clots that are impeding blood flow.

7.3.1.1 Antiplatelet Drugs Physiological hemostasis and thrombus formation depend largely on platelets. Additionally, TBI is linked to a higher risk of thrombosis. Antiplatelet therapy therefore plays a crucial role in the management of TBI but on the other hand hemorrhagic issues could arise by using them (Beynon et al. 2012). 7.3.1.2 Nonsteroidal Anti-Inflammatory Drugs These drugs inhibit COX enzyme irreversibly. The oldest and most extensively researched antiplatelet medication is aspirin. Aspirin irreversibly inhibits COX, therefore in order to restore platelet function, fresh platelets must be produced in the bone marrow. It is frequently employed to avoid brain injury episodes. 7.3.1.3 Thienopyridines Clopidogrel, ticlopidine, and prasugrel are thienopyridines that block P2Y12 receptors irreversibly to prevent ADP-mediated platelet activation. As the ADP-mediated reaction by platelets is irreversibly blocked after 7 days of drug withdrawal, normal platelet activity returns. 7.3.1.4 GpIIb/IIIa Inhibitors Glycoprotein (Gp)IIb/IIIa mediates platelet aggregation, and the transformation of fibrinogen bridges to fibrin stabilizes the thrombus. Blocking GpIIb/IIIa receptors is an effective way to inhibit platelet function. Abciximab, a monoclonal antibody, and the small-molecule antagonists eptifibatide and tirofiban are examples of GpIIb/IIIa inhibitors.

7.3.2

Anticoagulants

After a traumatic brain injury (TBI), anticoagulant medication can help to lower the possibility of thrombotic complications including venous thromboembolism (VTE)

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as well as stroke, but it also increases the chance of bleeding. In comparison to vitamin K antagonists (VKA), the advantages of direct oral anticoagulants (DOAC) include greater patient convenience and a lower chance of life-threatening bleeding (Antoni et al. 2022).

7.3.2.1 Heparin Low-molecular-weight heparin (LMWH) or unfractionated heparin (UH) administration is the current preferred standard of care for VTE prevention in adults. Antithrombin (AT) becomes an effective inactivator of coagulation factors once heparins attach to it and cause a conformational shift. By generating a ternary complex, unfractionated heparin prevents thrombin (factor IIa) from working. Many clinicians prefer UH over LMWH, especially in high-risk TBI patients, due to its shorter half-life and easy reversal. However, recent experimental studies have discovered that LMWH has neuroprotective effects that may save patients from secondary brain damage (van Erp et al. 2021). 7.3.2.2 Direct Thrombin Inhibitors The liver is the primary site of prothrombin synthesis, and plasma levels of this substance are micromolar. Factor Xa is produced when the intrinsic or extrinsic coagulation cascades are activated, and it breaks down prothrombin to thrombin. Therefore, brain injuries that cause blood to enter the brain, like a primary intracerebral hemorrhage and brain trauma, cause the blood’s prothrombin to immediately split into huge quantities of thrombin. Dabigatran, one of the thrombin inhibitors, inhibits the thrombin active site and thereby it prevents blood clot formation, used in TBI.

7.3.3

Thrombolytics

Tranexamic acid (TXA), a synthetic derivative of the amino acid lysine, is an antifibrinolytic agent used to reduce active bleeding. A recent CRASH-3 trial found that tranexamic acid lowers the risk of death in mild to moderate TBI patients when treatment is administered within 3 h, in a loading dosage of 1 g, following an infusion of 1 g for 8 h (Crash 2019).

7.3.4

Recombinant Tissue Plasminogen Activator (tPA)

As a thrombolytic therapy for ischemic stroke, it has FDA approval. Axon growth and synaptic plasticity are encouraged by the endogenous expression of tPA in glial and neuronal cells of the brain. The absence of endogenous tPA in mutant mice prevents the long-term recovery of white matter and cerebral function following TBI, according to an experimental investigation (Xia et al. 2018).

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Neuroprotectants

When the CNS experiences harm, neuroprotection is crucial. A successful neuroprotection strategy can stop the progression of the events that cause damage to the brain, even though the immediate effects of the injury are not always reversible.

7.3.5.1 Glutamate Antagonists The excitatory amino acids glutamate and aspartate have higher extracellular concentrations following traumatic brain injury (TBI). In a traumatized brain, glutamate excitotoxicity is accompanied by a metabolic energy crisis that impairs neurological function and causes the death of neurons as well as supporting cells. The binding of glutamate to receptors such as kainite, NMDA (N-methyl-D-aspartate), and AMPA (D, L-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) causes physiologic effects. Neurotoxicity caused by glutamate is largely mediated by activation of the NMDA subtype. 7.3.5.2 Magnesium Sulphate Numerous studies have revealed that the amount of free magnesium in the brain plays a significant role in the onset of subsequent traumatic and ischemic brain injury. Total serum and ionized magnesium concentrations fall after head traumas in humans. Magnesium supplementation is neuroprotective and reduces neuromotor dysfunction and cell death in the damaged cortex and hippocampus following an experimental traumatic brain injury. Through several mechanisms, including inhibition of presynaptic excitatory neurotransmitter release, inhibiting NMDA channels and blocking the voltage-gated calcium channels, potentiating presynaptic adenosine, and suppression of cortical spreading depression, magnesium can protect neurons from ischemic injury and help in neuronal survival after TBI. Magnesium also relaxes vascular smooth muscle, which could perhaps improve cerebral blood flow (Temkin et al. 2007).

7.3.6

Cannabinoids and Other Analogues

Cannabinoids such as phytocannabinoids, synthetic cannabis or endogenous cannabinoids (anandamide, 2-arachidonoyl glycerol, etc.) act on cannabinoid receptors type 1 and type 2 (CB1 and CB2). When it binds to the CB1 receptor, it produces the psychoactive effects of cannabis by directly inhibiting the continuous release of neurotransmitters like glutamate, acetylcholine, and GABA and indirectly modifies the signalling of opioids, dopamine, and serotonin. Cannabidiol (CBD), a most commonly occurring phytocannabinoids, is linked to neuroprotection because it increases levels of anti-inflammatory cytokines and decreases levels of pro-inflammatory cytokines (Hergert et al. 2021). A synthetic cannabis analogue with multiple beneficial effects is dexanabinol. It improves ICP and CPP regulation and reduces oxygen reactive species (ROS) in experimental animals.

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Hormone-Based Agents

7.3.7.1 Progesterone Progesterone is a potent neurosteroid present in the central nervous system, having neuroprotective properties. Progesterone is believed to improve motor, sensory, and cognitive recovery by reducing brain edema, assisting in maintaining the blood-brain barrier’s integrity, reducing apoptosis and necrosis, decreasing excitotoxicity by decreasing the impact of neuroinflammation, lowering oxidative stress, and modifying glutamate receptor activity. But none of these promising preclinical findings has shown a meaningful improvement in clinical outcomes (Ma et al. 2016). 7.3.7.2 Estrogen 17β-estradiol (E2), the most potent form of estrogen, has a significant impact on how TBI turns out. The effects of estrogen are not only limited to those of the reproductive system, also it has neuroprotective functions, preventing neuronal death by mediating upregulation of the antiapoptotic gene bcl-2, the antiapoptotic pro-survival factor, BDNF, etc. In addition to its direct antioxidant actions, estrogen also has effects on astrocytes, microglia, the regulation of the inflammatory response, cerebral blood flow and metabolism, and balancing glutamate excitotoxicity by increasing the glutamine synthetase (an enzyme present in astrocytes that produces glutamine from glutamate) activity (Kövesdi et al. 2020; Brotfain et al. 2016). 7.3.7.3 Erythropoietin It is a hemopoietin growth factor and a promising neuroprotective therapeutic agent in TBI, proven to stimulate hematopoiesis, and possess neuro regenerative effects through reduction of apoptosis, relieving inflammation, reducing oxidative stress, and modulating neuronal excitotoxicity, also prevent the loss of tight junctions’ protein zona occludens-1 and BBB dysfunction. In response to hypoxia, CNS cells release more erythropoietin, which in turn stimulates neurogenesis by acting Epo-R on neural progenitor cells. Patients with severe brain injuries who receive EPO have better outcomes because it has a direct neuroprotective impact. EPO is associated with reduced levels of BDNF, SDF-1, and NSE which are markers of brain tissue injury (Liu et al. 2020; Said et al. 2021). 7.3.7.4 Glyburide Glibenclamide (U.S. adopted name, glyburide) is a sulfonylurea class of drugs mainly used as oral hypoglycemic agents in type 2 diabetes mellitus patients, which act by inhibiting ATP-dependent potassium channels in pancreatic beta cells and thereby stimulate insulin secretion. The multifaceted protective effects of glibenclamide in the treatment of acute brain injury have reignited interest in this drug over recent years. According to preclinical research on traumatic brain injury (TBI), glyburide lessens contusion hemorrhage and edema (Shakkour et al. 2021).

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7.3.7.5 Synthetic Insulin-like Growth Factors Insulin-like growth factor-1 (IGF-1) is a growth-promoting peptide which is produced in the brain as well as peripheral areas, having a major role in the maintenance of neuroplasticity in a traumatized brain. It also regulates neurotransmission, maintains synapses and their long-term potentiation by increasing synaptic plasticity, and promotes cell differentiation and proliferation. When there is brain damage from an ischemic stroke or trauma, glutamate-induced excitotoxicity causes IGF-1 expression in astrocytes, microglia, and neurons to significantly increase. This is followed by a significantly increased activation of IGF-1R phosphorylation, which leads to activation of downstream signalling pathways, PI3K/AKT/mTOR and Rasmitogen-activated protein kinase (MAP kinase) pathway which are needed for the induction of many activities of IGF-1, including neuroprotection (Ge et al. 2022). In rodent models of TBI, post-injury treatment of IGF-1 has proven successful in developing learning and memory, reducing the loss of mature hippocampus neurons, and fostering neurogenesis.

7.3.8

Antioxidants

It is well known that after a TBI, brain tissue produces reactive oxygen species (ROS) and free radicals, which are crucial in causing molecularly harmful processes (like lipid peroxidation, DNA damage, and protein molecules oxidation) as well as aggravating glutamate excitotoxicity, mitochondrial dysfunction, and activation of cellular proteases.

7.3.8.1 ROS-Free Radical Scavengers Ascorbic acid, the most abundant water-soluble vitamin and antioxidant, rapidly reacts with a variety of ROS and RNS, including peroxynitrite and hydroxyl radicals, through one or two electron reactions due to its potent reducing properties. N-acetylcysteine (NAC) is being considered as a potential treatment for TBI. It works by either directly scavenging ROS and RNS or by increasing cysteine availability, which in turn increases GSH synthesis (Davis and Vemuganti 2022). 7.3.8.2 Lipid Peroxidation Inhibitors The process of adding a hydroperoxy group to a lipid is generally referred to as lipid peroxidation. Brain tissue samples from those patients who are having TBI have been found to contain higher levels of lipid peroxidation end products like 4-HNE, malondialdehyde, and isoprostanes. 7.3.8.3 Endogenous Superoxide Dismutase (SOD) Some endogenous enzymes, like the biological antioxidant reserve, are crucial in the removal of ROS and the damaging effects of related lipid peroxidation. One such enzyme is SOD, which converts superoxide into hydrogen peroxide. It has been demonstrated in laboratory experiments that neutralizing the superoxide anion with

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natural superoxide dismutase (SOD) or PEG-conjugated SOD (PEG-SOD) is advantageous in a variety of ischemic and traumatic injury types.

7.3.9

Immunomodulators and Immunosuppressants

The use of mesenchymal stem cells (MSCs) in regenerative TBI treatments appears promising. Preclinical studies have demonstrated that transplanting MSCs improved functional outcomes in experimental animals by fostering angiogenesis and neurogenesis, lowering secondary neurodegeneration and neuroinflammation. Still, MSC therapy has several downsides, such as tumor development, which can be prevented by using exosomes produced by MSCs (Das et al. 2019). Ciclosporin A (CsA) is a promising immunosuppressant which has been established in the management of TBI. Early after TBI, aerobic metabolism is seriously compromised. In isolated mitochondria an immunosuppressant, CsA, prevents the opening of the mitochondrial permeability transition pore (MPTP), preserving the calcium homeostasis and mitochondrial membrane potential. In diffuse axonal injury models, CsA treatment reduced axonal damage, whereas CCI TBI treatment lowered lesion size. However, CsA has a biphasic drug response curve, exhibits relatively limited brain penetration, and has negative immune system effects from extended usage (Loane et al. 2015).

7.3.10 Antiepileptics and Sedatives Some hospitalized TBI patients experience post-traumatic seizures. It has been proven that using antiepileptic drugs during the acute phase of treating TBI lowers the incidence of early seizures but does not stop the progression of epilepsy. So, to prevent early seizures following TBI (within 7 days of injury), prophylactic antiepileptic medication is advised (Thompson et al. 2015). If electroencephalogram (EEG) discharges occur, antiepileptic medication should be taken continuously. Mood stabilizers for psychomotor aggregation following TBI include carbamazepine and valproate, although the outcomes are disputable (Hicks et al. 2019). Phenytoin is advised by the Brain Trauma Foundation (BTF) for the early prevention of a post-traumatic seizure (PTS). However, Levetiracetam is frequently used since it has fewer medication interactions and prevents early seizures just as effectively as phenytoin. Till now, no randomized controlled studies have been carried out to demonstrate that one antiepileptic drug is superior to another in this situation. Sedatives are used to induce anesthesia, for maintenance of sedation, reduce the elevated ICP, terminate seizure activity, and facilitate ventilation in TBI patients. It has been observed that both barbiturates and propofol suppress cerebral metabolism, reduce oxygen consumption, lower ICP, and decrease the risk of seizures. Propofol is more frequently administered for the treatment of acute TBI in the ICU. Because of its quick onset and shorter duration, the effects of the medication are easier to

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manage. But caution is needed because high doses of propofol can cause morbidity (Wang et al. 2021).

7.3.11 Statins They have significant anti-inflammatory effects, which they partially achieve by reducing isoprenoid synthesis. Statins have been demonstrated to reduce the generation of proinflammatory mediators, glial cell activation, and cerebral edema in TBI models while enhancing BBB integrity. They reduce IL-1b, TNF-a, IL-6, and intracellular adhesion molecule 1 (ICAM-1) expression levels in post-TBI patients. Statins can regulate the inflammatory response by inhibiting the nuclear factor-kB (NF-kB) and toll-like receptor 4 (TLR4) signalling pathways. Preclinical studies show that statins inhibit a variety of secondary damage pathways and enhance functional recovery following TBI (Loane et al. 2015).

7.4

Conclusion

The basic pathophysiology of TBI is complex and poorly understood, thus the utility of a particular strategy may not be sufficient. Considering the pathophysiology of the early and late phases of TBI, targeting secondary phase targets would be more appropriate in both cases. The antioxidant strategy would be more appropriate for preventive or supportive measures, while antithrombotics, thrombolytics, and anticoagulants would be appropriate to limit thromboembolism. Hormone-based therapy, neuroprotectants, antiepileptics, statins, and antioxidants may be used as supportive therapy. Despite such a diverse line of therapy available, the management of TBI remains challenging, which requires a better understanding of its pathogenesis and more effective strategies for its management.

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Pathophysiology and Management Approaches for Huntington’s Disease, Multiple Sclerosis, and Other Neurological Disorder Chetana Ahire, Prachi Suman, and Awanish Mishra

Abstract

Huntington’s disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) are neurological disorders. HD is a hereditary neurodegenerative disease. The characteristic feature of HD is mutation in the HTT gene which is located on chromosome 4 which leads to expansion of CAG repeat, causing neurodegeneration of striatum and cortex of brain. Along with genetic predisposition other molecular mechanism such as excitotoxicity, dopaminergic pathway, and mitochondrial dysfunction play a key role in pathology of HD. Current treatment focuses only on symptomatic relief. Moreover, some advancements in treatment approaches such as stem cell therapy and gene-editing tools are the promising therapeutic approaches for HD treatment. While in MS, hyperactive immune response causes the infiltration of immune cells into the CNS and leads to demyelination of nerve fibers, neuroinflammation, and gliosis. Management strategies for MS mainly focuses on reducing the demyelination, inflammation by immunosuppressant or immunomodulators. But, some promising therapeutic approaches for management of MS such as BTK inhibitors, remyelination strategy are nowadays gaining attention and have shown to improve the patient’s quality of life. Furthermore, ALS is promptly fatal and is characterized by a focal onset of muscular weakening and persistent disease progression. The current review will give an overview of significant developments in the pathophysiology and management approaches of these neurological disorders.

Chetana Ahire and Prachi Suman contributed equally with all other contributors. C. Ahire · P. Suman · A. Mishra (✉) Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)—Guwahati, Changsari, Kamrup, Assam, India e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Mishra, H. Kulhari (eds.), Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities, https://doi.org/10.1007/978-981-99-6807-7_8

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Keywords

Huntington’s disease · Multiple sclerosis · Amyotropic lateral sclerosis · Therapeutic strategies · Disease-modifying agents

8.1

Introduction

Huntington’s disease (HD), multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) are the most common neurodegenerative diseases. HD is an autosomal hereditary neurodegenerative disorder first described by George Huntington 150 years ago. The global prevalence is about 2.7 per 100,000 people. A characteristic hallmark of HD is mutation in the HTT gene which is present in the region of chromosome 4 and has an expanded CAG codon repeat, which leads to increasing the polyglutamine (polyQ) domain at the N-terminus end of the HTT protein and causes the neurodegeneration of basal ganglia, striatum, and cortex region (Jurcau 2022). Normally, the CAG segment has 6–26 repeats and the individual having CAG repeat between 36 and 40 develops the risk for HD. Higher the length of CAG repeat, the more progression of the HD and early onset of symptoms (Kim et al. 2021). Other factors, such as genetic susceptibility and environmental changes, also play a key role in etiology and development of disease. Symptoms are characterized by impairment in motor, and cognitive behavior, and psychiatric disturbances. Patients between the ages of 30 and 50 are most affected by the condition. Management approaches majorly focus on symptomatic relief only (Ajitkumar and De Jesus 2023). MS is a cell-mediated autoimmune chronic inflammatory disorder of the brain and spinal cord. The characteristic hallmark of MS is demyelination, gliosis, neurodegeneration, and inflammation of the CNS. Worldwide prevalence is about 2.2 million people living with the condition especially females are more prone to MS. The age group of 20–40 is primarily affected (Cashion et al. 2023). MS are primary progressive MS (PPMS), secondary progressive MS (SPMS), and 85% account relapsing/remitting MS (RRMS). Symptoms include optic neuritis, paresthesia, tingling sensation, tremor, fatigue, slurred speech, depression, bowel and bladder dysfunction, and motor and cognitive impairment (Dhaiban et al. 2021). The definite cause of MS is not known. Genetic predisposition, environment, and lifestyle are responsible for the development of disease. Primarily is an immunemediated disease, hyperactive immune cells such as activated T cell (Th1 and Th17), B cell, antigen-presenting cell (APS) such as macrophage crosses the BBB and release chemokine that damages the oligodendrocytes myelinated cell which leads to demyelination of nerve fibers in CNS (Dighriri et al. 2023). Other risk factors include age, between 20 and 40 age group people most affected; sex, the female is more prone to condition (3:1), family history, infection such as Epstein–Barr, herpes simplex, chlamydia, and rabies, races, climate—more common in a temperate

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climate (Mulder et al. 2019; Ramagopalan et al. 2010). Vitamin D deficiency—vit D helps in the reduction of Th1-mediated proinflammatory cytokines, cigarette smoking, and injuries such as trauma and obesity. The progressive neurological disorder ALS is marked by the deterioration of both upper motor neurons, which are found in the motor cortex portion of the brain, and lower motor neurons, which are found in the brain stem and spinal cord. In addition, the frontal cortex and additional motor systems may also be compromised (Oskarsson et al. 2018). Which motor neurons in the body are damaged initially determines the earliest ALS symptoms. Early signs of limb-onset ALS include spasticity, stumbling, dropped feet, fasciculations, and writing difficulties. As a result, patients may have trouble doing manual agility-demanding tasks. While the earliest signs of bulbar-onset ALS include difficulties speaking, speech that may become slurred, dysphagia, and reduced tongue mobility. In addition, a small number of patients may potentially develop the third type of ALS, known as respiratory-onset ALS, in which the intercostal muscles are first impaired, making breathing difficult. About 95% of cases of ALS have no known cause and are referred to as sporadic ALS. While 5% of cases have genetic causes, often linked to the familial history of the disease, and is known as genetic/familial ALS. Till now, there is no curable treatment for ALS. The goal of treatment is to provide symptomatic relief or slow down the progression of disease, without any effect on reversing the damage being caused.

8.2

Pathophysiology

HD has a complex pathophysiology, genetic mutation, and molecular pathways which are major contributors to HD pathology, several studies found that mutation in the HTT gene as shown in Fig. 8.1 and glutamine proteins accumulate and form insoluble aggregate which causes the impairment in cell function and neurodegeneration of especially caudate nucleus, putamen, nucleus accumbens, and olfactory tubercule which all are part of striatum other areas like cortex

Fig. 8.1 Mutation of Huntington gene. “Created with BioRender.Com”

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(Magalhaes et al. 2020). Initially, the neurodegeneration of striatum GABAergic medium spiny projection neurons (MSNs). Other affected nerve cells are enkephalin-containing neurons and substance P-containing neurons. At a late stage of disease, degeneration of cortical neurons, orexinergic and somatostatin-positive GABAergic interneurons in the hypothalamus occur. Neuronal degeneration and accumulation of toxic mutated HTT protein through the following pathways: excitotoxicity in which overstimulation of striatal NMDA receptor leads to accumulation of intracellular calcium level resulting in ROS mediated apoptosis process (Perez-Navarro et al. 2006; Jurcau and Ardelean 2021; Raymond 2017). A biphasic dopaminergic pathway is seen in HD, and the DA level increases during the initial stage and later stage DA level will decline which causes the motor symptoms like chorea, bradykinesia, and dystonia and also reduces the toxic muHTT clearance rate. Further, oxidative stress mediated mitochondrial dysfunction aggervate the pathogenesis of HD. Since, mitochondria is an important source of ATP generation and maintenance of calcium homeostasis, the elevation of oxidative stress leads to mitochondrial damage resulting the impaired ATP production in the caudate, putamen, and cortex. Impairment of ubiquitin–proteasome pathway and autophagy results in reduction of muHTT clearance (Charvin et al. 2005; Chen et al. 2007). Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is an important transcriptional factor play a key role in mitochondrial biogenesis, apart of it altered expression of NF-κB and tumour suppressor p53 also contributes to HD (Lloret and Beal 2019; Reijonen et al. 2010; Kim et al. 2016). Intracytoplasmic and intranuclear aggregation of mutant HTT protein is seen in patient of HD. In addition, a reduced level of brain-derived neurotrophic factor (BDNF: an important neurotrophic factor for nerve growth) has also been recorded in the striatum of HD patient. MS is a cell-derived immunological disease, hyperactive immune cell attack on its own oligodendrocytes cells which leads to demyelination, neuroinflammation, axonal degeneration, and loss of myelin within CNS called lesions located especially in white matter near the ventricles, optic nerves, and area of the corpus callosum and cerebellar peduncles (Huang et al. 2017; Zéphir 2018). The immunological response is initiated by the interaction between the T lymphocytes cell and antigen-presenting cells (APCs) like B lymphocytes cells, microglia, macrophages, and dendritic cells. This interaction occurs both peripherally as well as centrally. Autoreactive T lymphocytes cross the BBB and enter into the CNS, as shown in Fig. 8.2, especially CD8+ T lymphocyte cells, CD4+ Th1 cells, and Th17 cells involve in the pathology of MS. Activated Th 1 and Th 17 cells release proinflammatory cytokines, that is, interferon gamma, interferon (IFN)-γ and tumor necrosis factor (TNF)-α, and IL-17, IL-21, IL-22 and IL-26 within CNS lead to demyelination of nerve fiber (Sandi et al. 2022). Peripheral B cells, T cells, monocytes, and macrophages recruit into CNS through surface VCAM- 1-mediated adhesion with alpha 4 integrin receptor over the surface of these cells which releases cytokines and attacks oligodendrocytes cells. Within CNS, T cells interact and activation of microglia and macrophages produces cytokines like TNF-α and IL-1β, and releases glutamate, ROS, and RNS leading

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Fig. 8.2 Pathophysiology of multiple sclerosis. “Created with BioRender.Com”

to neuronal mitochondrial dysfunction, demyelination, and axonal loss. B cells (CD20+ B) are transformed into plasma cell which produces antibodies called oligoclonal bands (OCBs) which attack on myelin protective sheath around the nerve fiber (Ward and Goldman 2022). It is still uncertain exactly how sporadic and familial ALS develops. The neuronal impairment that finally results in neuronal cell death owing to protein aggregation (in an unnatural manner) in nervous system cells is a characteristic of all neurodegenerative diseases. The development of an aberrant collection of proteins called Bunnia bodies in the cytoplasm of motor neurons is the pathogenic sign of ALS. The transactive response DNA-binding protein 43 kDa (TDP-43 protein) is thought to be the primary constituent of Bunnia protein in nearly all ALS patients (~97%). However, SOD1 protein and FUS protein are the primary components of Bunina protein in individuals who have mutations in Zn/Cu superoxide dismutase 1 (SOD1) and fused in sarcoma (FUS), respectively (Suk and Rousseaux 2020). Although the precise process causing the loss of neurons as a result of TDP-43 protein abnormalities is still not understood, it is most likely a mix of factors. All cell types include TDP-43, a DNA/RNA-binding protein that is mostly found in the nucleus but is also found in the mitochondria and cytoplasm. From the maturing phase to the decaying phase, these proteins determine what will happen to RNA transcripts. The recruitment of mRNA transcripts into stress granules, which are created by cellular stress, is one of its essential activities. These stress granules disintegrate promptly as stressful situations are lessened. However, dysfunction in

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TDP-43 and associated proteins might delay the normal dynamics of stress chunks, inhibiting the right stress reaction (Ling et al. 2013). According to research, TIA-1 (T cell intracellular antigen-1) mutations affect neuronal homeostasis by delaying the detachment of stress granules after stress and enhancing the aggregation of these granules that contain TDP-43. It is thought that additional pathological issues contribute to the deregulation of the stress granule and irregularities in RNA metabolism. Protein metabolism is also thought to be impaired, in addition to RNA metabolism. The development of ALS is influenced by mutations in genes that play a part in protein clearance, especially charged multivesicular body protein 2B, optineurin, sequestosome 1, valosin-containing protein, TANK-binding kinase 1, and ubiquitin 2 (Vucic and Kiernan 2009).

8.3

Management Approaches for HD, MS, and ALS

There are various categories of drugs available for the management of HD, MS and ALS neurodegenerative diseases which are discussed in the following: HD: Currently, there is no successfully available therapy for a complete cure of HD, drugs which are available for treatment are only based on symptomatic relief (motor, cognitive, and psychiatric symptoms), and supportive care and the major goal is enhancing the quality of life of patients. Treatment for motor symptoms: The American Academy of Neurology guidelines suggest the use of tetrabenazine (TBZ), deutetrabenazine which are vesicular monoamine transporter (VMAT2) inhibitor decreases dopamine level and give relief from chorea. Sedation, depression, and Parkinson-like symptoms are the main side effect of TBZ. Dopamine blockers also provide relief from chorea, agitation, and psychosis, thus neuroleptics could be a drug of choice for patients having both chorea and psychosis. Drugs used for chorea include haloperidol, olanzapine, aripiprazole, risperidone, quetiapine, and NMDA receptors antagonist (amantadine) MOA. It blocks the NMDA receptor and inhibits glutamate release. it gives relief from chorea as well as reduces the excitotoxicity in basal ganglia. Side effects observed are hallucination, sedation, drowsiness, gastrointestinal disturbances, confusion, livedo reticularis, and nightmares (dose: 100–300 mg). Dopamine Agonist: DA agonist for proven relief from hypokinesia and rigidity,. for example, levodopa. Management approaches for cognitive symptoms impairment: NMDA receptor antagonist: memantine is a noncompetitive NMDA receptor inhibitor which reduces excitotoxicity and neurodegeneration. Side effects observes gastrointestinal disturbances, somnolence, hypertension, drowsiness, and headache. Other drugs are Donepezil and Rivastigmine. Management for psychiatric symptoms: Depression: Citalopram, Fluoxetine, Paroxetine, Sertraline, Mirtazapine, and Venlafaxine all are selective serotonin reuptake inhibitors (SSRIs). Atypical neuroleptics such as olanzapine, risperidone, aripiprazole, and clozapine also use for those patients which are not responding to SSRIs.Other symptoms of HD management: For insomnia Zopiclone, Zolpidem for

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Table 8.1 Disease-modifying agents for multiple sclerosis Highly effective DMA Ocrelizumab Ofatumumab Natalizumab Alemtuzumab Rituximab

Moderately effective DMA Dimethyl fumarate Siponimod Fingolimod Ozanimod Cladribine

Modestly effective DMA Teriflunomide Glatiramer acetate IFN β-la IFN β-la IFN β-lb

bladder incontinence and Oxybutynin for constipation laxatives. Other drugs approaches: p38 MAPKa enzyme inhibitor and Neflamapimod blocks the enzyme domain p38 MAPKa which is responsible for inflammation in microglia and neurons. Activation BDNF function, for example, pridopidine is dopamine (D2) antagonist and sigma-1 receptor (S1R) agonist, stimulation of S1R increases the BDNF which is neuroprotective in nature. c. PGC-1α activator, for example, fenofibrate is agonist of peroxisome proliferator-activated receptor (PPAR) which improves the mitochondrial dysfunctioning which impaired in HD. Genetic manipulation: Newer therapeutic approaches for HD management is gene silencing technique. By using the complementary technique like zinc finger transcriptional repressor with mutant HTT gene. By using long zinc finger protein (ZFPs) which is complementary to expanded CAG repeat strongly bind to this repeat on chromosome 4 and reduces the expansion of toxic muHTT protein without compromising the adjacent gene. Major advantage of this approach is permanently deletion of expanded CAG repeat. Other approaches are CRISPR/Cas9 technique, synthetic antisense oligonucleotides (ASOs), for example, IONIS-HTTRx, transcription activator-like effector nuclease (TALEN) therapies, siRNA, shRNAs, and artificial miRNA. These all approaches directly targeting the CAG repat which is expanded in HD and reduces the muHTT (Palaiogeorgou et al. 2023). Stem cell therapy: Cellavita is a mesenchymal stem cell which is administered intravenously into the HD patient, which shows promising therapeutic benefit by regeneration capacity of neurons and cut out the damaged neurons (Rodrigues and Wild 2020). Deep brain stimulation (DBS); Alternative to surgical treatment, DBS effective for reducing chorea like symptoms in those patients whose chorea like symptoms is resistance to other medications (Ferguson et al. 2022). MS: The primary goal of management of multiple sclerosis is to reduce the number of relapses, disease progression, disability occur over a time period and reduces biological activity. Currently, the disease-modifying agents available as highly effective disease-modifying and moderately effective disease-modifying agents commonly used for treatment of MS. Other treatment strategies are immune suppressants and immune modulators by targeting B and T lymphocytes, antiinflammatory agents, mitochondrion-protective agents, remyelination strategies, and stem cell therapy are effective approaches for management MS. Diseasemodifying agents are summarized in Table 8.1); these drugs not cure the MS but they reduce the number of relapses, MS plaque, inflammation, and modify the disease progression by suppression or modulation of immune response.

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Highly effective disease-modifying agents include: Ocrelizumab which is a humanized monoclonal antibody that selectively inhibit CD20 B lymphocyte cell and thereby reduces the trafficking of B-Cell into brain. It reduces the proinflammatory cytokines production which attack on myelin sheath of neuron by inhibiting the B cell and T cell interaction. Ocrelizumab is effective in RMS patients. Major side effect are allergy or hypersensitive reactions, acute rhinitis, headache, herpes labialis, ulcerative colitis, agammaglobulinemia, reduction in neutrophil and carcinogenecity. Other antibodies which are in use includes - Rituximab, Natalizumab, Ofatumumab, Alemtuzumab. Moderately effective disease-modifying agents for MS: Dimethyl fumarate; it activates Nrf2 transcription factor and acts as anti-inflammatory and cytoprotective agent. Side effects are diarrhea, epigastric pain, lymphocytopenia, and increase liver aminotransferase level and multifocal leukoencephalopathy risk. Similarly, diroximel fumarate also uses 2. sphingosine-1-phosphate inhibitor (S1P), for example, Fingolimod, first oral drug approved for RMS patients. It reduces the secretion of lymphocytes from secondary lymphoid organ and prevent its infiltration into the CNS by inhibiting the S1P receptor. Dose—oral, once daily. Side effect like bradycardia, atrioventricular conduction block, macular edema. Ozanimod is newer S1P modulator. Siponimod—S1P modulator approved for RSM patients. Dose—oral, once daily. Side effects are headache, nasopharyngitis, and urinary tract infection. Modestly effective disease-modifying agent for MS: Teriflunomide; leflunomide active metabolite block the action of dihydroorotate dehydrogenase enzyme use for pyrimidine synthesis and reduces the proliferation of autoreactive T and B lymphocytes, brain atrophy. Dose—oral, once daily. Major side effects are hepatotoxicity and teratogenicity other are Headache, nausea, hair loss, and diarrhea. Cholestyramine is used for teriflunomide toxicity. Glatiramer acetate—acetate salt of mixture of four amino acids and maintain the balance between proinflammatory and regulatory cytokines. Effective for RMS patients. Dose—three times weekly or once daily or SC. Side effects are dyspnea, irregular heartbeat, anxiety after injection, and less commonly lipoatrophy, flushing, chest tightness etc. Interferons: IFN β-la (Rebif) interferon reduces the MHC complex on antigen presenting cells and inhibit the proinflammatory cytokines, infiltration of lymphocytes into CNS and increase the anti-inflammatory cytokines. Dose—three times weekly SC. Side effects are inflammation at injection site, flu-like symptoms, acute rhinitis, and headache. Other interferons use IFN β-la (Avonex) and IFN β-lb (Betaseron) (Hauser and Cree 2020). Bruton’s tyrosine kinase inhibitors (BTK): BTK is intracellular signalling pathway involves in development, emigration, survival, B cells and microglia cell activation, macrophage, chemotaxis, adhesion, immunoglobulin production, and release of cytokine which involve in MS progression. BTK inhibitors able to target immune cells both periphery as well as centrally and target both innate and adaptive immune response. Promising therapeutic and management approach for RMS and progressive form of MS. BTK inhibitors currently under clinical investigation of late stage (phases II–III). For example, evobrutinib, tolebrutinib, fenebrutinib, remibrutinib, and orelabrutinib (Krämer et al. 2023).

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Remyelination strategy: In MS oligodendrocytes cells loss the capacity of remyelination due to inhibitory signals .by targeting the inhibitory signals and stimulate the oligodendrocyte cell for remyelination is promising approach for treatment of MS. Drug use for this purpose is Opicinumab; Monoclonal antibody inhibit the leucine rich repeat and LINGO-1 inhibitory signal for remyelination and promote oligodendrocyte for remyelination. Other agents use elezanumab, bexarotene, domperidone, clemastine fumarate, and bazedoxifene acetate (Cree et al. 2022). Other agents; vidofludimus (T cell proliferation inhibitors), masitinib (tyrosine kinase inhibitor) which target microglia and mast cells. Simvastatin HMG-CoA reductase inhibitor having neuroprotective and anti-inflammatory action in MS.

8.3.1

Management Approaches for ALS

For promising treatments for ALS, there has been a lot of potential and just as much despair during the past three decades. Only two medications that are being approved by USFDA, riluzole and edaravone, have demonstrated a marginally favourable impact on the disease’s course. The ALS community is still looking for a powerful disease-modifying therapy for ALS.

8.3.2

Disease-Modifying Treatment of ALS

Antioxidants: Studies have elucidated that edaravone is having free radical scavenging action along with antioxidant properties. Edaravone is believed to scavenge and suppress the generation of hydroxyl radicals and peroxynitrite radicals (Yoshino 2019). It also prevents the opening of mitochondrial permeability transition pores (mPTP) in the brain, adding additional neuroprotective action. Although, the exact mechanism of action of edaravone in ALS has not been fully elucidated. Moreover, some preclinical evidence is also in favor to improve motor function, preventing motor neuron degeneration, slows down the symptom progression when performed in transgenic SOD1 rodent models (Cunha-Oliveira et al. 2020). Glutamate antagonist: Riluzole is having anti-glutaminergic activities, thereby inhibiting the release of glutamate from the presynaptic neurons. Furthermore, riluzole can block voltage-gated Na+ channels and also affects Cl-, and Ca2+ channels, thereby interfering with intracellular events following the binding of glutamate to its receptors (Saitoh and Takahashi 2020). It has been proposed that riluzole has some antioxidant properties which are negotiated by inhibiting protein kinase C (PKC) and phospholipase A (PLA), leading to attenuation in oxidative damage. Riluzole’s precise mode of action, however, is not well known. Since, riluzole has direct antioxidant action against ROS, but not against RNS, it can be hypothesised that combined treatment of riluzole with edaravone may produce more positive results.

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Advanced Therapies

The absence of disease-specific biomarkers is most likely the current barrier to the development of effective treatments, but several strategies are being investigated to address this shortcoming. These therapies include: Stem cell therapy: Current stem cell strategies are not meant to replace dead motor neurons; instead, they are primarily intended to assist in protecting surviving motor neurons through paracrine reactions (neuroprotection). The ability of mesenchymal stromal cells (MSCs) to release neurotrophic factors and regulate the immune system makes them the most commonly employed autologous stem cell therapy for ALS. A subset of patients may react to therapy, according to reports of subjective advantages and case studies, even though none of these early-phase studies have the power to demonstrate efficacy (Oskarsson et al. 2018). Tyrosine kinase inhibitor: An oral tyrosine kinase inhibitor called mastitinib is used to treat mastocytosis. In rat ALS (SOD1-G93A) animal models, this substance has shown encouraging benefits. The immunomodulatory features of ALS, which specifically target mast cells and activate microglia activity in both the central and peripheral nervous systems, have a neuroprotective effect on neurons (Corcia et al. 2021). Although, the exact mode of action has not been elucidated yet. Therapies targeting Mitochondrial failure: It has recently come to light that the copper complex diacetyl bis (N4-methylthiosemicarbazone) copper (II) (CuATSM) is a PET imaging agent that is effective in increasing the life span of animals in several neurodegenerative disease models. Although the exact mechanism causing this result is yet unknown, investigations have shown that this copper complex helps to keep copper levels in mitochondrial homeostasis stable (Barp et al. 2020).

8.5

Conclusion

HD, MS, and ALS remain one of the fatal neurodegenerative diseases affecting humans. Recent advancement in the pathophysiology and management approaches has improved our understanding; however, the management of these neurodegenerative diseases remains a great challenge. The advancement in nucleic acid-based therapy, cell-based therapy, and the use of biosimilars may give us new hope for the effective management of these neurogenerative conditions.

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Genes Encoding Ion Channels in Neurotherapeutics: Opportunities and Challenges Enes Akyuz and Habiba Eyvazova

Abstract

Neurotherapy measures and regulates the electrical signals produced by the neurons of the brain. The variation of the electrical activity in the measurement performed by electroencephalography determines the coefficient of application of neurotherapy. Serious changes in electrical activity lead to the onset of diseases including epilepsy, Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Recent devices producing electric current or magnetic field are used in neurotherapy, as well as molecules that regulate the chemical processes of cells as neurotherapeutics. The treatment of genes encoding ion channels is a great chance for the healing effect of devices on much larger biosystems. However, the type of mutations in the genes encoding these proteins, which are responsible for the transmission of information and direct the ionic movements of neurons, determine the degree of improvement of the related neurological diseases with neurotherapeutics. Mutations can cause changes in the structure that conducts the opening and closing of the ion channel, changing the number of ion transitions. In this case, the implementation of a treatment is essential while there are still limitations to the use of neurotherapeutics. In this chapter, studies on the amelioration of mutations in genes encoding ion channels with neurotherapeutics will be explained. In this narrative, opportunities and challenging conditions will be prioritized.

E. Akyuz (✉) Department of Biophysics, International School of Medicine, University of Health Sciences, Istanbul, Türkiye H. Eyvazova International School of Medicine, University of Health Sciences, Istanbul, Türkiye # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Mishra, H. Kulhari (eds.), Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities, https://doi.org/10.1007/978-981-99-6807-7_9

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Keywords

Neurotherapeutic · Ion channels · K+ channels · Gene therapy

9.1

Introduction

Neurological diseases negatively affect the physiological processes of the central nervous system (CNS). Recent studies in genetics and pharmacology have determined that dysfunctional cells in different neurological circuits cause brain dysfunction (Whittle et al. 2014). Genetic and environmental factors have roles in the pathophysiology of neurological disease (Deisseroth 2014). The increasing prevalence of neurological disorders indicates that new studies are needed to develop effective prevention and treatment strategies (GBD 2016 Neurology Collaborators 2019). Developed strategies target abnormal neural networks that regulate mental and physiological processes (Whittle et al. 2014). Uncovering the mechanisms of neurological disease allows the development of new neurotherapies (Fig. 9.1). Neurotherapy targeting changes in brain functions is a promising therapeutic approach for improving brain performance (Whittle et al. 2014). Measuring neural activities in treatment allows the regulation of the neural substrates underlying a certain pathology (Sitaram et al. 2017). Electroencephalography (EEG) or real-time functional magnetic resonance imaging (rtfMRI) techniques are used to measure neural activities (Zotev et al. 2014). In addition to investigating the molecules that regulate the chemical processes of cells, these techniques used in neurotherapy are important for the evaluation of brain function. EEG detects structural abnormalities by providing direct measurement of neural mass activity. Like the EEG technique, rtfMRI modulates the brain response and associated behavior. In addition to measuring the electrical activity of the brain, gene therapy methods are applied for gene modifications in neurological disorders. Gene therapies targeting mutated genes are currently a promising method for incurable neurological diseases (Martier and Konstantinova 2020). Gene therapies improve the ability of dysfunctional cells to make a missing protein by targeting specific genes. In this direction, gene therapies as well as magnetic resonance techniques can provide better control over ion channels that play an essential role in the pathophysiology of neurological diseases. Ion channels are membrane proteins commonly and selectively found in the brain, neurons, and astrocytes (Catterall et al. 2020; Elorza-Vidal et al. 2019). Ion channels in the cell membrane are responsible for shaping the action potential, especially the resting membrane potential, and transmitting electrical signals. Appropriate activation of cationic and anionic currents modulates cell excitability and neurotransmitter release. Observation of mutations in the genes encoding the ion channel causes neurological disorders by disrupting the excitability activity of neurons. Inherited and sporadic mutations in genes encoding ion channels adversely affect the membrane expression of the protein. Therefore, changes in ion channel gene expression are in the molecular diagnosis of CNS diseases (Noebels 2017).

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Fig. 9.1 Functional mechanism of ion channels in neurological diseases and the positive effect of neurotherapies. (1) Ion channel gene mutations impair the functionality of channel activity, reduce channel permeability, and adversely affect cell homeostasis. (2) Genetic therapy methods, which are current neurotherapy methods, increase ion channel expression by changing gene variants. This improves neurological disease phenotypes due to ion channel dysfunction

These mutations, which show phenotypic and genetic heterogeneity, are associated with neurodevelopmental disorders characterized by epilepsy, cognitive and behavioral deficits (D’Adamo et al. 2020). Functional characterization of newly identified mutations in ion channel genes allows the recognition of new phenotypes and broadening the clinical spectrum of known diseases (Noebels 2017). Current studies targeting rare structural variants in ion channel subunit proteins in the literature are insufficient to reveal the clinical severity of gene mutation. However, these studies provide the basis for understanding disease pathogenesis at the atomic level, guiding therapeutic intervention, and developing new pharmacological options for drugresistant disorders (D’Adamo et al. 2020). Depending on the severity of the disease, neurotherapy techniques targeting gene mutations in ion channels vary. Therefore, in this chapter, studies investigating the effect of neurotherapeutic treatments on gene mutations encoding ion channels have been compiled.

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Genes Encoding Ion Channels and Neurotherapies in Neurological Diseases

9.1.1.1 Epilepsy Epilepsy is a chronic brain disease characterized by recurrent seizures that cause abnormal excessive electrical discharge of cerebral neurons (Chang and Lowenstein 2003). Epilepsy affects all age groups. Epileptic seizures that develop due to abnormal excessive or synchronous neuronal activity in the brain cause behavioral changes such as loss of consciousness and shaking. Epileptic seizures vary in that they are focal, generalized, or of unknown onset (Fisher et al. 2017). The interaction of genetic and environmental factors triggers the heterogeneous epilepsy disease. Determining the etiology of epilepsy is important in terms of clinical management of patients and development of treatment methods (Thomas and Berkovic 2014). Genetic mutations that cause dysfunction of voltage and ligand-gated ion channels, which regulates of brain electrical activities contributing to the formation of epileptic seizures. Mutations of genes encoding Na+, K+, and Cl- voltage-gated ion channels responsible for cell membrane potential are associated with generalized epilepsy and infantile seizure syndromes. Gene mutations of ligand-gated ion channels such as nicotinic acetylcholine receptors and GABA receptor subunits trigger specific syndromes of frontal and generalized epilepsies (Scheffer and Berkovic 2003). Monogenic mutations detected in ion channel genes contribute to the idiopathic epilepsy phenotype (Weber and Lerche 2008). The heterogeneity of mutations identified in ion channels hinders the development of simple diagnostic tests. For this reason, it is important to increase and continue comprehensive studies to use mutations identified in different ion channels as biomarkers in individuals with epilepsy. Voltage-gated sodium channels (NaV), which contribute to the pathophysiology of epileptic seizures, are responsible for the formation and propagation of the action potential. A pathogenetic event or a genetic change in these ion channels triggers epileptogenesis. Mutations in the genes encoding the NaV channel cause dysregulated neuronal activity. These mutations affect channel activation and inactivation processes negatively by changing channel kinetics. As a result, sudden and uncontrolled discharges in neurons cause excessive stimulation of neurons. NaV1.1 mutations, one of the NaV channel subtypes, are widely described in epileptogenesis. Nonsense and missense mutations are the most observed mutation types in these channels. Mutations observed in the subtypes of the NaV channel, NaV1.1, NaV1.2, NaV1.3, NaV1.6, and NaV1.7, affect the electrophysiological functioning of the channel negatively by changing the epilepsy phenotype (Menezes et al. 2020). The SCN1A gene encoding NaV1.1 is predominant mutation target in genetic epilepsy syndromes (Catterall et al. 2010). SCN1A gene mutation contributes to the pathogenesis of epilepsy by causing an imbalance between the inhibition and excitation of channel activity (Yu et al. 2006). SCN1A gene mutations are associated with Dravet syndrome (DS), in which febrile seizures are frequently observed (Escayg and Goldin 2010). Considering the diversity of SCN1A gene mutations, it can be thought that these mutations may mediate different epileptic seizures. Therefore, there is a

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need for up-to-date studies that associate SCN1A gene mutation with epileptic clinical findings at the molecular level. In a recent study, mutations in the SCN1A were investigated in children with epilepsy with febrile seizures. According to the study findings, the R500Q gene variants located in the non-voltage area or the G1711D SCN1A gene variants located in the pore-forming area developed severe DS, while other SCN1A variants located outside the pore-forming area caused mild phenotypes (Ma et al. 2021). In conclusion, SCN1A gene mutations cause epilepsy accompanied by febrile seizures. A case-control study investigated the link between SCN1A gene polymorphism, drugresistant epilepsy, and generalized epileptic seizures in children. No significant relationship was found between SCN1A gene mutation and drug-resistant epilepsy (Mousavi et al. 2022). In conclusion, the SCN1A gene polymorphism has been associated only with generalized seizure findings in patients with epilepsy. In a similar study, the relationship between SCN1A gene polymorphisms and drugresistant epilepsy in pediatric patients was investigated. Intronic rs6730344, rs6732655, and rs10167228 polymorphisms were revealed in drug-resistant epilepsy, while single-nucleotide polymorphisms identified in the SCN1A gene exons were not associated with drug-resistant epilepsy (Margari et al. 2018). In conclusion, SCN1A gene mutations contribute to the pathogenesis of drug-resistant epilepsy, in which generalized epileptic seizures are frequently observed. A recent study investigated the lifetime characterization of epilepsy and comorbidities in mice with DS due to exon 1 deletion of the SCN1A gene. EEG recordings from mice with the SCN1A gene mutation revealed a high frequency of spontaneous recurrent seizures and sudden unexpected death in epilepsy (SUDEP) (Gerbatin et al. 2022). The results reveal new phenotypic features of SCN1A gene mutations for the diagnosis and treatment of epilepsy. SCN1A missense variants located outside the sodium channel core region cause the severe epilepsy phenotype. Study results showed that not all missense variants found outside the core region cause a mild phenotype (Fang et al. 2022). In conclusion, missense mutations in the SCN1A gene trigger severe clinical symptoms. In a similar study, SCN1A gene mutations were detected in idiopathic generalized epilepsy accompanied by febrile seizures. The study identified for the first time two cases of missense mutations p.(Arg1525Gln) and p.(Thr297Ile) in the SCN1A gene cis (Binini et al. 2017). The results revealed that NaV1.1 channels harboring both mutations resulted in more positive potentials in the activation curve. In conclusion, because SCN1A gene polymorphisms mediate the clinical symptoms of severe epilepsy, different neurotherapy techniques are being developed in recent studies. Antisense oligonucleotides decreased the incidence of seizures and SUDEP by increasing the expression of SCN1A in a mouse model of DS and targeted nuclear gene output (TANGO) technology was used to increase target gene and protein expression for improving disease phenotype in the mouse model (Han et al. 2020). The results revealed that TANGO can be used in the treatment of DS by increasing the expression of the SCN1A transcript and the NaV1.1 protein. In another study, GABA-selective adeno-associated virus (AAV) vector treatment used to upregulate the expression of endogenous SCN1A was observed to improve phenotypes in the

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mouse DS model. According to study data, AAV9, a vector-based, GABAergic neuron selective therapeutic agent, upregulated SCN1A gene expression (Tanenhaus et al. 2022). In conclusion, one-off applications of AAV9-based approaches permanently alter NaV1.1 protein expression in the brain compared to antisense oligonucleotide therapies, which must be readministered to patients throughout their lives. In a similar study, ETX101, a GABAergic interneuron-selective AAV-mediated gene therapy, was examined for the treatment of SCN1A variant DS in nonhuman primates. According to the study findings, a unilateral intracerebroventricular injection of ETX101 resulted in transgene expression throughout the brain, including the cerebral cortex and hippocampus (Belle et al. 2020). The results show that ETX101 is well tolerated in SCN1A variants and unilateral intracerebroventricular injection is the appropriate treatment route for this AAV-mediated gene therapy. A recent study revealed partial phenotypic improvements after gene therapy in the DS model. In this study, the effects of the AAV vector on the multifunctional β1 sodium channel helper subunit were investigated (Niibori et al. 2020). In conclusion, the therapeutic efficacy of the AVV vector resulted in overexpression of NaVβ1, facilitating the function of voltage-gated channels and ameliorating the DS phenotype in the SCN1A variant mouse model. In a recent study, dCas9-based SCN1A gene activation was found to activate inhibitory interneuron excitability and reduce seizures in DS mice. The study selectively increased SCN1A mRNA and NaV1.1 protein expression by the SCN1A-dCas9 activation system using AVV (Colasante et al. 2020). The results support the use of dCas9based gene activation as an effective treatment approach in epilepsy. In a similar recent study, CRISPR/dCas9-based SCN1A gene activation in inhibitory neurons was found to improve epileptic behavioral phenotypes in DS mouse models. The study designed a CRISPR-based gene therapy to trigger SCN1A transcription in vitro (Yamagata et al. 2020). The study results showed that the CRISPR/dCas9 gene therapy method could significantly improve phenotypes even when administered after the juvenile stages by upregulating SCN1A expression. In line with these results, therapeutics targeting NaV1.1 channel SCN1A gene variants improve epileptic phenotypes and reduce the frequency of seizures in the disease. Voltage-gated potassium channels (KV) are another ion channel responsible for contributing to the action potential. KV channelopathies lead in the disease mechanism of epilepsy. Different pathogenic variants in the KV channel gene tend to affect channel protein function differently. KCNA-, KCNB-, KCNC-, KCND-, KCNV-, KCNQ-, and KCNH- gene variants associated with the KV channel have been identified in the pathophysiology of epilepsy disease (Allen et al. 2020). Therefore, KV mutations cause heterogeneous clinical phenotypes. Compared to sodium and calcium channels, which initiate and maintain action potentials in presynaptic nerve terminals, KV channels mainly control neuronal excitability by displaying many different types and roles (Köhling and Wolfart 2016). The 12 monogenic variants identified in KV are strongly implicated in epilepsy. KCNQ2 gene polymorphisms encoding the KV7.2 channel are common in epilepsy (Allen et al. 2020). Since KCNQ2 gene mutations cause degenerative changes (encephalopathy) in brain tissue, the ion channel is being investigated in current studies.

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In a study, the phenotype of epileptic encephalopathy in newborn linked to the KCNQ2 gene was investigated. The study revealed that KCNQ2 mutations are frequently observed in patients with neonatal epileptic encephalopathy with electroclinical and radiological findings (Weckhuysen et al. 2012). In conclusion, KCNQ2 variants may be one of the main causes of refractory neonatal seizures of unknown origin. Another case-control study investigated the association of rare variants of KCNQ2 with biphasic and disseminated seizures in acute encephalopathy. It has been found that rare nonsynonymous variants of KCNQ2 are observed more frequently in patients than in controls (Shibata et al. 2020). The results of the study reveal the relationship between KCNQ2 variants and epileptic seizures in epilepsy pathology. In a recent study, the features of KCNQ2 variants causing benign neonatal epilepsy and epileptic encephalopathy were investigated. According to the study findings, KCNQ2 gene mutations detected in the KV7.2 channel S6 subunit cause developmental epileptic encephalopathies (Goto et al. 2019). In conclusion, KCNQ2 gene variants reveal different clinical symptoms by varying KV7.2 channel subunits. In another study, it was revealed that KCNA2 mutations detected in the KV1.2 channel similarly cause variation in clinical findings of epileptic encephalopathy. According to the electrophysiological findings of the study, loss of function in the KV1.2 channel due to KCNA2 gene mutation triggers dominant focal seizures. Gain of function in the KV1.2 channel due to KCNA2 gene mutation causes generalized seizures (Masnada et al. 2017). In conclusion, the loss or gain of function observed in the KV1.2 channel due to KCNA2 gene mutation triggers more severe epilepsy phenotypes. Therefore, new neurotherapy techniques can be developed by targeting gene mutations in different KV channel subtypes. In a research project, the reactivation of the mutated KCNQ gene and its therapeutic effects were studied. In the study, KCNQ2 gene R207W voltage sensor mutation caused increased susceptibility to both spontaneous seizures and induced seizures (Tian et al. 2022). According to the research results, the KCNQ activator HN37 ameliorates the severe epilepsy phenotypes associated with KCNQ2 by showing potent anticonvulsant activity. In a similar study, the effects of amitriptyline treatment method targeting KCNQ2 mutations were investigated. According to the study findings, developmental disorders were detected in patients with neonatal epilepsy carrying the R144 variant in the KCNQ2 gene (Miceli et al. 2022). In conclusion, amitriptyline, a KV7.2/7.3 channel blocker, may be a new treatment modality in newborns by targeting KCNQ2 variants. In a recent study, the clinical features and new treatment modalities of KCNQ2 epileptic encephalopathy were investigated. Sodium channel blockers including lamotrigine, oxcarbazepine, zonisamide, topiramate, and phenytoin used in the study were found to be effective in preventing clinical manifestations of epileptic encephalopathy (Kim et al. 2021). In conclusion, early recognition of KCNQ2 encephalopathy and early use of sodium channel blockers may help in seizure control. EEG, which is widely used in the treatment of epilepsy, provides early diagnosis and rapid treatment in KCNQ2related epileptic encephalopathy. In the study, the EEG patterns of seizures related to KCNQ2 were different from the EEGs of seizures with other etiologies (Lee et al. 2021). In conclusion, the use of EEG can be a valuable tool for early detection and

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rapid treatment of KCNQ2-related seizures. One study investigated the effects of gabapentin treatment in patients with KCNQ2 gene variant epileptic encephalopathy. According to study data, rapid EEG recovery was observed in epilepsy individuals after treatment with gabapentin (Soldovieri et al. 2020). The results show that gabapentin may be an effective treatment modality for patients with developmental epilepsy encephalopathy by improving KCNQ2 loss of function. In a similar study, the effect of retingabine on parvalbumin-expressing interneurons whose KCNQ2 gene was deleted was investigated. According to the findings, retingabine suppressed intrinsic membrane excitability in mouse models, preventing epileptic seizures (Jing et al. 2022). The results show that retingabine drug therapy may be an effective treatment option in individuals with epilepsy due to the KCNQ2 variant. Another study investigated the effect of 4-aminopyridine treatment in individuals with epilepsy with KCNA2 gain of function. According to the study findings, 4-aminopyridine, a K+ channel blocker, was able to tolerate the KV1.2 channel gain-of-function caused by variants in the KCNA2 subunit (Hedrich et al. 2021). In conclusion, 4-aminopyridine can be considered as a specific treatment option for KCNA2 variant epilepsy. As a result of these studies, gene therapies targeting KV channel mutations are effective in preventing epileptic seizures. In addition to gene therapies, drug treatments provide a short-term effect on channel functions. Therefore, drug treatment methods are not widely used in the later stages of the disease. As a result, it is important to investigate the source of epilepsy disease, which causes serious consequences, because patients with epilepsy receive the right treatment. In recent studies, the genetic causes underlying epilepsy trigger different seizure types. Epileptic seizures due to ion channel dysfunction negatively affect the quality of life of individuals with epilepsy. For this reason, studies targeting ion channel gene mutations in epilepsy are pioneers for the development of new treatment and therapy methods.

9.1.1.2 Parkinson Disease Parkinson’s disease (PD) is a disease characterized by progressive neurodegeneration of dopaminergic neurons in the substantia nigra region of the brain (Daniel et al. 2021). Dopamine release and firing activity of substantia nigra neurons are regulated by ion channels. Defects in these ion channels cause abnormal movement of various ions intra- and extracellular environment. Therefore, disruption of the intracellular signaling mechanism leads to changes in cellular homeostasis (Marsden 1990). Also, α-synuclein misfolding and aggregation, mitochondrial dysfunction, and oxidative stress increase disease severity by contributing to the molecular pathogenesis of the disease (Jankovic and Tan 2020). Autonomic and sensorimotor dysfunction and cognitive declines are observed in the later stages of the disease (Marsden 1990). Currently, there is no definitive treatment method for PD. The motor symptoms that occur in the disease are managed with the help of dopamine replacement therapies. However, these therapies lose their effectiveness in managing the symptoms of the disease over time, as not able to inhibit the underlying mechanism of the disease. Therefore, ion channels, contributes to the mechanism

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of PD neurodegeneration, are one of the new therapeutic targets for drug development. Disturbances in the voltage-gated calcium channel (CaV), which is responsible for maintaining cellular calcium concentrations, trigger neurological disorders. Changes in neuronal CaV expression have been associated with a neurodegenerative mechanism in PD (Hurley and Dexter 2012). In addition to the main role of α-synuclein aggregates in the mechanism of PD, L-type calcium (CaV1) channels contribute to the pathogenesis of PD. L-type calcium channels contribute to several important physiological processes of the brain, including modulation of the brain’s mesoacumbal dopamine signaling pathway. In the literature, dysfunctions of CaV1.2 and CaV1.3 channels, which are L-type calcium channel isoforms, have been widely reported in PD. CaV1.3 channels have part in the consolidation of fear memories and neurodegenerative mechanisms while CaV1.2 channels contribute to the formation of spatial memory (Berger and Bartsch 2014). Therefore, dysfunctions in CaV1.2 and CaV1.3 channels reveal the clinical symptoms of PD, which are cognitive functions, behavioral disorders, and sleep abnormalities. Studies show that CaV channel functioning is dependent on the activity of the ubiquitinproteasome system (UPS) (Mukherjee et al. 2017). In the pathophysiology of PD, decreased expression of Parkin, the E3 enzyme of UPS, is associated with the expression of L-type channels (Sandoval et al. 2022). Therefore, functional changes of CaV channels are thought to be key in the pathogenesis of PD. The symptoms of the PD model were exacerbated by blocking the microglial CaV1.2 channel and dopaminergic neuron degeneration were observed due to CaV1.2 dysfunction in mice with PD genotype (Wang et al. 2019). This observation showed that CaV1.2 channel dysfunction exacerbates PD disease phenotypes. In another study, CaV1.3 channels were found to control D2 dopamine autoreceptor responses. According to the study findings, CaV1.3 channels regulate these responses in substantia nigra dopamine neurons through neuronal calcium sensor1 (NKS-1) (Dragicevic et al. 2014). Accordingly, CaV1.3 channels also contribute to the clinical symptoms of PD besides CaV1.2 channels. In a similar study, CaV1.3 channels were found to increase the sensitivity of substantia nigra dopaminergic neurons in a mouse model of PD and mRNA levels of CaV1.3 channel were found to be higher in the substantia nigra region compared to the cortex (Verma and Ravindranath 2020). This higher expression showed that CaV1.3 channel expression may contribute to the neurodegenerative effect of PD. These studies show that L-type calcium channel dysfunctions lead to the molecular pathogenic mechanism of PD. Therefore, the examination of gene mutations that cause CaV channel dysfunction is important in terms of determining new treatment methods for PD neurodegenerative disease. In a recent study, genetic silencing of striatal CaV1.3 ameliorated the side effects of the drug levedopa used in PD. The study revealed that vector-mediated genetic silencing of striatal CaV1.3 in rats with PD was effective in preventing levodopainduced dyskinesias (Steece-Collier et al. 2019). These results suggest that genetic silencing of CaV1.3 is an effective treatment modality for severe PD phenotypes. In another study, silencing of CaV2.3 channels resulting in dopaminergic neuron loss

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was investigated in models of PD. In the study, silencing of CaV2.3 reduced nigral somatic Ca2+ signals and Ca2+-induced hyperpolarization observed (Benkert et al. 2019). This observation helps to understand the treatment modalities targeting CaV2.3 channels provide complete protection against PD degeneration. A recent study examined the effect of isradipine on L-type CaV channels in dopaminergic neurons in the substantia nigra. According to the study findings, isradipine treatment method could not provide neuroprotective effect in CaV1.3 α1-subunit splice variants (Ortner et al. 2017). As a result, gene silencing treatment methods targeting the CaV channel yield more effective results compared to drug treatment methods. In current studies, ion channels have role in the pathophysiology of PD neurodegenerative disease are targeted in different contexts. In this direction, new treatment methods are being developed. Today, therapeutic agents targeting gene mutations are used in addition to levodopa therapy in the treatment of PD. For this reason, it is important to continue and increase studies targeting PD ion channel gene mutations in terms of developing new treatment and therapy methods.

9.1.1.3 Schizophrenia Schizophrenia is a serious mental disorder characterized by behavioral and cognitive decline accompanying psychotic symptoms. Today, schizophrenia continues to be an etiological and therapeutic challenge (Owen et al. 2016). Schizophrenia, which is a heterogeneous disease that occurs in adolescence and early adulthood, is caused by genetic or environmental factors negatively affecting brain development. Cortical stimulant-inhibitor imbalance has role in the development of cognitive and negative symptoms of schizophrenia disorder (McCutcheon et al. 2020). Dysfunction of dopaminergic neurotransmission contributes to the formation of psychotic symptoms (Owen et al. 2016). Also, studies have revealed that GABAergic, serotonergic and noradrenergic system interactions have a role in the neurotransmitter systems of schizophrenia (Gill and Grace 2016). The functional specificity of neurotransmitter systems is governed by the neurotransmitter-specific proteins (i.e., receptors, transporters, and metabolic enzymes) expressed here as well as by ion channels expressed within the system (Beaulieu and Gainetdinov 2011). Therefore, ion channels help in determining the underlying mechanisms of hallucinations and delusions, which are the clinical findings of schizophrenia. Genetic studies in the literature show that the genetic structure of schizophrenia at the population level is affected by locus, allelic and different trait heterogeneity (Mäki et al. 2005). Although progress has been made in mouse model research at both the phenotype and brain system levels, the molecular and genetic mechanisms of schizophrenia have not been fully resolved (Askland et al. 2012). Due to the ongoing research on the pathophysiology of the disease, antipsychotic drugs combined with psychological therapies, social support and rehabilitation are used in the treatment of schizophrenia. Advances in genomics and neuroscience have led to great advances in the understanding of disease mechanism, leading to the delivery of more effective treatments (Owen et al. 2016). In conclusion, targeting different ion channels in current studies allows the development of new therapies.

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BK channel with potassium conductivity have role in the pathogenesis of schizophrenia. Due to its regulation of neuronal excitability, the BK potassium ion channel contributes to the disease mechanism of schizophrenia. Calcium-activated BK potassium channel KCNN3 gene variants are one of the gene polymorphisms frequently studied in schizophrenia (Askland et al. 2012). The KCNN3 gene mediates neuronal excitability by regulating the slow component of hyperpolarization. Therefore, KCNN3 gene polymorphisms are suggested as functional candidates for the pathogenesis of schizophrenia (Ritsner et al. 2002). Genome and gene-wide studies in the literature have revealed the link between schizophrenia and various voltage-gated ion channels (KCNH2, KCNQ channels, KCNA1, KCNE2, CACNA1C, CACNA1B, CACNA1F, and CACNA5). Also, pharmacological and translational studies have revealed that physiological and pathophysiological mechanisms, especially in the ion channel families, including voltage-gated potassium channels, affect the schizophrenia disease phenotype (Askland et al. 2012; Singh et al. 2022). Ion channels may be one of the therapeutic targets in the pathogenesis of schizophrenia due to their basic roles in various physiological processes and their relationship with neuropathological diseases (Camerino et al. 2008). In this respect, it is important to increase and continue research aimed at detecting ion channels that contribute to schizophrenia. In a recent study, potassium channel gene associations with white matter disorders in schizophrenia were investigated. As a result of the study, rs8234, a single-nucleotide polymorphism, was detected in the 3′ untranslated region of KCNQ1, which is a voltage-gated potassium channel. It has been observed that Rs8234 affects KCNQ1 expression levels and accordingly neuronal action potentials change (Bruce et al. 2017). The results suggest that KCNQ1 dysfunction may contribute to decreased white matter integrity and increased risk of schizophrenia. In another study, the KV2.1 potassium channel complex was found to elicit phenotypes associated with schizophrenia. In the study, a relationship between schizophrenia and KCNB1 rare gene polymorphism in the KV2.1 channel was found (Peltola et al. 2016). The results reveal the involvement of the KV2.1 channel in schizophrenia-related behavioral disorders, suggesting that the KV2.1 channel KCNB1 gene is a strong marker for schizophrenia spectrum disorders. A cohort study investigated the relationship between voltage-gated sodium channel (SCN1A) polymorphism and short-term memory performance in schizophrenia. rtfMRI taken during the working memory task detected the activation differences depending on the SCN1A allele in brain regions (Papassotiropoulos et al. 2011). In conclusion, it can be thought that SCN1A plays an important role in memory problems observed in schizophrenia. In a project, the relationship of the KCNH2 gene with schizophrenia neurocognitive disorders was investigated. Mice with the KCNH2 gene variant have lower IQ scores, attention deficit and lower performance in memory (Hashimoto et al. 2013). Study data suggest that the KCNH2 polymorphism may be associated with schizophrenia-related neuropsychological deficits and risk of schizophrenia disease. The selective expression of the KCNS3 potassium channel α-subunit in GABA neurons in the human prefrontal cortex was investigated. In line with the findings, it was determined that KCNS3 gene variants cause molecular changes in

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cortical GABA neurotransmission (Georgiev et al. 2012). In conclusion, studies targeting KCNS3 gene variants provide an opportunity for the development of new treatments in schizophrenia. A genome-wide analysis of peripheral blood cells from patients with schizophrenia was performed in a study in the Han population of China. According to the study findings, epigenetic changes in KCNQ4, which encodes the KV7 channel that triggers neuronal excitability, worsen the clinical symptoms of schizophrenia (Li et al. 2021). In conclusion, ion channel gene mutations observed in schizophrenia patients can be targeted in the development of new treatment modalities, as they are potential biomarkers. In a recent study, it was revealed that ASP2905 provides a psychoactive effect in schizophrenia by inhibiting KV12.2 encoded by the KCNH3 gene. According to the findings, ASP2905 significantly improved learning performance and reduced cognitive impairments caused by schizophrenia such as attention deficit (Takahashi et al. 2020). The results show that ASP2905 is more effective than other antipsychotic treatments on the broad-spectrum symptoms of schizophrenia, including cognitive impairments. Another study investigated the effect of proteasome inhibition on disease pathogenesis in the voltage-gated potassium channel isoform KV11.1–3.1 associated with schizophrenia. Proteasome degradation inhibition had a positive effect on channel cellular expression and membrane trafficking (Calcaterra et al. 2016). These findings reveal the importance of the proteasome inhibition method in voltage-gated potassium channel expression and regulation in schizophrenia. In a South African study, variation in voltage-gated calcium channel genes and the effect of antipsychotic treatment response on gene variants were investigated in a cohort of schizophrenia. According to the findings, the CACNA1B rs2229949 CC genotype was associated with negative symptomology in schizophrenia (O’Connell et al. 2019). In conclusion, antipsychotic treatment had a positive effect on calcium channel subunits gene variants and increased channel activation. In a study conducted in the USA, the genome of patients with schizophrenia was examined and the effect of drug use on gene variants was investigated. According to the study findings, voltage-gated calcium channel CACNA1C, CACNB2, and CACNA1I gene mutations were observed more frequently (Lencz and Malhotra 2015). The results showed that VLCC drug treatment was effective in regulating neurotransmitter release and neuronal gene transcription of calcium channels. In line with these data, different neurotherapy techniques targeting ion channel gene mutations are used in current studies. These techniques reduce the severity of the disease by inhibiting the clinical symptoms of schizophrenia. In conclusion, it is important to investigate the psychiatric disorder of schizophrenia in terms of ion channels. In line with current studies, therapeutic agents targeting ion channel gene mutations are being developed in the treatment of schizophrenia. Today, studies targeting schizophrenia ion channel gene mutations are pioneers for the development of new treatment and therapy methods.

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Conclusion

Ion channels provide a direct link between genetic variants, gene function and neurological disease pathogenesis such as epilepsy, Parkinson’s disease, and schizophrenia. Today, gene set-based analytical applications allow the detection of singlenucleotide polymorphisms of ion channels by gene mapping procedures. In addition, the development of new gene set-based analytical approaches to whole genome sequencing data will aid the investigation of ion channel genes on a larger scale. At the same time, gene-based therapies offer the possibility of altering the expression and functioning of specific ion channels. In addition to genetic applications, diseaserelated functional variants in ion channel genes have an important role for pharmacological agent development. Today, integration of the newly developed drugs into the treatment processes of neurological diseases is considered since they have increased activity in Ca2+ and Na+ channels. In conclusion, ion channel gene variants may be an important therapeutic target in developing new neurotherapy techniques for modulation of neurological diseases.

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Herbal Approaches for the Management of Neurological Disorders

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Vikas Yadav, Sandeep Guin, Sudipta Nayak, and Awanish Mishra

Abstract

Neurological disorder like epilepsy, Alzheimer’s, and Parkinson’s disease is manifested by extensive morbidity, disability, along high rate of mortality, which actively compromising human life worldwide. Even though, clinically acceptable effective agents for therapeutics are anyhow at present underlying. As a result, discovering the neuroprotective candidates along least side effects and more desirable effect to aid the well-being of patients is a compelling question. Plant-based secondary metabolites such as, flavonoids, alkaloids, glycoside, and saponins have extensive medicinal antiquity. It has promising action on neurological disorder. Here, impact as well as fundamental appliance of few secondary metabolites for use of neurological disorder is cited and explained based on prior research survey. By abstracting the previous analysis, we put in place that secondary metabolites may play a crucial part of neuroprotective effect by means of several pharmacological action such as anti-inflammatory, antioxidant, antiapoptotic protection. So, they are promising natural neuroprotective agent to become as exceptional way for finding a novel candidate for the management of the neurological disorders. Keywords

Neurological disorders · Traditional medicines · Herbal approaches · Flavonoids · Alkaloids · Glycosides · Saponins

Vikas Yadav and Sandeep Guin contributed equally with all other contributors. V. Yadav · S. Guin · S. Nayak · A. Mishra (✉) Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)—Guwahati, Changsari, Kamrup, Assam, India e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Mishra, H. Kulhari (eds.), Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities, https://doi.org/10.1007/978-981-99-6807-7_10

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Introduction

In recent years, there has been a notable resurgence of interest and research in the field of herbal medicine, with a particular focus on its applications within the realm of neurological disorders. Herbal approaches lends support to the utilization of herbal remedies and plant-derived compounds for the prevention, treatment, and effective management of diverse neurological conditions. This comprehensive investigation dives into the intricate domain of herbal interventions, illuminating the potential therapeutic advantages and underlying mechanisms that offer promise in tackling the intricate challenges associated with neurological disorders. Encompassing a spectrum from conditions like epilepsy and Alzheimer’s disease to Parkinson’s disease and beyond, this compilation seeks to provide valuable insights into the emerging herbal strategies that have the potential to transform our understanding and approach to addressing neurological health in the contemporary era. Epilepsy, Alzheimer’s, and Parkinson’s disease contributes to majority of neurological disorders which enhances the socioeconomical burden (Singh et al. 2023; Kundu et al. 2023; Khan et al. 2023; Bandopadhyay et al. 2021, 2022; Kaur et al. 2022; Mishra et al. 2021a, b; Maan et al. 2020; Mandal et al. 2020). Currently available FDA-approved drugs, for the management of neurological disorders, are very limited due to serious side effects with resistance in certain individual. The intricating of neurological disorders—affiliated fundamental pathophysiological mechanism wish the finding novel multitargeting candidates. In medicinal aspects, recent years have made some progression. There is a widespresd interest in the search for natural product including secondary metabolites phytochemicals agent, which have multitargeted therapeutics feature such as antioxidant, anti-inflammatory, and neuroprotective, along least side effects. Accordingly, they have acquired consideration for support novel pharmacological candidates (Di Paolo et al. 2019; Gravandi et al. 2023). Latterly, a considerable number of preclinical and clinical data have been conducted to explore the potential contribution of phytochemicals, namely, flavonoids, alkaloids, glycoside, and saponin, in the management and prevention of neurological disorders and their associated comorbidities, as well as their underlying mechanisms (Paula et al. 2019). This chapter aims to provide an overview of the recent existing information about phytochemicals as a natural and potentially effective adjunct therapy for the same neurological disorders. And will critically evaluate the strengths and future direction of the existing research.

10.2

Secondary Metabolites in Neurological Disorders

Through ages, people have conventionally depended on active constituents obtained from the plant such as secondary metabolites (SMs) to treat the various diseases with fewer side effects contrast to synthetic approaches. Classically, several plants were also utilized to aid the neurological disorders (Akhtar et al. 2023). These SMs are small, organic components not directly crucial for plant growth, though for plant

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survival. They are subclassified into three major classes: phenolics, nitrogencontaining compound, and terpenoids (Elshafie et al. 2023). Phenolics comprising secondary metabolites such as flavonoids acquiring naturally from distinct sources like herbs, fruits, grains, and some vegetables, which has been widely explored for the therapeutics and avoidance of several neurological illness (Ikram et al. 2019). As per chemical structure flavonoids can be organized into different subclasses (Biswas et al. 2023). These flavonoids exhibits range of health benefits such as antiinflammatory, anti-apoptotic and antioxidant effect, and activating the antioxidant enzymes (Khan et al. 2020). The nitrogen-containing secondary metabolites including alkaloids are a mixed class of naturally occurring organic component that typically contain basic nitrogen atoms are found in wide range of plants, fungi (Kooshki et al. 2023). It is firmly stable that alkaloids are array of propitious applicant to execution of neurological disorder along with favorable possessions to across distinct disease with promising pharmacological properties including antioxidant, antiinflammatory, neuroprotective activity, and even conserving cognitive impairment, behavioral changes, cell death, and decreasing protein-processing dysfunctions against neurological disorders (Kooshki et al. 2023). Glycosides is a group of natural compounds discursively present in fruits, vegetables, and Chinese herbal medicines. Due to their hydrophilicity, the pharmacological properties and biological activities of glycosides have got more concentration (Hao et al. 2022). Saponins are another class of scondary metabolites, consist of polycyclic aglycone attached to a carbohydrate unti, with variations either steroidal or triterpenoidal saponins, and they are commonly extracted from different plant parts, with the tendency to be more concentrated in plant roots (Hussein and El-Anssary 2019), and their neuroprotective role in neurological disorder has been explored including anti-inflammatory, antioxidant, and antiapoptotic action (Zhang et al. 2022). These plant-based SM-phytoconstituents drew the curiosity of huge scientists from various research arena in plant biology and biotechnology. As a result, they have studied for their biological properties related with neurological disorders. Even several in vivo and in vitro experiment have revealed that phytoconstituents do have antioxidant, anti-inflammatory, and neuroprotective action, thus helps in treating neurological diseases (Jayaraman et al. 2023). As several evidences suggest the therapeutic role of phytoconstituents, but still more studies are required to study their safety and efficacy of these phytoconstituents-based medicines. Utilizing the previously published research articles as the base for the additional research, like preclinical studies and clinical trials. So, phytoconstituents can be a safer alternative approach contrast to synthetic drugs treatments for aiding a spectrum of neurological disorders. Wide variety of plants are comprising several essential constituents that give hope for the management of the neurological diseases. In this chapter, we described some of the most bioactive plant-based secondary metabolites such as phenolics, saponins, and nitrogen-containing compound, for example, alkaloids and their role in neurological disorders.

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10.2.1 Role of Flavonoids in Neurological Disorders The potential role of several flavonoids has been extensively explored in neurological disorders such as epilepsy, Alzheimer’s disease, and Parkinson’s disease. A list of data supporting the role of distinct flavonoids in different neurological disorders is provided in (Table 10.1).

10.2.1.1 Role of Flavonoids in Epilepsy Several flavonoids have exhibited anticonvulsant and neuroprotective properties, suggesting their potential as therapeutic agents for mitigating epilepsy. Some in vivo and in vitro studies have demonstrated their role. Genistein, a flavonoid, has been found to exhibit anticonvulsant properties by reducing the duration and intensity of seizures. Additionally, it has been observed to improve cognitive functions such as memory and learning. The entity in question exhibits protective properties by suppressing the activation of microglia and astrocytes, as well as the JAK2/ STAT3 signaling pathway. Moreover, it has been observed that it augments the expression of antiapoptotic protein and facilitates neuronal survival through the stimulation of the keap1 and Nrf2 pathways (Hu et al. 2021). Hesperidin treatment resulted in a significant increase in seizure latency and a reduction in hyperactive responses induced by PTZ. The findings indicate that hesperidin incubation in PTZ-exposed larvae led to a noteworthy decrease in c-FOS expression, which provides additional evidence of the inhibition of neuronal excitation. The therapeutic intervention elicited a modulation of larval brain-derived neurotrophic factor (BDNF) expression, concomitant with a reduction in interleukin-10 (IL-10) expression (Sharma et al. 2021). The administration of quercetin has demonstrated efficacy in mitigating seizures and cognitive decline in epileptic mice induced with kainic acid. The protective effects of this entity are manifested through the attenuation of ferroptosis via the SIRT1/Nrf2/SLC7A11/GPX4 pathway, thereby preventing neuronal death induced by seizures (Xie et al. 2022). Baicalin has been found to exhibit neuroprotective effects by preventing cognitive and emotional comorbidities in epilepsy, as well as increasing seizure latency. The potential mechanism of action involves a reduction in astrocyte polarization and aberrant expression of AQP4 and Kir4.1, leading to a potential decrease in hippocampal neuron autophagy and subsequent cell death. Baicalin has been found to exhibit inhibitory effects on autophagy, apoptosis, and lipopolysaccharide-induced C3 + A1 astrogliosis in PC12 cells (Li et al. 2022a). Morin has been observed to demonstrate prophylactic properties against necroptotic changes and mitochondrial fragmentation triggered by PTZ. This is achieved through the suppression of p-RIPK-1/p-RIPK-3/p-MLKL and PGAM5/ Drp-1 cues, as well as the enhancement of caspase-8. Morin has been found to exhibit anti-inflammatory properties by reducing the levels of pro-convulsant receptor/cytokines such as TNFR-1, TNF-α, IL-1β, and IL-6, as well as hippocampal IL-6/p-JAK2/p-STAT3/GFAP signaling. Morin has been observed to decrease the levels of MDA, NOX-1, and keap-1 in the hippocampus, thereby reinstating the equilibrium of antioxidant enzymes (Abd El-Aal et al. 2022).

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Table 10.1 Experimental evidence supporting the role of flavonoids in various neurological disorders Experimental model

Animal/cell lines

PTZ-induced rat model of epilepsy

Rat (60–80 g)

Hesperidin (1, 5 and 15 μM) for 1 h before PTZ

PTZ-induced zebra fish larvae model of epilepsy

Zebra fish larvae

Quercetin (50 mg/kg, i. g.) daily for 21 days

Kainic acid (20 mg/ kg, i.g.)-induced mice model of epilepsy

Male C57BL/6 J mice

Baicalin (50 and 100 mg/kg, p.o.)

PTZ (40 mg/kg)induced rat model of epilepsy and LPS-induced C3 + A1 astrogliosis in PC12 cells

Male Sprague Dawley rats and PC12 cells

Dose and route Epilepsy Genistein 5 or 15 mg/ kg, i.p.)

Outcomes

Ref.

Reduced seizure duration, intensity, and improved learning and memory possibly by inhibition of microglia/astrocyte activation via JAK2/ STAT3 pathway. Neuroprotective effect via antioxidant (NRF2 pathway) and antiapoptotic effect Hesperidin decreased the hyperactive reactions brought on by PTZ and lengthened seizure latency via downregulation of c-fos expression and upregulation of brainderived neurotrophic factor Prevents seizures and cognitive impairment. Attenuates ferroptosis via SIRT1/Nrf2/ SLC7A11/GPX4 to prevent seizureinduced neuron death Prevents cognitive and emotional comorbidities and increased the seizure latency. Reduce hippocampus neuron autophagy and death by reducing astrocyte polarisation and aberrant AQP4 and Kir4.1 expression. BAL suppresses autophagy, apoptosis, and lipopolysaccharideinduced C3 + A1

Hu et al. (2021)

Sharma et al. (2021)

Xie et al. (2022)

Li et al. (2022a)

(continued)

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Table 10.1 (continued) Dose and route

Morin (10 mg/kg, i. p.)

Experimental model

PTZ (35 mg/kg, i.p.)induced rat model of epilepsy

Alzheimer’s disease Quercetin Triple transgenic (100 mg/kg) (3 × Tg-AD) mice in every 48 h for 12 months

Engeletin (5–40 μM)

Aβ1–42: 5 μM for 24 h

Naringin (100 mg/kg, p.o.) per day for 20 days

Aβ25–35 (5 μL of 1 mM) rat model of AD

Animal/cell lines

Male Wistar rats (8–10 weeks old, weighing 180 ± 20 g)

Triple transgenic 3 × Tg-AD mice (PS1M146V knock-in, APPswe, taup301L) Age: 6 months Murine microglia BV-2 cells

SpragueDawley rats (male)

Outcomes astrogliosis in PC12 cells Prevented necroptotic alterations and mitochondrial fragmentation by suppressing p-RIPK-1/ p-RIPK-3/p-MLKL and PGAM5/Drp-1. Also suppressed the pro-convulsant receptor/cytokines TNFR-1, TNF-α, I L-1β, and IL-6 and hippocampus IL-6/pJAK2/p-STAT3/ GFAP cue Quercetin decreases extracellular β-amyloidosis, tauopathy, astrogliosis and microgliosis in the hippocampus and the amygdala. Quercetin improve performance on learning and memory in AD model Engeletin reduces oxidative stress increased by Aβ1–42 in BV-2 cells by reducing ROS, MDA, NO production, and by increasing GSH-Px and SOD activity. It also has antiinflammatory action by inhibiting IL-1β, IL-6, and TNF-α production Naringin improvs object recognition memory, avoidance memory and spatial recognition memory in Aβ induced rats. Naringin has

Ref.

Abd El-Aal et al. (2022)

Paula et al. (2019)

Huang et al. (2020)

Choi et al. (2023)

(continued)

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Table 10.1 (continued) Dose and route

Experimental model

Animal/cell lines

Luteolin (100 mg/kg/ day)

Amyloid-β (Aβ)1–42 oligomers-induced mice model of AD

Mice

Nobiletin (10 mg/kg/ day)

Aβ1–40-induced rat model of AD

Rat

Parkinson’s disease LPS (10 μg/2 μL)α-cyperone (10 mg/kg, i. induced rat model of p.) PD

Rat

Barbigerone (10 and 20 mg/kg/ day)

Rotenone (0.5 mg/kg. s.c daily for 28 days)induced rat model of PD

Wistar rat

Naringin (80 mg/kg, i. p.)

Rotenone (injected 2 μL with 0.2 μL/min flow rate)-induced PD

Rat

Outcomes therapeutic potential to reduce neuronal inflammation and apoptosis induced by Aβ related with the BDNF/TrkB/CREB signaling Luteolin and exercise combination therapy prevented Aβ1–42 oligomers-induced cognitive impairment, possibly by decreasing neuroinflammation and enhancing autophagy Nobiletin has neuroprotective and anti-dementia properties due to its antioxidant, antinitrosative, and antiinflammatory properties by modulating TLR4/NFkB/Nrf2 pathways Ameliorated motor dysfunction, inhibited the reduction of dopaminergic neurons though actuating Nrf2/ HO-1 and holding down NF-κB signaling pathway Improved the motor symptoms and neuroprotective activity via inhibiting inflammatory and oxidative stress activity Reduced behavioral abnormalities and neuroprotective activity via Nrf2mediated pathway

Ref.

Tao et al. (2023)

GhasemiTarie et al. (2022)

Huang et al. (2023)

Alharthy et al. (2023)

Garabadu and Agrawal (2020) (continued)

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Table 10.1 (continued) Dose and route Apigenin (50 mg/kg, i. p.) and (25 and 50 mg/kg, p. o.)

Kurarinone (5, 10, and 20 mg/kg)

Experimental model MPTP (25 mg/kg. i. p.)-induced PD and LPS (5 μg/5 μL)induced PD

MPTP (20 mg/kg)induced mice model of PD

Animal/cell lines Mice and rat

Mice

Outcomes Neuroprotective action through attenuating the neuroinflammation and attenuating the alteration, motor impairment, oxidative stress, neuroinflammation, in rat brain by modulating NF_kB and Nrf2 signaling pathway Neuroprotection effect via attenuated neuroinflammation

Ref. Yarim et al. (2022)

Sun et al. (2022)

10.2.1.2 Role of Flavonoids in Alzheimer’s Disease Similarly, flavonoids have been reported to improve the learning and memory functions in different Alzheimer’s disease models. Their antioxidant and antiinflammatory property play an important role to mitigate oxidative stress and neuroinflammation-mediated neuronal damage. The neuroprotective properties of flavonoids, specifically quercetin, have been observed to reduce β-amyloidosis, tauopathy, astrogliosis, and microgliosis in various regions of the brain. Additionally, quercetin has been shown to enhance cognitive function in the triple transgenic (3 × Tg-AD) mice AD model (Paula et al. 2019). Other findings suggest that naringin may enhance memory and cognition in rats with Alzheimer’s disease induced by Aβ, as well as provide protection against Aβ-induced apoptosis through the BDNF/TrkB/ CREB signaling pathway (Choi et al. 2023). The study conducted on a rat model of Aβ1–40 indicates that nobiletin exhibits potential neuroprotective and anti-dementia effects by inhibiting oxidative stress and neuroinflammation through the modulation of TLR4/NF-kB/Nrf2 pathways (Ghasemi-Tarie et al. 2022). The flavonoid luteolin has been reported to possess anti-inflammatory characteristics. When combined with exercise, it has been observed to prevent cognitive impairment induced by Aβ1–42 oligomers in mice (Tao et al. 2023). Engeletin, a flavonoid compound, has been reported to exhibit anti-inflammatory and antioxidant properties in murine microglia cells treated with Aβ1–42. Engeletin has been found to inhibit the production of ROS, MDA, and NO, as well as the production of TNF-α, IL-1β, and IL-6 (Huang et al. 2020). 10.2.1.3 Role of Flavonoids in Parkinson’s Disease Furthermore, various animal and cell model of PD have extensively documented that natural products are having neuroprotective activity with anti-inflammatory activity (Huang et al. 2023). In this connection, flavonoids possess wide therapeutic

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promising such as antioxidants, anti-inflammatory, neurotrophic, and neuroprotective, build them one of the potential approaches to report tasks prevalent in health area, and suggesting that they may be alternative novel therapeutic approaches against PD (Ahmad et al. 2021). So, neuroprotective role of distinct flavonoids such as α-cyperone is an established Chinese medicine, delineated to have key role in Parkinson’s disease by mitigate motor dysfunction, constraining the declination of dopaminergic neurons by way of triggering Nrf2/HO-1 and extinguishing NF-kB signaling pathway in LPS-induced rat model of PD (Huang et al. 2023). Barbigerone is a naturally existing pyronoisoflavone found in seed of Tephrosia barbigera is able to made better the motor symptoms and neuroprotective activity against rotenone-induced Wistar rat model of Parkinson’s disease via holding down inflammatory and oxidative stress activity (Alharthy et al. 2023). Naringin, a potent flavonoid that is mostly found in grapefruits and citrus in robust concentration, to have neuroprotective action in 6-(OHDA) and MPTP-induced animal models of PD. In addition, it displays the anti-inflammatory and antioxidant activities in other neurological disorder in experimental studies. Moreover, recently it has been recorded that naringin reduce behavioral abnormalities and neuroprotective activity against rotenone-induced rat model of PD via regulating mitochondrial dysfunction and apoptosis (Garabadu and Agrawal 2020). Apigenin is a member of the flavone present in fruits and vegetables, has explored to display the antioxidant, antiinflammatory activity, and recently it has been documented the neuroprotective role and attenuated the alteration, motor impairments, oxidative stress, neuroinflammation against MPTP and LPS-exposed mice model of Parkinson’s disease via attenuating neuroinflammation and modulating NF-kB and Nrf2 signaling pathway (Yarim et al. 2022). Kurarinone is major active ingredients concentrate in conventional Chinese medicine sophorae flavescentis Radix, or kushen in Chinese (the root of sophorae flavescentis). Having distinct pharmacological properties like anti-inflammatory and antioxidant activities. However, recent data has been stated that kurarinone exert the neuroprotective effect upon MPTP-exposed mice model of Parkinson’s disease via attenuated neuroinflammation (Sun et al. 2022). Overall, flavonoids have demonstrated promising results in protecting against these neurological illness and related complication. The specific mechanisms of action and possible therapeutic uses of these substances in the treatment of neurological illness require further investigation.

10.2.2 Role of Alkaloids in Neurological Disorders Various alkaloids have been investigated for their efficacy neurological disorders is listed out in Table 10.2.

10.2.2.1 Role of Alkaloids in Epilepsy Recent studies have shown that piperine, a natural alkaloid, may have potential therapeutic effects in neurological disorders. One proposed mechanism is its ability

Pilocarpine (40 mg/kg)-induced rat model of epilepsy

Scopolamine (10 mg/ kg)

Isorhynchophylline (IRN) (20 and 400 mg/ kg) daily for 4 months

TgCRND8 mice AD model

PC12 cells Aβ-induced AD like condition in PC12and APP/PS1 mice AD model

Kainic acid (15 mg/kg, i.p.)induced rat model of epilepsy

Neferine (10 and 50 mg/ kg, i.p.)

Alzheimer’s diseases Magnoflorine (1 and 10 mg/kg)

Sprague Dawley rats (weighing 200–225 g)

Kainic acid (15 mg/kg, i.p.)induced rat model of epilepsy

Male TgCRND8 mice

APP/PS1 (APPswe/PSEN1dE9) double-transgenic mice (8 months, 30–32 g, female)

Female Sprague Dawley rats (8 weeks, weight of 200–220 g)

Male Sprague Dawley rat (weighing 150–200 g)

Animal/cell lines

Experimental model

Dose and route Epilepsy Piperine (10 and 50 mg/ kg, i.p.)

Table 10.2 Experimental evidence supporting the role of alkaloids in various neurological disorders

Magnoflorine reduces Aβ-induced PC12 cell apoptosis and intracellular ROS generation, and significantly improves cognitive deficits and AD-type pathology Isorhynchophylline (IRN) improves cognitive impairment in TgCRND8 transgenic mice via reducing Aβ generation and deposition, tau hyperphosphorylation and

Piperine reduced seizures, by reducing glutamate level, hippocampus neuronal injury, and cognitive impairment by upregulating the NGF/TrkA/Akt/ GSK3β signaling pathways Neferine reduced kainic acidinduced hippocampal seizure severity, neuroprotection, and neuroinflammation by reducing NLRP3 inflammasome activation and inflammatory cytokine release Scopolamine reduced cognitive impairment, and neurodegeneration and prevented aberrant mossy fiber sprouting in the lithium-pilocarpine model

Outcomes

Li et al. (2019)

Zhong et al. (2023)

Meller et al. (2021)

Lin et al. (2022)

Hsieh et al. (2022), Mishra et al. (2015)

Ref.

228 V. Yadav et al.

3 × Tg AD mice model

TgAPPswe/PS1dE9 AD mouse model

Rotenone (10 mg/kg)-induced rat model of PD

MPTP (30 mg/kg, i.p.)-induced mice model of PD

Berberine (100 mg/kg) daily for 4 months

Neoline (0.5 or 0.1 mg/ kg)

Parkinson’s disease Vinpocetine (5, 10 or 30 mg/kg)

Rhynchophylline (2, 5, or 10 mg/kg)

Mice

Rat

Mice

3 × Tg AD mice model expressing human mutant genes including APPswe, PS1M146V, and tauP301L

Neuroprotective effect through inhibiting the neuroinflammation and maintaining metabolic homeostasis Improved the behavioral aberration, diminished the depletion of dopaminergic neurons, and everted inflammatory cytokines level and oxidative damage by mean of decreasing neuroinflammation and balancing metabolic homeostasis

neuroinflammation through inhibiting the activation of JNK signaling pathway It ameliorates cognitive impairments in AD mice, reduced the Aβ accumulation, inhibits the apoptosis, promotes the formation of micro vessels in the mouse brain by enhancing brain CD31, VEGF, N-cadherin, Ang-1 Neoline improved memory and cognition impairment and reduced the number of amyloid-beta plaque in the brain of AD mice. The chronic administration of neoline-reduced hippocampal tau, amyloid-β, and BACE1 expression and induces phosphorylation of AMPK

Herbal Approaches for the Management of Neurological Disorders (continued)

Zhang et al. (2023)

Ishola et al. (2023)

Liu et al. (2021)

Ye et al. (2021)

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Experimental model SNCA/α-synuclein-transgenic PD SNCA/α-synuclein-induced PD

MPTP (25 mg/kg/d, i.p.) and MPP+ (50 uM)-induced mice and cellular model of PD

Dose and route Piperine (25, 50, and 100 mg/kg, p.o.) Harmol (20 and 40 mg/ kg)

Dendrobine (10 or 20 mg/kg, p.o.)

Table 10.2 (continued)

Mice and SH-SY5Y cell line

SNCA/α-transgenic mice

Animal/cell lines Mice

Outcomes Exerts neuroprotective effects via promotion of autophagy flux Advance motor impairment and falling α-syn levels in Parkinson’s brain Diminish dopaminergic neuron apoptosis and correct motor activity through MANF-mediated ER stress suppression Li et al. (2022c)

Ref. Li et al. (2022b) Xu et al. (2022)

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to upregulate the NGF/TrkA/Akt/GSK3β signaling pathways, which are involved in neuronal plasticity and survival. This suggests that piperine could enhance the brain’s ability to adapt and recover from injury or disease (Hsieh et al. 2022). Another promising alkaloid is scopolamine, which has been found to exert antiepileptogenic activity in animal models. Specifically, it appears to increase the remission of epilepsy through a new mechanism of disease modification (Meller et al. 2021). Neferine is another type of alkaloid found in the seed embryo of Nelumbo nucifera, which has been shown to possess anticonvulsant effects. Neferine reduces kainic acid-induced hippocampal seizure severity, neuroprotection, and neuroinflammation by downregulating glutamatergic hyperactivity and the NOD-like receptor 3 (NLRP3)-mediated inflammatory signaling pathway and reducing inflammatory cytokine release (Lin et al. 2022).

10.2.2.2 Role of Alkaloids in Alzheimer’s Disease Alkaloids have also been extensively studied in Alzheimer’s disease and dementia. Research has indicated that magnoflorine could decrease the production of reactive oxygen species (ROS) and apoptosis in PC12 cells that have been treated with Aβ. Additionally, it has been found to notably enhance cognitive impairments and alleviate Alzheimer’s disease-like pathology in APP/PS1 mice Alzheimer’s disease model (Zhong et al. 2023). According to studies, isorhynchophylline (IRN) has been shown to enhance cognitive function in TgCRND8 transgenic mice by decreasing the production and accumulation of Aβ, as well as preventing tau hyperphosphorylation and neuroinflammation by inhibiting the activation of the JNK signaling pathway (Li et al. 2019). Another study suggests that neoline has demonstrated efficacy in enhancing memory and reducing cognitive impairment, as well as mitigating the formation of amyloid plaque in the brains of Tg-APPswe/ PS1dE9 AD mice. The administration of neoline resulted in the phosphorylation of AMPK and a reduction in the expression of tau, amyloid-β, and BACE1 in the hippocampus (Liu et al. 2021). Study indicates that berberine has the potential to impede neuronal apoptosis, Aβ accumulation, and ameliorate cognitive deficits in 3 × Tg AD mice (Ye et al. 2021). 10.2.2.3 Role of Alkaloids in Parkinson’s Disease Moreover, alkaloids also have been probed to have compelling promising for multitargeted approaches for the hopeful dealing with PD. In addition to antiinflammatory properties to alleviating the oxidative influence, MAO suppression in order to neuroprotection and anti-fibrillation toward the synucleinopathies (Lawal et al. 2023). Vinpocetine, an alkaloid obtained from vincamine, periwinkle sequester, which is having neuroprotectant action. Interestingly, one study has shown that vinpocetine ameliorated the oxidative stress and TNF-α expression against paraquatexposed mice model of PD (Ishola et al. 2018). In addition, recently it has been documented the neuroprotective effect of vinpocetine against rotenone-exposed mice model of PD through inhibiting the neuroinflammation and controlling metabolic physiology (Ishola et al. 2023). Rhynchophylline, a tetracyclic oxindole alkaloid present in uncaria rhynchophylla, has distinct neuropharmacological action,

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being an anti-inflammatory, antidepression, and anti-neurodegenerative action. It has documented that rhynchophylline having a neuroprotective action against PD. Moreover, rhynchophylline improved the behavioral aberrancy, diminished the damaged dopaminergic neuron, and decreased the level of inflammatory cytokines and oxidative damage against MPTP-induced mice model of PD by alleviating neuroinflammation and maintaining metabolic homeostasis (Zhang et al. 2023). Piperine, an alkaloid isolated from the Piper longum L, is used as an antiinflammatory and antioxidant activity. Previous studies had found that piperine alkaloid had neuroprotective effect and attenuated motor deficit in PD model induced by MPTP, rotenone, and 6-OHDA (Liu et al. 2016). Furthermore, currently it was found that piperine exerts neuroprotective effects against SNCA/α-synucleininduced mice model of PD via promotion of autophagy flux (Li et al. 2022b). Harmol, a β-carboline alkaloids, exhibits antioxidant and neuroprotective, is enable to advance the motor aberrant and decrease α-syn levels against SNCA/α-synucleininduced transgenic mice model of PD (Xu et al. 2022). Dendrobine is a widely accepted Chinese medicine, increasing attraction has disclosed the effect of dendrobine on age-related neurological disease like PD (Li et al. 2021). Currently, data showed that dendrobine alleviant the neuronal damage (6-OHDA)-induced model. Moreover, dendrobine has shown to decrease the apoptosis of dopaminergic neurons and advances motor activity against MPTP and (MPP+)-induced mice and SH-SY5Y cellular model of Parkinson’s disease via MANF-mediated ER stress suppression (Li et al. 2022c). These findings suggest that alkaloids could be a valuable source of new treatments for neurological disorders, particularly those involving neuronal dysfunction or degeneration. Further research is needed to fully understand the mechanisms underlying these effects and to develop safe and effective therapies based on these compounds.

10.2.3 Role of Glycoside in Neurological Disorder Various animal studies demonstrated that, glycosides have been shown to have potential neuroprotective effects, and their mechanism of action may vary depending on the specific glycoside used. Growing research attempted to elucidate the underlying mechanisms through which glycoside exerts pharmacological properties, including antioxidative and anti-inflammatory potential. The mechanism underlying the therapeutic efficacy of certain glycosides in the treatment of various neurological diseases like, epilepsy, AD, and PD is provided in Table 10.3.

10.2.3.1 Role of Glycoside in Epilepsy Gastrodin, a glycoside compound derived from Gastrodia elata, was found to reduce the severity of seizure, and prevent status epilepticus. The findings of the study indicate that gastrodin effectively maintained the transmission of GABAergic signals by impeding the degradation of the GABAA receptor α1 subunit. However,

PTZ (36 mg/kg, i.p.)-induced mice model of epilepsy

Pilocarpine (60 mg/kg, i.p.)-induced mice model of epilepsy

PTZ (80 mg/kg, i.p.)-induced mice model of epilepsy

PTZ (35 mg/kg, i.p.)-induced rat model of epilepsy

Arbutin (25 or 50 mg/kg)

16-O-acetyldigitoxigenin (1.8 mg/kg, i.p)

Acteoside (10, 25, and 50 mg/kg)

Salidroside (50 mg/kg/ day, i.p.)

Adult male Wistar rats (weighing 250–300 g)

Male Swiss albino mice (25–30 g, 8–10 weeks old)

ICR male mice (20–25 g)

Adult male NMRI mice (weighing 25–35 g)

Adult male Sprague Dawley rats (weighing 200–300 g)

Pilocarpine (60 mg/kg, i.p.)-induced rat model of epilepsy

Reduced the severity of acute seizures and prevented status epilepticus. It prevented the protein degradation of the GABAA receptor α1 subunit but did not modify the expression of any other GABA shunt enzymes Reduced seizures and memory impairment. It reduced IL-6, TNF-α, astrocyte activation, and neuronal loss Inactivates the inflammatory cytokines and inhibits the activation of the p-mTOR/p 70S6K signaling pathway, all of which contribute to the attenuation of the epileptic seizure that is generated by pilocarpine Protected against PTZ-induced epilepsy by increasing GABA and GABAA receptor expression and decreasing glutamate levels Improved cognitive impairment and increased the number of pyramidal neurons in the CA3 areas. Treatment with salidroside reduced oxidative stress and neuroinflammation via the Nrf2ARE signal pathway

(continued)

Wu et al. (2020)

Viswanatha et al. (2020)

Tu and Qian (2019)

Ahmadian et al. (2019)

Yang et al. (2021)

Ref.

Dose and route Epilepsy Gastrodin (50 mg/kg, i. p.)

Outcomes

Table 10.3 Experimental evidence supporting the role of glycosides in various neurological disorders Animal/cell lines

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Experimental model

10 233

Mice

5 × FAD mouse model

APP/PS1 (APPswe, PSEN1dE9) 85Dbo mice on C57BL/6 J

OLE-enriched diet (695 μg/kg) daily for 3 months

Geniposidic acid: 25 mg/ kg/day for 90 days

C57BL/6 J mice strain age: 6–7 months

C57BL6 Strain of mice

Wistar rat

Streptozotocin (STZ-ICV): 3 mg/kg

APPswe/PSEN1dE9 (APP/PS1) transgenic mice, with human APPSwe and PS1-dE9 mutations

Animal/cell lines

Experimental model

Echinacoside (50 mg/kg/ day) for 3 months

Dose and route Alzheimer’s disease Andrographolide (2 mg/ kg, i.p.; three times per week)

Table 10.3 (continued)

Attenuated the memory impairments, and astrocyte activation in the PFC. Also decreases activated microglia cells in the hippocampus rats Decreases the expression of BACE1 through activating PI3K/AKT/Nrf2/ PPARγ pathway and inhibits senile plaques deposition. Improves cognitive function and suppresses glia cell activation, IL-1β and TNF-α release, and NLRP3 inflammasome formation via TXNIP/Trx-1 signaling pathway Minimizes the neuroinflammation by inhibiting the NF-kB pathway, NLRP3 inflammasomes, and RAGE/HMGB1 pathways. Increases clearance and lowers generation of Aβ, increases BBB integrity and activity, and enhances memory performance Improves cognitive impairment, reducing Aβ accumulation and neuronal apoptosis and alleviates inflammation and axonal injury. Modulates the gene expression of major AP-1 and NF-kB family members (c-Fos, c-Jun, and p65) and downregulates the gene expression of HMGB-1 receptors (TLR2, TLR4, and RAGE)

Outcomes

Chen et al. (2022)

Abdallah et al. (2022)

Qiu and Liu (2022)

Souza et al. (2022)

Ref.

234 V. Yadav et al.

MPTP (30 mg/kg, i.p.)-induced PD

MPTP (15 mg/kg, i.p.)-induced PD

Paeoniflorin (30 mg/kg, i. P.)

Polydatin (20 and 80 mg/ kg, i.p.)

Mice

Mice

Caenorhabditis elegans and C6 glial cellular model

Rotenone (5.4 μg/2 μL DMSO) and LPS-induced model of PD

Swertiamarin (100 mg/ kg, i.p.) (25, 50, and 100 μg/mL)

Male Wistar rats (200–250 gm)

Mice

Streptozotocin (STZ-ICV): 3 mg/kg

MPTP (30 mg/kg, i.p.)-induced PD

Parkinson’s disease Arbutin (50 mg/kg, i.p.)

Honokiol (5, and 10 mg/ kg, i.p.)

Improved the motor activity through diminishing the function of the A2AR and advancing action of cAMP Neuroprotective activity, suppression of microglial and astroglia activation and anti-inflammatory activity via reduction in pro-inflammatory cytokines levels Ameliorate behavioral impairment and upregulate the expression of dopamine neuron by inhibiting JNK/p53 pathway Neuroprotection by enhancing MEF2D through the inhibition of GSK3β

Honokiol effectively protects by lowering inflammation, AChE levels, neurofibrillary tangles, and NF-kB activation

Zhang et al. (2020)

He et al. (2022a)

Sharma et al. (2022)

Zhao et al. (2021)

Singh and Singh (2023)

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there was no observed alteration in the expression of other enzymes involved in the GABA shunt (Yang et al. 2021). The glycoside arbutin, derived from the bearberry plant, exhibited the ability to mitigate seizures and ameliorate memory impairment through the attenuation of inflammatory mediator release (specifically TNF-α and IL-6) from reactive glial cells. Furthermore, arbutin exhibited a reduction in astrogliosis and prevented neuronal loss (Ahmadian et al. 2019). 16-Oacetyldigitoxigenin treatment attenuated the pilocarpine-induced seizure through inhibiting the activation of p-mTOR/p-70S6K signaling pathway and inactivation of inflammatory cytokines (Tu and Qian 2019). Acteoside, a glycoside found in several plant species, was able to protect against PTZ-induced epilepsy by increasing GABA and GABAA receptor expression and decreasing excitatory neurotransmitter, glutamate levels (Viswanatha et al. 2020). Salidroside, which is present in Rhodiola rosea, has been observed to enhance cognitive function, prevent the development of kindling, and mitigate oxidative stress and inflammation by activating the Nrf2-ARE signaling pathway (Wu et al. 2020).

10.2.3.2 Role of Glycoside in Alzheimer’s Disease Glycosides like andrographolide has been found to have an inhibitory effect on learning impairments and astrocyte activation in the prefrontal cortex (PFC) of rats treated with streptozotocin (STZ). Furthermore, it has been observed that the compound inhibits the activation of microglia in the hippocampus of rats induced with STZ (Souza et al. 2022). Study investigated the effects of echinacoside on senile plaque deposition and BACE1 expression in an APP/PS1 mice model of Alzheimer’s disease. The results indicate that echinacoside significantly reduces the accumulation of senile plaques and decreases BACE1 expression. These effects are mediated by PI3K/AKT/Nrf2/PPARγ pathway. Furthermore, it has been observed to impede the release of inflammatory cytokines and the formation of NLRP3 inflammasome (Qiu and Liu 2022). According to reported studies, the compound oleuropein has been found to decrease neuroinflammation through the inhibition of the NLRP3 inflammasomes and RAGE/HMGB1 pathways, as well as the activation of the NF-κB pathway. Moreover, it has been observed that there is a decrease in the overall accumulation of amyloid-beta in the brain, coupled with an enhancement in its elimination (Abdallah et al. 2022). The administration of geniposidic acid has been found to have a significant positive impact on cognitive impairment in mPrP-APPswe/PS1De9 AD transgenic mice. This effect is attributed to a reduction in Aβ accumulation, neuronal apoptosis, inflammation, and axonal injury. GPA modulated the gene expression of major AP-1 and NF-kB family members (c-Fos, c-Jun, and p65) and downregulated the gene expression of HMGB-1 receptors (TLR2, TLR4, and RAGE) (Chen et al. 2022). Study reported, honokiol has been observed to exert a significant protective effect in a streptozotocin induce Alzheimer’s disease model by its antioxidant properties, ability to reduce inflammation and AChE levels, restoration of neurofibrillary tangles, and prevention of NF-kB activation (Singh and Singh 2023).

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10.2.3.3 Role of Glycoside in Parkinson’s Disease Thus, neuroprotective potential of various glycoside has been explored for the treatment of PD. Arbutin is a natural glycoside that acquires neuroprotective properties such as antioxidant and anti-inflammatory. Additionally, a fresh study explored that arbutin improved the motor activity against MPTP-induced mice model of PD through diminishing the function of the A2AR and advancing the action of enhancing the effects of cAMP (Zhao et al. 2021). Swertiamarin (SWE), a secoiridoid glycoside, has exhibited assuring anti-inflammatory action by mean of by various mechanism (Pandey et al. 2021). Currently, swertiamarin probed its neuroprotective properties against α-syn-overexpressing transgenic and (6-OHDA)-exposed Caenorhabditis elegans models of PD. In addition, it has also investigated for the same action of swertiamarin against lipopolysaccharide LPS and rotenone -exposed in-vitro and in vivo model of PD via reducing neuroinflammation, α-syn deposition, and dopaminergic neurodegeneration (Sharma et al. 2022). Paeoniflorin, a key ingredient of Radix paeoniae Alba, having neuroprotective activity against animals’ model of PD. In addition, currently Paeoniflorin has shown to restore the motor impairment against MPTP-induced mice model of PD via controlling the α-synuclein/PKC-δ signaling pathway to lower the neuronal apoptosis (He et al. 2022a). Polydatin is the major active ingredient of polygonum cuspidatium Sieb. Recently, study showed that polydatin could protect against substantia nigra dopaminergic deterioration in rodent model of PD. Moreover, a current study explored the neuroprotective activity of polydatin against MPTPinduced mice model of PD by enhancing MEF2D through the inhibition of GSK3β (Zhang et al. 2020).

10.2.4 Role of Saponins in Neurological Disorders Saponins are a heterogeneous class of phytochemicals that exhibit a diverse array of biological properties such as anti-inflammatory and antineoplastic effects. At present times, there has been a growing attraction in exploring the potential therapeutic applications of saponins for neurological disorders like epilepsy, AD, and PD. A comprehensive list of data supporting the role of various saponins in various neurological disorders is provided in Table 10.4.

10.2.4.1 Role of Saponins in Epilepsy Various saponins (astragaloside IV, ginsenoside Rb1, saikosaponin A, and protodioscin) have been investigated in animal models of epilepsy. A preclinical study revealed that astragaloside IV exhibited inhibitory effects on the expression of inflammatory factors in astrocytes that were upregulated by penicillin induced epilepsy. This saponin also reduced the levels of phosphorylated mitogen-activated protein kinase (p MAPK) in the astrocytes. These actions suggest that astragaloside IV has anti-inflammatory properties and can protect astrocytes from damage (Zhu et al. 2018). Another study revealed that ginsenoside Rb1 was found to reduce

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Table 10.4 Experimental evidence supporting the role of saponins in various neurological disorders Dose and route Epilepsy Astragaloside IV (20, 40, 80 and 160 μmol/L) 2 h

Experimental model

Animal/cell lines

Outcomes

Ref.

Penicillininduced rat model of epilepsy

1–5 days postnatal Sprague Dawley male rats

Zhu et al. (2018)

Ginsenoside Rb1 (15, 30, 60 mg/ kg, i.p.)

PTZ (60 mg/kg, i.p.)-induced rat model of epilepsy

Male Sprague Dawley (SD) rats (220–240 g)

Protodioscin (2.5, 5, 10 mg/kg, i.p.)

Pilocarpine (350 mg/kg, i. p.)-induced mice model of epilepsy

Male Swiss mice (25–30 g)

Astragaloside IV significantly suppressed the expression of penicillin-induced inflammatory factors in the astrocytes. The levels of members of the phosphorylatedmitogen-activated protein kinase (p-MAPK) were noticeably decreased Ginsenoside reduced iNOS, oxidative stress, and PTZ-induced hippocampus neuron injury. Ginsenoside Rb1 activates Nrf2/ARE to reduce epileptic seizure-induced brain damage Protodioscin reduced convulsions by boosting GABA activity. It increased Bcl-2 and decreased Bax and caspase-3 to protect the brain Jujuboside A induces the expression of HSP90β through the Axl/ERK pathway and maintains PPARγ levels. This leads to enhanced clearance of Aβ42 and notable improvement in cognitive deficits in APP/PS1 transgenic mice with Alzheimer’s disease

Zhang et al. (2018)

Alzheimer’s disease APPswe/PS1Δ9 Jujuboside A: (0.5, 1.5, or 5 mg/ transgenic mice model of AD kg/d) for 7 days

B6C3-Tg (APPswe, PSEN1dE9)85Bdo/ J) transgenic mice (male) age:8 months body weights: 35–40 g

Shi et al. (2018)

Song et al. (2018)

(continued)

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Table 10.4 (continued) Dose and route Astragaloside IV (10, 20, and 40 mg/kg/day, i. g.)

Experimental model AβO-ICV (5 μg per site)

Animal/cell lines Male C57BL/6 mice (5–6 weeks old, 20–25 g)

Esculentoside A: 5 or 10 mg/kg) for 8 consecutive weeks

Triple transgenic AD mice

Triple transgenic mice (3 × Tg-AD) 8 months old

Cycloastragenol (20 mg/kg) for 6 weeks

Aβ-induced mice model of AD

Mice

Parkinson’s diseases MPP+ Dioscin (50, 100, 200, 400, and (250–2000 μM)800 ng/mL) induced cellular model of PD

SH-SY5Ycell line

Outcomes Reduces AβO infusion-induced memory impairment, neuronal loss, tau phosphorylation, and synaptic impairments. In AD-like animals, inhibiting PPARγ attenuated AS-IV effects on BDNF, neuroflammation, and pyroptosis Improves the cognitive deficits, decreases Aβ formation, oxidative and ER stress and neuronal death through PPARγ expression reducing the degrees of oxidative and ER stress, and mitigating neuronal apoptosis through the increase of PPARγ expression Modulates neurotrophic process and oxidative stress, neuroinflammation, apoptotic cell death, and memory impairment in the mouse model of AD. Major MAPK pathways (JNK/p38/ERK) downregulate by cycloastragenol

Ref. Wang et al. (2021)

Neuroprotective activity through autophagy induction and suppression of the mitochondrial apoptosis pathway

Azam et al. (2022)

He et al. (2022b)

Ikram et al. (2021)

(continued)

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Table 10.4 (continued) Dose and route Platycodin D (0, 10, 20, or 40 μM)

Experimental model MPP+(0, 0.125, 0.25, 0.5, and 1.0 mM)induced PD

Animal/cell lines BV-2 cell line

Astersaponin I (5 and 15 mg/kg, p.o.) and (5 and 10 μM)

MPP+ and MPTP-induced mice and cellular model of PD

Mice and SH-SY5Y cell line

Ginsenoside re (0.4 μM) and (2.5, 5, and 10 μM)

Rotenone (515 μM) and (0.3 μM)induced PD model

Drosophila and SH-SY5Y cellular model

Outcomes Suppressed inflammatory cytokines such (TNF-α), (IL-1β), and IL-6 by diminishing the provocation of TLR4/MyD88/NFκB pathway Advanced mice behavioral abnormalities, conserved dopamine synthesis, TH and α-synuclein expression in mouse brain through provocating the Erk/AMPK/mTOR signaling pathways Assured neuronal mitochondrial and oxidative damage through inducing Nrf2/heme oxygenase 1 expression and provocation of the dual PI3K/AKT and ERK pathways

Ref. Sun and Liu (2020)

Zhang et al. (2021)

Qiao et al. (2022)

oxidative stress and PTZ-induced hippocampal neuron injury by activating Nrf2/ ARE. Therefore, ginsenoside Rb1 may have antioxidant and neuroprotective effects in epilepsy (Shi et al. 2018). Interestingly, in another preclinical investigation demonstrated that protodioscin can reduce excessive neuronal excitability and stop seizures by boosting GABA action. Furthermore, the administration of protodioscin resulted in an upregulation of Bcl-2 expression and a downregulation of Bax and caspase-3 expression. The findings suggest that protodioscin has the potential to mitigate neuronal death caused by epilepsy (Song et al. 2018).

10.2.4.2 Role of Saponins in Alzheimer’s Disease The study found that jujuboside A induces the expression of HSP90β through the Axl/ERK pathway and maintains PPARγ levels. This leads to enhanced clearance of Aβ42 and notable improvement in cognitive deficits in APP/PS1 transgenic mice with Alzheimer’s disease (Zhang et al. 2018). Other study showed that astragaloside IV had a significant impact on improving memory impairment, reducing neuronal loss, and decreasing tau phosphorylation in mice with AD-like phenotypes induced by Aβ (Wang et al. 2021). Another study suggests that the administration of

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esculentoside A in transgenic AD mice (3 × Tg-AD) results in a reduction of oxidative stress, ER stress, and neuronal cell death, as well as an improvement in cognitive deficits (He et al. 2022b). The compound cycloastragenol has been found to exhibit inhibitory effects on oxidative stress, neuroinflammation, and apoptotic cell death, while also improving memory impairment in mice induced with Aβ. Cycloastragenol has been reported to regulate the major MAPK pathway (JNK/p38/ ERK) (Ikram et al. 2021).

10.2.4.3 Role of Saponins in Parkinson’s Disease Similarly, various in vitro and in vivo model of PD has explored the neuroprotective activity of distinct saponins. Few of them is reviewed like, dioscin is a steroidal saponin, abundantly present in distinct medicinal plants, including Diosocorea nipponica Makino and Disocorea rizhoma and is famous for the treatment of aging-related disease and having anti-inflammatory activity. Likewise, a recent study concluded that neuroprotective activity of dioscin against (MPP+)-indued SH-SY5Y cellular model of PD through autophagy induction and suppression of the mitochondrial apoptosis pathway (Azam et al. 2022). Platycodin D (PLD) is a triterpene saponin extracted from platycodin grandiflorum possessing anti-inflammatory and neuroprotective effects. However, a current data suggested platycodin D suppressed inflammatory cytokines such as TNF-α, IL-1β, and IL-6 against MPP+-induced BV-2 cellular model by way of diminishing the provocation of TLR4/MyD88/NF-κB pathway (Sun and Liu 2020). Astersaponin I (AKNS-2) found in Aster koraiensis Nakai (AKNS), their neuroprotective effect was probed in in vitro and in vivo model of PD. Furthermore, a current study showed astersaponin advanced mice behavioral abnormalities, conserved dopamine synthesis, TH and α-synuclein expression in mouse brain tissues against MPTP and (MPP+) -nduced mice and SH-SY5Y cellular model of PD through provoking the Erk/AMPK/mTOR signaling pathways (Zhang et al. 2021). Ginsenoside is one of the cardinal active principles of ginseng having antioxidant and neuroprotective properties in array of neurodegenerative disease in in vivo and in vitro model. Likewise, it has been probed that, ginsenoside reassure neuronal mitochondrial and oxidative damage against rotenone-induced drosophila and SH SY5Y cellular model of PD through inducing Nrf2/heme oxygenase 1 expression and provocation of the dual PI3K/AKT and ERK pathways (Qiao et al. 2022). Overall, these studies suggest that saponins may exert their neuroprotective effects through various mechanisms, including anti-inflammatory, antioxidant, ion channel modulation, and GABAergic and antiapoptotic mechanisms in neurological disorder. However, further research is required to thoroughly explain the pharmacological properties and clinical potential of these compounds.

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Conclusion and Future Prospective

Secondary metabolites isolated from various medicinal sources show a significant action in the prevention and management of neurological disorders. The in vivo and in vitro investigation has emphasized the protective role of the secondary metabolites such as antioxidant, anti-inflammatory, and antiapoptotic. Although numerous preclinical studies have emphasized the potential involvement of secondary metabolites in diverse neurological conditions, there is presently a lack of clinical evidence, primarily attributable to their inadequate bioavailability and metabolic stability. The implementation of diverse formulation techniques and the synthesis of secondary metabolite analogues are potential techniques to address the pharmacokinetic obstacles linked with secondary metabolites. Possible academic rewrite: Various strategies can be employed to enhance the pharmacological properties of active compounds, such as encapsulating them within lipidic, polymeric, or inorganic nanoparticles, which can increase their metabolic stability and therapeutic efficacy. These approaches may pave the way for further preclinical and clinical studies of these agents.

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Part III Drug Delivery Strategies in Neurological Disorders

Essential Considerations for Brain Delivery of Nanoformulations

11

Sunaina Chaurasiya and Hitesh Kulhari

Abstract

Drug delivery to the brain has been a great hurdle due to the blood-brain barrier (BBB). BBB is a tight junction of blood vessel and endothelial cells; their robust eviction transport systems protect the invasion of harmful substance to the brain. A majority of the therapeutic agents used in treatment of CNS related disorders such as Parkinson’s diseases (PD), Alzheimer’s diseases (AD), migraine, schizophrenia diseases, brain tumors, multiple sclerosis (MS), etc. have suffered the loss of their efficacy due to the BBB, which led people suffering with CNS disorders have limited treatment options. To overcome these challenges for effective therapeutics delivery to the CNS, the nanomedicine is the field of research that has grown very fast in recent years with promising results. It is the combination of the nanotechnology, chemistry, and pharmacy. Various nanomedicines are successfully developed and investigated for the improved delivery of drugs to the brain disorders. The effective delivery and penetration across the endothelial cells of brain can be achieved by considering various physiochemical factors of nanoparticles and of drugs while designing and formulation development. Additionally, the surface modification of the nanoparticle with the targeted ligand can improve the more targeted drug delivery to the brain. In this chapter, we summarize the factors related to the physicochemical properties of nanoparticles and of drugs, which should be considered during designing of formulation for brain delivery. Another section highlights the factors related to the non-invasive and invasive drug administration to brain with examples. Finally, the toxicity caused by the administered drug formulation to the neuron is discussed.

S. Chaurasiya · H. Kulhari (✉) School of Nano Sciences, Central University of Gujarat, Gandhinagar, Gujarat, India e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Mishra, H. Kulhari (eds.), Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities, https://doi.org/10.1007/978-981-99-6807-7_11

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Keywords

Blood-brain barrier (BBB) · Central nervous system (CNS) · Drug delivery · Brain diseases · Nanoparticles · Nanomedicines

11.1

Introduction

The failure of the majority of therapeutics to travel through the blood-brain barrier (BBB) is a serious problem for therapeutic development for treating conditions of the central nervous system (CNS) (Correia et al. 2022; Khan et al. 2017; Pinheiro et al. 2021). The delivery of therapeutics to the brain are hindered from invading brain tissue by the BBB’s tight junctions of blood vessel endothelial cells and their robust eviction transport systems. Regardless of the substantial advancement in nanocarriers in order to treat the disorders related to CNS including Alzheimer’s, Parkinson’s, migraine, schizophrenia diseases, and brain tumors, yet more targeted and innovative nanocarriers are required for these disorders (Wairkar and Patravale 2021; Goyal et al. 2014; Grimaudo et al. 2022; Agrahari et al. 2019). The presence of BBB is a major challenge to deliver the therapeutics to the brain. The BBB is a fragile network of blood vessels with tightly organized endothelial cells that differentiates the brain from the circulatory system and it also prevents the invasion of the infectious agents (Rasmussen et al. 2022; Bhunia and Chaudhuri 2022). The hydrophilic, charged compounds, proteins are incapable to pass through the BBB, while lipophilic therapeutics including hormones, tranquilizers, and antidepressants can readily travel through the endothelial cells of the brain (Hersh et al. 2016; Rankovic 2015). Patients with CNS disorders require episodic medication. A majority of the therapeutic agents used in the treatment of CNS-related disorders have suffered with the low efficacy due to the BBB. As a result, people suffering with CNS disorders have limited treatment options (Upadhyay 2014; Xie et al. 2019). The non-invasive route of therapeutic administrations to the brain is highly demanding for CNS disorders and glioblastoma which requires episodic treatment (Bukari et al. 2020). The nasal route of drug administration is a most effective alternative to attain the effect of targeted drug at minimal doses while lowering the side effects in the treatment of chronic disorders (Erdő et al. 2018; Md et al. 2018). The administration of therapeutics through transmucosal via olfactory route to brain by crossing the BBB is mainly known as the intranasal drug delivery to brain. This is the only pathway by which the brain connects to outside ambience. This route has gained immense attention for its potential in administration of a broad spectrum of the therapeutics agents ranging from small component by protecting it from enzymatic degradation and improves the therapeutics effects without side effects to the peripheral organ. The successful delivery of therapeutic agents from the direct nose to brain has been investigated in both animal and human studies (Gharbavi et al. 2023; Kapoor et al. 2016; Gupta and Kumar 2012). Various drug delivery systems were shown to enhance nasal permeability, increase muco-adhesion, enable sustained

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drug release, or elevate the accumulation at olfactory epithelium leading in successful administration of desired therapeutics by nose to brain route (Shaikh et al. 2011; Bourganis et al. 2018). Nanomedicine is the field of research that has grown very fast in recent years with promising results. It is the combination of the nanotechnology, pharmacy, and chemistry. There are various nanomedicine-based drug delivery systems are successfully being explored for the improved drug delivery to the brain disorders (Afzal et al. 2022; Huynh et al. 2009; Teleanu et al. 2018). This chapter highlights the factors related to the physicochemical properties of nanoparticles and of which should be considered during designing of formulation for brain delivery. Another section highlights the factors related to the different routes of therapeutic administration to brain with examples.

11.2

Factors Affecting the Physicochemical Properties of Nanoparticles for Brain Delivery

The therapeutic effects of nanomedicines significantly depend on physiochemical properties of the nanocarriers. The physiochemical properties include major factors such as size, shape, surface charges, agglomeration, and functionalization of the nanoparticles (Fig. 11.1).

Fig. 11.1 Factors affecting the physicochemical properties of nanoparticles/nanocarriers in brain delivery

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11.2.1 Size The presence of tightly packed junction of blood vessels, it is very challenging to cross this highly defined barrier to deliver the drugs. The size of nanoparticles/ nanocarriers or drug delivery systems plays a very important role in the delivery of the drugs to the brain. The efficiency of a nanoparticle is highly influenced by size, and has additionally been shown to have a major phenomenon to regulate the pharmacology, targeted delivery, and cellular internalization (Jo et al. 2015; Barua and Mitragotri 2014). In various studies it was found that particle with the size ranging between 2 and 200 nm are more efficient to pass the BBB than the particles with size more than it (Euliss et al. 2006; Moghimi et al. 2001; Sartaj et al. 2022). It is important to develop the nanoparticle in a such a way that can successfully enter to targeted desired tissues by escaping reticuloendothelial system and elimination by lung, liver, spleen, and kidney. Although they can be removed and cleared from the target tissues, very small nanoparticles are resistant to removal (Alexis et al. 2008; Parmar et al. 2022). Soo Choi H. et al., reported an in vivo study using fluorescent-labelled quantum dots and showed that hydrodynamic diameter of the nanoparticles is a key factor in their renal excretion. The nanoparticles with the DH < 5.5 nm are quickly removed by the renal system. Furthermore, even after escaping kidney excretion, a nanoparticle with very small size 100 cannot cross this barrier. Furthermore, the maximum limit of the length of any dimensions of the nanoparticles is ~200 nm; however, it is also determined by the shape of the nanoparticles. A huge size nanoparticle >2 μm are taken up by lung blood vessels. The nanoparticles size >200 nm can be scavenged by the reticuloendothelial systems (RES) specially Kupffer cells (liver) and macrophages (spleen) (Kang et al. 2019; Tang et al. 2019). Further, the cellular internalization of nanoparticles is also governed by their size (Jo et al. 2015; Li et al. 2017).

11.2.2 Shape Nanoparticles of various shapes like sphere, needle, sheet, wormlike, oblate ellipsoidal, elliptical discoidal, and circular discoidal have been reported and can be

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developed by using different approaches. The shape of nanoparticles plays a vital role in cellular internalization, transportation, and excretion process (Truong et al. 2015; Liu et al. 2012). A shape-dependent study was reported Alzheimer’s disease using high-density lipoprotein (HDL) nanoparticles. The NPs were composed of lipids and associated apolipoprotein AI (Apo I) formed with the different shapes like spherical and discoidal-shaped nanoparticles. The experimental and mathematical representation showed that Apo I-associated discoidal-HDL nanoparticles are crossed the BBB more efficiently, caused greater reduction of the beta-sheet concentration on β-amyloid fibrils and stimulate the structural breakdown of β-amyloid plaques than the spherical nanoparticles (Nowak et al. 2020; Jin et al. 2021; Ribovski et al. 2021; Stukas et al. 2014).

11.2.3 Surface Charge After the size and shape of the nanoparticles, the surface charge of the nanocarrier is a major factor that determines the transportation of the nanoparticles to the brain. The cationic nanoparticles are more effectively taken by the cells than the anionic nanoparticles (Xiao et al. 2011). The nanoparticles surface charges also affect their circulation time, and clearance process from the body. For instance, a highly ionic charged nanoparticle is more susceptible to adsorption of plasma and attached surface protein, that eventually causes agglomeration and clearance from the system without accomplishing its desired function (Duan and Li 2013; Yue et al. 2011). In a study by A. Bonaccorso et al., the effect of surface charge of nanocarrier on their delivery to brain was studied. For this, they used two different surface-charged rhodamine B labelled polymeric nanoparticles: (1) positive chitosan/poly-l-lactide-coglycolide nanoparticles and (2) negative poly-l-lactide-co-glycolide nanoparticles with the average < 250 nm and these were administered through intranasal route of administration. In fluorescent microscopy, the localization of both NCs in various part of brain was analyzed. It was found the surface charge influenced the administration route for translocation from nasal cavity to CNS. There, positively charged nanoparticles slowed down in reaching to the brain by trigeminal route, whereas negatively charged nanoparticles may be delivered by the nasal route or through circulatory/systemic route (Bonaccorso et al. 2017). A study reported by Mayer et al. examined the effects of physiochemical properties of the NPs like size and the surface charge of the nanoparticles on activation of complement cascade, stimulation of aggregation, hemolysis, and induction of granulocytes and thrombocytes. It has been proven that a positively charged NPs induce aggregate formation and activate the complement cascade (de la Harpe et al. 2019).

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11.2.4 Agglomeration The NPs agglomeration is known to stimulate the complement cascade (Ekdahl et al. 2019). Fulop et al. investigated the effect of iron core and surfaces decorated six different highly used super paramagnetic iron oxides NPs. The obtained results suggest that iron oxide (Sinerem) is an effective activator of the complement cascade. The NPs tracking analysis showed that these iron oxide nanoparticles were heterogeneously distributed in size and showed a substantial amount of aggregation, supporting the hypothesis that NPs agglomeration induces the activation of complement cascade and NPs complement activation-related pseudo allergy (Fülöp et al. 2018).

11.2.5 Functionalization Functionalization of nanoparticles with the targeting ligands can improve the drug delivery to the brain by binding selectively to the receptors to the endothelial cells of brain. Various targeting ligand have been used for drug delivery to the brain. Transferrin (Tf) (Zhang et al. 2021), lactoferrin (Lf) (Li and Guo 2021), and RGD peptide (Ruan et al. 2017) are well-known proteins, which can bind to the specialized respective receptors of the endothelial cells of brain and it is extensively used in the drug delivery of peptides, small-size molecules, and nanoparticles to the brain. Apolipoprotein E (ApoE) (Topal et al. 2020) and angiopep-2 (Habib and Singh 2022) are peptide that can bind to low-density lipoprotein receptors on brain endothelial cells. Apolipoprotein E is used to transport drug-loaded liposomes and nanoparticles, and angiopep-2 is used to deliver siRNA to the brain. The targeted ligand-mediated drug delivery showed improved delivery of drug to the brain. However, more study is required to optimize its use to formulate novel targeting ligand for more selective and efficient drug delivery to the brain.

11.3

Physiochemical Properties of Therapeutics for Brain Delivery

The BBB is important to protect the brain from the invasion of the foreign pathological particulates, but on the other hand, because of its high selectivity, it makes difficult to cross for the therapeutics agents to treat various CNS disorders. The challenge of crossing the BBB is of the utmost importance for successful and beneficial treatment. There are several key factors that are related to the physiochemical properties for effective administration of potential therapeutic compounds which are used to treat brain disorders. The suitability of therapeutic agents for brain delivery depends on the parameters such as lipophilicity, molecular size, degree of ionization, physical forms, chemical nature, and dosage forms of the drugs as shown in Fig. 11.2 (Khan et al. 2017; Daneman and Prat 2015; He et al. 2018).

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Fig. 11.2 Factors affecting the physicochemical properties of drug/therapeutic agents in brain delivery

11.3.1 Lipophilicity Generally, the lipophilic molecules have more permeability than hydrophilic molecules. Lipophilic properties of a therapeutically active agents can be achieved by the prodrug method. Its a chemical modification of a biologically active molecule to customize its lipophilic nature, aqueous solubility, and improve permeability. The presence of the highly hydrophilic membrane, hence the drugs should be designed such a way to across the BBB by enabling the lipophilic nature. Therapeutic compounds that have the hydrocarbon cycle, halogen functional group, aromatic ring, and steroid nucleus show high lipid solubility (Khan et al. 2017; Pavan and Dalpiaz 2011).

11.3.2 Molecular Size The molecular size of drugs significantly affects their absorption and permeability across the biological membranes. A small molecule size shows faster absorption and higher permeability than the large molecular size molecules. The bigger molecular size undergoes passive diffusion, while the small size molecules passage through lipid channels (Fong 2015).

11.3.3 Degree of Ionization It is found that the ionized forms of drugs show less absorption and low permeability than their unionized forms. A drug molecule may be acidic, basic, or neutral. However, its ionization is determined by the pKa value. The proportion of ionized

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and unionized forms of drug is completely influenced by the pH of the medium in the body. Generally, the acidic therapeutic compounds remain unionized in the acidic, while basic drugs are unionized in the basic medium (Levine 1970).

11.3.4 Physical Forms The therapeutics can exist indifferent physical states such as solids, liquids, or gases. The gases are absorbed faster than the liquids, while liquids get absorbed faster than solid form. As a result, the drugs in syrup forms are more likely to absorb than the capsule or tablets form. In anesthesia, the commonly used gases are absorbed at very faster rate by the pulmonary pathway.

11.3.5 Chemical Nature The route of administration is basically depending on the chemical nature of the therapeutics agents. The therapeutics agents which cannot be absorbed by the GIT are given by the parental route. Heparin is one example, which has a high molecular weight and cannot be administered orally. Similarly, benzyl penicillin is given parentally, as it gets degraded in the GIT. The salt form of therapeutic agents is more readily absorbed than the organic compound when administered through oral route. The therapeutic agents in different ionic form shows different rate of absorption, for example iron in Fe+2 form is more readily absorbed than it’s Fe+3 form.

11.3.6 Dosage Forms Dosage forms affect the rate and extent of absorption for a molecule. A drug can be given in the various dosage forms like powder, tablets, capsules, transdermal patches, gel, etc. Similarly, the efficacy of nanoparticles formulation wise depends on its dosage form. Nanoparticles can be formulated as powder, tablets, or filled in capsules and administered through oral route. Water-insoluble nanoparticles may be dispersed in water and can be administered as suspension formulation.

11.4

Route of Therapeutics Administration to Brain

The treatment of CNS diseases is constrained due to the insufficiently distribution of drug molecules to the targeted sites. To treat the CNS diseases effectively, it is important to therapeutic agents to cross the BBB. Regardless of substantial advances in the nanocarriers for the treatment of CNS diseases such as brain tumor, migraine, schizophrenia, multiple sclerosis, and Parkinson’s and Alzheimer’s disease, there is still a need for more efforts to improve brain-targeting nanocarriers. A person suffering with CNS disease requires episodic drug dosage, which results in side

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Fig. 11.3 Different routes for brain drug delivery

effects to the healthy and undesired part. The route of administration of nanoparticles plays a major role in its therapeutic efficiency. The nanoparticles administered through different route like oral, intravenous, or nasal show varying therapeutic efficiencies. Invasive and non-invasive approaches for the drug delivery to brain. Invasive approaches include (1) focus ultrasound and microbubble delivery, (2) craniotomy-based drug delivery, (3) convection-enhanced delivery, and (4) polymeric wafers and microchip technology. Noninvasive approaches include (1) oral route, (2) intravenous route, (3) intranasal route, and (4) transdermal route as mentioned in the Fig. 11.3.

11.4.1 Oral Route Oral route is the most commonly used for the treatment in both gastrointestinal and systemic conditions. Instead of having broad spectrum advantages, oral route faces challenges like the presence of intestinal epithelial barrier (IEB) and the BBB, which limits the drug delivery from GIT to brain (Johansson et al. 2013; Yun et al. 2015). Nanotechnology-based drug carriers help to prevent the degradation of nanocarriers in harsh environment of GIT, improve the diffusion across the GIT mucosa, and enhance the circulation half-life to overcome the insufficient concentration in the

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plasma for transporting through BBB (Reinholz et al. 2018; Farokhzad and Langer 2009). In a recent study by Miao Y. B. et al., an oral prodrug-based nanocarrier system was prepared to overcome the challenges of IEB and BBB noninvasively for treating glioblastoma (GBM). A prodrug system was developed by conjugating on β-glucans (anticancer drug) by disulphide link. The prepared prodrug system was administered in glioblastoma bearing mice. The administered system induces the activation of the microfold or M cells and transported through the IEB, phagocytosed by the macrophages cells, and passed to the circulatory system through lymphatic system circumventing BBB. The disulphide bond in prodrug then degraded by the high level of glutathione in glioblastoma, enhancing its therapeutic value. The obtained results showed that the prepared prodrug system may be used as an oral drug delivery system treating glioblastoma (Miao et al. 2021).

11.4.2 Intravenous Route The IV route of drug administration to brain provides immediate response with extensive control of the drug rate diffusion into body. This route is also highly preferable for the drugs, which cannot be absorbed through GI tract or drug which are not suitable for injection into muscles or other cells. Hence, it is more important to eliminate the pre-systemic metabolism. The IV route is an effective way to deliver high-cost drugs like peptides and proteins, and it also prevents the metabolic degradation of the administered drugs (Djupesland et al. 2014; Giunchedi et al. 2020). Dalargin (hexapeptide leu-enkephalin derivative) was the very first drug to cross the BBB in combination with poly(butyl cyanoacrylate) (PBCA) nanoparticles, after direct administration via IV route enables the opoid activity. Since, dalargin cannot cross the BBB, this unable to stimulate the analgesic effect after IV administration. The introduction of dalargin in polysorbate 80 surfacefunctionalized nanoparticles showed dose and time-dependent antinociceptive effect in the hot plate and tail-flick tests after IV injection (Alyautdin et al. 1995). In comparison with the controls, the NPs coated with polysorbate 80 showed substantially increased antinociceptive effect after IV administration. Due to highly hydrophobic nature of doxorubicin, it is not possible to cross the BBB. In a study, the poly (butyl cyanoacrylate) NPs conjugated with polysorbate 80 used for the loading of doxorubicin. The DOX-loaded NPs were evaluated in the brain with concentrations of 6 μg/g after IV injection at a dose of 5 mg/kg to rats, and the control concentrations were 0.1 μg/g. Further, the nanoparticles significantly decreased the DOX concentration in heart after 2 h. The therapeutic potential of DOX is limited by its major cardiac toxicity; hence the obtained results are extremely important.

11.4.3 Intranasal or Trigeminal Nerve Route In the past two decades, intranasal or nose to brain drug delivery has gained more attention. The intranasal route has many advantages including easy and needle-free

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drug usage, highly effective penetration of small molecular-size drugs, faster absorption and immediate action, circumvention of metabolic degradation, stimulation of immune responses after administration, high flow of blood, escape the first-pass liver metabolism, and immediate access to the nasal mucosa. This route consists of two pathways: the first is intracellular, and the second is extracellular. In the intracellular pathway, the drugs are firstly taken up by olfactory sensory cells through endocytosis before being transported via axons to their synaptic cleft within the olfactory bulb (site of exocytosis). This process is repeated from one synaptic to other by olfactory neurons to distribute the drugs to the rest of the parts of the brain. In case of extracellular pathway, the drugs are delivered directly into the CSF by passing through paracellular fluid across epithelium of nose, then travels through the perineural region to the subarachnoid region in the brain. There are several factors which affect the nose to brain drug delivery. The physicochemical characteristics of drugs do not affect the transportation in case of low-molecular-weight drugs. For developing the novel nanoformulation, the ideal size range should be 5–10 μm. Polymorphism stability and purity of the drug delivery must be considered for designing nasal nanoformulation. In addition to this the pH of nasal mucosa and pKa of the drugs are major parameter to be taken care of while formulating drug delivery system. Acyclovir’s L-aspartate-ester prodrug was developed, which offered enhanced nasal epithelial permeability and protection from enzymatic metabolism (Md et al. 2018; Bonaccorso et al. 2017; Mistry et al. 2009). Drug delivery through nasal route required additional solubilization approaches due to poor water solubility of drug. Additionally, the therapeutic agents that have difficulty in nasal mucosal membrane penetration can be improved by using surfactants, permeation enhancers, or organic polymers. A study Nonaka et al. reported that the nasal passage to the brain of galanin neuropeptide was improved by threefold after the functionalization with the enhancer α-cyclodextrin (Nonaka et al. 2008).

11.4.4 Transdermal Route Transdermal route for the delivery of the drugs to brain is s novel approach if applied at particular topical sites. The non-steroidal anti-inflammatory drugs are well known for preventing Alzheimer’s disease (AD), although exhibiting inadequate bioavailability. The transdermal-cervical patches are the most effective method for sustained drug delivery for spinal-related conditions. The targeted drugs diffuse through intervertebral disk space, passes through the periosteal and meningeal layer. Rotigotine transdermal patches was found most effective in the treatment of Parkinson’s disease (PD). Melatonin patches are successfully utilized to reduce any alternation in the brain function or structure/encephalopathy symptoms associated connected with perinatal-asphyxia conditions (Frampton 2019).

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11.4.5 Focus Ultrasound-Microbubble-Enhanced Delivery A focused ultrasound (FUS) can be used to disrupt the BBB, and for targeted drug delivery, it is combined with intravenous injected microbubbles (MBs) to open the tight junction and intercellular cleft (Wang et al. 2022; Timbie et al. 2015). This method is well known as sonoporation, which is based on the mechanical motion of the gas MBs in ultrasonic waves. These MBs are a lipid or protein shell incorporated with heavy gases with the size around 1–10 μm in diameter (Duan et al. 2020). These heavy gases can be discharged by exhalation. These MBs are widely being used in drug delivery. For instance, liposomes were prepared and labelled with two different fluorescents to treat tumor cells. In sonoporation-treated tumors, the liposomes concentration was enhanced by two times than the untreated cancer cells, and it has also enhanced the ability of liposomes to excrete out of the blood vessels. MBs can be used to deliver stem cells and viral vectors. Further, a magnetic coating of MBs can also enhance the targeted drug delivery. This sono-permeation method has numerous advantages: (1) It can be focused to the targeted site for action in the brain; (2) The targeted site does not require a high-energy ultrasound; hence it does not cause damage in intermediate cells; (3) But this can cause heat damage and disturb the blood flow at the targeted site; (4) The damaged membrane cells can regenerate very fast probably within an hour after the treatment. Although this technique can cause certain inflammation, it does not interfere with the blood flow (ischemia), apoptosis, or any damage to neurons (Raymond et al. 2008; Park et al. 2012).

11.4.6 Craniotomy-Based Drug Delivery Craniotomy method is based on the direct way of drug delivery to the targeted site of the brain (ventricles and subarachnoidal space) without damaging the nearby cells via intracerebral or by intraventricular injection (Pardridge 1997). In the intraventricular route, the drug encapsulated nanoparticles inserted in the scalp allows sustained drug release and is attached to the ventricles in the brain by catheter. Further, a very effective drug delivery can be achieved without drug dispersion in the cerebrospinal fluid (CSF) (Fowler et al. 2020). This technique is most effective against the treatment of meningioma and metastatic (CSF) cells. In intracerebral route, the therapeutic agents are directly administered into parenchyma of brain through catheter. This route works on the diffusion mechanism, provides gradual drug dispersion in the brain, and decreases in the dispersion in proximity. Intracerebral route requires high doses of therapeutics for targeted delivery (Pardridge 2002, 2003).

11.4.7 Convection-Enhanced Delivery To overcome the challenges faced by the intracerebral approach convectionenhanced delivery (CED) thought to most effective approach. CED utilizes

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continuous diffusion approach and gradient pressure to deliver high drug doses to the target site by injecting intracranial catheter (D’Amico et al. 2021). This approach has some major drawbacks such as drug exposure to healthy cells, difficult to prepare desired ideal formulations, stability issue with drug, and the drug concentration in the targeted tissue. In a study reported by Nordling-David M. M. et al., they have combined CED with liposomes for enhanced effectiveness of CED for targeted drug delivery. Liposomes were prepared, and the surface was modified with PEG (polyethylene glycol). The PEGylated liposomes encapsulated with antitumor drug temozolomide (TMZ) were evaluated in rat with glioblastoma multiforme (GBM). The obtained result showed that administration of the PEGylated liposomes significantly inhibited the tumor growth with increased survival rate. Further, CED was improved using efflux-mediated resistant infusion with cannula to enhance the in vivo of administration, and the liposomal delivery was monitored by MRI. A PLGA (poly-lactic-co-glycolic acid) NPs based on CED approach were evaluated in mice bearing intracranial tumor for sustained and controlled delivery. A significant increase in NPs distribution to the targeted site was observed (Nordling-David et al. 2017).

11.4.8 Polymeric Wafers and Microchip Technology It is a breakthrough in polymeric-based approaches and gaining massive attention for controlled and targeted effective drug delivery. The administration of polymeric nanocarriers for targeted and sustained drug release into intracranial tumor by crossing BBB is a milestone in the domain of polymeric nanotechnology (Sartaj et al. 2022; La Barbera et al. 2022). Polyanhydride-based wafers were inserted in the tumor excision spatial, penetrated the BBB, and slowly released the therapeutic agent into the targeted brain site. Gliadel® (carmustine implant) is an FDA-authorized wafer for the treatment of high-grade and newly diagnosed glioma. It is an adjunct to surgery and radiation for person suffering with a chronic severe brain tumor. In phase III clinical trials, the synergistic administration of Gliadel®, TMZ, and radiotherapy increased the average survival duration by up to 60 days. The clinical trial studies proved that Gliadel® has substantial potential in the prognosed brain tumor treatment. It has gained the massive importance in treating the therapeutic value of drugs that have lost efficacy caused by the impermeability to BBB (Caraway et al. 2022). Camptothecin (CPT) has failed in the clinical trial for showing the toxicity, but after the incorporation with polyanhydride-based polymer showed effective drug delivery with no significant toxicity. However, these polymeric wafers have some serious limitations such as lacking in deep insertion into brain tissue, cyst growth, meningitis, poor healing of wounds, and formation of abscesses. The microchips are well-programmed intracranial devices for sustained and targeted drug delivery. There are two types chips, as micro-electromechanical system (MEMS) and by passive chip. The chip technology can be utilized for the delivery of single drug dose or multiple drug doses. MEMS-based active microchips incorporated with desired drug-filled compartment on silicon chip enable incredibly

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programmed drug delivery (Storm et al. 2002; Sanjay et al. 2016; Drapeau and Fortin 2015). This technology provides the development of multiple reservoirs, each holding a different drug to be released at the desired same or different times points. The gradual drug release in passive chips depends on slow degradation of the polymer-coated micro reservoir. Both the active and passive chip technology avail various application over the conventional polymer-based drug delivery. The preclinical trial of temozolomide and carmustine in a mouse with glioblastoma were evaluated using MEMS and passive chip. These chips have delivered the drug more effectively and improved the survival rate (Masi et al. 2012). In a study by Kim G. Y. et al., the anticancer activity of 1,3-bis (2-chloroethyl)-1-nitrosourea (BCNU) was evaluated in rats with glioblastoma using passive microchip and it was found that BCNU was highly effective for treating glioblastoma (Kim et al. 2007; La Rocca and Maximilian Mehdorn 2009).

11.5

Neurotoxicity

Although the advancement in NPs development holds enormous potential for novel pharmacological approaches in brain diseases. It is important to take into consideration that the BBB act as a defence channel of CNS against neurotoxins nanostructures, etc. (Xie et al. 2019; Nguyen et al. 2021; Mitchell et al. 2021). The evaluation of toxicity of NPs for brain drug delivery in vivo and clinical study data needs more validations. Due to the lack of standard procedure for the characterization of novel NPs at physiochemical and biological stages, it has consistently been challenged to assess the toxicity of formulated nanodrugs/NPs in initial phase of testing. As a result, the developed formulation failed in the final phase of clinical trials. It must be mentioned that certain NPs types, which had showed promising properties and applications in animals at initial stage, and gradually eliminated after demonstrating the toxicity. Carbon nanotubes and quantum dots are two well-known example that have showed toxicity in vivo. Therefore, their potential use in therapeutics is likely to be confined in vitro testing. The toxicity caused by NPs has been claimed, the neurological repercussion was observed in mice exposed to MnO and SiO2 NPs (Schrand et al. 2010; Sawicki et al. 2019; Máté et al. 2016). The in vivo study proved that NPs have certain neurological toxicity by activating the transientmicroglia and stimulates the TLR-2 promoter in mice because of these reasons. The advantages and disadvantages of using NPs to treat CNS diseases should be carefully taken into account while designing each new type of NPs. During evaluation of neurological toxicities of NPs, several aspects should be taken into consideration like the core structure of NPs, surface modification generally used for targeted drug delivery can also result in the immune response and induces the neural toxicity. Hence, it is important to take this into account. In addition, it needs to be emphasized that toxic effects may be caused by the disruption of the endothelial of BBB induced by NPs (Hutter et al. 2010; Re et al. 2012). A study by Olivier et al. showed that poly (butylcyanoacrylate) (PBCA) NPs stimulated the permeabilization of BBB, which was probably driven by the toxicity of the nanocarrier (Olivier et al. 1999).

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Liposomes and iron oxide nanoparticles have been reported to be the safest NPs for the CNS. Since they are made of naturally occurring lipids, liposomes show negligible toxicity and it has been known since 1960s (Tsou et al. 2017). Similarly, iron oxide-based NPs are considered to be barely toxic to the CNS. The conjugation of NPs with cationic proteins may be another cause of neurotoxicity. The toxicity can be investigated only when such protein can lead to the toxicity is injected into the heterologous animals. In addition, the cationization of recombinant human protein should be used in human. Whereas, PEGylation of these cationic proteins/molecules could be a promising alternative to reduce their immunogenic response (Suk et al. 2016; Gupta et al. 2017). Acknowledgements The authors would like to thank Central University of Gujarat, Gandhinagar for the support and encouragement.

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Drug Delivery Strategies in Alzheimer’s Disease

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Govind Hake, Akshada Mhaske, and Rahul Shukla

Abstract

Over the past few decades, a concern over neurodegenerative disorders is growing proportionately with age, changing lifestyles, hereditary neurodegenerative disorders, head injury, and Down’s syndrome. Among the plethora of various neurological diseases, Alzheimer’s disease (AD) ranks first with nearly 47 million incidence rates in the year 2021. According to Alzheimer’s Association International Conference (AAIC), 10 in every 100,000 patients develops primary Alzheimer’s symptoms ranging from dementia, cognitive impairment, and paranoid and depressive behavior. Despite a lot of clinical and preclinical studies still, the key treatment therapies are rivastigmine, donepezil, memantine, and galantamine are already evaluated for AD. Other than these conventional therapies, neuromodulator agents like antioxidant agents, nitric oxide synthase inhibitors, polyphenolic compounds, and metal chelators have also proven their efficacy in Alzheimer’s treatment. Such neuromodulators can be advantageous for the early staging of AD. Although various neuroprotective medicaments are available for the management of AD, but their efficacy is limited due to bloodbrain barrier obstruction, high lipophilicity, and poor bioavailability profile. For a successful neuroprotective brain delivery, drug internalization within the brain compartment is a crucial parameter. Drugs’ inherent physicochemical properties can be modulated with the assistance of nanotechnology. The nanotechnological platform allows for overcoming blood-brain barrier hindrance, compromised bioavailability, and off-target drug delivery. This chapter will provide relevant information about AD pathology, current management approaches, and

G. Hake · A. Mhaske · R. Shukla (✉) Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER)-Raebareli, Lucknow, Uttar Pradesh, India e-mail: [email protected] # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Mishra, H. Kulhari (eds.), Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities, https://doi.org/10.1007/978-981-99-6807-7_12

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pharmaceutical nanotechnology-based approaches including liposomes, polymeric nanoparticles, metallic nanoparticles, dendrimers, carbon dots, solid lipid nanoparticles, cubosomes, nanoemulsion magnetic nanoparticles, and transdermal approaches along with clinical updates relevant with the Alzheimer’s disease. Keywords

Alzheimer’s disease · Neurofibrillary tangle · Blood-brain barrier · Therapeutic strategy · Transport · Neurological disorders · Nanoemulsion · Dendrimers · Nanoparticles

12.1

Introduction

Over the past few decades, the gigantic elevation in Alzheimer’s dementia cases reported worldwide. Alzheimer’s disease is reportedly correlated with anomalous protein accumulation within brain compartment. Alzheimer’s disease (AD) is neurodegenerative diseases with the most ubiquitous type of dementia and is identified by behavioral impairments and cognitive loss. The development of neurofibrillary tangles and neuronal deterioration are the indicator of disease progression. Such pathogenic alterations in AD resulted in enhanced neuroinflammation, oxidative stress, and declined acetylcholine levels (Banks 2012). The WHO believes that the cumulative expected dementia occurrence in community would double in upcoming decades, exceeding greater than 131 million by 2050. The neuropathogenesis of AD is described by intracellular tau protein aggregation and extracellular protein deposition in the cerebral cortical and hippocampal regions (Tiwari et al. 2019). The precise biochemical pathways that potentiate pathogenesis in AD are still unknown. While researchers have focused on the existence of Aβ/tau crosstalk in terms of the documented intracellular signaling cascades. Insufficient outcomes from clinical investigations of AD disease-modifying treatments have highlighted the necessity for further tailoring of target populations and assessment techniques. Hence, methods for both prompt identification and intervention of AD may be the most demanding and urgent issues in contemporary medicine. While the existing of FDA-approved acetylcholinesterase inhibitors such as tacrine, rivastigmine, galantamine, donepezil, and memantine (NMDA inhibitors) can lessen the development of AD symptoms, but these agents do not help in the reduction in neuronal damage (Wilson and Geetha 2020). Natural neuroprotective agents have become a potential avenue of hope for the management of CNS disorders, transfer of these drugs to specific sites of the central CNS shows many hurdles including low solubility, low bioavailability, and decreased efficacy due to the restriction of BBB (blood-brain barrier) to the drugs. Recent improvements in nanotechnology offers opportunities to bypass drug delivery-related hurdles. Recent developments in nanodrug delivery strategies have improvised the bioavailability, penetrability, and bypasses the hurdles associated with the inherent nature of drug molecules. Currently, different nanocarriers, including metal-based carriers, solid lipids

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nanoparticles, carbon nanotubes, polymers, solid lipid carriers, lipocarriers, and emulsions, have been modified to create feasible treatments with better efficacy and prolonged release. This chapter discusses relevant information about AD pathology, current management approaches, biomarkers, and pharmaceutical nanotechnology-based approaches.

12.2

Etiological Elements of AD

There are several concepts that attempt to elucidate the fundamental pathophysiology of AD. The exact etiology of AD is yet not known. According to research, signs related to Alzheimer’s disease can be identified in the brain 20 or more years prior to symptoms appearing (Wong et al. 2019). By understanding the early alteration within the brain, researchers can successfully develop feasible potential therapies to mitigate the early alterations in the brain. The symptoms begin to manifest when the modifications can no longer fully be reversed. The proposed hypothesis of AD includes various approaches such as tau hypothesis, amyloid hypothesis, cholinergic hypothesis, excitotoxicity hypothesis, genetic hypothesis, and mitochondrial cascade hypothesis are the most well-known explanations that have been put forth (Wen et al. 2017). ROS, nitric oxide (NO), and inflammatory mediators also play a crucial character in the progression of AD, in addition to these major hypotheses (Wen et al. 2017). The major contributing factors associated with development and progression of AD are represented in Fig. 12.1.

12.2.1 Amyloid Hypothesis The amyloid concept is mainly focused on the generation of Aβ plaques in the brain, which is followed by the death of neurons. Various cell types express the type 1 transmembrane glycoprotein known as the amyloid precursor protein (APP) present intracellularly and intercellularly within the brain parenchyma. The cleavage of the amyloid precursor protein (APP) by a series of secretase enzymes provides a rationale for this mechanism. APP is cleaved by the β-secretase and γ-secretase enzymes into several subunits, such as Aβ40 and Aβ42. Aβ occurs typically in plasma and CSF and is also constantly produced by mammalian cells. Insoluble Aβ42 which attaches to surfaces of cells, because of its adherent nature, other proteins entangle or clump together with it to form β-amyloid protein plaques and accumulate within the brain. These accumulating protein aggregates are detrimental, causing neurotoxicity, cytotoxicity, and eventually leading to the progression of Alzheimer’s disease (Wen et al. 2017; Harilal et al. 2019). Glenner and Wong in 1984 were successfully isolated the Aβ plaques in the cerebral spinal fluid of AD patients (Contestabile 2011). Based on this theory, a few anti-amyloid treatments, such as rosiglitazone, pioglitazone, and semagacestat, have been considered and further investigated (Mangialasche et al. 2010).

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Fig. 12.1 Illustrates the contributing factors associated with development of Alzheimer’s disease

12.2.2 Tau Hypothesis Tau proteins are the foundational elements of the abnormal filaments that build up in neurons and glial cells further in diseased conditions leads to formation of neurofibrillary degeneration. It includes in the family of (MAP) microtubules-associated proteins; three microtubule-associated proteins (MAPs) tau’s MAP 1A, MAP 1B, and MAP 2 are present in a healthy neuron (Congdon and Sigurdsson 2018). Axonal transportation is mediated by the tau protein, which is physiologically linked to the microtubules. Normal phosphorylation of native tau proteins occurs on a considerable proportion of serine or threonine sites. The level of tau proteins phosphorylation is based on the compartments of cells, monoclonal antibody tau 1 showed that tau is less phosphorylated in axons (Iqbal et al. 2010). The level of phosphorylation of tau controls its biological function, the aberrant hyperphosphorylation of tau in AD brains hinders its ability to attach to microtubules, when phosphorylation increases the tau proteins reduce their capability to attach to microtubules. This results in the development of neurofibrillary tangles and dementia (Wong et al. 2019; Harilal et al. 2019). This theory states that tau proteins create paired helical pieces called neurofibrillary tangles (NFTs), which obstruct axonal transport and result in neuronal death.

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Lithium, valproate, and nicotinamide are some of the anti-tau medications that have been investigated (Mangialasche et al. 2010).

12.2.3 Cholinergic Hypothesis It was the first theory that describes the occurrence of AD pathogenesis, mainly memory loss and cognitive dysfunction are caused due to significant presynaptic cholinergic insufficiency, which was discovered in the brain samples of AD patients. Cholinergic insufficiency can be enhanced by modifying using acetylcholinesterase inhibitors and nicotinic (N) and muscarinic (M) acetylcholine receptors. Most cholinergic medicines are acetylcholine esterase inhibitors; these inhibitors improve cholinergic neurotransmission by blocking acetylcholine esterase. Donepezil, galantamine, tacrine, and rivastigmine are the acetylcholine esterase inhibitors that received FDA approval. Memantine inhibits the NMDA receptors and thereby fulfills cholinergic deprivation; this drug received FDA approval in the year 2003. The development of muscarinic receptor agonists has met with only minimal success owing to its difficulty in finding medications with few side effects. The talsaclidine which acts as agonist and enhances the activity of the M1 muscarinic receptor, AF-102B, and AF-267B (NGX-267) can also influence the generation of Aβ. Agonists for nicotinic receptors have also been studied to improve cholinergic transmission. Ispronicline (AZD-3480), a selective nicotinic receptor α4β2 agonist, has enhanced cognition in both normal individuals and those with age-related Alzheimer ‘s dementia (Mangialasche et al. 2010).

12.2.4 Mitochondrial Hypothesis A huge number of studies are indicating that mitochondrial energy metabolism problems have crucial player in the etiology of AD. Oxidative stress or proteasome malfunction due to somatic mutations during DNA replication results in inadequate ATP synthesis that leads to mitochondrial degeneration. Within the AD patients’ brains, Aβ plaque development and NFT are also driven by mitochondrial dysfunction. One of the main areas of focus for treatment of AD is the evolution of mitochondrial damage, which in aging terrine has an impact on the survival and health of the neurons. Numerous medications, including latrepirdine, have been explored as potential treatments for mitochondrial dysfunction (Wen et al. 2017).

12.2.5 Excitotoxicity Hypothesis N-methyl-D-aspartate (NMDA) receptors play a significant role in the plasticity, memory processes, and synaptic transmission. The stimulation of the neuronal survival pathway further suggests that they are crucial for the viability of neurons. The viability of the neuron is impacted by insufficient NMDA receptor activation at

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the synaptic site. However, excessive activation of glutamatergic transmission results in excitotoxicity of NMDA receptor, which in turn causes neuronal degeneration and death (Wilson and Geetha 2020). In cortical and hippocampal neurons, glutamate serves as a major excitatory neurotransmitter. In the brains of people with AD, glutamine synthetase is oxidized, which results in an excess of glutamate. Neuronal degeneration is driven on by glutamate’s excessive activation of NMDA receptors, which makes CNS neurons more susceptible (Shah et al. 2008). Glycine and glutamate attach to it and activate it, allowing Ca2+ and Na+ to flow into the cell. According to studies, the excessive stimulation of NMDA receptors leads to release of excessive Ca2+, which sets off a series of events that ultimately result in apoptosis. Memantine (brand name Namanda, Forest) inhibits glutamate-gated NMDA channels, preventing pathological activation while maintaining healthy activation. Memantine is authorized for treating AD in its advanced stages, in contrast to ACIs, which are only permitted for treating the early and middle stages of the disease (Wen et al. 2017).

12.2.6 Genetic Hypothesis The development and evolution of AD is attributed to at least 20 genes, according to GWAS (Genome-Wide Association Studies). Two gene mutations that appear to function as threat elements for late-onset AD have been recognized through genetic linkage studies, and three causal genes that are directly responsible for the beginning of early-onset AD have also been identified. Among them, Premenilin 1 (PS1), amyloid precursor protein (APP) and presenilin 2, are appeared to hasten the production and deposition of Aβ that leads to cause neurodegeneration (Iqbal et al. 2010). One of the most popularly recognized genes in AD is apolipoprotein E (ApoE). ApoE is linked with glucose metabolism and neuronal signaling also control Aβ aggregation and clearance within brain compartments. Additionally, ApoE controls the structural integrity of tight junctions, alteration in availability of ApoE availability can cause BBB disruption. The orientation BBB and chemical transfers across the BBB are influenced by other genes. While ABCA7 gene downregulation may have an impact on cholesterol and amyloid interactions at the BBB, the ABCA7 gene is intimately associated with the excessive deposition of amyloid peptides (Wong et al. 2019).

12.3

Diagnostic Modalities

The NIA-AA (National Institute on Aging and Alzheimer’s Association) upgraded their assessment standards for AD in 2018, which changed from a clinical to a biological diagnosis of the condition. Alzheimer’s disease (AD) is currently thought of as a continuum that can be recognized by neuropathological findings and biomarkers. Earlier the three different clinical categories that it was earlier considered (mild cognitive impairment, dementia, and cognitively unimpaired). Thus, the

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goal of diagnostic methods has changed from proving the existence of symptoms of AD to detecting the disorder in the initial stages of the disease. Thus, the introduction of biomarkers in clinical trials would improve subject enrollment’s ability to accurately diagnose “pure biological AD” expediting the discovery of medications for this population. The tau aggregates, amyloid aggregates, and neurodegeneration profile is evaluated using different biofluids such as cerebrospinal fluid, blood, saliva, and other pathological biomarkers.

12.3.1 Pathological Biomarkers Considerable deterioration of the white matter pathways with myelinated axons and dense neurofilaments that seem to be functional in AD patients. When compared to healthy controls, patients with AD shows higher NFL (neurofilament light) levels in their CSF. The NFL concentrations may raise in other neurological disorders, hence adding them to the fundamental CSF biomarkers for AD is not recommended just yet. The DIAN (Dominantly Inherited Alzheimer Network) longitudinal cohort assessment report revealed a strong correlation between serum NFL and CSF concentrations that were diagnostic of neurodegeneration. Recent research has explored the PDGF-B (platelet-derived growth factor) receptor, a protein that is extensively produced in brain capillaries pericytes and detected in CSF, as a preliminary prognostic marker for BBB disintegrate early in AD, even prior amyloid and tau development (Khoury and Ghossoub 2019). Saliva can be easily acquired without causing any harm to the body. While certain blood components can be readily released in saliva via the salivary glands, others can enter the saliva via active transport, passive diffusion, or microfiltration. A few potential biomarkers like lactoferrin, Ab42, p-tau, and t-tau are also released in saliva. To determine the diagnostic efficacy of these markers, more research with huge sample volumes and consistent sampling, processing, and analytical techniques is required. Additionally, when evaluating biomarker levels, it is important to consider people with AD who have poor oral hygiene as well as the impact of slowed saliva flow rates. In biological sampling, blood is one that is frequently used in both clinical and research scenarios. The ultralow quantities of AD biomarkers make it challenging to measure them in human blood, necessitating the development of a very sensitive technical technique to spot tau and Aβ proteins in human plasma, such as immunomagnetic reduction. In the survey of 12 patients with Alzheimer’s disease, there was a noticeably reduced threshold of plasma total Ab42/40 and a tendency toward reduces levels of free Aβ42/40. Neurofilament light levels had a strong predictive power for changes in cognitive scores, neurodegenerative imaging measurements, and hypometabolism imaging assessments (Khoury and Ghossoub 2019).

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12.3.2 Cerebral Biomarkers for AD Alzheimer’s disease-related dementia has dramatically increased the prevalence rate within society and healthcare systems since the modern ages. It is predicted that AD will affect 131 million people will inhabit the globe by 2050. It is extremely difficult to develop surrogate biomarkers to accurately assess and track disease progression. A biomarker is a marker of typical biochemical pathways, pathological processes, or pharmaceutical effects of a therapeutic treatment that is tested and analyzed scientifically. The specificity, sensitivity, and ease of utilization are the crucial aspects that ultimately determine the diagnostic values of a biomarker (Humpel 2011). APP, Aβ, tau, isoprostane, inflammatory, proteomics, and imaging are the markers of Alzheimer’s disease.

12.3.2.1 Senile Plaques The histopathological assessment of an Alzheimer’s disease brain after death depends on the existence of senile plaques and neurofibrillary tangles. A proteolytic segment of the amyloid precursor protein called amyloid (A) forms up these senile plaques (APP). If AD is caused by amyloid precursor protein’s (APP) proteolytic cleavage is affected, measurements of APP or its components may be used as diagnostic biomarkers. The preliminary research of Ghiso et al. (1989) shows the enhanced level of the APP or its secreted forms in the CSF. Reduced amounts of APP, the soluble substance released after APP is cleaved by α-secretase, have been noticed in the CSF of AD patients in multiple investigations. Due to these contradictory results from different research, CSF APP is not currently considered to be a reliable biomarker for AD (Craig-Schapiro et al. 2009). 12.3.2.2 Amyloid Beta (Ab) Extracellular Aβ plaque accumulations are a key trait of AD. Secretases break the massive amyloid-precursor protein into Aβ, which is then processed through amyloidogenic pathways to create the 42-amino-acid peptide Aβ (1-42), which can accumulate in the brain under specific circumstances. Analysis of CSF Aβ (1-42) with a 500 pg/ml cutoff reveals a significant decrease in AD patients to control. In addition to increased consolidation and plaque development in the brain, a suggestion has been made that decreased extent of Aβ (1–42) in the CSF is carried on by decreased evacuation of Aβ to the blood/CSF from the brain (Craig-Schapiro et al. 2009). 12.3.2.3 Tau Protein The key protein in neurofibrillary tangles is tau which is associated with microtubule protein that has also been considered reliable as a prognostic marker. Recent investigations have shown that AD patients have higher levels of CSF embedded with tau. The ELISAs (enzyme-linked immunosorbent assay) have been designed to identify different phosphorylated epitopes including serine 199, 235, 396, and 404 and threonine 181 and 231 because tau suffers anomalous hyperphosphorylation across many sites in AD. This abnormal phosphorylation renders difficulty in tau

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binding and microtubular stabilization that ultimately results in axonal degeneration. The rise observed tau in CSF is the result of neuronal damage-induced tau breakage and then diffusion within the CSF. Researchers have started investigating tau phosphorylated isoforms specifically as AD diagnostic biomarkers (Craig-Schapiro et al. 2009).

12.3.2.4 Isoprostane There is strong evidence that oxidative exposure may contribute to the pathogenesis of AD. As by-products of lipid peroxidation, isoprostanes, particularly the effects of F2-isoprostanes on Alzheimer’s dementia has been studied. They have been identified to be more pronounced in the temporal and frontal cortex of Alzheimer’s disease brains when correlated with control and FTD brains, indicating exactitude for AD. According to investigations, both postmortem ventricular CSF from autopsy-verified AD cases and antemortem CSF from people who have been diagnosed with AD dementia contain higher levels of F2-isoprostanes (CraigSchapiro et al. 2009). 12.3.2.5 Inflammatory Cytokines AD brains exhibit signs of inflammatory processes in addition to the traditional pathological hallmarks of neurofibrillary tangles and amyloid plaques. The extensively researched potential hallmark of inflammation in AD is serine protease inhibitor 1-antichymotrypsin (ACT), which colocalizes with Aβ in neuritic plaques and senile. Initial ACT experiments produced hybrid results, with several studies reporting amplified ACT levels in AD serum and others reporting unchanged levels in AD serum or CSF. Additionally, ACT was found to be expressed differently in AD when compared to controls utilizing a proteomics strategy that used mass spectrometry and gel electrophoresis. These results were validated using ELISA in a separate sample collection. CSF interleukin-6 (IL-6) levels have been observed to elevate, reduce, or unchanged in AD patients. Cytokine levels can change significantly over time, depending on a person’s genetic makeup, coexisting systemic inflammatory conditions, use of anti-inflammatory medications, and disclosure of environmental elements (Craig-Schapiro et al. 2009). Instead of utilizing the traditional method of analyzing the levels of one or more possible biomarkers that have been connected to the progression of AD, the latest development in biomarker research is concentrating on the objective profiling of human fluids to find new biomarkers. Proteomics has become a potent tool for the finding of biomarkers due to advancements in mass spectrometry (MS) methods. Protein preparation through two-dimensional techniques protein-chip arrays, liquid chromatography, and gel electrophoresis are common methodologies in proteomic studies. Protein identity is then determined via tandem mass analysis, mass spectrometer, and database searches. Many investigations have identified potential diagnostic markers by comparing the protein expression extents in AD and control CSF samples.

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Current Remedial Approaches for Alzheimer’s Disease

12.4.1 Synthetic Neuroprotectants Cholinesterase inhibitors are the medications that inhibit acetylcholinesterase (AChE) and restrict acetylcholine (ACh) from being hydrolyzed, increasing the amount and duration of ACh’s activity for neurotransmission. They are successful in treating the symptoms of AD and assist in halting the depletion of ACh brought on by the degeneration of cholinergic neurons. While the existing of FDA-approved AChE inhibitors such as galantamine, rivastigmine, donepezil, tacrine, and memantine (NMDA inhibitors) can lessen and momentarily slow the progression of AD symptoms, they do not stop the deterioration of the brain (di Stefano et al. 2011). A list of synthetic neuroprotectants has been summarized in Table 12.1 and described below.

Table 12.1 Synthetic neuroprotectants Drugs Rivastigmine

Brand name Exelon TM

Donepezil

Aricept@

Acetylcholinesterase (AChE) inhibitor

Galantamine

Reminyl@

Acetylcholinesterase (AChE) inhibitor

Memantine

Ebixa@

NMDA receptor inhibitor

Memantine and donepezil

Namzaric

NMDA receptor inhibitor and acetylcholinesterase (AChE) inhibitor

Categories Acetylcholinesterase (AChE) inhibitor

MOA Reversible inhibition of (AChE) and (BChE) and increases acetylcholine Inhibit hydrolysis of Ach by AChE and enhance Ach in cortical region of brain Increases acetylcholine by reversible, competitive inhibition of AChE acts as an allosteric modulator of nicotinic acetylcholine receptors Noncompetitively blocks NMDA receptors and reduces the activity of the glutamic system Combined action

Ref Bond et al. (2012), Atri (2019) Al Asmari et al. (2016), Bond et al. (2012), Atri (2019) Fornaguera et al. (2015), Bond et al. (2012), Atri (2019)

Mangialasche et al. (2010), Shah et al. (2008) Bond et al. (2012), Atri (2019)

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12.4.1.1 Rivastigmine Rivastigmine is reversible acetylcholinesterase and butyrylcholinesterase blocker, which freely binds to both estearic and anionic site of acetylcholine esterase. Such binding protects acetylcholine from cholinesterase-mediated destruction. Rivastigmine solubilizes slowly as compared to acetylcholine esterase and its metabolite formation takes place at the synaptic region by acetylcholinesterase and butyrylcholinesterase action. The leading hurdle associated with the utilization of rivastigmine is mild to severe side effects like anorexia, nausea, weight loss, vomiting, dyspepsia, and asthenia and lastly prolong use may resulted into bettertolerated therapy. Recently various attempts are made for transdermal delivery of rivastigmine via patch. As transdermal route ensures continuous controlled release with better tolerability and patient compliance (di Stefano et al. 2011). 12.4.1.2 Donepezil Donepezil is a piperidine ring containing indanobenzyl derivative as an acetylcholinesterase blocker popular as a second line of anti-Alzheimer’s therapy. Donepezil was primarily approved in the year 1996 and its prolonged-release formulation in combination with memantine was approved by FDA in 2014 for different ranges of dementia. While recently in 2022, FDA-approved transdermal donepezil delivery system for the therapeutic relief of severe dementia in Alzheimer’s patients. Donepezil is known for its reversible selective acetylcholinesterase inhibitor. Such hindrance in enzymatic metabolism improves the overall cholinergic coordinative release. Also, donepezil involves in the inhibition of glutaminergic excitatory neurotransmission via NMDA receptor-mediated downregulation that resulted in healthy functioning of amyloid precursor proteins (Wilson and Geetha 2020). 12.4.1.3 Tacrine Tacrine is parasympathomimetic agent with anti-acetylcholinesterase activity for the management of dementia and palliative care connected with Alzheimer’s patients. Tacrine is known for its strengthening ability on cholinergic nerve transmission. As acetylcholine availability in synaptic cleft is altered as the cognitive impairment progresses. This condition can be improved with the pharmacological action of tacrine by reversible arrest of acetylcholinesterase along with maintains cholinergic neuronal health (di Stefano et al. 2011). 12.4.1.4 Galantamine Galantamine being an acequinoline alkaloidal moiety with reversible competitive inhibition activity against the acetylcholinesterase enzymes have made it as a first line of therapy. Being a primary acetylcholinesterase inhibitor galantamine also serves a dual role by nicotinic acetylcholine receptor activation via allosteric binding. Galantamine is currently available in the form of extended and immediaterelease dosage forms.

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12.4.1.5 Memantine Memantine is a noncompetitive N-methyl-D-aspartate inhibitor that antagonizes glutaminergic overstimulation for the protection against NMDA-mediated neurotoxicity. Memantine can be given for moderate to severe forms of dementia as solitary or combinatorial therapy with other acetylcholinesterase. Also, memantine antagonizes the calcium influx within neuronal cells due to effect of chronic NMDA overexcitation, it also restores the synaptic tone without hindering normal neurotransmission rate. Memantine possess low selective binding affinity with NMDA receptor, it can be easily displaced by glutamate in a concentrationdependent fashion which hinders the lengthening of NMDA blockage (Wilson and Geetha 2020; di Stefano et al. 2011).

12.4.2 Herbal Neuroprotectants Various plants and their phytoconstituents are mentioned in traditional medicinal literature to alleviate the cognition abilities and other complications associated with the neurological impairments. In traditional medicinal system, one or combination of phytoconstituents and bioactive were recommended to remodulate the neurological complications in a synergistic pathway or target inflammatory pathways. Rationale for selection of herbal neuroprotectants is (a) usage of plant-based neuroprotectants is supported in traditional medicinal systems, (b) due to advancements in medicinal science, deciphering the actual role and mechanistic pathway is possible for AD treatment, (c) various clinical and preclinical have suggested the profound role of improvement in cognition and relieving from the dementia symptoms. The concoction of conventional plant-based neuroprotectants accompanied with medicinal science and screening will significantly enhance the overall scenario in the drug therapy for AD.

12.4.2.1 Curcumin Curcumin is a polyphenolic bioactive phytoconstituent extracted from roots of Curcuma Longa Linn, also commonly refer as turmeric being a member of Zingiberaceae family. Curcumin is mentioned in various Indian and Chinese medicinal literature owing to its anti-inflammatory, anticancer, neuroprotective, and potent antioxidant activities (Eghbaliferiz et al. 2020). Curcumin exhibited antiinflammatory properties due to its suppressive impact on inflammatory cytokines which escalates to inhibition nitric oxide synthase and cyclooxygenase-mediated inflammation (Menon and Sudheer 2007). Various line of experiments pointed out the interaction between curcumin and Aβ, as curcumin posse phenyl and methoxy terminals that ensure hydrophobic binding with the nonpolar terminals of Aβ fragments (Babu et al. 2019). Furthermore, hydroxyl and di-ketone groups allow to form hydrogen bonding with Aβ fragments. Besides, numerous in vivo experimental data pointed out that curcumin inhibits Aβ aggregation and significantly lowers the size of Aβ plaque. Subsequently, curcumin destabilizes Aβ fragments and various by-products of curcumin inhibit Aβ metabolism, owing to such characteristic

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curcumin hinders the self-assembling tendency of Aβ protein which reduces the chances of Aβ plaque formation (Shabbir et al. 2020). Although with all the neuroprotective benefits of curcumin its actual applications are hindered due to many factors such as poor hydrophilicity, low chemical stability, and reduced bioavailability. For the successful application of curcumin as a neuroprotective entity pharmaceutical approach for solubility enhancement and nanotechnology can help in utilizing curcumin to its maximum potential. Various nanotechnological platforms have successfully encapsulated curcumin in inorganic nanoparticles, nano-lipid carriers, nanoemulsion, nanogels, etc. Utilization of nanotechnological outlook has shown improved in vivo performance in different studies.

12.4.2.2 Quercetin Quercetin is a predominant plant-based flavonoid isolated from various fruits and vegetables. Quercetin showed various important characteristics such as prominently antioxidant, anticancer, anti-inflammatory, and antipsychotic properties. Flavonoids are rigorously analyzed for their anti-inflammatory and profound antioxidant behavior; these features are directly correlated with the secondary pathogenesis mechanism associated with Alzheimer’s progression. Flavonoid ring structure allows easy BBB infiltration ability owing to its structural orientation and physicochemical properties (Zhang et al. 2016). Various experimental data documented the poor bioavailability, low aqueous solubility, reduced absorption profile and quick metabolism are the major challenges associated with quercetin. Mechanistically quercetin reduces mitochondrial oxidation, lowers neuroinflammation by suppressing pro-inflammatory mediators, and helps to neuroregeneration and preserve dopaminergic neurons from degeneration. It mainly targets the oligomeric neurotoxic-Aβ synthesis and competitively inhibits the acetylcholine esterase in concentrationdependent manner. Quercetin specially emphasizes its neuroprotective impact mainly by maintaining the mitochondrial action potential and reducing reactive oxygen species production. Other than these characteristic pharmacological effects, quercetin is also proved as a memory-enhancing herbal moiety in various studies (Khan et al. 2019). 12.4.2.3 Resveratrol Resveratrol is a phytoconstituent isolated from peanuts, mulberries and various species of grapes. Resveratrol being a phytoalexin is a polyphenolic in origin and belongs to the class of stilbenes. Various studies have confirmed the role of resveratrol as an anti-inflammatory, antiproliferative, antioxidant, and profound neuroprotective moiety. Several in vitro and in vivo experiments suggested the antioxidant and anti-inflammatory impact of resveratrol. Resveratrol can easily bypass the BBB obstruction owing to excellent physicochemical properties (Andrade et al. 2015). Resveratrol is also stated to have neuroprotective effect due to its anticarcinogenic effect against neuron along with protection from neuronal death. Mechanistically resveratrol remodulates the oligomeric amyloid fibrillary tangles in soluble form and thereby inhibit the Aβ tangles formation. It also inhibits the pro-inflammatory cytokines which escalates into lowering microglial activation.

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Antiapoptotic behavior of resveratrol facilitates protection against neuronal death. Although with all benefits offered by resveratrol as a neuroprotectant its clinical usage are limited due to poor aqueous solubility, low bioavailability, quick onset of metabolic degradation, and fast clearance rate (Marambaud et al. 2005). These shortcomings have compromised the overall wide-scale application of resveratrol.

12.4.2.4 Baicalein Baicalein is chemically 5,6,7-trihydroxyflavone containing phytoconstituents isolated from the roots of Scutellaria baicalensis, mainly flavone in chemical composition. Baicalein is reported for its antiproliferative, anti-infective, antiinflammatory, antioxidant, anticonvulsive, and neuroprotective properties. Earlier studies have documented the effectiveness of baicalein in amelioration of cognitive difficulties, prolong cerebral hypoperfusion, and enhancement in various preclinical animal models. Furthermore, evidence suggest the befitting role of baicalein in Aβ-induced neurotoxic implication in vast in vitro vast in vivo analysis (Zhang et al. 2013). 12.4.2.5 Piperine Piperine is nitrogenous pungent alkaloid commonly termed as a black pepper, extracted from Piper nigrum. Piperine has already demonstrated its vivid characteristics as an antioxidant, anticarcinogenic, anti-inflammatory, and versatile phytoconstituent for CNS disorders treatment. Various in vivo studies revealed neurological abnormalities and behavioral challenges are improved after treatment with piperine. Nevertheless, clinical application of piperine is challenged due to compromised solubilization capacity and bioavailability (Shrivastava et al. 2013). 12.4.2.6 Silymarin Silymarin showed a stronger impact on acetylcholinesterase and pseudoacetylcholinesterase inhibition which reduces the amyloid plaque formation. Silymarin is also reported to reduce oxidative stress and nitrative stress induced by amyloid plaque-mediated ROS. As silymarin protect against oxidative insults by inhibiting the synthesis of peroxyl and oxygen radicals. Various in vivo and in vitro studies have suggested the administration of silymarin reduces the intensity of Aβ fibrillation along with revert the formed amyloid β plaques interiority by forming soluble amyloid fibrils. 12.4.2.7 Genistein Genistein is chemically 4′, 5,7-trihydroxyisoflavone flavonoid compound obtained from the various plants from the Leguminosae family. Genistein is one of the prominent polyphenolic compounds with antioxidant property mainly activated via hydrogen bonding and its ability to gradually interact with the various pro-cytokine and oxidative cytokines. As α-secretase has crucial role in reduction of amyloid plaques formation via activation of protein kinase C which causes formation of soluble amyloid protein. Whereas β-secretase activation leads to formation of neurotoxic amyloid plaques by attenuation of protein kinase C and assemblance of

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amyloid plaque. Various experimental in vivo studies suggested enhancement in α-secretase and inhibition of β-secretase via promotion of protein kinase C signaling mechanism. Formed amyloid β plaque induce neurotoxic impact via formation of reactive oxygen species which initiates neuronal apoptosis via activation of caspase and DNA damage reactions. In vitro cell line studies in PC12 cell lines have reported genistein’s profound antioxidant effect by inhibiting mitochondrial permeability pore which arrest the reactive oxygen species release. Genistein is also involved in preservation of mitochondrial membrane viscosity, membrane potential, and glutathione or oxidized glutathione fraction. All such neuroprotective impacts have made genistein as a versatile candidate for neuroprotective agents against Alzheimer’s disease. Although with such an advantage its clinical utilization is limited due to its insufficient oral bioavailability and unpredictable pharmacokinetic profile. Pharmaceutical approaches can alter this physicochemical hindrance of nascent genistein by incorporating genistein in receptor specific nanocarriers (Zhou et al. 2014).

12.4.3 Metal Chelators The current available experimental evidence recognized the correlation between metal-induced cerebral dyshomeostasis in the Alzheimer’s patient. The development of metal ion chelator with low toxicity profile and capacity to reestablish the cerebral homeostasis in AD patients seems to be more smart approach for AD treatment. The chief metals recognized with neurotoxic potential are copper, zinc, lead, and iron. Among all the mentioned copper is more prone to cause the cerebral dyshomeostasis owing to its ability to facilitate Aβ agglomeration and induction of proinflammatory mediator-induced reactive oxygen species formulation. Zinc-medicated cerebral dyshomeostasis via extracellular deposition of zinc within amyloid fibers and intracellular overload. Various studies are mainly focused on the development of copper chelation therapy compared to zinc and iron chelation. As copper has higher affinity with the amyloid precursor protein and Aβ proteins compared to zinc and iron metal ion. Ideally, metal chelator should have potential to sequester a metal ion with points of coordination, thereby offering bidentate and multidentate chelators. To ameliorate metal toxicity situation, the formed metal ion-chelator complex should possess strong thermodynamic stability with multidentate sites, thereby requires low chelator molecules to gain complete sequestration of free metal ion. Copper ions also involved in high extent of oxidative stress production which leads to neuronal damage or loss of neurons. Therefore, considering above challenges associated with metal neurotoxicity metal chelation can be more suitable approach for AD treatment. Chelator molecules to participate with Aβ against free metal ion, its affinity should be higher than the Aβ fragments (Wilson and Geetha 2020). The use of chelators to suppress the expression of APP inside of cells, the fibrilization of Aβ, and the development of Aβ-dependent metal oxidative stressinduced neurotoxicity may result in significant advancement in AD treatment. The progression of AD is positively impacted by the chelation of several cations, including Cu2+, Zn2+, and Fe3+, and it is advisable to research natural compounds

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like flavonoids. Nanoparticles can also be used; for example, morin was seen to cause Ab1-42 protofibril destabilization. Although many efficient synthetic chelators were discovered, their practical importance in the treatment of AD cannot be emphasized. Chelation of cations focusing on the oxidative stress, inflammation, and metabolism of amyloidal plaques in AD is widely investigated. The most significant contribution from natural compounds in this regard comes from derivatives of flavanols like tea catechins, which are thought to be promising in regulating brain damage during aging and neurodegeneration. This situation benefits from the application of epigallocatechin-3-gallate, which chelates Fe and Cu and reduces oxidative stress. These polyphenolic compounds can be obtained from the diet and act as a preventative measure against the disease’s progression. In APP transgenics, 5-chloro-7-iodo-8-hydroxyquinoline disaggregates, in addition to suppressing fibril development with Zn2+, metal chelation causes aggregates of Aβ1 to 40 and dissolves Aβ with around 30 times the rate and efficiency of Aβ vaccination therapy. Additionally, it forms a relatively stable complex with a specific affinity for Cu2+ and Zn2+. Deferoxamine slowed down the development of β-pleated amyloidal fibrils or it triggered the dissolving of febrile amyloidal plaques (Bandyopadhyay et al. 2010).

12.4.4 Repurposed Neuroprotectants The discovery of effective treatments for Alzheimer’s disease has been made possible by drug repurposing. Drug repositioning and repurposing can accelerate the creation of innovative medicines for Alzheimer’s disease patients and enhance attempts to create novel drug delivery strategies for moderate cognitive impairment, and dementia (summarized in Table 12.2) while some additional strategies to target brain disorders have been summarized in Table 12.3. This strategy has the significant benefit of not requiring any additional chemical optimization, or toxicology studies, preclinical safety testing, because the safety of the potential chemical has been previously validated. This considerably reduces the time and cost necessary to progress a promising medicine into clinical trials (Ballard et al. 2020).

12.5

Hurdles Associated with the Drug Delivery

There are many hurdles that limit the successful treatment of Alzheimer’s disease. Despite extensive research into the pathophysiology of AD over the past three decades, little has been accomplished in the way of viable cures or preventative measures. If a cure is not discovered over the next few years. In the context of the sharp increase in AD cases, society will face significant economic and social challenges. Additionally, it is noteworthy that improvements in AD therapy approaches that result in even minor delays in AD onset or progression will greatly lessen the disease’s overall burden. The main issues that restrict the development of nanotherapy in AD are low intracranial delivery efficiency and limited targeting.

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Table 12.2 Repurposed neuroprotectants Drug candidates Fasudil

Categories ROCK inhibitor

Phenserine

AChE inhibitors

Penciclovir, aciclovir, foscarne, valaciclovir

Antiviral drugs

Perindopril, lisinopril, ramipril, captopril

ACE inhibitors

MOA In vitro reduction of Aβ levels via the Wnt-PCP pathway driven by Dkk1. Reduction in inflammation, protection against synaptic damage, and impairment arborization of the dendrites Inhibition of IL-1 production, reduce glutamate-induced excitotoxicity, mitigated of oxidative stress, reduction in Aβ levels, increased BDNF production, inhibition of APP and -synuclein synthesis, and the preprogrammed cell death pathway is protected Acceleration of HSV and accumulation of amyloid, promote abnormal tau phosphorylation Reduction in tau phosphorylation and amyloid deposition, reduction in BP, and protection against oxidative stress

Future studies To assess the impact of fasudil on cognitive performance, a robust RCT involving people with AD or MCI is required

Ref Sellers et al. (2018)

Verification of mechanism of action in humans

Seyb et al. (2008)

Well-powered RCT is needed, at least two small RCTs in a combined total of 163 individuals with AD Epidemiological evidence is weak; RCTs are needed to distinguish between the effect of hypertension control and the specific effects of ACE inhibitors

Wozniak et al. (2009, 2007)

AbdAlla et al. (2013), Sultana and Ballard (2018)

12.5.1 Drug-Related Challenges Even though many pharmaceutical candidates have been investigated against several molecular targets of AD, only a limited of them such as acetylcholinesterase inhibitors are being employed as the current therapeutic approach. Conventional drug delivery methods do not efficiently deliver medications into the brain, making them unusable for treating CNS diseases that are a part of Alzheimer’s disease. There are several challenges with the targeted drug delivery of these drugs to the CNS

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Table 12.3 Brief account of various therapeutic strategies to target neurodegenerative diseases Drugs Morphine

Diseases –

Approaches Intranasal route

Gallotannin

PARG inhibitor Anticancer agents

Intranasal route Intracerebral infusion

Olanzapine

Antipsychotic agents

Intranasal mucoadhesive microemulsion

NAD+

Antioxidant cofactor

Intranasal route

GDNF

Parkinsonism

Nerve growth factor

Nerve factor

Intracerebral ventricular route Intracerebral implant

Cytosine arabinoside

Interferences Adequate cerebral concentration was found to be after crossing the nasal mucosa into CSF Reduce the level of ischemic brain injury in rats Diffusion enhances the cerebral blood level more than IV, intranasal, intraventricular route High concentration in the brain due to its mucoadhesive nature and enhanced solubility Reduced brain damage in rats

Higher cerebral concentration was found to be in parkinsonism Recovery in brain damage

Ref Westin et al. (2006)

Wei et al. (2007) Groothuis et al. (2000)

Kumar et al. (2008)

Wei and Wang (2007), Nutt et al. (2003) Nutt et al. (2003) Lane et al. (2013)

(central nervous system), including poor solubility, little permeability, reduced BA (bioavailability), and decreased effectiveness (Karthivashan et al. 2018).

12.5.2 Physiological Challenges Many neuroprotectants are unable to treat brain disorders due to the lack of successful delivery to the brain. Although there is high blood flow, drug delivery to the brain is difficult. Two physiological barriers control the passage of substances to the brain, that is, blood-cerebrospinal fluid (BCF) and blood-brain barrier (BBB). The BBB severely restricts substance transport into the brain, in contrast to peripheral capillaries, which provide free passage of material across cells. The BBB serves as both a biochemical barrier and a physical barrier. It conveys several cytosolic enzymes, including peptidases, as well as a Pg-P efflux (p-glycoprotein) system that helps in the drug diffusion back into the blood from endothelial cells of the brain, further assisting in its protective behavior toward the brain microenvironment. As a result, the BBB frequently regulates the rate at which therapeutic medications permeate the brain. A medicine delivered systemically must pass the BCSFB (bloodcerebrospinal fluid barrier) before this could enter the CNS. The CSF that is secreted

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by it, which is situated at the choroid plexus epithelium, flows into the ventricles and around the outside of the spinal cord and brain (Alam et al. 2010).

12.5.3 Disease-Related Challenges There have been no successful therapeutic attempts to date, including those to reduce Aβ production, aggregate it, and remove it from the brain. There could be four main causes for the failure of Aβ-based treatments, based on what is now known about AD. First off, β-amyloid might not even be a disease-causing factor but merely a non-degenerative marker. It is generally known that up to 30% of healthy older people have the same levels of b-amyloid plaques as typical AD cases and that the number of plaques in AD does not correspond with the severity of dementia. Only a few of the presenilin-1 and presenilin-2 mutations that cause AD increases the levels of Ab in the brain; other mutations that cause AD either have no effect on brain Ab levels or cause them to reduce. Aβ has been shown to be neurotoxic in cultured cells and in experimental animals, although these discoveries were only made after Aβ was either overexpressed or treated with a very high nonphysiologically concentration. Second, the therapies based on Aβ used up until now were not strong enough to minimize the disease. The gut microbiota is a diverse community of microbial species that live in our gastrointestinal environment and whose changes can affect not just different gut disorders but also disorders of the CNS, such as AD. The microbiota-gut-brain axis is a bidirectional communication system that involves neurological, immunological, endocrine, and metabolic processes but is still poorly understood. Microbiota dysbiosis may mediate or have an impact on the development of AD and other neurodegenerative diseases, particularly those that are age-related, due to the increased permeability of the gut and blood-brain barrier. Furthermore, the bacteria that constitute the gut microbiota have the capacity to generate high amounts of amyloids and lipopolysaccharides, which may help to alter signaling pathways and produce proinflammatory cytokines linked to the pathogenesis of AD (Jiang et al. 2017).

12.6

Pharmaceutical Approaches to Overcome Drug Delivery Hurdles

Only a limited number of candidates, such as acetylcholinesterase inhibitors, are presently used as an efficient therapeutic treatment, even though many drug candidates have been tested against different molecular targets of AD (Karthivashan et al. 2018). Drugs released through conventional drug delivery approaches do not reach the brain effectively, making them ineffective for treating CNS disorders that affect Alzheimer’s disease. Enzymes and the blood-brain barrier (BBB) also limit access to substances necessary for sustaining the internal environment of the brain. However, because of the obstructions of the blood-brain barrier, targeted delivery of

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Fig. 12.2 The currently explored nanocarriers for the Alzheimer’s disease are polymeric nanoparticles, nanoemulsion, nano-lipid carriers (NLC), liposomes, solid lipid nanocarriers (SLN), and dendrimers

these medications to the central nervous system demonstrates several difficulties, encompassing poor solubility, low BA, and decreased effectiveness (Alam et al. 2010). Nano-drug delivery technologies carry the potential in addressing a few therapeutic moieties by facilitating drug molecule penetration through the CNS and enhancing their bioavailability. Therefore, it is necessary to innovate and design strategies that precisely target the CNS in a well and more efficient manner. The nanocarriers for the targeting of AD are shown in Fig. 12.2.

12.6.1 Route-Specific Administration 12.6.1.1 Intravenous Delivery For administering higher amounts of medication into the body, the intravenous (IV) route is most frequently used. It can potentially transport medicines to the brain and delivers medications directly into circulation by circumventing first-pass metabolism. The surface area of the brain is structurally made up of a capillary

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network that spreads over an area of about 20 m2, hence drug delivery via a transvascular route is effective at targeting the brain. This method is thought to offer a huge potential to transport medications to practically all the brain’s neurons since the blood capillaries and neurons in the brain are closely related, allowing the delivered drug to pass through the vascular barrier and enter the brain. In addition, the availability of medicines in the brain by IV route is mainly influenced by the rapid metabolism of drugs, plasma half-life, degree of nonspecific binding to plasma proteins, as well as the drug’s permeability over the BBB and into perivascular tissues. When administered by this route, several medications have demonstrated therapeutic potential in clinical trials. The intravenous delivery of the gene expression from an external source into the brain was determined to be robust and showed high expression levels in all neurons. When delivered with an appropriate carrier system, such as lipid carriers, polymeric depots, or liposomes, the route’s results were found to be extremely effective in delivering medications to the brain (Alam et al. 2010).

12.6.1.2 Intranasal Delivery The intranasal route has been used to deliver medications for systemic activity since the substance crosses the nasal mucosa and enters the bloodstream directly. Because the drug passes directly from the submucosa space of the nose to the CSF compartment of the brain, a superior targeted effect can be accomplished. Intranasal delivery is a noninvasive technique for delivering therapeutic molecules and peptides to the CNS without going to cross the BBB. The high permeability of nasal epithelium facilitates quick absorption of drug to the brain due to its huge surface area, porous endothelium membrane, relatively high blood flow, and ability to bypass first-pass metabolism. A few therapeutic substances (small molecules and macromolecules) can be delivered to the CNS via the trans nasal technique. Many CNS-active drugs are more effective when administered intranasally, and this approach has the benefits of a minimal dose, self-administration, and avoiding sterile practices. Several pharmaceuticals and peptides have been successfully administered through the intranasal route in recent years. NAD+ administration significantly reduced peroxidative cell death and brain damage in a rat model of acute localized ischemia. Gallotannin can also be administered intranasally. The (ADP-ribose) glycohydrolase (PARG) inhibitor demonstrated a significantly reduced ischemic brain injury that occurred in rats. Olanzapine demonstrated increased brain drug delivery efficacy when administered intranasally as a mucoadhesive microemulsion formulation. Buspirone hydrochloride mucoadhesive formulation was administered to mice by intranasal inhalation and exhibited improved brain concentration in mice. 12.6.1.3 Intracerebral Delivery Drugs are administered via intracerebral infusion directly into the brain’s parenchyma. Intrathecal catheters and controlled release matrices can be used to deliver drugs directly (by bolus or infusion) into the brain. Cytosine arabinoside an anticancer drug was delivered intraparenchymal, where it had a concentration that was 10 times higher than intraventricular, 100 times higher than intranasal, and

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1000–10,000 times higher than intravenous. Similarly, paclitaxel, immunotoxin, lipoplexus, and DNA are successfully delivered by utilizing the CED-mediated drug delivery technique. Devices called intracerebral implants allow for the controlled delivery of medications at the target site in the brain. Drug-encapsulating polymers that are both biodegradable and nonbiodegradable comprise implants. Diffusion is the fundamental process underlying medication release from these devices. There are numerous cases where this strategy has already been employed to treat disorders with brain implants. For the treatment of a quadriplegic patient, a brain implant with nerve growth factor produced greater results from spinal cord damage.

12.6.1.4 Transcranial Drug Delivery Like earlier methods, intraventricular routes allow for the direct administration of therapeutic drugs into the cerebral ventricle while circumventing the BBB. As it primarily delivers medicines into the ventricles and subarachnoid region of the brain, this route is designed specifically for the treatment of meningiomas and metastatic CSF cells. Unlike intracerebral administration, a major advantage of this route is that it is not connected to the brain’s interstitial fluid. As a result, the medication has a larger concentration in the brain than in its extravascular distribution. The GDNF (glial-derived neurotrophic factor) was administered for the first time via intracerebroventricular (ICV) injection to treat Parkinson’s disease, and it demonstrated improved extents in the brain parenchyma. The diffusion phenomenon is the primary determinant of drug concentration in the brain because it allows drugs to enter the brain from the site of administration. And as the distance from the injection site to the ependymal surface of the brain increases by 1 mm, the diffusion also reduces logarithmically. In treating neoplastic meningitis, slow intraventricular infusion of cytosine arabinoside was 71% more effective than intrathecal administration. 12.6.1.5 Intrathecal Delivery Using the intrathecal approach, medications are directly administered into the brain’s cisterna magna to deliver neurotherapeutic substances to the brain. Despite being considerably less invasive than intraventricular delivery, this approach does not cause drug accumulation in deep brain parenchymal structures, which is crucial for sustained drug release. When etoposide was supplied through this route to dogs, ataxia and loss of muscle coordination resulted, it was realized that this route’s main drawback is the potential for the drug to diffuse throughout the distal space of the spinal canal. Due to this, the intrathecal approach is especially suitable for medication delivery in the therapy for spinal disorders and disseminated meningeal diseases but not in the treatment of severe parenchymal diseases such as parenchymal malignancies like glioblastoma.

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12.6.2 Nanotechnological Assistance The fact that medications cannot pass the blood-brain barrier or are poorly soluble when taken orally is the main cause of the lack of treatment options. To bypass the BBB, a variety of drug delivery systems techniques have been developed, including, solid lipids and polymeric NPs (SLNs), liposomes, solid lipid carriers, hydrogels, liquid crystals, and microemulsions (Harilal et al. 2019). Drugs might fail as pharmacotherapeutics due to their physicochemical properties, such as extensive metabolization, poor bioavailability, hydrophilicity or lipophilicity, ionization, high molecular weight, and undesirable effects. Because drugs administered in this way can circumvent the blood-brain barrier and directly transport drugs to the CNS, these restrictions can be overcome by using these novel techniques, which also offer an alternate, noninvasive method of brain delivery of the drugs. Recent updates on nanotherapeutics in AD management are summarized in Table 12.4.

12.6.2.1 Liposomes Liposomes are non-immunogenic, biodegradable, low toxicity, flexible, and biocompatible, liposomes, which were first identified in the 1960s, and have gained significant attention. They have the potential of transporting hydrophilic, lipophilic, and amphoteric medicinal molecules either entrapped inside or on their micellar surface. Since a few decades ago, these have inspired a lot of attention in drug delivery technologies, particularly for the brain. Typically, phospholipids are utilized to create liposomes, which can range in size from SUVs (small unilamellar vesicles) to multilamellar vesicles. Phospholipids produce a self-sustaining bilayered structure (MUV) (Alam et al. 2010). Advanced liposomal technology allows for improved site-specific activity. Drug molecules can be directly encapsulated in surface-modified liposomes and delivered to sick tissues or organs. By conjugating suitable targeting vectors, it is possible to modify the distribution of long-circulating liposomes in the brain (Alam et al. 2010). Mourtas et al. (2014) created multifunctional liposomes using a curcumin derivative and a BBB transport mediator. Liposomes containing the curcumin derivative and anti-TRF demonstrated a strong affinity for amyloid plaques, according to an analysis of postmortem brain samples from AD patients (Mourtas et al. 2014). Donepezil liposomal formulation was recently created and tested by Al Asmari et al. Following intranasal delivery in healthy male Wistar rats weighing 200–250 g, they studied its brain and plasma pharmacokinetics. The basic lipid film hydration approach was used to create liposomes that included PEG. These liposomes demonstrated great entrapment efficiency and prolonged release behavior. These liposomes were found to significantly enhance the bioavailability of donepezil in the brain when administered intranasally compared to the traditional dose form (Al Asmari et al. 2016). Yang et al. developed rivastigmine liposomes and liposomes modified with CPP (cellpenetrating peptide) to enhance the rivastigmine circulation in the brain, improve the utilizing intranasal delivery, pharmacodynamics is maximized while adverse effects are reduced (Yang et al. 2013). Galantamine has also been developed into ligandfunctionalized nanoliposomes for targeted delivery (Fonseca-Santos et al. 2015).

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Table 12.4 Novel nanotherapeutics for the treatment of Alzheimer’s diseases Nanocarriers Liposomes

Therapeutic agents Curcumin

Liposomes

Donepezil

Liposomes

Rivastigmine

Polymeric nanoparticles

Tacrine

Polymeric nanoparticles Dendrimers

Galantamine

Dendrimers

Gallic acid

SLNs

NCLs

Curcumin and donepezil Vinpocetine

Inferences Liposomes containing the curcumin derivative and anti-TRF demonstrated a strong affinity for amyloid plaques Demonstrated great entrapment efficiency and prolonged release behavior and intranasally enhanced brain bioavailability as compared to the traditional dose form Intranasal delivery of rivastigmine enhances the distribution in the brain and reduced adverse effects The concentration of coated tacrine NPs in the brain was higher (170 ng/mL) than uncoated Good encapsulation efficiency and sustained release drug was observed Attenuated the neurotoxic effects of b-amyloid in plaque Decrease the proportion of prefibrillar forms in the system by accelerating fibril formation Intranasal drug delivery produces a higher level of drug concentration in the brain than intravenous and reduced oxidative damage Increased oral bioavailability

NCLs

Resveratrol

Increase brain bioavailability

SLNs

Ferulic acid

Decrease in the formation of ROS

Nanoemulsion

Curcumin

Nanoemulsion

Ketoprofen

Nanoemulsion

Carvacrol

Mucoadhesive nanoemulsions had the maximum flow across sheep nasal mucosa when compared to drug solution In-vitro release of the drug revealed a fastrelease pattern and greatly increased brain bioavailability Inhibition of the TNF-α-induced nuclear factor kappa-light chain-enhancer of activated B cells (NF-κB)

Sialic acid

Ref Mourtas et al. (2014) Al Asmari et al. (2016)

Yang et al. (2013) Wilson et al. (2008) Fornaguera et al. (2015) Patel et al. (2007) Klajnert and Bryszewska (2007) Sood et al. (2013) Zhuang et al. (2010) Frozza et al. (2013) Trombino et al. (2013) Sood et al. (2014) Choudhury et al. (2017) Hussein et al. (2017)

12.6.2.2 Polymeric Nanoparticles Polymeric nanoparticles (NPs) are nanocarriers into which drugs are loaded in either solid or liquid form, and which are noncovalently or chemically linked to the surface. These delivery methods provide sustained drug release, low immunogenic response, low toxicity, and good stability in addition to being simple to produce. Different preparation methods such as polymerization, emulsion solvent evaporation, ionic

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gelation or coacervation, spontaneous emulsification or solvent diffusion, spraydrying, nanoprecipitation, and supercritical fluid technology have been employed based on the polymer and drug characteristics to create NPs for CNS administration using a variety of polymers. Drug administration through the BBB to the brain may have major advantages over currently employed methods while causing no damage to the BBB. The greater both the retention of the NPs and their adsorption to the capillary walls in the blood-brain vessels can be used to explain how NPs are transported across the BBB. The concentration gradient is increased because of these events, which improves delivery to the brain by increasing transport across the endothelial cell layer (Fonseca-Santos et al. 2015). Wilson et al. created tacrineloaded poly (n-butyl cyanoacrylate) nanoparticles by using emulsion polymerization and coating with polysorbate 80. Tacrine levels in the kidneys and lungs were not statistically different between the two groups. The correlation between the endothelial cells in the brain microvessels and the polysorbate 80 coating has been hypothesized by the authors as a method for delivering the coated polysorbate 80 NPs to the brain. When coated NPs were utilized, the tacrine was present in the brain at a level of around 170 ng/mL. This outcome was significant (P, 0.001) when compared to the usage of the free drug or uncoated NPs (Wilson et al. 2008). To treat Alzheimer’s disease, rivastigmine is delivered to the brain in a targeted manner. Wilson et al. created poly (n-butyl cyanoacrylate) NPs coated with polysorbate 80. Joshi et al. created rivastigmine-loaded PBCA and PLGA NPs using emulsion polymerization techniques and modified nanoprecipitation, respectively. Fornaguera et al. created galantamine-loaded PLGA NPs for intravenous delivery utilizing nanoemulsion templates made from O/W nanoemulsions with continuous drug release and good encapsulation efficiency. To attach to aβ plaques, a single emulsion solvent evaporation process was employed to create curcumin NPs coated with PLGA. An in vitro reduction in the size of the protein aggregate was stated (Fornaguera et al. 2015). In further work, donepezil-loaded PLGA NPs with a polysorbate 80 coating were synthesized by using a solvent emulsification diffusion-evaporation process for long-lasting release and effective parenteral delivery to the brain. The prolonged brain concentrations of donepezil given by coated NPs and their high brain absorption may assist in treating AD (Baysal et al. 2017). To establish the effectiveness of the planned distribution strategy, however, additional thorough clinical investigations are required.

12.6.2.3 Solid Lipid Carriers SLNs are typically spherical and range in diameter from 10 to 1000 nm when dispersed in water. Lipophilic compounds can be solubilized by the lipid core matrix observed in SLNs. The lipid core, which usually consists of tristearin, glyceryl behenate, glycerol monostearate, fatty acids, steroids, and cetyl palmitate, surfactants stabilize the particles, although a combination of emulsifiers may be more efficient to avoid particle agglomeration. A variety of techniques, including high-pressure homogenization, solvent evaporation, high-shear, solvent emulsification-diffusion, ultrasonication, ME-based, spray-drying, supercritical fluid, double emulsion, and precipitation, can be used to create SLNs or NLCs

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from lipids, an emulsifier, and water or another solvent. The BBB can be bypassed via SLNs or nanocarrier lipids for drug administration to the brain because these formulations can pass through the BBB or be administered intranasally to avoid it. The process of emulsification-solvent diffusion was used to create piperine SLNs with a polysorbate 80 film. For intranasal administration to the brain, Sood et al. prepared NCLs loaded with curcumin and donepezil. According to the studies, intranasal drug delivery produces a higher level of drug concentration in the brain than intravenous dosing. When compared to the group that received the free medicine, a mouse model demonstrated better learning and memory. In virtue of this, the acetylcholine levels in the NLC-treated groups were increased and oxidative damage was minimized (Sood et al. 2013). Zhuang et al. synthesized vinpocetine-loaded NCLs using a high-pressure homogenization process to improve oral bioavailability. In comparison to a vinpocetine suspension, pharmacokinetic tests revealed a 0.35-fold decrease, a threefold increase, a twofold rise, and an elimination constant, maximum duration, and maximum concentration in plasma (Zhuang et al. 2010). Frozza et al. prepared NCLs with oil-based cores loaded with resveratrol to increase brain bioavailability. In the brain, kidneys, and liver, of mice treated with the NCLs as compared to mice treated with free resveratrol, the results revealed drug concentrations that were 2.5fold, 6.6-fold, and 3.4-fold higher, respectively (Frozza et al. 2013). As a potential treatment for AD, Bondi et al. prepared ferulic acid-loaded SLNs utilizing the ME method. Unloaded SLNs failed to exhibit any cytotoxicity in this investigation against human neuroblastoma, but they did demonstrate cell penetration. Compared to cells treated with the free medication, cells treated with ferulic acid-loaded SLNs displayed a better decrease in the formation of ROS. These results suggest that drugloaded SLNs are potentially effective carriers for cholinergic agent drug delivery since they show that drug-loaded SLNs have a better defensive function than the free drug against oxidative stress caused in neurons (Trombino et al. 2013).

12.6.2.4 Nanoemulsion O/W nanoemulsions are a heterogeneous system with oil droplets dispersed in water that are stabilized by one or more surfactants and cosurfactants. Nanoemulsion is an intriguing drug delivery method since the size of their oil droplets ranges from 10 to 100 nm. Additionally, the oil droplets can be used to solubilize and preserve lipophilic compounds, and it is simple to scale up laboratory manufacturing techniques to an industrial scale. These systems have certain drawbacks, such as deterioration over storage that causes phase separation and affects drug release. Despite the features of nanoemulsion and their usage to enhance drug delivery, since have numerous studies reported the utility of nanoemulsion systems for brain delivery. Sood et al. investigated the delivery of curcumin for the treatment of AD using a nanoemulsion approach spontaneous emulsification method was used to prepare the nanoemulsion. In vitro nasal ciliotoxicity and cytotoxicity investigations showed that the proposed formulation was safe and nontoxic. To deliver poorly soluble curcumin intranasally, mucoadhesive nanoemulsion had the maximal flow over sheep nasal mucosa against drug solution and nanoemulsion (Wen et al. 2017).

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A pullulan-stabilized nanoemulsion containing ketoprofen was prepared by Ferreira et al. Studies on the in vitro release of the drug revealed a fast release pattern and greatly increased bioavailability, which leads consequence improved brain penetration (Choudhury et al. 2017). Hussein et al. examined the anti-inflammatory, antineuronal injury, and anti-homocysteine effects on a rat model of diabetes induced by streptozotocin of a nanoemulsion containing carvacrol. They discovered that these effects were due to the suppression of the nuclear factor kappa-light chainenhancer of activated B cells (NF-jB), which is produced by tumor necrosis factoralpha (TNF-α) (Hussein et al. 2017). The flavonoid naringenin has a restricted ability to cross biomembranes but can guard neurons from free radicals and inflammation. According to Shadab et al., naringenin nanoemulsion could potentially be used as an AD treatment because it attenuated the neurotoxic effects of b-amyloid plaque and the levels of phosphorylated tau in the SHSY5Y cell line (Harilal et al. 2019).

12.6.2.5 Dendrimers The “polymers of the twenty-first century” have been referred to as dendrimers. Dendrimers have been shown in studies to have the ability to act as drug carriers for AD and to solubilize sparingly soluble compounds in aqueous conditions. Dendrimers are made up of branched nanoscale macromolecular structures. They have three structural parts: a central core, an inside dendritic portion, and a functionalized surface on the outside. During their step-by-step synthesis, they can be attached to and modified for their structure. These specific structural characteristics of dendrimers have increased significantly interest in the research. Patel et al. prepared sialic acid-conjugated dendrimers, sialic acid receptors are present on cell surfaces and attenuated the neurotoxic effects of b-amyloid in plaque. They concluded that these drugs might be helpful in reducing the harmful consequences of b-amyloid plaque in AD (Patel et al. 2007). The impact of gallic acid triethylene glycol dendrimer coated with 27 terminal morpholine groups ([G3]-Mor) on the aggregation of Alzheimer’s peptide was studied by Klajnert et al. (Klajnert and Bryszewska 2007). In comparison to mature fibrils, prefibrillar species were more harmful. The toxicity of A was greatly decreased by [G3]-Mor, which was attributed to a decrease in the proportion of prefibrillar forms in the system by accelerating fibril formation. The ability of phosphorus-containing dendrimers (CPDs) to regulate the aggregation of amyloid and MAP-tau was reported by Wasiak et al. To assess the cytotoxicity of the fibrils and intermediates generated during the aggregation of A (1-28), the authors utilized the neuro-2a cell line. They demonstrated that CPDs may have a positive impact by minimizing their toxicity. The results indicate that phosphorus dendrimers may be employed in the future as agents modulating the fibrilization processes in AD.

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Status of Preclinical and Clinical Evaluation of Drug Intervention for Alzheimer’s Disease

Huge research efforts have been made to study the cytological, genetic, biochemical, and molecular elements of the illness. Despite the higher number of patients suffering from AD, only fewer viable and effective treatments are available (Zvěřová 2019). N-methyl-D-aspartate (NMDA) receptor antagonists and cholinesterase inhibitors are the most common medications used to treat AD. The four FDA-approved medications that are frequently used are rivastigmine, donepezil, memantine, and galantamine, while memantine and donepezil are sometimes used in combinatorial therapy. Unfortunately, as these drugs do not directly target the etiology of AD, instead simply allow for curative management of symptoms. Nevertheless, all these medications improve quality of life by controlling cognitive impairment, dementia, and learning abilities (Fish et al. 2019). Memantine, is the first NMDA receptor antagonist to receive USFDA approval for the treatment of moderate-to-severe AD, that shows improvements with better cognition, attention, language, reasoning, and interpretation skills. Due to adverse effects such as headache, constipation, confusion, and dizziness, the FDA denied extending the use of memantine to moderate AD in 2005. Rivastigmine simultaneously inhibits butyrylcholinesterase and acetylcholinesterase while selecting the G1 form of the enzyme over the G4 form. Rivastigmine does not undergo liver metabolization, unlike the other approved treatments, and does not cause the harmful drug interactions caused unlike other medications. Tacrine was withdrawn from the market due to strong hepatic adverse effects, although it also inhibits acetylcholinesterase and butyrylcholinesterase. Galantamine marketed in 4, 8, and 12-mg tablets and indicated to use twice a day at a dose of 16 mg/day, its dosage can be raised to 24 mg each day as per the severity of disease progression. In a recent, substantial trial, treatment respondents show little progress in cognitive decline over almost a year. The most frequent side effects of galantamine are nausea and vomiting, which are typically self-limiting and show little acetylcholinesterase selectivity. It also modifies the activation of nicotinic receptors, which is different from the other approved medicines. Donepezil has advantages over the other medications described above in treating AD. Due to its prolonged pharmacokinetic and pharmacodynamic half-life, donepezil is typically given as 5- or 10-mg tablets once a day before bed. As a selective acetylcholinesterase inhibitor, it has been shown to improve cognition, general function, and behavior in AD patients. The FDA has also permitted the use of donepezil and memantine in blend for the management of moderate-to-severe Alzheimer’s disease in patients who have been taking donepezil hydrochloride (10 mg) (Harilal et al. 2019).

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Future Prospective and Current Outlooks

Alzheimer’s disease has dramatically increased in prevalence in society and within healthcare systems over the past few decades. It is extremely difficult to develop surrogate biomarkers that accurately assess and track disease progression (Hampel et al. 2011). The participation of a wide range of biological elements and the complex character of the AD prevents conventional therapeutic approaches from effective addressing of AD. However, despite ongoing research, therapies for AD are inadequate, highlighting the limitations between promising research insights and appropriate clinical trial development (Iqbal and Grundke-Iqbal 2011). The Aβ and tau proteins act as a pavement for the repair, neuronal growth and enrichment in healthy conditions. But in terms of dementia condition, hyperphosphorylated tau and Aβ often breach the overall integrity of blood-brain barrier. Generally, the common way of administration is via peroral delivery. Hence the crucial factors that the therapeutic molecule may encounter is BBB. For successful targeting, neuroprotective moiety must circumvent the hurdle imposed by BBB. Once the drug molecule gains access in neuronal compartment, drug may have face other challenges like poor solubility, early metabolism and inadequate distribution in CNS compartment limits the overall efficiency of therapy. Thus, intranasal administration of neuroprotectant is another elite noninvasive and effective way to overcome the BBB and directly distributes within the central nervous system. The advantages of intranasal route of administration involves noninvasiveness, avoid the need of high drug dose, eliminate the chances of off target effects. Various researchers have utilized the applicability of intranasal administration for the preclinical evaluation of various neuroprotective molecules for AD. Despite the benefits of intranasal administration, this route may offer challenges due to low volume of administration, low availability of olfactory epithelial surface area, and acute retention interval limits the overall advantages. Various literature and experimental studies have pointed toward suitability of herbal and synthetic neuroprotectants for the treatment of AD with limited adverse events. However, the complete mechanism of AD development and progression is completely not deciphered as AD is accompanied with multifactorial pathological implications. Herbal bioactive molecules with neuroprotective property are new ray of hopes for the therapeutic relief from the dementia and other AD like symptoms. However, explicit research is essential for understanding the complete pharmacological and pharmaceutical performance of herbal and synthetic molecules. Additionally, few challenges associated with the neuroprotective molecules such as instability in physiological medium, poor bioavailability, and low portioning behavior have hampered the overall applicability of these modalities.

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Conclusion

One of the most often recognized neurodegenerative diseases associated with aging is AD, which is typically identified by behavioral and cognitive dysfunction. The regular and economic involvement of an individual in an aging society is subsequently impacted by this clinical issue. A limited number of AD therapies have been FDA-approved; however, they were used to treat AD-indicating symptoms, and therapeutics to slow or cease AD progression are currently being developed. Here, we discussed the etiological elements of AD, biomarkers, and recent developments on several nano-drug delivery methods that show promise for the management of AD, along with prospective novel therapeutic approaches and physiological hurdles, and pharmaceutical approaches to overcome drug delivery hurdles. Acknowledgements The authors acknowledge the Department of Pharmaceuticals, Ministry of Chemical and Fertilizers, Govt. of India for supporting financially. The NIPER-R communication number for the review article is NIPER-R/Communication/391. Conflict of Interest The authors declare no conflict of interest among themselves.

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Drug Delivery Strategies in Parkinson’s Disease

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Gurpreet Singh, Anupama Sikder, Shashi Bala Singh, Saurabh Srivastava, and Dharmendra Kumar Khatri

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disorder affecting around ten million people worldwide. PD is an age-related disorder observed in 1% of the population over 50. The neuropathological manifestations of PD include α-synuclein aggregation in the dopaminergic neurons, mitochondrial dysfunction, neuroinflammation, oxidative stress, blood-brain permeability, and epigenetics. In PD, delivering therapeutic moieties like phytochemicals and hydrophilic drugs to the brain is challenging due to their incapability to cross the blood-brain barrier (BBB). The conventional treatment methods used in PD suffer from various unmet needs like poor bioavailability, less accumulation in the brain, and associated side effects. To overcome these drawbacks, novel drugdelivery strategies, including the employment of nanocarriers, device-based delivery techniques, etc., have been developed. These will depict enhanced therapeutic efficacy with reduced doses and aid in efficient BBB crossing of the drugs with minimum side effects. This chapter explains the pathophysiological mechanism involved in developing PD, conventional drug-delivery methods, and their challenges. Advancements in the delivery of drugs, including the role of nanocarriers and delivery devices for PD, have also been conveyed.

G. Singh · S. B. Singh · D. K. Khatri (✉) Molecular and Cellular Neuroscience Lab, Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India A. Sikder · S. Srivastava (✉) Pharmaceutical Innovation and Translational Research Lab (PITRL), Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, Telangana, India # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Mishra, H. Kulhari (eds.), Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities, https://doi.org/10.1007/978-981-99-6807-7_13

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Keywords

Parkinson’s disease · Pathophysiology · Unmet needs · Drug-delivery strategies

13.1

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting around ten million people worldwide. PD characterized by the main symptoms are tremors, muscle stiffness, slow movement, and impaired balance (Marxreiter et al. 2013). The chief hallmarks of PD are an aggregation of α-synuclein, neuroinflammation, mitochondrial dysfunctions, oxidative stress, and epigenetic changes (Balestrino and Schapira 2020). Dopaminergic neurons are majorly affected in PD, so dopamine (DA) replacement therapy or DA agonist is widely used for treatment or symptomatic relief in PD. Levodopa therapy is currently used in treating PD and others are anticholinergic drugs, MAO-B inhibitors, DA agonists, Anti-glutamatergic medication, novel treatments that target attenuation of α-syn misfolding, and neuronal regeneration therapies also have been developed (Jankovic and Poewe 2012). Presently, researchers focus on new medicines and targets for PD. Still, after in vitro studies, when new treatments come into clinical stages, they fail due to the inability to cross the blood-brain barrier (BBB). The BBB is a physiological barrier in the brain, composed of endothelial cells (ECs), pericytes, and astrocytes in the junction. BBB creates obstacles between the brain and blood vessels. It controls the exchange of substances between the brain and blood (Andreone et al. 2017; Martinelli et al. 2020). The progression of nanoscience and nanotechnology has facilitated the improvement in the effectiveness of drug-delivery systems. Several strategies like nanocarrier-based delivery of drugs to enhance the easy crossing of the BBB, including nanocarriers, have been established. Hydrophobic moieties find ease in crossing the BBB (Saraiva et al. 2016). Hence several researchers are employing these strategies to fabricate hydrophobic drug-delivery systems. The delivery methods bypassing the BBB including injectables like intrathecal and intracerebroventricular infusions, techniques like convection-enhanced delivery (CED) and focussed ultrasound, iontophoresis, and deep brain stimulation-mediated delivery are being utilized by the neuroscientists for the direct delivery of drugs to the brain (Padmakumar et al. 2022; Khatoon et al. 2021; Nguyen et al. 2021). These methods will aid in reducing the toxic effects of the anti-PD drugs and improving their therapeutic efficiency for the effective management of PD. In this chapter, we have covered the pathogenesis of PD along with the conventional drug-delivery methods. The potential unmet needs associated with PD have been discussed. Novel strategies that could be employed to deliver drugs effectively have been included.

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Pathophysiology of Parkinson’s Disease

13.2.1 a-Synuclein Aggregation The α-synuclein (α-syn) aggregation is one of the primary markers in the pathogenesis of PD. In all forms of PD, the neuropathological hallmarks involve an increased Lewy body (LB) level in the substantia nigra (Schulz-Schaeffer 2010). These LB bodies are generated due to mutation in the α-syn gene and aggregation of α-syn in parts of the brain, especially in the midbrain. Which further leads to neuronal death and contributes to neuroinflammation in PD. Structurally, the α-syn is a 14 kDa protein consisting of 140 amino acids composed of three domains: N-terminal lipidbinding alpha-helix, the second one is non-amyloid-component (NAC), and the third one is acidic C-terminal tail (Wang et al. 2016). The posttranslational modifications, such as phosphorylation of α-syn at the serine-129 position in the C-terminal domain, increases the aggregate formation. Various studies reported the accumulation of phosphorylated α-syn in the brain of PD patients (Foulds et al. 2011). The exact cause of synucleinopathies is still unknown; many research studies proved that the aggregation of α-syn is linked with genetic factors. If we focus on genetics in disease progression, the SNCA is directly linked with PD progression. According to genetic researchers that mutations in the SNCA gene cause PD. The missense mutation and multiplication mutations in SNCA significantly contribute to the α-syn aggregation. The SNCA is the first identified gene that causes dominant PD, and the A53T mutation is the first SNCA mutation. In contrast, H50Q mutation was reported in sporadic cases (Liu et al. 2021). Furthermore, the relationship between α-syn and the autophagy-lysosomal pathway (ALP) plays a crucial role in PD. Autophagy is a catabolic process that mediates the degradation of long-lived proteins in the organism. In PD, dysregulation in autophagy causes the accumulation of α-synuclein protein in neuronal cells (Lynch-Day et al. 2012). The inhibition of autophagy significantly increases endogenous α-syn in wild-type animal models. α-syn and LRRK2 are involved in autophagy, while PINK1 and PARKIN play roles in mitophagy (Zhang et al. 2015).

13.2.2 Neuroinflammation The neuroinflammation is extensively involved in PD pathogenesis. There are various studies held that prove the link between neuroinflammation and the use of the anti-inflammatory drug (Wahner et al. 2007). Recent data from a clinical study demonstrate that patients on treatment with ibuprofen have less risk of PD than regular patients (Fyfe 2020). In PD, neuroinflammation is supported by both innate and adaptive immune systems. Microglia and astrocytes are widely involved in the neuroinflammatory pathway (Joe et al. 2018). Any damage in neuronal cells causes m microglia activation and initiates the phagocytosis of damaged debris. The α-syn aggregates act as DAMPs and PAMPs, activating the toll-like receptors (TLRs) on microglia (Kouli et al. 2019). The activated TLRs contribute to neuroinflammation

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via activation of NF-κB, NLRP3 inflammasome, and inflammatory markers like cytokines, TNF-α, etc. apart from the microglia, the astrocytes have a significant role in PD pathogenesis (Yang et al. 2019). Astrocytes are a double-edged sword, they have a neuroprotective role, but on the other hand, activation of astrocytes leads to the release of inflammatory markers that develop PD (Cabezas et al. 2013). Moreover, the aggregation of α-synuclein only happens in protoplasmic astrocytes; that is why the astrocyte is more relevant to the progression of PD. Furthermore, the DJ-1 protein is expressed in astrocytes; in the case of PD, the DJ-1 gets downregulated, which leads to neuroinflammation. The overexpression of DJ-1 protein in astrocytes shows a neuroprotective effect in PD (De Miranda et al. 2018). Unlike microglia, immune cells, such as T-cells, also participate in the neuroinflammation in PD. The activated T-cells promote neurodegeneration in PD; T-cells bind to major histocompatibility complex molecules and activate cytokines signalling in CNS (Chen et al. 2018). Furthermore, glycosphingolipids are present in neurons to regulate the inflammatory process in PD. The deregulation of glycosphingolipids was reported in PD patients. There is a solid link between neuroinflammation and glycosphingolipids in PD. The accumulation of glycosphingolipids leads to the activation of inflammatory markers that promote neuroinflammation (Belarbi et al. 2020).

13.2.3 Oxidative Stress Oxidative stress plays a vital role in the pathogenesis of PD. Oxidative stress means an imbalance of the body’s free radicals generation and antioxidant system (Blesa et al. 2015). Free radicals which cause cell damage include hydrogen peroxide, nitric oxide, and superoxide radicals. Oxidative stress is central to PD; oxidative stress is significantly associated with mitochondrial dysfunction and neuroinflammation (Dias et al. 2013). As we know, the mitochondria are the primary site for reactive oxygen species (ROS) production. ROS increases oxidative damage of dopaminergic neurons and loss of mitochondrial complex-1 activity in PD (Henchcliffe and Beal 2008). Many clinical and preclinical research studies prove that deficiency in complex-1 is due to high oxidative stress. Furthermore, the low level of GSH promotes ROS generation in the case of PD; in a research study, it was reported that the postmortem brain of PD patients has a low level of GSH compared to regular patients (Bjørklund et al. 2021). Similarly, metals like iron, calcium, and lipids act as cofactor for the antioxidant enzymes, so an imbalance in these cofactors increases ROS generation. Additionally, the Nrf2 signalling plays a crucial role in oxidative stress generation in PD. Nrf2 is a transcription factor that regulates gene expression with antioxidant response elements in their promoters (Zhang et al. 2019). The activated Nrf2 promotes antioxidant enzymes such as heme-oxygenase 1 (HO-1), quinone reductase 1 (NQO1), and GSH. In the case of PD, Nrf2 expression decrease due to keap1 and GSK-3β activation; keap1and GSK-3β bind to Nrf2 and decreases the Nrf2 expression level, which leads to oxidative damage to neuronal cells,

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therefore keap1 inhibitors are used as Nrf2 activators that decrease ROS generation in PD (Golpich et al. 2015).

13.2.4 Mitochondrial Dysfunctions The mitochondrial dysfunction or damage is directly or indirectly linked with tremendous oxidative stress and neuroinflammation in PD (Picca et al. 2020). As we know, mitochondria are the intracellular powerhouse of cells involved in producing energy through the mitochondrial respiratory chain (RC) and regulating cell death, metabolism of calcium, etc. (Morán et al. 2012). Mitochondria is the leading site for ROS generation; therefore, increased ROS levels contribute to mitochondria dysfunction. Additionally, the mutation in mitochondrial DNA leads to damage in Parkinsonism. Mitochondria dysfunction occurs due to both genetic and environmental factors. Environmental factors such as an environmental toxin, lifestyle, aging, and genetic factors, a mutation in genes most common are PARK PD associated genes such as PINK1, DJ-1, Parkin, and LRRK2 cause mitochondrial dysfunction in PD (Dodson and Guo 2007). Furthermore, mitochondria dysfunctions are contributed by various pathologic mechanisms like mitochondrial ubiquitinproteasome system (UPS) dysfunction, leading to the accumulation of misfolded proteins and oxidative stress (Ross et al. 2015). Other mitochondrial dysfunction mechanisms include mitochondrial dynamics-fusion, mitophagy, and excitotoxicityinduced mitochondrial dysfunctions. The mitochondria dynamic processes involve fusion, fission, and mitophagy. Fusion of mitochondria required for repair of damaged mtDNA fission is crucial for mitochondrial; it plays in the segregation of mitochondria into daughter cells in cellular division and maintain distribution of mitochondria structure. Various trigger factors for fission or fusion in mitochondria, as toxins like MPP+ and rotenone, causes mitochondria to fission in DA cell lines (Alberio et al. 2012). Excitotoxicity contributes to various neurodegenerative diseases, including PD. Excitotoxicity means when the membrane potential is between -60 mV and -30 mV, leading to magnesium blocking in NMDA receptors (Loopuijt and Schmidt 1998). The activation of NMDA receptors increases the Ca2+ accumulation in neurons. The excess Ca2+ level causes neurotoxicity via activation of nitric oxide synthase, and high-level Ca2+ ions cause mitochondria dysfunction and decrease ATP production, finally cause DA neurons death in PD (Pivovarova and Andrews 2010). The lipid transporter like caveolae protein Cav-1 promote the mitochondrial dysfunction in the PD (Singh et al. 2023).

13.2.5 Epigenetic Mechanism Epigenetics means the alteration of gene expression without changes in the DNA sequence. There are several factors responsible for epigenetic modification in the system. Most important is lifestyle and environmental factors (Coppedè 2012). Epigenetics has a significant role in the brain’s neurogenesis and cognitive functions.

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Epigenetic mechanism mainly includes DNA methylation, posttranscriptional modification of histone, and noncoding RNA-mediated changes (Feng et al. 2015). As we know, α-synuclein or SNCA gene expression is a critical risk factor in PD; the face of this gene regulates ted by DNA methylation. Recent research has shown hypo-methylation of the SNCA the A gene in PD patients. Furthermore, the methylation of CpG promotes the SNCA expression and causes PD development (Xu et al. 2015). Therefore, DNA methylation in leukocyte acts as a biomarker for PD. The methylation of the MAPT gene also promotes PD pathogenesis; several studies prove that the alteration of the MAPT is higher in men than women (Wüllner et al. 2016). Furthermore, histone modification majorly contributes to epigenetic changes; in PD, the hyper-acetylation of H3 or H4 is a crucial regulator of epigenetic changes in dopaminergic neurons (Harrison and Dexter 2013). Specific neurotoxins are also responsible for epigenetic changes via histone modifications; neurotoxin like dieldrin neurotoxin causes the death of dopaminergic neurons, which is supported by hyper-acetylation of H3 and H4 in dopaminergic neurons (Wang et al. 2020). Additionally, the interaction of PINK1 with histone-methylation modulators like EED/WAIT1 reduces the trimethylation of H3-K27 in PD. Therefore, PINK1 regulates histone methylation and gene expression (Miller and Muqit 2019). Next, one of the essential epigenetic changes involves miRNA-mediated changes; MicroRNA (miRNAs) are small noncoding RNAs that include 21–24 nucleotides. The dysregulation of miRNA expression contributes in PD pathogenesis (Khan et al. 2022). These miRNA expressions regulate gene expression, lies miR-7 has access to the SNCA gene expression and level miR-7 low in the case of PD, which indicates effect of miRNAs on protein or gene expression. There are several miRNA which target particular protein in disease pathogenesis (Filatova et al. 2012). The various pathological manifestations leading to the death of dopaminergic neurons is represented in Fig. 13.1.

13.3

Prevalence and Incidence Rates

PD is a complicated and age-related neurodegenerative disease that involves DA deficiency and motor and non-motor deficits. The incident rate of PD is 5 in 100,000 to more than 35 in 100,000 new cases yearly (Poewe et al. 2017). A recent study found that the prevalence rate of PD in Asia was lower, that is, 646 per 100,000, when compared with the same age group in Europe, North America, and Australia, which is 1602 per 100,000 cases (Haddad and Khreisha 2021). The incidence rate of PD is not constant; it decreases or increases yearly. The incidence reported that the rate of Parkinsonism was lower between 2000 and 2011 compared with the study held in 1990 and 2000. Various studies found that the prevalence of the disease is from 1% to 2% of 1000 in the population. Cases of PD are rare in the age group before 50 years, and the prevalence rate is 4% in the aged population, according to the health insurance review and assessment service database. The prevalence of drug-induced PD increased from 7.3 per 100,000 persons in 2012 to 15.4 per

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Fig. 13.1 Schematic representation of pathological mechanisms contributing to the death of dopaminergic neuron in PD

100,000 persons in 2015, and the incidence of drug-induced PD rose from 7.1 per 100,000 person-years in 2012 to 13.9 per 100,000 person-years in 2015 in Korea (Han et al. 2019). Additionally, the health claim data found that the prevalence is 797 to 961/100000 persons, and the standardized incidence rate was 192 to 229/100000 in similar age groups. The prevalence and incidences were found to be higher in men compared to women (Nerius et al. 2017).

13.4

Conventional Drug Delivery Strategies

The conventional strategies emphasize combating any disease’s associated symptoms and improving the quality of the patient’s life (Ellis and Fell 2017). Traditional treatments for managing PD include medicines, occupational, speech and physical therapies (Radder et al. 2017). Levodopa, the gold standard for managing PD, is the most widely used conventional treatment available in the market. It is combined with other drugs like carbidopa, which will help reduce the drug’s dose and side effects (Pathan and Alshahrani 2018). Other medications available in the market for the treatment of PD include selegiline, apomorphine, benserazide, rotigotine, etc. (Gupta et al. 2019). Apart from these treatments, other therapies include stress management, yoga, acupuncture, and alternative therapeutic systems like Ayurveda and Chinese medicines (Ghaffari and Kluger 2014). These conventional medications are available in various dosage forms like tablets, capsules, etc., tabulated in Table 13.1.

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Table 13.1 Conventional methods for the management of PD Name of drug Levodopa (LD)

Formulation Extendedrelease, Rytary (IPX066) Accordion Pill

Capsule (ODM-101) Apomorphine

Tolcapone Selegeline

Rotigotine

Sublingual apomorphine (APL-130277) Oral film-coated tablets Sublingual disintegrating tablets Transdermal patches

Mode of drug delivery Releasing levodopa with different speed in GIT system Prolonged gastric release

Capsule high of LD/CD than normal capsule, capsules release into GIT for longer time Rapid onset of action, easy access via the oral cavity and bypass, hepatic metabolism Slowly release the drug in GIT Release of selegiline in sublingual cavity and bypass hepatic metabolism and fast acting Slowly and long term release of drug in skin blood vessels from the patches, which improve the motor dysfunction in PD patients Drug absorb in GIT and undergo hepatic metabolism

Amantadine

Tablet

Biperiden

Oral controlled release tablet

Trihexyphenidyl

Tablet

Orphenadrine

Tablet

Drug release in GIT after proper disintegration and dissolution

LD/benserazide

Oral tablets dispersible

LD/carbidopa/ entacapone

Tablet

Quick disintegration and quick dissolution in mouth bypass the hepatic metabolism Drug release in GIT after proper disintegration and dissolution

Release the drug for longer time and absorb in GIT to improve the muscle movement in Parkinson patients Drug release in GIT after proper disintegration and dissolution of tablet

References Mittur et al. (2017) LeWitt et al. (2019) Muller et al. (2013) Agro et al. (2016) Craft et al. (2022) Ondo et al. (2011) Sanford and Scott (2011) Thomas et al. (2010) Carvalho et al. (2021) Schwab and Doshay (1962) Di Stefano et al. (2009) Di Stefano et al. (2009) Gordin et al. (2004)

Despite their vast popularity, conventional therapies suffer from certain drawbacks, including poor accumulation in the brain, meager bioavailability, and several associated side effects. To overcome these challenges, novel drug-delivery techniques could be employed to efficiently deliver the drugs to the brain and thereby manage PD, which have been discussed in upcoming sections of the chapter.

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Unmet Needs Associated with Drug Delivery in PD

All the existent treatments for PD mainly focus on reducing the symptoms, but a complete cure for this manifestation remains a challenge. One of the goals of treating PD is achieving neuroprotection (Koller and Tse 2004). As of now, none of the medications has depicted efficiency in decelerating disease progression. Some DA agonists like apomorphine, bromocriptine, and pramipexole have been employed to facilitate neuroprotective activity in cell lines and animal models (Olanow and Schapira 2013). However, pramipexole failed to depict neuroprotective effects at 15 months (Elhak et al. 2010). Likewise, monoamine oxidase inhibitors portray disease-modifying effects but only with a particular dose range of drugs (Stocchi 2006). The associated adverse effects including cardiovascular and gastrointestinal of the drugs become another bottleneck for managing PD (Tabar and Studer 2014). The first-line treatment of PD is levodopa, but it further aggravates dyskinesia and motor dysfunctions (Boi et al. 2019). Another unmet need is the lack of proper and effective diagnosis and therapy for non-motor symptoms of PD including hallucinations, sweating, sialorrhea, and anxiety. (Taylor et al. 2020).

13.6

Novel Drug-Delivery Strategies

13.6.1 Nanocarriers for Drug Delivery in PD Despite the available conventional therapies for PD, the paramount unmet need is the lack of efficient and controlled drug delivery to the brain (Ahmad et al. 2022). The current treatment strategies for PD emphasize reducing the motor symptoms achieved by increasing the DA levels in the central nervous system (CNS) (Teleanu et al. 2019). The first-line therapy, levodopa, is effective in PD but suffers from inadequate absorption, extensive metabolism, and causes levodopa-induced dyskinesia (Sprenger and Poewe 2013). The advent of nanotechnology has elevated novel opportunities that will open better treatment strategies by improving the pharmacokinetic limitations of conventional treatments (Sahoo et al. 2007). Due to their size in the nano range (1–100 nm), nanocarriers also render several benefits like easy penetration and higher accumulation into the brain, defending the encapsulated drug from degradation, increasing target specificity, etc. (Bhatia 2016). This section discusses several novel, invasive, and noninvasive strategies employed to manage PD in drug delivery.

13.6.1.1 Polymeric Nanocarriers Polymeric nanoparticles depict various structures composed of chemically or naturally originated polymers (Kamaly et al. 2016). This class of nanocarriers is gaining more importance among scientists due to their inherent advantages, including enhanced bioavailability, greater compatibility shielding the drug from harsh environments, thereby increasing its therapeutic window, limiting the toxic effects of drugs and improving circulation time (Bajracharya et al. 2019; Agrawal et al.

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2021). Polymeric nanoparticles comprise two categories: nanospheres, a matrix system, and nanocapsules, a reservoir system (Aleksandra et al. 2020). Some of the FDA-approved polymers which are employed to prepare polymeric nanoparticles include chitosan, polylactic acid (PLA), polyethylene glycol (PEG), and poly (lactic-co-glycolic acid) (PLGA) (Makadia and Siegel 2011; Mohammed et al. 2017; Marin et al. 2013). Researchers have loaded monoamine oxidase (MAO) inhibitors in polymeric nanoparticles to manage PD. Gulati et al. prepared chitosan nanoparticles to be administered intranasally and encapsulated selegiline hydrochloride to facilitate dose reduction, enhance its therapeutic activity, and achieve sustained release effective for PD (Gulati et al. 2014). Zhao et al. employed poly (ethylene glycol)-co-poly(ε-caprolactone) (PEG-PCL) (PEG-co-PCL) nanoparticles to load a naturally obtained drug ginkgolide B to achieve a neuroprotective effect in PD (Zhao et al. 2020).

13.6.1.2 Lipid-Based Nanocarriers Lipid nanoparticles being lipidic are gaining more prominence in treating brainrelated disorders. These nanoparticles render the loaded drugs to bypass hepatic firstpass metabolism (Jagaran and Singh 2022). The lipid nanoparticles effective in managing PD include micelles, liposomes, solid lipid nanoparticles, nanostructured lipid carriers, and naturally derived exosomes (Singh et al. 2022; Sikder et al. 2022). Lipidic carriers offer extended protection from degradation in the systemic circulation, enhance the drug’s bioavailability, and help reduce toxicity and associated adverse effects (Onoue et al. 2014). Dudhipala et al. fabricated ropinirole-loaded nanostructured lipid carriers (NLC) and solid lipid nanoparticles (SLN) loaded in hydrogels effective for the oral and topical administration in PD. Overall findings portrayed an enhancement in distribution and bioavailability of 3.3 and 3.0-fold by NLC and SLN both in oral as well as topical routes (Dudhipala and Gorre 2020). Hsu et al. designed liposomes encapsulating apomorphine in order to potentiate its brain delivery. Results depicted that the prepared liposomes portrayed better stability in the physiological fluid along with rapid brain uptake in vivo which was confirmed by bioluminescence imaging (Hsu et al. 2011). 13.6.1.3 Inorganic Nanocarriers Inorganic nanoparticles like carbon nanotubes, gold, silver, and iron oxides have engrossed substantial attention as potential drug-delivery candidates in the management of PD (Mousa and Mohammad 2022). These nanocarriers depict a minimal size (below 25 nm) (Ma et al. 2015). Some of these nanocarriers are emerging in clinical trials, like the gold nanoparticles in Phase II clinical trials for managing PD (Dewey et al. 2019). The most widely accepted FDA-approved inorganic nanoparticles are the iron oxide nanoparticles (Anselmo and Mitragotri 2015). The administration of certain DA agonists may lead to various dose-dependent gastrointestinal, cardiac, and cognitive side effects (Borovac 2016). Hence, modified-release formulations of such drugs will benefit in providing simplified administration in patients, thereby reducing the dose and daily intake of the drugs. Tzankov et al. developed MCM-41 mesoporous silica nanoparticles for the delivery of pramipexole

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effective against PD. The nanoparticles portrayed greater prevention in oxidative stress in SH-SY5Y cells depicting its efficacy in the treatment of PD (Tzankov et al. 2019). Kalcec et al. presented a cost-effective, time-saving technique to bind drugs to nanoparticles and studied the binding process among gold nanoparticles and L-dopa. These nanoparticles were functionalized using peptidoglycan monomer, adamantylglycine, polyethylene glycol, and adamantylamine. Uv and fluorescence results depicted the effective binding potential of L-dopa and peptidoglycan monomer-functionalized gold nanoparticles (Kalčec et al. 2022).

13.6.2 Devices for Drug Delivery in PD Drug-delivery devices are specialized equipment that enables a drug or therapeutic agent to be administered through a specific route of administration (Ranade and Hollinger 2003). Even though oral medications are adequately calibrated, many PD patients experience debilitating response variations, prompting the advent of three types of device-aided therapy directed at accomplishing continuous dopaminergic stimulation (Timpka et al. 2017). Firstly, deep brain stimulations (DBS) involve the utilization of high-frequency impulses targeting the basal ganglia (Vachez and Creed 2020). Secondly, the advent of focused ultrasound delivery of drugs is a novel FDA-approved lesion technique that utilizes high frequencies and is effective against tremors (Baek et al. 2022). Lastly, convection-enhanced delivery (CED) employs bulk flow to deliver drugs to the brain (Faraji et al. 2020). Other approaches include iontophoresis (Singhal et al. 2021), pump therapies (Karlsborg et al. 2010), etc. This section discusses some of the devices utilized for drug delivery in PD.

13.6.2.1 Convection-Enhanced Delivery CED is gaining highlights among researchers. This technique employs hydraulic pressure to directly deliver the drugs to the desired location in the brain, thereby bypassing the BBB (Kanner 2007). CED is a promising method to provide therapeutic moieties to the PD-affected striatum (Barua et al. 2014). A stereotactic catheter is inserted in the striatum and the drug is distributed in the brain via continuous infusion (Lam et al. 2011). The factors influencing CED include the drug dose, flow rates, infusion volumes, and pathologic conditions (Barua et al. 2014). One of the causes of PD is the loss of dopaminergic neurons in the substantia nigra region of the brain (Van Der Perren et al. 2011). Researchers have employed CED to deliver neurotrophic factors like glial cell line-derived neurotrophic factors (GDNF) in preclinical PD models and achieved regeneration of dopaminergic neurons in the nigrostriatal region of the brain (Kells et al. 2010). Some of the therapeutic moieties in clinical trials which were delivered via CED included AAV2neurturin (CERE-120) and recombinant AAV vector-mediated transfer of glutamic acid decarboxylase (GAD) (AAV-GAD) (Jain 2013). However, the clinical trial data initially depicted acceptable safety and efficacy results, and the later trials demonstrated severe adverse events. Hence, despite acceptable effects in preclinical models, the clinical translation of this technique remains a bottleneck.

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13.6.2.2 Focused Ultrasound Focused ultrasound (FUS) assists in reversible BBB disruption leading to enhanced permeability by concentrating the acoustic energy to a focal spot, which could be used for brain-targeted drug delivery (Burgess et al. 2015). FUS utilizes the experience of lesion surgery but without cutting into the skull or brain (Fishman and Frenkel 2017). FUS treatments can be performed on awake patients, eliminating the need for general anesthetic and permitting real-time patient feedback (Jolesz 2009). To enhance the BBB disruption and reduce the damage to surrounding normal brain cells, many kinds of gas microbubbles were used as cavitation nuclei to focus and convert the acoustic energy into mechanical power (McDannold et al. 2011). FUS can noninvasively and precisely intervene in essential circuits that drive common and challenging brain conditions (Meng et al. 2021). A curved transducer is utilized to concentrate the pressure in a small target region and not to normal cells making it a potential replacement to surgery (Jolesz et al. 2011). Wang et al. delivered gastrodin with the aid of microbubbles amalgamated with FUS. Overall study portrayed the efficient opening of the BBB by FUS in MPTP mice model for PD. Drug delivery via FUS depicted higher neuroprotective effects than the control and free drug group. A significant rise in the levels of BDNF, PSD-95, and SYN was observed in FUS mediated GAS group (P < 0.05) (Wang et al. 2022). 13.6.2.3 Iontophoresis The iontophoresis technique is a noninvasive method to achieve drug molecules’ transdermal or dermal delivery (Akhtar et al. 2020). It incorporates mild electric currents to deliver therapeutic moieties (Dhal et al. 2020). In this method, the drug’s action is controllable and peak plasma levels can be achieved in desired time intervals without much inter or intra-patient variability. This method is preferred over conventional transdermal drug delivery as it permits the programming of flux required by modulating the electric current and allowing a hasty start and end of the drug administered when anticipated (Dhote et al. 2012). Kalaria et al. administered rasagiline (RAS) and pramipexole (PRAM) via co-iontophoresis to manage PD. Results depicted passive permeation of 16.0 ± 2.9 μg/cm2 and 15.7 ± 1.9 μg/ cm2 of RAS and PRAM across the skin, respectively. At 0.5 mA/cm2 a 27- and 38-fold increase in RAS and PRAM permeation was observed over passive permeation. In vivo pharmacokinetics studies in rats revealed that both drugs could be coadministered using transdermal iontophoresis in humans (Kalaria et al. 2018). In another study, Li et al. designed an iontophoretic patch to deliver apomorphine solution regulated by the device’s electric current density of around 250 μA/cm2. The study aimed to probe the in vivo activity of the patch in PD patients with and without pre-surfactant treatment. Results demonstrated a 1.3-fold superior bioavailability and steady flux of pretreated patients than the non-pretreated groups (Li et al. 2005). 13.6.2.4 Deep Brain Stimulation Deep brain stimulation (DBS) or lesion surgery is a novel bilateral surgical approach employed for the management of PD (Li et al. 2017). It mainly targets the basal

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ganglia, but US FDA has approved other brain targets including the globus pallidus internus, thalamus and subthalamic nucleus (Williams et al. 2014). This method is useful in overcoming the associated symptoms in PD including tremors and motor dysfunction (Habets et al. 2018). DBS is a medical device including a batteryoperated neurostimulator which will help in conveying the electric stimulations to the desired target of the brain which is responsible for causing the symptoms of PD (Thonnard 2012). This technique is usually commenced in patients whose symptoms cannot be managed with the prescribed drugs. DBS is an effective and permanent resolution which is independent of stimulation tuning adjustments and battery replacement making it a preferable treatment option (Parastarfeizabadi and Kouzani 2017). Scientists have exploited potential benefits of DBS and fabricated diode implants capable of emitting near-infrared lights in the substantia nigra region, thereby treating PD (Md et al. 2011).

13.6.3 Injectables for Drug Delivery in PD In treatment with first-line therapies for PD, many patients develop adverse effects like dyskinesia, motor fluctuations, and psychiatric impediments (Higazy 2020). These are mainly attributed to the pharmacokinetic aberrations caused by oral therapy of drugs and could be mended by delivering them via injectables (Müller 2012). Continuous dopamine delivery (CDD) encompasses a steadier treatment without portraying any on-off fluctuations as observed in conventional therapies of PD (Van Wamelen et al. 2018). CDD techniques include subcutaneous injections, intracerebroventricular infusions, intrathecal infusions, etc. (Alajangi et al. 2022). Among them, intrathecal and intracerebroventricular infusions will avoid side effects and peripheral interventions as the DA will be directly delivered into the cerebrospinal fluid (Abraham et al. 2021). Both intrathecal and intracerebroventricular systems comprise a pump and a catheter to facilitate drug delivery. This will facilitate a continuous supply of DA to the CNS and assist in avoiding absorption, transport competition, and preventing peripheral toxic effects of the drug (Abraham et al. 2021). The various drug-delivery strategies discussed in the aforementioned sections are epitomized in Fig. 13.2.

13.7

Conclusion and Future Perspective

PD is one of the most common neurodegenerative diseases after Alzheimer’s disease (AD), affecting millions worldwide. To summarize, we overviewed the pathological mechanism contributing to PD progression. Different pathological mechanisms contribute to PD development in the human body. The most common are α-synuclein aggregation, neuroinflammation, mitochondrial dysfunction, and epigenetic mechanism. Furthermore, different treatment and drug-delivery strategies for PD treatment have been developed. Conventional drug-delivery formulation includes tablets, fast-dissolved tablets, capsules, sublinguals, etc., which are more

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Fig. 13.2 Pictographic representation of various drug delivery strategies for PD

accessible for patients and more convenient. Still, traditional drug delivery has limitations related to the drug’s bioavailability and incomplete absorption in systemic circulation. BBB permeability has significant issues with anti-Parkinson drugs. There are advancements in drug delivery, making drug delivery more efficient and effective. Novel drug strategies in PD have developed, like nanocarrier-based delivery, focused ultrasound, convection-enhanced delivery, deep brain stimulation, and injectables. Despite of impeding benefit illustrated in the animal models of PD, there is an urging requirement for human trials in the management of PD, various bottlenecks associated with the translational aspect include high cost, reproducibility, and safety. These aspects should be carefully looked upon for designing effective and safe drugdelivery systems which could be employed for combating PD. Acknowledgments The authors would like to acknowledge the research funding support by Department of Pharmaceuticals (DoP), Ministry of Chemicals and Fertilizers, Govt. of India to National Institute of Pharmaceutical Education and Research (NIPER) Hyderabad, INDIA. Conflict of Interest Reported none.

References Abraham ME, Gold J, Dondapati A, Gendreau J, Mammis A, Herschman Y (2021) Intrathecal and intracerebroventricular dopamine for Parkinson’s disease. Clin Neurol Neurosurg 200:106374 Agrawal M, Prathyusha E, Ahmed H, Dubey SK, Kesharwani P, Singhvi G et al (2021) Biomaterials in treatment of Alzheimer’s disease. Neurochem Int 145:105008

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Nanotechnological Drug Delivery Strategies in Epilepsy

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Gerard Esteruelas, Lorena Bonilla, Miren Ettcheto, Isabel Haro, María José Gómara, Eliana B. Souto, Marta Espina, Antonio Camins, Mª. Luisa García, Elena Sánchez-López, and Amanda Cano

Elena Sánchez-López and Amanda Cano contributed equally to this work. G. Esteruelas Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, Barcelona, Spain L. Bonilla · M. Espina Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain M. Ettcheto Centre for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED), Carlos III Health Institute, Madrid, Spain Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain Institute of Neurosciences, University of Barcelona, Barcelona, Spain I. Haro · M. J. Gómara Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, Barcelona, Spain E. B. Souto Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Porto, Portugal REQUIMTE/UCIBIO, Faculty of Pharmacy, University of Porto, Porto, Portugal A. Camins Centre for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED), Carlos III Health Institute, Madrid, Spain # The Author(s), under exclusive license to Springer Nature Singapore Pte Ltd. 2023 A. Mishra, H. Kulhari (eds.), Drug Delivery Strategies in Neurological Disorders: Challenges and Opportunities, https://doi.org/10.1007/978-981-99-6807-7_14

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Abstract

Epilepsy is a chronic disease of the central nervous system characterized by an electrical imbalance in neurons. It is the second most prevalent neurological disease, with 50 million people affected worldwide. Although there are a wide range of drugs approved for epilepsy, 30% of the patients do not respond to these treatments. In this context, nanomedicine constitutes a promising alternative to enhance the central nervous system bioavailability of antiepileptic drugs. The encapsulation of different active compounds in nanocarriers gives rise to enhanced effectiveness mainly due to their targeting and penetration into the deepest brain regions as well as the protection of the encapsulated drug. Thus, in this chapter we explore the recent advances in the development of different controlled drug delivery systems for the management of epilepsy disorders. Keywords

Epilepsy · Nanomedicine · Drug delivery · Blood–brain barrier · Nanocarriers

Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Porto, Porto, Portugal REQUIMTE/UCIBIO, Faculty of Pharmacy, University of Porto, Porto, Portugal M. L. García Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain Centre for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED), Carlos III Health Institute, Madrid, Spain E. Sánchez-López (✉) Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, Barcelona, Spain Centre for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED), Carlos III Health Institute, Madrid, Spain e-mail: [email protected] A. Cano (✉) Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Barcelona, Spain Centre for Biomedical Research in Neurodegenerative Diseases Network (CIBERNED), Carlos III Health Institute, Madrid, Spain Ace Alzheimer Center Barcelona – Universitat Internacional de Catalunya, Barcelona, Spain e-mail: [email protected]

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Abbreviations AEDs AMT BBB CNS CPP EGCG ILAE NLC NPs PEG PLGA SLNs

14.1

Antiepileptic drugs Adsorptive-mediated transcytosis Blood–brain barrier Central nervous system Cell penetrated peptide Epigallocatechin-3-gallate International League Against Epilepsy Nanostructured lipid carriers Nanoparticles Polyethylene glycol Poly lactic-co-glycolic acid Solid lipid nanoparticles

Epilepsy Paradigm Worldwide

Epilepsy can be defined as one of the most frequent disorders that affect the central nervous system (CNS) (Sirven 2015). According to the World Health Organization (WHO), epilepsy is a noncontagious neurological disease characterized by the appearance of frequent seizures that can present different clinical manifestations such as involuntary movements, vocalizations, or loss of consciousness. It affects more than 50 million people worldwide. According to the WHO statistics, 10 out of every 1000 people worldwide suffer from this pathology (World Health Organization 2019). In general, the majority of epilepsy cases occur in countries with few resources (Ali and Nabi 2014; Joudi Mashhad et al. 2020). This may be due to different reasons such as the lack of a health system, the higher incidence of diseases that can lead to some type of epilepsy, as well as a higher rate of injuries (Sirven 2015) (Fig. 14.1). The epileptic patient presents a mortality rate of 2–3 times higher compared to the general population (Puteikis and Rūta 2021). This fact represents a reduction in life expectancy between 2 and 10 years. Approximately, in 70% of patients the origin of epilepsy is idiopathic (Beghi et al. 2019), whereas in the remaining 30%, there are a wide variety of causes such as traumatic accidents or secondary epilepsy derived from another pathology such as dementia, cardiovascular accidents, infections, congenital anomalies or tumoral processes (Thijs et al. 2019; Dreier et al. 2022). Moreover, epilepsy represents an economic burden for patients and society. Although expenses differ between countries, globally, it is estimated to cost 119.27 trillion dollars per year (Begley et al. 2022).

Fig. 14.1 Representation of the distribution of global prevalence (P) and deaths (D) caused by epilepsy worldwide annually (data extracted from (Beghi et al. 2019))

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The Physiopathology of Epilepsy

Epilepsy is a chronic disease of the nervous system characterized by abnormal functioning of the electrical discharges produced by neurons in an area of the CNS (Thijs et al. 2019; Fisher et al. 2005a). The International League Against Epilepsy (ILAE) defined epilepsy, from a clinical point of view, as a brain disease characterized by one of the following premises: (1) at least two reflex seizures of more than 24 h; (2) a reflex seizure and a probability of having a new seizure over the next 10 years similar to the overall risk of recurrence (at least 60%) after the appearance of two unprovoked seizures; or (3) the diagnosis of an epileptic syndrome (Fisher et al. 2005a). Epileptic seizures refer to abnormal activity of neurons that produce a series of characteristic symptoms and signs due to neuronal overexcitation and lack of coordination, leading to the appearance of seizures that are generally unpredictable and periodic (Sirven 2015; Bereda 2022). Depending on the brain area where these seizures appear, they will occur with very diverse symptoms such as alterations in sensorial, taste, motor, or cognitive functions. At the same time, the study of the origin and spread of these convulsions allows the classification of these crises into two large groups, partial or focal crises and general crises (Vaca et al. 2018; Perucca et al. 2018).

14.2.1 Types of Seizures 14.2.1.1 Focal Seizures Focal seizures are characterized by being limited to one of the brain hemispheres and could either be localized or diffuse as well as complex or partial (Table 14.1). Complex partial seizures are the most common type seizures in adults and are characterized by a loss of consciousness during the crisis. By contrast, in simple partial seizures the patient maintains consciousness and can be concomitant to changes of the superior cortex, presenting psychic symptoms or hallucinations. In turn, depending on the location of the symptoms, simple partial seizures can be divided into (1) motor seizures, that present mobility disorders, with aberrant movements of the eyes, head, and abnormal vocalization of sounds; (2) autonomic seizures, which affect the medial temporal lobe with sweating, pupillary changes, or piloerection; and (3) sensory seizures, with alterations of the senses, vertigo, flashing lights, or auras (Thijs et al. 2019; Falco-Walter 2020; Pack 2019). 14.2.1.2 General Seizures In addition to focal seizures, there are generalized epileptic seizures that affect different brain regions. There are six different types of generalized epileptic seizures (Fisher et al. 2005b; Falco-Walter et al. 2018): • Generalized tonic seizures: they occur with muscle rigidity usually in extremities and back. Loss of consciousness may also occur.

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Table 14.1 Main clinical manifestations and affected brain regions of focal epilepsies Type of epileptic seizure Temporal lobe seizure

Affected Brain region Temporal lobe

Occipital lobes seizure Frontal lobes seizure

Occipital lobes Frontal lobes

Parietal lobes seizure

Parietal lobes

Clinical manifestations Simple focal: Sensory disturbances of taste and smell, hallucinations Vocal and audition disturbances Heart and respiratory rate alterations Abdominal discomfort Complex focal: Confusion and absence Unvoluntary facial movements Vocalizations or screaming Disorientation Visual disturbances such as color changes or flashes are usual Simple focal: Motor twitching lasting a reduced short-time Complex focal: Alterations of consciousness Spasmodic and involuntary movements of limbs and head Mood alterations Disturbances of sexual behavior Tingling or numbness that can start in a finger and end up affecting the entire limb. Usually in only one side of the body

• Generalized atonic seizures: they are associated to loss of muscle control, usually affecting the legs. • Generalized clonic seizures: they cause repetitive and uncontrollable spasmodic movements of facial muscles. • Myoclonic crises: they are associated with violent sudden movements that usually occur in the upper body and extremities. • Generalized tonic–clonic seizures: these seizures are the most intense epileptic seizures and cause loss of consciousness together with the appearance of aberrant spasmodic movements. Additionally, decontrol of the sphincters may also occur. • Absence seizures: they are characteristic of pediatric patients who, for a short period of time (seconds), remain completely immobile without microgestures and fixed gaze. Absence seizures can occur daily up to 100 times per day (Barone et al. 2020).

14.2.2 Epileptic Syndrome There is a wide variety of clinical manifestations to classify patients according to their symptoms and pathophysiological process. These symptoms significantly condition their prognosis, as well as the treatment. The ILAE classifies these manifestations in different epileptic syndromes. Some of the most important, due

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to their high prevalence, usually occur in childhood (Bereda 2022; Swanson and Ahmed 2022; Wirrell et al. 2022): • Dravet syndrome: this occurs with prolonged clonic and tonic–clonic collusion accompanied by feverish symptoms in infants 4–12 months of age. It is also called myoclonic epilepsy of infancy. • West syndrome: this occurs with a high number of myoclonic spasms in infants. • Rolandic epilepsy: generally, this affects 30% of children with epilepsy between 5 and 13 months and occurs with spasmodic movements during sleep, mainly of the facial muscles. • Doose’s epilepsy: it is associated with a genetic component in 30% of the cases. It is characterized by various myoclonic and atonic seizures as well as absence or tonic–clonic seizures of a general nature. In 50% of the patients, the crises are difficult to control. • Temporal lobe epilepsy: it is the most common form in adults and highly difficult to treat, leading to refractory epilepsies (Joudi Mashhad et al. 2020; Allone et al. 2017). This type of epilepsy involves a genetic component and it is the most common type of focal onset epilepsy. It generally occurs with mild symptoms where seizures are infrequent and controllable, although it can also lead to sensory disturbances, auras, cognitive disturbances, or stomach problems. It is originated in the temporal lobe and can spread to neighboring regions such as the insula or the temporo-parieto-occipital junction (Allone et al. 2017; Tang et al. 2017). Furthermore, it is important to highlight that there are other epileptic syndromes such as the Lennox-gastaut syndrome characteristic of infants up to 3 years of age; Juvenile myclonic epilepsy, infantile absences, or epileptic encephalopathy with spike wave during sleep.

14.2.3 Treatment Approximately 70% of epileptic seizures can be controlled with antiepileptic drugs (AEDs), this being the first-line treatment. AEDs can be classified in first, second, or third generation and possess different mechanisms at the neuronal synapse level (Fig. 14.2) (Bereda 2022; Hanaya and Arita 2016). First-generation drugs are the first line of medication and were discovered before 1970. This group includes AEDs such as Benzodiazepines, Carbamazepine, Ethoxuximide, Phenytoin, Phenobarbital, or Valproic acid. Afterward, secondgeneration AEDs appeared between the decades of 1980 and 1990, which improved therapeutic efficacy and reduced adverse effects. Drugs included in this group are Felbamate, Gabapentin, Lamotrigine, Levetiracetam, Oxcabamazepine, Pregabalin, Tiagabine, Topiramates, Rutabatrin, and Zonisamide. The third-generation AEDs were aimed to reduce resistance. These can be divided in analogues of existing AEDs such as Hydroxycarbamazepine, Eslicarbazepine acetate, Fluofelbamate,

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Fig. 14.2 AEDs main mechanisms based on (Málaga et al. 2019)

Carisbamate, Bricaracetan, Seletracetam, or Valnoctamide or novel molecules such as Safinamide, Rufinamide, Lacosamide, Antipamezole, Retrigabiana, or Stiripentol (Bereda 2022; Hanaya and Arita 2016). Different mechanisms are involved for each drug. Specifically, at the neuronal synapse, AEDs can act as (Fig. 14.2): • Na+ channel inhibitors, which may limit the repetitive discharge of neurons, generally effective in generalized tonic–clonic seizures of focal seizures. • Inhibitors of voltage-dependent Ca2+ channels specifically responsible for effective T-type Ca2+ subunit α2δ.

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• • • •

K+ channel activators. Glutaminergic inhibitors as well as pharmacomodulations of the GABA receptor. NMDA (N-methyl-D-aspartic acid) receptor inhibitors. AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonists. • Binding to synaptic vesicle proteins S2vA. • GABA (gamma-aminobutyric acid) agonist. Although there are different AEDs, approximately 30% of the patients continue having epileptic seizures despite following the prescribed medication developing refractory epilepsy due to resistance to AEDs (Tang et al. 2017; Kaur et al. 2016).

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Overcoming the Blood–Brain Barrier

One of the main causes that compromises drug effectiveness is the difficulty of AEDs to overcome the blood–brain barrier (BBB) and reach their therapeutic target (Oby and Janigro 2006; Han et al. 2017; Marchi et al. 2012). The BBB is one of the most restrictive barriers of the body and it is composed of the capillaries that irrigate the brain. Some of its most important functions are the transport of O2, CO2, glucose, and other essential nutrients, prevention of the entry of exogenous molecules, and clearance of cellular metabolic waste (Han et al. 2017). The BBB is part of the neurovascular unit characterized by the presence of endothelial cells without fenestrations, which are joined by tight junctions as well as adherent junctions that restrict the transcellular transport. In general, only molecules with a low molecular weight (