Progress in Nanomedicine in Neurologic Diseases (Advances in Neurobiology, 32) [1st ed. 2023] 3031329961, 9783031329968

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Advances in Neurobiology 32

Hari Shanker Sharma Aruna Sharma   Editors

Progress in Nanomedicine in Neurologic Diseases

Advances in Neurobiology Volume 32

Series Editor Arne Schousboe Department of Drug Design & Pharmacology University of Copenhagen Copenhagen, Denmark

Advances in Neurobiology covers basic research in neurobiology and neurochemistry. It provides in-depth, book-length treatment of some of the most important topics in neuroscience including molecular and pharmacological aspects. The main audiences of the series are basic science researchers and graduate students as well as clinicians including neuroscientists (neurobiologists and neurochemists) and neurologists. Advances in Neurobiology is indexed in PubMed, Google Scholar, and the Thompson Reuters Book Citation Index.

Editor-In-Chief Arne Schousboe University of Copenhagen

Editorial Board Members Marta Antonelli, University of Buenos Aires, Argentina Michael Aschner, Albert Einstein College of Medicine, New York Philip Beart, University of Melbourne, Australia Stanislaw Jerzy Czuczwar, Medical University of Lublin, Poland Ralf Dringen, University of Bremen, Germany Mary C. McKenna, University of Maryland, Baltimore Arturo Ortega, National Polytechnic Institute, Mexico City, Mexico Vladimir Parpura, University of Alabama, Birmingham Caroline Rae, Neuroscience Research Australia, Sydney Ursula Sonnewald, Norwegian University of Science and Technology, Trondheim Alexei Verkhratsky, University of Manchester, UK H. Steve White, University of Washington, Seattle Albert Yu, Peking University, China David Aidong Yuan, Nathan S. Klein Institute for Psychiatric Research, Orangeburg

Hari Shanker Sharma • Aruna Sharma Editors

Progress in Nanomedicine in Neurologic Diseases

Editors Hari Shanker Sharma Department of Surgical Sciences Anesthesiology and Intensive Care Medicine Uppsala University Hospital Uppsala, Sweden

Aruna Sharma Department of Surgical Sciences Anesthesiology and Intensive Care Medicine Uppsala University Hospital Uppsala, Sweden

ISSN 2190-5215 ISSN 2190-5223 (electronic) Advances in Neurobiology ISBN 978-3-031-32996-8 ISBN 978-3-031-32997-5 (eBook) https://doi.org/10.1007/978-3-031-32997-5 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 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 Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland

Preface

There are no small problems. Problems that appear small are large problems that are not understood. (Santiago Ramón y Cajal 1897. Reglas y Consejos sobre Investigacíon Cientifica: Los tónicos de la voluntad)

Neurological diseases influence all vital functions of the body since ages as mentioned in Ayurveda about 600 BC in ancient Indian literature and in China (108–208 AD) [1, 2]. However, the father of modern neurology is British medical scientist and founder of Royal Society of London for improving natural knowledge in 1663 Thomas Willis (1621–1675) who described the “circle of Willis” that supplied more than 80% of oxygenated blood to the brain [3]. In 1885 German scientists and in 1908 Nobel Prize winner Paul Ehrlich (1854–1915) in Berlin described blood-brain barrier (BBB), a physiological barrier that doesn’t allow vital dyes like Trypan blue to stain the brain or the cerebrospinal fluid (CSF) when injected into the systemic circulation [4]. However, when one of his students Edwin Goldmann (1862–1913) injected Trypan blue in subarachnoid space, that stained the brain and spinal cord with the dye confirming the BBB function [5]. These early studies confirmed the presence of the BBB that is protecting the central nervous system (CNS) and on the other hand also preventing drug delivery to the brain [6]. Due to the presence of the BBB, drug treatments to brain diseases pose serious problems regarding their bioavailability within the nervous system for effective therapy [7]. Several strategies were thus evolved to overcome the BBB with regard to drug delivery to the brain for treating brain diseases [8]. In this regard, nanodelivery of drugs is one of them to improve their penetration across the BBB for effective therapy for brain disorders [9]. Research in Uppsala University using TiO2 nanowired delivery of drugs to induce neuroprotection in spinal cord injury was carried out in 2007 [10] and opened a new avenue for nanodelivery of drugs for neuroprotection. The US patent was granted on nanowires in 2012, leading to further explore novel drug delivery using nanowired technology for neuroprotection in neurologic diseases in experimental medicine [11, 12]. Several lines of research suggest that BBB is a gateway to the neurologic diseases [13–15]. Thus, emphasis

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was made to reduce BBB breakdown in neurologic disease using nanodelivery of drugs for neuroprotection [16, 17]. However, either neurodegenerative disease or other emotional, traumatic, or metabolic insults to the CNS are often accompanied with other comorbidity factors complicating the disease processes that require novel strategy for therapy. In such situations, single treatment strategies are often insufficient to induce neuroprotection. Thus, a combination of various pharmacological agents together with antibodies to key elements of inducing brain pathology needs to attenuate or neutralize in vivo for achieving superior neuroprotection using their nanodelivery. This volume presents a combination of disease or modifying agents associated with comorbidity factors in neurodegenerative diseases or insults to the brain or spinal cord using nanodelivery approaches that may induce superior neuroprotection. The volume is collection of ten peer-reviewed chapters written by renowned experts on various aspects of neurologic diseases with state of the art of the subject in relation to contemporary advances in the literature along with authors’ own efforts in inducing superior neuroprotection using nanodelivery of therapeutic agents in combination. In chapter “Nanowired Delivery of Cerebrolysin Together with Antibodies to Amyloid Beta Peptide, Phosphorylated Tau, and Tumor Necrosis Factor Alpha Induces Superior Neuroprotection in Alzheimer’s Disease Brain Pathology Exacerbated by Sleep Deprivation”, Aruna Sharma (Uppsala, Sweden) discusses influence of sleep deprivation on Alzheimer’s disease, a feature very common in military personnel [14], and presents experimental pharmacological therapy in reducing the burden of Alzheimer’s disease brain pathology. Anca Buzoianu (Cluj-Napoca, Romania) presents new results on histaminergic mechanisms in modulating Parkinson’s disease–induced brain pathology in chapter “Nanodelivery of Histamine H3/H4 Receptor Modulators BF2649 and Clobenpropit with Antibodies to Amyloid Beta Peptide in Combination with Alpha Synuclein Reduces Brain Pathology in Parkinson’s Disease” in relation to current knowledge available in the literature. In chapter “Co-Administration of Nanowired DL-3-n-Butylphthalide (DL-NBP) Together with Mesenchymal Stem Cells, Monoclonal Antibodies to Alpha Synuclein and TDP-43 (TAR DNA-Binding Protein 43) Enhance Superior Neuroprotection in Parkinson’s Disease Following Concussive Head Injury”, Lianyuan Feng (Shijiazhuang, China) describes the neuroprotective effects of DL-3-n-butylphthalide in attenuating Parkinson’s disease–induced brain pathology in relation to its pharmacological actions in great detail based on the current knowledge. Hari Sharma (Uppsala, Sweden) in chapter “Neuroprotective Effects of Nanowired Delivery of Cerebrolysin With Mesenchymal Stem Cells and Monoclonal Antibodies to Neuronal Nitric Oxide Synthase in Brain Pathology Following Alzheimer’s Disease Exacerbated by Concussive Head Injury” describes concussive head injury as a major risk factor in developing Alzheimer’s disease based on the current concepts and showed the neuroprotective role of mesenchymal

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stem cells together with a combination of several neurotropic factors with blockade of neuronal nitric oxide synthase in a model of Alzheimer’s disease. In chapter “Co-Administration of Nanowired Monoclonal Antibodies to Inducible Nitric Oxide Synthase and Tumor Necrosis Factor Alpha Together with Antioxidant H-290/51 Reduces SiO2 Nanoparticles-Induced Exacerbation of Pathophysiology of Spinal Cord Trauma”, Aruna Sharma (Uppsala, Sweden) examines the influence of silica intoxication on spinal cord injury with reference to recent literature and explores the involvement of oxidative stress in association with inhibition of nitric oxide and inflammatory cytokine tumor necrosis factor-alpha. In chapter “Nanowired Delivery of Cerebrolysin with Mesenchymal Stem Cells Attenuates Heat Stress-Induced Exacerbation of Neuropathology Following Brain Blast Injury”, Dafin Muresanu (Cluj-Napoca, Romania) discusses blast brain injury in hot environment that is very common in military personnel living in the high ambient temperature zone and presents new results on cerebrolysin treatment with mesenchymal stem cells in attenuating brain pathology together with relevant contemporary literature in the field. Ala Nozari (Boston, MA, USA) in chapter “Co-administration of Nanowired Oxiracetam and Neprilysin with Monoclonal Antibodies to Amyloid Beta Peptide and p-Tau Thwarted Exacerbation of Brain Pathology in Concussive Head Injury at Hot Environment” describes adverse effects of hot environment on concussive head injury and shows that oxiracetam together with neprilysin enzyme is able to induce neuroprotection in relation to available knowledge in current research trends. José Vicente Lafuente (Bilbao, Spain) in chapter “Nanowired Delivery of Mesenchymal Stem Cells with Antioxidant Compound H-290/51 Reduces Exacerbation of Methamphetamine Neurotoxicity in Hot Environment” describes adverse effects of methamphetamine neurotoxicity in hot environment and involvement of oxidative stress in detail based on current information present in the literature and presents neuroprotective effects of mesenchymal stem cells together with an inhibitor of lipid peroxidation compound, H-290/51. In chapter “TiO2-Nanowired Delivery of Chinese Extract of Ginkgo biloba EGb-761 and Bilobalide BN-52021 Enhanced Neuroprotective Effects of Cerebrolysin Following Spinal Cord Injury at Cold Environment”, Lars Wiklund (Uppsala, Sweden) discusses exacerbation of spinal cord pathology in cold environment and effective treatment with combined Chinese Gingko biloba and cerebrolysin based on recent literature. Giovanni Tosi (Modena, Italy) discusses the role of curcumin in methamphetamine neurotoxicity in relation to dopamine and brain-derived neurotrophic factor level in the brain based on scientific literature in the field. We feel that these novel chapters included in this volume could provide new evidences for neuroprotection using nanotechnology in achieving superior beneficial effects in neurologic diseases in future. The volume is indispensable for students, policy makers, healthcare professionals, researchers, teachers, and lawmakers for their wide understanding of nanotechnology for the treatment of brain diseases in clinics.

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We sincerely hope that the volume will encourage new research in nanodelivery of drugs for the advancements of health care in victims of neurological diseases toward improvement of their quality of life. Uppsala, Sweden

Hari Shanker Sharma Aruna Sharma

References 1. Mamidi P, Gupta K. Neurological conditions in Charaka Indriya Sthana – an explorative study. Int J Complement Alt Med. 2020;13(3):107–19. https://doi.org/10.15406/ijcam.2020.13. 00503. 2. Tubbs RS, Riech S, Verma K, et al. China’s first surgeon: Hua Tuo (c. 108–208 AD). Childs Nerv Syst. 2011;27:1357–60. https://doi-org.ezproxy.its.uu.se/10.1007/s00381-011-1423-z. 3. Hughes JT. Thomas Willis (1621-1675). J Neurol. 2000;247(2):151–2. https://doi.org/10. 1007/pl00007800. 4. Ehrlich P. Das Sauerstoffbedürfnis des Organismus. Eine Farbenanalytische Studie. Berlin: Hirschwald; 1885. 5. Goldmann EE. Vitalfärbung am Zentralnervensyatem. Beitrag zur Physio-Pathologie des plexus chorioideus und der Hirnhäute. Abh preuss, Akad Wiss Phys-Math Kl. 1913;1:1–60. 6. Saunders NR, Dreifuss J-J, Dziegielewska KM, Johansson PA, Habgood MD, Møllgård K, Bauer H-C. The rights and wrongs of blood-brain barrier permeability studies: a walk through 100 years of history. Front Neurosci. 2014;8:404. https://doi.org/10.3389/fnins.2014.00404. Published online 2014 Dec 16. 7. Pardridge WM. CSF, blood-brain barrier, and brain drug delivery. Expert Opin Drug Deliv. 2016;13(7):963–75. https://doi.org/10.1517/17425247.2016.1171315. Epub 2016 Apr 11. 8. Helms HCC, Kristensen M, Saaby L, Fricker G, Brodin B. Drug delivery strategies to overcome the blood-brain barrier (BBB). Handb Exp Pharmacol. 2022;273:151–83. https:// doi.org/10.1007/164_2020_403. 9. Tang W, Fan W, Lau J, Deng L, Shen Z, Chen X. Emerging blood-brain-barrier-crossing nanotechnology for brain cancer theranostics. Chem Soc Rev. 2019;48(11):2967–3014. https:// doi.org/10.1039/c8cs00805a. 10. Sharma HS, Ali SF, Dong W, Tian ZR, Patnaik R, Patnaik S, Sharma A, Boman A, Lek P, Seifert E, Lundstedt T. Drug delivery to the spinal cord tagged with nanowire enhances neuroprotective efficacy and functional recovery following trauma to the rat spinal cord. Ann N Y Acad Sci. 2007;1122:197–218. https://doi.org/10.1196/annals.1403.014. 11. Tian ZR, Epstein J. Titanate nanowire, titanate nanowire scaffold, and processes of making same. Patents Granted; 2012. Retrieved from https://scholarworks.uark.edu/pat/49. Patent Number US8318297. 12. Dong W, Zhang T, McDonald M, Padilla C, Epstein J, Tian ZR. Biocompatible nanofiber scaffolds on metal for controlled release and cell colonization. Nanomedicine. 2006;2(4):248– 52. https://doi.org/10.1016/j.nano.2006.10.005. 13. Sharma HS. Blood–central nervous system barriers: the gateway to neurodegeneration, neuroprotection and neuroregeneration. In: Lajtha A, Banik N, Ray SK, editors. Handbook of neurochemistry and molecular neurobiology: brain and spinal cord trauma. Berlin/Heidelberg/New York: Springer; 2009. p. 363–457.

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14. Sharma HS, Westman J. The blood-spinal cord and brain barriers in health and disease. San Diego: Academic; 2004. p. 1–617. (ISBN-13. 978-0126390117 Release date: Nov. 9, 2003). 15. Sharma A, Menon P, Muresanu DF, Ozkizilcik A, Tian ZR, Lafuente JV, Sharma HS. Nanowired drug delivery across the blood-brain barrier in central nervous system injury and repair. CNS Neurol Disord Drug Targets. 2016;15(9):1092–117. https://doi.org/10.2174/ 1871527315666160819123059. 16. Ozkizilcik A, Williams R, Tian ZR, Muresanu DF, Sharma A, Sharma HS. Synthesis of biocompatible titanate nanofibers for effective delivery of neuroprotective agents. Methods Mol Biol. 2018;1727:433–42. https://doi.org/10.1007/978-1-4939-7571-6_35. 17. Sharma HS, Muresanu DF, Sharma A. Alzheimer’s disease: cerebrolysin and nanotechnology as a therapeutic strategy. Neurodegener Dis Manag. 2016;6(6):453–6. https://doi.org/10.2217/ nmt-2016-0037. Epub 2016 Nov 9.

Acknowledgments

We are grateful to William Lamsback, Senior Editor, Neuroscience at Springer Nature Group, New York, for continuous support and encouragement during the preparation of the book volume. Thanks to Merry Stuber, Senior Editor, Biomedical Engineering and Cell Biology at Springer Nature, New York, for her excellent support during the initial period of book preparation. We thank Vishnu Prakash, Springer Nature group, Chennai, India, for sincere help during production of the volume. Uppsala, Sweden

Hari Shanker Sharma Aruna Sharma

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Contents

Part I

Neurodegenerative Diseases

Nanowired Delivery of Cerebrolysin Together with Antibodies to Amyloid Beta Peptide, Phosphorylated Tau, and Tumor Necrosis Factor Alpha Induces Superior Neuroprotection in Alzheimer’s Disease Brain Pathology Exacerbated by Sleep Deprivation . . . . . . . . . . Aruna Sharma, Lianyuan Feng, Dafin F. Muresanu, Z. Ryan Tian, José Vicente Lafuente, Anca D. Buzoianu, Ala Nozari, Igor Bryukhovetskiy, Igor Manzhulo, Lars Wiklund, and Hari Shanker Sharma Nanodelivery of Histamine H3/H4 Receptor Modulators BF-2649 and Clobenpropit with Antibodies to Amyloid Beta Peptide in Combination with Alpha Synuclein Reduces Brain Pathology in Parkinson’s Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Anca D. Buzoianu, Aruna Sharma, Dafin F. Muresanu, Lianyuan Feng, Hongyun Huang, Lin Chen, Z. Ryan Tian, Ala Nozari, José Vicente Lafuente, Lars Wiklund, and Hari Shanker Sharma Co-administration of Nanowired DL-3-n-Butylphthalide (DL-NBP) Together with Mesenchymal Stem Cells, Monoclonal Antibodies to Alpha Synuclein and TDP-43 (TAR DNA-Binding Protein 43) Enhance Superior Neuroprotection in Parkinson’s Disease Following Concussive Head Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Lianyuan Feng, Aruna Sharma, Zhenguo Wang, Dafin F. Muresanu, Z. Ryan Tian, José Vicente Lafuente, Anca D. Buzoianu, Ala Nozari, Lars Wiklund, and Hari Shanker Sharma

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Contents

Neuroprotective Effects of Nanowired Delivery of Cerebrolysin with Mesenchymal Stem Cells and Monoclonal Antibodies to Neuronal Nitric Oxide Synthase in Brain Pathology Following Alzheimer’s Disease Exacerbated by Concussive Head Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Hari Shanker Sharma, Dafin F. Muresanu, Ala Nozari, José Vicente Lafuente, Anca D. Buzoianu, Z. Ryan Tian, Hongyun Huang, Lianyuan Feng, Igor Bryukhovetskiy, Igor Manzhulo, Lars Wiklund, and Aruna Sharma Part II

Central Nervous System Trauma

Co-Administration of Nanowired Monoclonal Antibodies to Inducible Nitric Oxide Synthase and Tumor Necrosis Factor Alpha Together with Antioxidant H-290/51 Reduces SiO2 Nanoparticles-Induced Exacerbation of Pathophysiology of Spinal Cord Trauma . . . . . . . . . . . 195 Aruna Sharma, Dafin F. Muresanu, Z. Ryan Tian, Ala Nozari, José Vicente Lafuente, Anca D. Buzoianu, Per-Ove Sjöquist, Lianyuan Feng, Lars Wiklund, and Hari Shanker Sharma Nanowired Delivery of Cerebrolysin with Mesenchymal Stem Cells Attenuates Heat Stress-Induced Exacerbation of Neuropathology Following Brain Blast Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 231 Dafin F. Muresanu, Aruna Sharma, Z. Ryan Tian, José Vicente Lafuente, Ala Nozari, Lianyuan Feng, Anca D. Buzoianu, Lars Wiklund, and Hari Shanker Sharma Co-administration of Nanowired Oxiracetam and Neprilysin with Monoclonal Antibodies to Amyloid Beta Peptide and p-Tau Thwarted Exacerbation of Brain Pathology in Concussive Head Injury at Hot Environment . . . . . . . . . . . . . . . . . . . 271 Ala Nozari, Aruna Sharma, Zhenguo Wang, Lianyuan Feng, Dafin F. Muresanu, Z. Ryan Tian, José Vicente Lafuente, Anca D. Buzoianu, Lars Wiklund, and Hari Shanker Sharma Part III

Stress and Drugs of Abuse

Nanowired Delivery of Mesenchymal Stem Cells with Antioxidant Compound H-290/51 Reduces Exacerbation of Methamphetamine Neurotoxicity in Hot Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 José Vicente Lafuente, Aruna Sharma, Lianyuan Feng, Dafin F. Muresanu, Ala Nozari, Z. Ryan Tian, Anca D. Buzoianu, Per-Ove Sjöquist, Lars Wiklund, and Hari Shanker Sharma

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TiO2-Nanowired Delivery of Chinese Extract of Ginkgo biloba EGb-761 and Bilobalide BN-52021 Enhanced Neuroprotective Effects of Cerebrolysin Following Spinal Cord Injury at Cold Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353 Lars Wiklund, Aruna Sharma, Dafin F. Muresanu, Zhiqiang Zhang, Cong Li, Z. Ryan Tian, Anca D. Buzoianu, José Vicente Lafuente, Ala Nozari, Lianyuan Feng, and Hari Shanker Sharma Nanowired Delivery of Curcumin Attenuates Methamphetamine Neurotoxicity and Elevates Levels of Dopamine and Brain-Derived Neurotrophic Factor . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385 Ilaria Ottonelli, Aruna Sharma, Barbara Ruozi, Giovanni Tosi, Jason Thomas Duskey, Maria Angela Vandelli, José Vicente Lafuente, Ala Nozari, Dafin Fior Muresanu, Anca Dana Buzoianu, Z. Ryan Tian, Zhiqiang Zhang, Cong Li, Lianyuan Feng, Lars Wiklund, and Hari Shanker Sharma Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 417

Part I

Neurodegenerative Diseases

Nanowired Delivery of Cerebrolysin Together with Antibodies to Amyloid Beta Peptide, Phosphorylated Tau, and Tumor Necrosis Factor Alpha Induces Superior Neuroprotection in Alzheimer’s Disease Brain Pathology Exacerbated by Sleep Deprivation Aruna Sharma, Lianyuan Feng, Dafin F. Muresanu, Z. Ryan Tian, José Vicente Lafuente, Anca D. Buzoianu, Ala Nozari, Igor Bryukhovetskiy, Igor Manzhulo, Lars Wiklund, and Hari Shanker Sharma

Abstract Sleep deprivation induces amyloid beta peptide and phosphorylated tau deposits in the brain and cerebrospinal fluid together with altered serotonin metabolism. Thus, it is likely that sleep deprivation is one of the predisposing factors in precipitating Alzheimer’s disease (AD) brain pathology. Our previous studies indicate significant brain pathology following sleep deprivation or AD. Keeping these

A. Sharma · L. Wiklund · H. S. Sharma (✉) International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden e-mail: [email protected]; [email protected] L. Feng Department of Neurology, Bethune International Peace Hospital, Shijiazhuang, Hebei Province, China D. F. Muresanu Department Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania “RoNeuro” Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania Z. R. Tian Department Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA J. V. Lafuente LaNCE, Department Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain A. D. Buzoianu Department of Clinical Pharmacology and Toxicology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. S. Sharma, A. Sharma (eds.), Progress in Nanomedicine in Neurologic Diseases, Advances in Neurobiology 32, https://doi.org/10.1007/978-3-031-32997-5_1

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views in consideration in this review, nanodelivery of monoclonal antibodies to amyloid beta peptide (AβP), phosphorylated tau (p-tau), and tumor necrosis factor alpha (TNF-α) in sleep deprivation-induced AD is discussed based on our own investigations. Our results suggest that nanowired delivery of monoclonal antibodies to AβP with p-tau and TNF-α induces superior neuroprotection in AD caused by sleep deprivation, not reported earlier. Keywords Sleep deprivation · Alzheimer’s disease · Brain pathology · Nanowired delivery · Nanomedicine amyloid beta peptide · Phosphorylated p-tau · Serotonin6 receptor antagonist · Monoclonal antibodies · Neuroprotection

1 Introduction Sleep deprivation is quite frequent among military personnel and medical emergency officials [1–5]. Sleep deprivation leads to several vital problems including stress and alters hormonal response to the individuals [6–9]. Recent data show that even one night of sleep deprivation could enhance amyloid beta peptide (AβP) deposits and increases phosphorylated tau (p-tau) within cerebrospinal fluid (CSF) [10– 14]. These changes could lead to Alzheimer’s disease or precipitate in Parkinson’s disease affecting brain pathology [15–19]. The psychological and mental stress associated with sleep deprivation causes blood–brain barrier (BBB) breakdown and allows serum proteins and other unwanted substances to enter into the brain fluid environments [20–22]. Infiltration of serum proteins into the brain fluid environment causes formation of brain edema and affects neuronal networks precipitating abnormal behavioral symptoms and brain damage [23–25]. Thus, sleep deprivation-induced pathophysiology needs to be explored in great details leading to novel therapeutic measures in reducing the burden of brain pathology caused by sleep deprivation. Our laboratory showed earlier that stress induced by forced swimming, restraint, or environmental heat exposure leads to

A. Nozari Anesthesiology & Intensive Care, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA I. Bryukhovetskiy Department of Fundamental Medicine, School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia Laboratory of Pharmacology, National Scientific Center of Marine Biology, Far East Branch of the Russian Academy of Sciences, Vladivostok, Russia I. Manzhulo Laboratory of Pharmacology, National Scientific Center of Marine Biology, Far East Branch of the Russian Academy of Sciences, Vladivostok, Russia

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breakdown of the BBB and blood–CSF barriers (BCSFB) to large molecules and serum proteins [26–34]. As a result, brain pathology and changes in neuronal, glial, and axonal structures are seen [35–37]. Sleep deprivation for 12–72 h in rats also lead to BBB breakdown and results in brain pathology [38, 39]. Thus suggests that sleep deprivation is one of the profound stressors that alters brain fluid microenvironment and induces cell damage in the central nervous system (CNS) [26–34]. Sleep deprivation is one of the key risk factors in precipitating Alzheimer’s disease brain pathology [40–42]. Thus, it would be interesting to see how sleep deprivation could affect development of Alzheimer’s disease using rodent models in our laboratory. Sleep deprivation or Alzheimer’s disease alters several neurotrophic factors in the brain and enhances the deposit or reduction in the clearance of AβP or p-tau within the brain [43–45]. Thus, it is quite likely that additional supplement of several neurotrophic factors and antibodies to AβP and p-tau could neutralize the toxicity of these agents into the brain microenvironment. Recent research also suggests that tumor necrosis factor-alpha (TNF-α) a cytotoxic cytokine is enhanced following sleep deprivation or Alzheimer’s disease in the CNS or microfluid brain environment [46, 47]. Thus, addition of TNF-α antibody may also help in reducing brain pathology of sleep deprivation. Our laboratory is focused in neurological disease associated with several co-morbidity factors that exacerbate disease processes and enhance brain damage in patients. Under these multiple disease processes, no single drug treatment or agents could reduce all the pathological processes in the brain. Thus, co-administration of drugs and antibodies are the need of the hour to treat brain pathologies associated with co-morbidity factors in patient care practice. Keeping these views in consideration, we evaluated co-administration of several key agents in brain pathology induced by co-morbidity factors in sleep deprivation for superior therapeutic effects in model experiments for the enhanced patient care. In this direction, the present investigation, we examine the effect of sleep deprivation on Alzheimer’s disease-induced neurodegenerative changes in a rat model. Furthermore, drugs and antibodies using TiO2 nanowired delivery are explored to induce superior neuroprotection as compared to conventional drug treatments of the identical agents. In present investigation, nanowired cerebrolysin together with monoclonal antibodies (mAb) of AβP (1-40), p-tau, and TNF-α is administered for achieving superior neuroprotection in sleep deprivation induced exacerbation of Alzheimer’s disease brain pathology.

1.1

Sleep Deprivation and Alzheimer’s Disease

Alzheimer’s disease affects the worldwide populations with advancing age [48]. However, so far no suitable therapy is available in reducing the deterioration in quality of life of the victims. About 5 million people are suffering from Alzheimer’s disease in America that induces huge financial burden to caregivers in order to enhance the quality of life of these Alzheimer’s disease patients [49]. Thus, exploring the risk factors for developing Alzheimer’s disease is of paramount importance at this moment. Finding the potential risk factors early will help slowing the development of this dreaded disease in populations suffering across the globe.

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A number of recent data suggest that sleep deprivation is a major risk factor for developing Alzheimer’ disease brain pathology [41]. This is evident from the fact that human subjects with poor sleep quality for less than 5–6 h including sleep apnea suffer from poor memory and deteriorating higher cognitive function deficits [50]. Further data show that sleep deprivation induces Alzheimer’s disease like dementia in 60–75% cases worldwide [51]. Rough estimate shows that this could affect more than 80 million people by 2040 according to World Health Organization (WHO) report [48, 51]. An analysis of more than 198 k people over 12-year followup study revealed that sleep deprivation or disturbances lead to roughly 1.5-fold greater risk for developing Alzheimer’s disease as compared to individuals with no sleep disturbances [52]. Likewise, people with insomnia, breathing disorders during sleep, or other form of sleep disturbances enhances the risk of developing Alzheimer’s disease pathology [52]. Postmortem studies of human cases in sleep disturbances found significant loss of neurons in the hippocampus [53] indicating that sleep quality is an important factor in maintaining the health of the central nervous system (CNS). The hallmarks of Alzheimer’s disease include increased levels of amyloid beta peptide (AβP) in the interstitial fluid or in the cerebrospinal fluid (CSF) together with the microtubule-associated protein (MAP) tau [54]. Studies show that when the extracellular tau interacts with the intracellular tau, neurotoxicity develops that is often known as taupathies [55]. Increased levels of AβP are associated with amyloid plaque formation that induces neurotoxicity [56]. Sleep duration and quality is often associated with the AβP levels in the brain or CSF [57]. In healthy male subjects, AβP level in CSF varies during according to day or night [58]. During the day, AβP levels are increased and reaches its peak at night while decreases overnight. This indicates that sleep duration and quality is important factor for metabolism of AβP in the brain. Measurement of AβP levels in CSF showed marked elevation in patients with sleep deprived or sleep disturbed group associated with memory dysfunction [59]. In animal studies, when mice were sleep deprived from 6- to 12-h period, the AβP level rises sharply in the interstitial fluid [60]. Interestingly, when these mice were put to sleep again for 6 h, the AβP level declined in the interstitial fluid [61]. During chronic sleep deprivation in mice, there was a significant increase AβP pathology in the brain that was 50% reduced when these mice were allowed to sleep again for 6 h [62]. These observations point out to the fact that sleep quality and duration are important key factors in reducing Alzheimer’s disease pathology. Alternatively, sleep deprivation and Alzheimer’s disease are interrelated.

2 Sleep Deprivation Is Frequent Among Military Personnel Sleep deprivation is very common in military personnel due to operation limitations that could continue even after 32 h of work [63–65]. Active service members when engaged in combat operation or peacekeeping mission hardly find time to sleep for 4–5 h or less [5]. These sleep deprivation or sleep debt is one of the causes of risky

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behaviors in military personnel. Even these military personnel when work in nonmilitary operations, their sleep patterns are usually less than 6 h per night. This leads to several memory and emotional problems. Although the recommendations for sleep per night is about 7–9 h but these military personnel working under normal conditions during daytime report about 6-h sleep per night [66]. During civilian duty of military personnel, about 15% reported sleep less than 6 h per night. These facts are cause for concern as sleep deprivation leads to pathological changes in the brain that affect the decision-making and quality of service, attention, and alertness in the military population. It is well known that sleep loss is associated with risky decision or high-risk behavior. During high-risk behavior, the person is consciously aware about the negative consequences of such behavior such as making harm to self or others including financial loss of legal troubles. Thus such high-risk behaviors are often related to the individuals to poor sleep quality or duration associated with or without drugs of abuse and/or violent behaviors during childhood [67–70]. However, it appears that sleep disturbances or poor sleep quality and duration is responsible for such high-risk behaviors in military. Insufficient sleep is commonly associated with military-specific high-risk behaviors, and service members are often linked with such behaviors. Thus, sufficient sleep duration and quality of sleep is needed in military population for attention, decision-making, and required alertness on active duty. Sleep loss affects decision-making probably by altering prefrontal cortical activation that is either much lower activation than normal or blunted activation that allows learning as well as loss of memory functions. Changes in prefrontal activation are largely based on emotion and there are reports that sleep-deprived soldiers who are indulged in high-risk behaviors fail to understand the gravity of the situation or learn from their past mistakes or use previously acquired knowledge [71–73]. However, further studies are needed in this area to understand the mechanisms of sleep deprivation and high-risk behaviors in future investigations.

2.1

Alzheimer’s Disease and Military

The prevalence of dementia or Alzheimer’s disease may be enhanced in military populations because of their routine indulgence in sleep loss and frequent association with repeated combat-related head injury [74–77]. Head injury is a well-known risk factor in causing dementia or Alzheimer’s disease in veterans. About more than 1.5 million veterans engaged in war in Iraq and Afghanistan sustained mild-tosevere traumatic brain or head injury during their course of deployment [78, 79]. Mild TBI (mTBI) cases or concussion due to blast injury also induces dementia or Alzheimer’s disease in veterans over the years [80–83]. Repeated mTBI leads to the development of post-traumatic stress disorders (PTSD) associated with

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depression in several cases of veterans in the United States [84–87]. In Sweden, national patients registry analysis revealed that PTSD or acute stress reaction are associated with more than 30% higher risk of neurodegenerative diseases such as Alzheimer’s disease and more than 80% greater risk for vascular neurodegenerative diseases [88, 89]. Analysis in the United States suggests that PTSD is responsible for greater risk in developing dementia in both military and nonmilitary populations. With improved health in military and prolonged survival rates following combatrelated injuries, veterans face strong risk of dementia or Alzheimer’s disease in their later periods of life [90–92]. These stress factors including PTSD are always associated with sleep loss or sleep disturbances [42, 93–96]. Thus, sleep deprivation by itself leads to greater risks for PTSD and Alzheimer’s disease brain pathology.

3 Sleep Deprivation and Traumatic Brain Injury Has Many Similarities There are several similarities between sleep deprivation and TBI. This is evident from the findings that both TBI and chronic sleep deprivations are able to induce BBB breakdown and brain pathology associated with alterations in neurotransmitter metabolism [97–100]. Our previous studies show that plasma and brain serotonin levels are enhanced following sleep deprivation or brain injury that contributes to BBB disruption and alterations in neuronal networks [101–105]. Altered neuronal networks appear to play key roles in cognitive dysfunction, memory dysfunction, and stress reactions apart from normal physiological behaviors. Neuroimaging studies using positron emission tomography (PET) show that sleep deprivation is associated with reduced metabolic activity in prefrontal cortex, anterior cingulate area, basal ganglia, cerebellum, and thalamus that are important for attention, information processing system, and executive control mechanisms and cognitive performances [106–108]. Functional magnetic resonance imaging (fMRI) studies show that sleep deprivation is associated with reduced activation of frontal and parietal network involving thalamic connections [109–113]. These neuroimaging studies show that sleep deprivation results in impaired functioning of neuronal networks maintaining attention and enhance disengagement with sensory input. Following TBI, loss of attention network and reduced sensory input also occurs leading to cognition deficits [114–117]. Thus, sleep deprivation that leads to dementia and Alzheimer’s disease associated with AβP, tau, and TDP-43 anomalies is very similar to that of mTBI or head injury [118–123]. In uninjured athlete, effect of insufficient sleep is very similar to concussed state exhibiting symptoms [124–126]. These include a combination of physical, emotional, cognitive, and sleep-related problems. This suggests that mTBI and sleep deprivation induces similar brain response.

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Thus, exploration of novel drug delivery strategies is needed together with antibodies to key pathological components of brain pathology in sleep deprivation, TBI, or Alzheimer disease to develop suitable therapeutic strategies to enhance quality of lives of military personnel and civilians alike. The novel strategies for neuroprotection in sleep deprivation and Alzheimer’s disease are discussed below.

4 Neurotrophic Factors in Sleep Deprivation Sleep duration for normal 7–8 h per night is essential component for cognitive functions, memory balance, and emotional stability. This is evident from the findings that hippocampal long-term memory potentiation (LTP) is impaired during sleep deprivation [127–129]. Extracellular signal-related kinase (ERK) and mitogenactivated protein kinases (MAPKs) together with cAMP response element binding protein (CREB) are actively involved in essential signaling in hippocampus synaptic plasticity and LTP [130–134]. Sleep deprivation alters the level of signaling within the hippocampus, cerebral cortex, and striatum affecting cognitive and memory processes [127–136]. In this process, neurotrophins play key roles within the sleep mechanisms and memory processes [43, 137–140]. The BDNF is the most abundant neurotrophin that regulates neuronal plasticity and modulates LTP and memory function. During early developmental stages, BDNF is expressed throughout the developing brain together with low-affinity p75 neurotrophin receptor (p75NTR) as well as high-affinity BDNF tyrosine kinase B (TrkB) receptor [137, 138]. In adult brain, p75NTR is present to the basal forebrain, striatum, and hypothalamus, although TrkB is widely expressed throughout the adult brain [141–144]. Several non-neural cells such as cerebral endothelium, glial cells, and blood mononuclear cells produce BDNF but the cerebral cortical neurons are the major producers of BDNF in the adult brain [145, 146]. The cortical neurons also induce BDNF production in plasma that are stored within platelets and are released during stress or exercise [147, 148]. Abundant expression of BDNF occurs in the frontal cortex, hippocampus, and olfactory bulb from where BDNF is retrogradely transported to the basal ganglia and the brainstem [149–151]. Plasma levels of BDNF partially reflect brain BDNF concentration. This is evident with the finding of decrease plasma BDNF in patients with depression and that is restored after antidepressant therapy [152, 153]. Likewise, sleep deprivation or sleep loss is also associated with a reduction in plasma BDNF [154]. Studies show that sleep deprivation is associated with perturbation in LTP induction. Significant reduction in BDNF occurs in CA1 and dentate gyrus of hippocampus after 24–48 h of sleep deprivation. These observations indicate that sleep deprivation downregulates BDNF expression in hippocampus [43]. The BDNF regulates sleep drive and memory encoding during sleep and awakening [see 43]. Diurnal variations in BDNF expression occur in the cerebral cortex and basal ganglia in rodents that correlates with sleep–wake cycles. Higher

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expression of BDNF, CREB, and p-CREB occurs during wakefulness and daytime [42, 43]. Accumulation of BDNF in GABergic neurons within the cortex is needed for sleep drive. This is evident from the findings that when cortical or intracerebroventricular BDNF is injected this results in sleep activity in rodents. The BDNF expression in hippocampus and basal ganglia are restored near normal levels after sleeping again following sleep deprivation [41–43]. These observations strongly point out a clear role of BDNF and neurotrophins in sleep deprivation or sleep loss. Thus, exogenous supplement of neurotrophins in sleep deprivation may restore memory impairments and cognitive functions.

4.1

TNF-Alpha in Sleep Deprivation

Tumor necrosis factor-alpha (TNF-α) is a pro-inflammatory glycoprotein cytokine discovered in 1975 and is involved in host defense and wound healing [47, 155– 160]. When TNF-α becomes deregulated, it contributes to severe inflammatory responses leading to cellular stress and tissue damage. The TNF-α signaling is associated with several brain diseases including narcolepsy, depression, and neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s disease as well as multiple sclerosis [46, 161, 162]. Data suggest that TNF-α is involved in sleep and wakefulness cycles and fatigue during infectious diseases. There are evidences to show that TNF-α regulates hypocretin system affecting sleep and cognition as well as learning and memory functions [156–159]. Experimental evidences show that TNF-α decreases the endothelial nitric oxide synthase (eNOS) and argininosuccinate synthase in aorta [163]. TNF-α increases p38 phosphorylation indicating that hypocretin expression by TNF-α is mediated through p38 kinase [164]. Hypocretin system is impaired in narcolepsy patients with fragmented sleep pattern showing excessive sleepiness during daytime. Neurodegenerative diseases such as Alzheimer’s disease or Parkinson’s disease are associated with excessive daytime sleepiness and increased TNF-α in plasma of these patients [165, 166]. TNF-α downregulates hypocretin through a cellular inhibition of apoptosis (cIAP)-mediated ubiquitination mechanisms; however, it is also likely that TNF-α modulates other systems involved in sleep–wake cycle [156]. The TNF-α is a key signal in the bidirectional cross-talk between sleep processes and the immune system. TNF-α with cytokine interleukin-1 (IL-1) is considered as a sleep regulatory factor under physiological conditions [156]. This is supported from the fact that during wakefulness, release of TNF-α occurs and the level of TNF-α fluctuates with the sleep–wake cycle. During sleep deprivation, TNF-α production in the brain is increased. Also chronic sleep deprivation is also associated with increased levels of TNF-α in circulation that is also seen in patients with insomnia. Other cytokines such as IL-1 and IL-6 are also increased together with C-reactive protein (CRP) indicating systemic inflammation leading to inflammatory diseases. In these situations, high levels of TNF-α are produced from activated macrophages and monocytes [156, 158].

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These observations suggest that TNF-α is one of the key factors in regulating sleep deprivation. It would be interesting to block TNF-α release or neutralize TNFα levels in circulation using monoclonal TNF-α antibodies (mAb-TNF-α) to minimize adverse effects of sleep deprivation on brain function. This is a feature that is currently being examined in our laboratory.

5 Neurotrophic Factors in Alzheimer’s Disease Alzheimer’s disease as mentioned earlier is one of the prominent neurodegenerative diseases affecting more than 45 million population above 60 years across the globe. Unfortunately, so far no significant pharmacological therapy has evolved to reduce, contain, or slow down the disease progression. Alzheimer’s disease occurs due to impaired functions and communication between neurotrophic factors and their receptors that are playing a crucial role in neurodegeneration. Using neurotrophins for therapy in Alzheimer’s disease improves the cognitive functions and associated dementia and reduces neurodegenerative changes in the brain [39, 103, 105]. Neurotrophins family includes neurotrophins, neurokines; glial cell-derived neurotrophins as well as recently discovered cerebral dopamine neurotrophins and mesencephalic astrocyte-derived neurotrophins [see 167]. Alzheimer’s disease is characterized by presence of senile plaques, intracellular neurofibrillary tangles and degeneration or loss of cholinergic neuron within the basal forebrain regions. Amyloid beta peptide aggregates result in formation of senile plaques, whereas neurofibrillary tangles are developed following hyperphosphorylation of microtubule-associated protein tau [168, 169]. Altered expression of neurotrophins such as brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), and glial cell-derived neurotrophic factor (GDNF) correlates well with cognitive impairment, dementia, and neurodegeneration in Alzheimer’s disease [170]. In Alzheimer’s disease, decrease in NGF is associated with degeneration of cholinergic neurons, and exogenous administration of NGF is associated with regeneration of cholinergic neurons in AD cases [171]. Apart from NGF effects on regeneration of cholinergic neurons, NGF also reduces oxidative stress and repair cell damage. Serum BDNF is also decreased in Alzheimer’s disease patients and correlates well with the cognitive impairments [170]. Thus, exogenous supplement of BDNF reduces dementia and progression of Alzheimer’s disease in patients. BDNF also induces regeneration of cholinergic neurons, increases acetylcholinesterase release in hippocampal synapses, and improves memory function in Alzheimer’s disease [172]. Another neurotrophins family NT3/NT4 also enhances survival and differentiation of noradrenergic and dopaminergic neurons in hippocampus in Alzheimer’s disease [173]. NT3 expression in dentate gyrus of hippocampus and interaction with Trk-C receptors indicates its role in memory function. NT3/4 levels are also

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decreased in Alzheimer’s disease; however, therapy with this neurotrophin in Alzheimer’s disease needs further investigation. Neurokines belong to neurotrophic cytokines including ciliary neurotrophic factors (CNTF), leukemia inhibitory factor (LIF), neuropoitin (NPN), and other related proteins such as cardiotrophin-1 (CT-1) [174, 175]. Among neurokines, CNTF is used in Alzheimer’s disease therapy. Within the brain, CNTF is secreted by astrocytes and binds to CNTF receptor (CNTFR) located into the astrocytes as well as in neurons. CNTF together with BDNF acts synergistically in rescuing choline acetyl transferase-positive nerve cells in Alzheimer’s disease model experiments [176]. Interestingly, BDNF alone enhances threefold survival of neuronal survival but when BDNF and CNTF act synergistically, there is eightfold enhancement of neuronal survival in Alzheimer’s disease [167]. CNTF induced neuronal survival with NT4 but not with NGF in cerebral sensory neurons and hippocampal nerve cells [167, 176]. These observations point out a significant neuroprotective role of CNTF in Alzheimer’s disease. Another neurotrophic factor derived from glia, GDNF belongs to TGF-beta (TGF-β) family that is working through GDNF family receptors GFRa1, a2, a3, and a4 and supports neurorestorative effects in basal forebrain, hippocampus, and dopaminergic neurons along with motor and sensory neurons in neurodegenerative diseases [167, 177]. Thus, GDNF are also extensively used in Alzheimer’s disease therapy for neuroprotection. Decreased level of GDNF in Alzheimer’s disease leads to excitotoxicity via release of excessive glutamate [see 167]. GDNF level is decreased in the serum of Alzheimer’s disease patients and postmortem reports show decreased GDNF in the middle temporal gyrus in Alzheimer’s disease [178]. These results suggest that decrease in GDNF in Alzheimer’s disease leads to brain pathology. Other neurotrophic factors that are implicated in neuroprotection in Alzheimer’s disease are cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocytes-derived neurotrophic factor (MANF) [167, 179]. These proteins are widely expressed in hippocampus; thalamus, striatum, cerebral cortex, and cerebellum are capable to reduce endoplasmic reticulum (ER) stress that is a prominent feature seen in early Alzheimer’s disease [180, 181]. ER stress is often associated with activation of cellular stress response or unfolded protein response (UFR) induces cell death seen in Alzheimer’s disease. CDNF and MANF reduce UFR response, and intracerebral administration of CDNF improves long-term memory in Alzheimer’s disease model experiments [167, 180, 181]. CDNF also exhibits neuroprotection in AβP-induced neurotoxicity in hippocampus. Likewise MANF protects neuronal cell death caused by AβP neurotoxicity [167]. These observations suggest CDNF and MANF could be used as new therapeutic tools in reducing Alzheimer’s disease brain pathology in future. Taken together, it appears that a combination of several neurotrophic factors and active peptide fragments in cerebrolysin could be one of the important tools in reducing Alzheimer’s disease brain pathology. This effect of cerebrolysin is further enhanced after nanowired delivery in Alzheimer’s disease model in rodents.

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5.1

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TNF-Alpha in Alzheimer’s Disease

Alzheimer’s disease induced cognitive impairment; dementia and brain pathology are the target of more than 200 clinical trials since two decades without any promising results so far. However, those pharmacological agents that are able to reduce TNF-α level in Alzheimer’s disease show some promising effects in Alzheimer’s disease-induced cognitive dysfunction [46]. TNF-α is a transmembrane protein produced by microglia and macrophages in the brain [182]. Macrophages are one of the key agents involved in systemic inflammation through TNF-α mediated mechanisms [46, 182]. As stated earlier, TNF-α is a pro-inflammatory cytokine that binds to TNF-α receptors TNFR1 and TNFR2 and downregulates immune system, resistance to infectious agents, cytotoxicity, and sleep regulation [183]. In addition, TNF-α also induces prostaglandins and platelet activating factor together with nuclear facto κB and thus potentiate inflammatory signals through cytokine and interleukin signaling pathways [184]. Chronic production of TNF-α by microglia induces neuroinflammation seen in Alzheimer’s disease and contributes to AβP plaques and phosphorylation of tau protein accumulation in patients [185]. Based on these factors, TNF-α is also known as master regulator of inflammation in neurodegenerative diseases. TNF-α blocking agents are mainly monoclonal antibodies (mAb) that bind to TNF-α including adalimumab, infliximab, or golimumab [186]. However, TNF-α inhibition leads to potential side effects such as lymphoma, heart failure, and/or demyelinating diseases [46, 186]. However, the systemic anti-TNF-α therapies improve cognition and reduce AβP and p-tau accumulation in hypothalamus in nondemented Alzheimer’s disease [see 46]. Peripheral lowering of TNF-α reduces cerebral inflammation [46, 187]. Thus, further studies using blockade of TNF-α using mAb against TNF-α with or without delivery using nanotechnology is needed to further investigate neuroprotective ability in Alzheimer’s disease [188–191].

6 Our Investigations on Sleep Deprivation and Alzheimer’s Disease We are exploring brain pathology and its modulating factors following sleep deprivation able to exacerbate neurodegenerative diseases such as Alzheimer’s or Parkinson’s diseases using rodent models in our laboratory. In these reviews, effects of sleep deprivation on Alzheimer’s disease brain pathology are examined using standard protocol. Our investigations show that sleep deprivation exacerbates Alzheimer’s disease brain pathology and nanowired delivery of cerebrolysin together with monoclonal antibodies (mAbs) against TNF-α and nNOS in combination enhanced superior neuroprotection. The salient features of this investigation and functional significance are discussed.

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Animals

Experiments were carried out on inbred male Sprague Dawley rats (200–250 g body weight; age 12–15 weeks) housed at controlled ambient temperature (21 ± 1 °C) with 12-h light and 12-h dark schedule. The rat food pellets and tap water supplied ad libitum. All experiments and handling of animals were carried out according to National Institute of Health (NIH) guidelines for the care and use of laboratory animals [192] and approved by the local ethics committee (National Research Council 2011). All experiments commenced between 8:00 and 9:00 AM in order to avoid diurnal variations.

6.2

Sleep Deprivation

Animals were subjected to sleep deprivation using an inverted flowerpot model as described earlier [39, 193]. In brief, an inverted flower pot (16.5 cm diameter) is kept in a pool of water filled in a Plexiglas chamber in such manner that water surface was 1 cm below the surface of the inverted flowerpot platform. The water temperature was maintained to 30 ± 1 °C as described earlier. Food and tap water were supplied ad libitum. This method allows rats to slow wave sleep but paradoxical sleep is largely absent [39]. The duration of sleep deprivation was 24- or 48-h period. The control group of rats was identically placed on the inverted flowerpot without water in the Plexiglas chamber with food and tap water were supplied ad libitum [see 39].

6.3

Alzheimer’s Disease Model

For Alzheimer’s disease model, simulations in the rat intracerebroventricular administration in the left lateral ventricle of amyloid beta peptide (AβP) was done once daily for 4 weeks through a chronic cannula implanted aseptically 1 week ago as described earlier. AβP (1-40 Rat, Tocris, Madrid, Spain; 200 ng/30 μl) in sterile saline (0.9% NaCl) was administered into the lateral cerebral ventricle using a constant infusion pump slowly (6 μl/min) for 5 min [194, 195]. This dose and speed delivers drug to the whole ventricular system without raising the intracranial pressure in the rat (Sharma HS, unpublished observations). Control group of rats received sterile saline (30 μl) in identical manner once daily for 4 weeks.

6.4

Parameters Measured

The following parameters are measured in sleep deprivation with Alzheimer’s disease model experiments.

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6.5

15

Physiological Variables

The mean arterial blood pressure (MABP), arterial pH, and blood gases (PaO2, PaCO2) were measured using standard protocol as described earlier [196]. In brief, left carotid artery was cannulated aseptically 1 week before and the polyethylene cannula (PE 10) was advanced retrogradely toward heart and secured there. At the time of recording, the anterior end of the cannula was connected to a Statham Pressure transducer (USA) and the output was recorded on a chart recorder. Before connecting to the pressure transducer, about 1 ml of arterial blood was withdrawn for later measurements of arterial pH and blood gases using a Radiometer apparatus (Copenhagen, Denmark). Rectal temperature was measured by Thermistor probe (Yellow Springfield, USA) connected to 12-channel telethermometer. The rectal probes were inserted into the rectum about 5–6 cm deep to record visceral temperature. Thermal pain sensitivity was used to assess pain perception of the animals. The rat-tail was scrapped and applied paraffin oil and placed over a thermal tail flick apparatus at 52 °C. The time taken for tail flick was recorded manually [196].

6.6

Blood–Brain Barrier Permeability

The blood–brain barrier (BBB) permeability was measured using Evans blue albumin (EBA) and radioiodine ([131]-I-Na) tracers as described earlier [29, 197]. In brief, EBA (2% sterile solution in 0.9% NaCl) and radioiodine (100 μCi/kg) were administered into the right femoral artery through an indwelling cannula (PE 10) implanted earlier. The tracers were allowed to circulate for 10 min in systemic circulation. At the end of the experiments, the intravascular tracers were washed out by in vivo perfusion of 0.9% cold saline (50 ml) through heart at 90 mmHg perfusion pressure. Before saline perfusion, about 1 ml of arterial blood was withdrawn from the left ventricle after cardiac puncture for determination of whole blood concentrations of EBA or radioiodine. After perfusion, the brains were taken out and examined for blue due extravasation within the brain dorsal, ventral surfaces and after a mid-sagittal section within the ventricular space. After inspection of blue dye leakage, small pieces of brains were dissected, weighed, and radioactivity counted in a well-type Gamma Counter (Packard USA). After counting the radioactivity, the samples were homogenized in a mixture of analytical grade acetone with 0.5% sodium sulfate to extract EBA from the brain tissues [29]. After centrifugation (900 × g for 10 min), the dye was measured in the supernatant in spectrophotometer at 620 nm wavelength. The dye entered into the brain was calculated from the standard curve of EBA concentrations measured earlier. Extravasation of radioactivity was expressed as percentage increase from the whole blood radioactivity as describe earlier [29, 197].

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Brain Edema Formation and Volume Swelling

Leakage of BBB to proteins often leads to brain edema formation and volume swelling (%ƒ) [198]. Brain edema formation was measured using brain water content as described earlier [199]. Small pieces of the dissected brain removed after the end of the experiments (sample sizes 65–150 mg) weighed immediately and placed in an oven at 90 °C for evaporation of water content. After 72 h, when the dry weight became constant after 3 consecutive measurements, the percentage brain water content was calculated from the differences between wet and dry weights of the sample [200]. From changes in brain water content between the control and experimental group, the % ƒ was calculated according to the formula of Elliott and Jasper (1949) as described earlier [201]. About 1% increase in brain water reflects roughly 4% increase in volume swelling (% ƒ).

6.8

Morphological Analyses

Breakdown of the BBB and edema formation leads to brain pathology [198]. The cell changes in the brain were examined by light microscopy using standard histopathological procedures. The ultrastructural changes were examined at transmission electron microscopy using standard protocol as described earlier.

6.9

Perfusion and Tissue Fixation

At the end of the experiments, intracardiac infusion of cold 0.1 M phosphate buffered saline (pH 7.0, 100 ml) was done to washout the intravascular blood followed by 4% buffered paraformaldehyde solution (250 ml) at 90 mmHg perfusion pressure [199, 200]. After the perfusion, the animals were wrapped in aluminum foil and kept at 4 °C in a refrigerator overnight. On the second day, the brains were dissected out and about 3 mm coronal sections were cut from different levels of the brain and processed for paraffin embedding using automatic tissue processor (Sakura FineTek, USA Inc., Torrance, CA, USA) [196].

6.10

Light Microscopy

About 3-μm thick sections were cut and stained with Nissl, Toluidine Blue or Haematoxylin and Eosin (HE) and examined under a Carl-Zeiss Inverted microscope (AxioVert 200 M, Oberkochen, Germany) and digital microphotograph were obtained with the digital camera (Zeiss Axiocam 500 color, Thornwood, NY, USA) and processed in an Apple Macintosh Power Book (System Mc Oss, El

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Capitan, 10.11.6) using commercial software Adobe Photoshop CSS extended version 12.0.4 × 84 (San Jose, CA, USA) using identical contrast and color filters as described earlier [196].

6.11

Immunohistochemistry

For immunohistochemistry of albumin, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), and amyloid beta peptide (AβP), the animals were perfused after phosphate buffered saline (PBS) with either Somogyi fixative (300 ml) or paraformaldehyde buffered fixative (300 ml) through cardiac perfusion at 90 mmHg [195, 196]. In addition, immunohistochemistry of NMDA (Anti-NMDAR1 antibody [N308/ 48], abcam ab 193310, Cambridge, MA, USA); S-100 (Anti-S100 alpha 6/PRA antibody [EPR13084-69], abcam ab 181975, Cambridge, MA, USA), and Iba1 (Anti-Iba1 antibody [EPR16589] abcam, ab 283319, Cambridge, MA, USA) was examined on cerebral cortex in sleep deprivation associated with Alzheimer’s disease in paraffin sections using standard commercial protocol. Recombinant rabbit antibovine monoclonal albumin antibody (1:500, Abcam, EPR12774, Cambridge, UK); recombinant rabbit monoclonal anti-GFAP-antibody GFAP (1:500, ab68428, EPR1034Y, Cambridge, MA, USA); recombinant rabbit monoclonal antimyelin basic protein antibody (1:200, ab 133620, EPR 6652, Cambridge, UK); and recombinant rabbit monoclonal antibeta amyloid antibody (1:6000 ab 205340, mOC23, Cambridge, MA, USA) were employed on paraffin sections according to standard protocol. The immunoreactions were visualized using AvidinBiotin-complex (ABC technique, Burlingame, CA, USA) according to commercial protocol as described earlier. Myelin was also visualized using histological Luxol Fast Blue (LFB) staining in addition to MBP immunostaining [195, 202, 203].

6.12

Transmission Electron Microscopy

For ultrastructural studies, small pieces of brain tissues were postembedded in osmium tetraoxide (OsO4) and embedded in plastic (Epon 812) [204, 205]. About 1-μm thick sections were cut and stained with Toluidine blue and examined under a laboratory microscope. The desired are for ultrastructural analysis, the blocks were trimmed, and ultrathin sections (50 nm) were cut on Ultramicrotome (Ultracut E Reichert-Jung, Bayreuth, Germany) and placed on a one whole copper grid (600 μm, Stansted, Essex, UK) [204, 205]. Some of the sections were contrasted with lead citrate and uranyl acetate and examined under a Phillips 400 Transmission Electron Microscope (TEM) and images were collected on the attached digital camera system (Gatan K3 IS camera, Pleasanton, CA, USA) and processed using identical software on the Apple Power Book. The ultrastructural analysis was focused on neuropil, synapses, and perivascular areas including myelin and axons as earlier.

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Biochemical Measurements

Enzyme-linked immunosorbent assay (ELISA) procedures were examined as described in commercial protocol. The fluorescence spectrophotometer in the CSF or plasma according to standard protocol. Amyloid beta peptide (AβP) was measured in the CSF or plasma using rat amyloid beta peptide 1-40 (Ab1-40) ELISA kit from Biomatik (EKU02329, Wilmington, DE, USA) sensitivity 4.84 pg/ml [195]. Phosphorylated-tau (p-tau) was measured in CSF or plasma using Rat p-tau (phospho Tau Protein) ELISA Kit (MBS2510503, My BioSource, San Diego, CA, USA) sensitivity 1 pg/ml [206]. Tumor necrosis factor alpha was measured in the plasma or CSF using Rat Tumor necrosis factor alpha (TNF-αlpha) ELISA Kit (MBS282960, My BioSource, San Diego, CA, USA) sensitivity 3.1 pg/ml [207]. Albumin in CSF was measured using rat albumin ELISA kit (ab108790, Cambridge, MA, USA) sensitivity 0.7 μg/ml [39]. Glial fibrillary acidic protein (GFAP) was measured in CSF using rat glial fibrillary acidic protein ELISA Kit (MBS2886354, My BioSource, San Diego, CA, USA) sensitivity 7.8 pg/ml [208]. Myelin basic protein (MBP) was measured in the CSF using rat myelin basic protein (MBP) ELISA Kit (MBS450557, My BioSource, San Diego, CA, USA) sensitivity 0.057 pg/ml [209]. For serotonin (5-hydroxytryptamine, 5-HT), measurement in the CSF, plasma, and brain Fluorescence Spectrophotometer F-7000 (Hitachi, Krefeld, Germany) was used according to standard commercial protocol [206, 207].

6.14

Treatment Strategies

For neuroprotection in sleep deprivation followed by Alzheimer’s disease, a balanced composition of several neurotrophic factors and active peptide fragmentscerebrolysin (EverNeuroPharma, Austria) was used [210]. In addition, co-administration with cerebrolysin was done with antibodies of amyloid beta peptide, phosphorylated p-tau, and TNF-α [211].

6.15

Nanowired Drug Delivery

The identical strategies of drugs and antibodies treatments were repeated with nanowired delivery. The TiO2 nanowired drug and antibodies delivery was prepared as described earlier [35, 39, 195, 212, 213]. In brief, the nanowires hydrogen titanate-based single crystalline ceramic biomaterial (diameter 50–60 nm) chemical stability was used. The TiO2 powder (Degussa P25) added to 40 ml of 10 M alkali

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solution in a 150 ml Teflon-lined autoclave container for 1–15 days at temperatures above 180 °C results in a white paper-like product that is washed with distilled water. Drugs and antibodies were tagged separately to nanowires after sterilization in 70% ethanol and rinsed with sterile 0.9% saline. After that, the membrane (1.0 × 1.0 cm) was soaked in a 1.0 ml solution of 1 × 106 drugs or antibodies at room temperature for 12 h and then washed again with deionized water. The nanowired labeled with drugs and antibodies were administered according to a protocol in an identical manner [213].

6.16

Experimental Protocol

Group I. A set of six to eight rats was subjected to sleep deprivation for 24- and 48-h period. Control group comprising minimum five rats was subjected to same condition but no water around. Group II. A set of animals (six to eight) was infused AβP into the lateral cerebroventricle once daily for 4 weeks. Control group received physiological saline instead of AβP under identical conditions. Group III. In six to eight rats, AβP infusion (i.c.v.) was done in rats subjected to sleep deprivation for 24 or 48 h. Control rats received saline instead in identical manner. Group IV. In a group of six to eight rats, nanowired cerebrolysin (NWCBL) with nanowired monoclonal antibodies to AβP, p-tau, and TNF-α was administered together in sleep deprivation for 24 h or 48 h. Control groups received saline instead in identical manner. Group V. In a group of six to eight rats, NWCBL with NWAβP, NWp-tau, and NWTNF-α antibodies was administered in a group of rats subjected to AβP infusion for 4 weeks. The drug and antibodies treatment started at the end of 3 weeks and continued for 1 week once daily. Control groups received saline instead in identical manner. Group VI. In a group of six to eight rats, nanowired drugs and antibodies were administered that were subjected to sleep deprivation of 24 h or 48 h and then injected with AβP for 4 weeks. The treatment associated with NWCBL with NWAβP, NWp-tau, and NWTNF-α was initiated at the end of third week and continued for 1 week once daily. Control groups received saline instead in identical manner. In these experimental or control groups, all parameters were measured as above.

6.17

Statistical Analyses

ANOVA followed by Dunnett’s test for multiple group comparison was used to analyze statistical significance of data obtained using StatView5 in Classic

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Macintosh Apple computer environment. The mean and standard deviations were used for all calculations using StatView5 (abacus concepts, USA) software. A P-value less than 0.05 was considered significant.

7 Our Observations in Sleep Deprivation and Alzheimer’s Disease 7.1

Physiological Variables

Rectal temperature showed slight but significant progressive decrease in sleep deprivation depending on the duration of exposure (Table 1). Slight but significant decrease in body temperature also seen following Alzheimer’s disease that was further enhanced when combined with sleep deprivation (Table 1). However, thermal pain response as evident with tail flick latency did not differ in any group as compared to the controls (Table 1). Regarding changes in mean arterial blood pressure (MABP) sleep deprivation induced a slight but significant progressive increase from the control group (Table 1), whereas Alzheimer’s disease model has further enhanced the MABP that was still continued in association with sleep deprivation 48 h (Table 1). The arterial pH was not affected by sleep deprivation but showed significant partial decline following Alzheimer’s disease that decreased further in association with sleep deprivation (Table 1). The arterial PaO2 levels slightly but significantly enhanced progressively following sleep deprivation and similar increase is also seen with Alzheimer’s disease alone or in association with sleep deprivation (Table 1). Interestingly, PaCO2 levels also exhibited similar significant increase following progressive increase with sleep deprivation duration and following Alzheimer’s disease alone or in with sleep deprivation (Table 1). These observations suggest that both sleep deprivation and Alzheimer’s disease affect body temperature and physiological variables without affecting thermal sensations.

7.2

Blood–Brain Barrier Disruption

Sleep deprivation depending on duration enhanced progressive BBB breakdown to both EBA and radioiodine tracers in various parts of the brain including frontal, parietal, occipital, temporal, and piriform cortices. The cerebellar vermis and lateral cerebellar cortices also showed mild-to-moderate blue staining indicating that cerebellum is also vulnerable to BBB breakdown in sleep deprivation or Alzheimer’s disease alone and in combination. The walls of lateral and fourth ventricles were also stained mild-to-moderate blue indication breakdown of the blood–cerebrospinal fluid barrier (BCSFB). The underlying brain structures such as hippocampus, caudate putamen, colliculi, thalamus, and hypothalamus also exhibited mild-to-

6±4

35.21 ± 0.11*

V. AD +SD 48 h

130 ± 6*

134 ± 8**

128 ± 6*

124 ± 3*

119 ± 6

MABP torr

7.30 ± 0.07*

7.32 ± 0.08*

7.34 ± 0.06

7.36 ± 0.08

7.38 ± 0.04

Arterial pH

Physiological variables

81.22 ± 0.10*

81.19 ± 0.13*

81.25 ± 0.17*

81.12 ± 0.15*

80.34 ± 0.23

PaO2 torr

35.18 ± 0.23*

35.24 ± 0.1*3

35.37 ± 0.12*

35.21 ± 0.18*

34.56 ± 0.34

PaCO2 torr

2.36 ± 0.18**

1.94 ± 0.21**

1.98 ± 0.14**

1.58 ± 0.10**

0.20 ± 0.08

EBA mg %

-I-Na %

3.28 ± 0.32**

2.83 ± 0.21**

2.76 ± 0.18**

2.10 ± 0.11**

0.34 ± 0.06

[131]

BBB permeability

77.10 ± 0.21**

76.58 ± 0.18**

76.73 ± 0.15**

76.23 ± 0.21**

75.21 ± 0.32

Brain water %

+8

+5

+6

+4

Nil

Swelling % ƒ

Brain edema formation

Values are mean ± SD of six to eight rats at each point. AD Alzheimer’s disease model induced by AβP infusion intracerebroventricularly (i.c.v.) for 4 weeks. SD sleep deprivation AD+SD After 48 h of sleep deprivation, AβP was infused i.c.v. for 4 weeks once daily. Rectal temperature was recorded using thermal probe inserted into rectum (about 5–6 cm deep) and data recorded on a 12-channel telethermometer. Volume swelling (%ƒ) was calculated from differences between control and experimental group brain water according to formula of Elliott and Jasper [201]. About 1% increase in brain water leads to roughly 4% increase in volume swellings. Tail flick response was obtained by placing animal’s tail on a thermal plate (52 °C) and the duration of withdrawal of tail from the hotplate was recorded manually. For details, see text ANOVA followed by Dunnett’s test for multiple group comparison from one control. *P < 0.05; **P < 0.01

5±3

5±3

35.87 ± 0.08*

35.80 ± 0.04*

6±2

36.24 ± 0.14*

II. SD 24 h

III. SD 48 h

5±1

36.80 ± 0.21

I. Control

IV. AD

Tail flick (Sec)

Rectal temp (°C)

Type of expt.

Table 1 Body temperature, physiological variables, blood–brain barrier permeability, and brain edema formation in sleep deprivation and Alzheimer’s disease

Sleep Deprivation and Alzheimer’s Disease Brain Pathology 21

22

A. Sharma et al.

moderate blue staining. These observations show that sleep deprivation could affect widespread BBB dysfunction (results not shown). Interestingly, Alzheimer’s disease also affected similar BBB and BCSFB breakdown in various brain areas that was further enhanced in association with sleep deprivation (Table 1). Extravasation of radioiodine followed almost similar pattern in sleep deprivation and Alzheimer’s disease alone or in combination with sleep deprivation. The extravasation of radioiodine was more pronounced as compared to EBA tracer indicating that smaller size of tracers could extensively penetrate across the BBB in sleep deprivation or Alzheimer’s disease alone or in combination (Table 1).

7.3

Brain Edema and Volume Swelling

Breakdown of the BBB is accompanied with brain edema formation and volume swelling leading to brain pathology. In sleep deprivation or Alzheimer’s disease, BBB breakdown is associated with edema formation and volume swelling. The brain edema and volume swelling in sleep depression was progressive depending on the duration from 4% to 6% (Table 1). Likewise Alzheimer’s disease-induced volume swelling was about 5% that further exacerbated in combination with sleep deprivation to 8% (Table 1). These observations are in line with the idea of a profound brain pathology in sleep deprivation or Alzheimer’s disease that is exacerbated in combination with sleep deprivation and Alzheimer’s disease (Table 1).

7.4

Biochemical Markers Measurement

Measurement of key markers of sleep deprivation and Alzheimer’s disease AβP, p-tau, and TNF-α in CSF and in plasma showed significant increases in these conditions. AβP level showed significant increase in sleep deprivation in CSF and in plasma and this increase was higher in Alzheimer’s disease (Table 2). Interestingly, a combination of sleep deprivation and Alzheimer’s disease caused exacerbated increase in AβP in both plasma and in CSF. Likewise p-tau followed similar rises in the CSF, whereas plasma levels rose only slightly following the combination of sleep deprivation and Alzheimer’s disease model (Table 2). The CSF increase in p-tau was robust in Alzheimer’s disease as compared to sleep deprivation. However, the combination of sleep deprivation and Alzheimer’s disease exacerbated p-tau in the CSF about threefold increase from the control value (Table 2). The TNF-α level measurement showed extensive rise in CSF and plasma following sleep deprivation. This rise of TNF-α was much higher in Alzheimer’s disease model in both plasma and in CSF. However, a combination of sleep deprivation and Alzheimer’s disease further exacerbated TNF-α levels in CSF as well as in plasma (Table 2). These observations suggest that Alzheimer’s disease brain pathology in sleep deprivation causes exacerbate brain damages.

AβP (pg/ml) CSF Plasma 7±2 27 ± 5 11 ± 3* 32 ± 4* 18 ± 3* 38 ± 7* 28 ± 6* 46 ± 8*

p-tau (ng/ml) CSF 248 ± 24 345 ± 13* 623 ± 15* 734 ± 18* Plasma 5±1 6±2 7±2 9 ± 3*

TNF-α (pg/ml) CSF 7.5 ± 0.6 23.4 ± 3.6* 89.6 ± 3.5* 96.8 ± 3.4* Plasma 12.4 ± 2.3 31.7 ± 2.8* 63.9 ± 4.6* 74.7 ± 6.3*

Albumin (pg/ml) CSF 0.14 ± 0.06 28.34 ± 3.45* 50.68 ± 3.24* 67.43 ± 5.29*

GFAP (ng/ml) CSF 9.8 ± 2.3 23.6 ± 3.2* 63.8 ± 4.6* 72.6 ± 5.3*

MBP (ng/ml) CSF 5.6 ± 1.2 12.8 ± 3.1* 19.3 ± 2.4* 26.7 ± 3.6*

Values are mean ± SD of six to eight rats at each point. AD Alzheimer’s disease model induced by AβP infusion intracerebroventricularly (i.c.v.) for 4 weeks. SD sleep deprivation AD+SD After 48 h of sleep deprivation, AβP was infused i.c.v. for 4 weeks once daily. TNF-α tumor necrosis factor-alpha, GFAP glial fibrillary acidic protein, MBP myelin basic protein. For details, see text ANOVA followed by Dunnett’s test for multiple group comparison from one control. *P < 0.05

Type of expt. I. Control II. SD 48 h III. AD IV. AD+SD 48 h

Table 2 Enzyme-linked immunosorbent assay (ELISA) of AβP, p-tau, TNF-α, albumin, GFAP, and MBP in sleep deprivation and Alzheimer’s disease

Sleep Deprivation and Alzheimer’s Disease Brain Pathology 23

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A. Sharma et al.

Measurement of cellular pathology markers such as albumin, GFAP, and MBP levels in CSF are in agreement with the findings in sleep deprivation or Alzheimer’s disease alone and in combination. Thus, albumin level in CSF increased extensively from the control group after sleep deprivation (Table 2). However, these values are even higher almost twofold after Alzheimer’s disease as compared to sleep deprivation. These values further increased when the sleep deprivation and Alzheimer’s disease model are combined (Table 2). GFAP levels increased in CSF almost 2.5fold after sleep deprivation whereas GFAP increased to sevenfold following Alzheimer’s disease. A combination of sleep deprivation and Alzheimer disease enhanced GFAP in CSF by eightfold from the control level (Table 2). In sleep deprivation, MBP level saw significant increase in CSF by more than twofold, and this level was further increased to about fourfold in Alzheimer’s disease. When the sleep deprivation and Alzheimer’s disease are combined, the MBP level in CSF is enhanced by more than fivefold (Table 2). These observations indicate that damage to BBB leads to astrocytes and MBP degradation after sleep deprivation and Alzheimer’s disease.

7.5

Measurement of Serotonin (5-HT) Levels in Plasma, CSF, and Brain Regions

Both sleep deprivation and Alzheimer’s disease represent severe stress reactions that affect plasma and brain serotonin levels significantly. Plasma and CSF levels of serotonin exhibited progressive significant rise following sleep deprivation depending on the duration. In Alzheimer’s disease model, serotonin elevation in plasma and CSF was mild bud significantly higher that controls. When sleep deprivation and Alzheimer’s disease were combined, the value excessively increased more than fivefold in plasma and about greater than sixfold in CSF (Table 3). However, alterations in regional brain serotonin level in sleep deprivation and Alzheimer’s disease showed marked variations in level from control (Table 3). In cerebral cortex, hippocampus, cerebellar cortex, thalamus, hypothalamus, and brain stem, the increase in regional brain serotonin was significantly progressive from the control values (Table 3). However, in Alzheimer’s disease model, the regional variations in brain serotonin levels show significant decrease in cerebral cortex, cerebellar cortex, and thalamus, whereas other brain regions such as hippocampus, hypothalamus, and brain stem exhibited mild but significant increase. On the other hand, when sleep deprivation and Alzheimer’s disease models are combined excessively, higher increases in regional brain serotonin levels were seen in almost all brain regions examined (Table 3).

7.6

Morphological Changes in Brain of Sleep Deprivation and Alzheimer’s Disease

Using light microscopy, sleep deprivation causes pronounced progressive neuronal injuries in the neuropil that was associated with activation of astrocytes and decrease

1.49 ± 0.06* 1.89 ± 0.08*

1.38 ± 0.08*

1.98 ± 0.12*

II. SD 24 h

III. SD 48 h

IV. AD

V. AD+SD 48 h

0.30 ± 0.07*#

0.36 ± 0.02*#

V. NWCBL + mAbAβP + p-tau+TNF-α + AD

VI. NWCBL + mAbAβP + p-tau + TNF-α + AD + SD 48 h

0.38 ± 0.08*#

0.32 ± 0.04*#

0.38 ± 0.03*#

0.64 ± 0.04*#

0.54 ± 0.09*#

Cerebellar cortex

0.23 ± 0.05*#

0.18 ± 0.03*#

0.16 ± 0.04*#

0.45 ± 0.06*#

0.24 ± 0.04*#

0.96 ± 0.05*#

1.88 ± 0.06*

1.42 ± 0.03*

1.34 ± 0.07**

0.89 ± 0.08**

0.26 ± 0.04

Thalamus

0.46 ± 0.05*#

0.45 ± 0.09*#

0.38 ± 0.06*#

0.52 ± 0.08*#

0.48 ± 0.06*#

1.03 ± 0.10*#

1.76 ± 0.10*

1.51 ± 0.08*

1.46 ± 0.13**

0.78 ± 0.10**

0.38 ± 0.09

Hypothalamus

0.44 ± 0.07*#

0.38 ± 0.010#

0.40 ± 0.02*#

0.56 ± 0.07*#

0.44 ± 0.06*#

0.87 ± 0.07*#

1.85 ± 0.09*

1.36 ± 0.07*

1.19 ± 0.09**

0.69 ± 0.09*

0.25 ± 0.08

Brain stem

0.43 ± 0.06*#

0.33 ± 0.05*#

0.22 ± 0.06*#

0.48 ± 0.05*#

0.20 ± 0.04*#

0.60 ± 0.05*#

0.67 ± 0.05*

0.24 ± 0.04*

0.87 ± 0.08**

0.46 ± 0.14*

0.16 ± 0.04

Plasma (μg/ml)

0.48 ± 0.09*#

0.51 ± 0.09*#

0.48 ± 0.07*#

0.66 ± 0.05*#

0.54 ± 0.08*#

0.93 ± 0.07*#

1.86 ± 0.07*

1.34 ± 0.05*

1.23 ± 0.06**

0.87 ± 0.08**

0.28 ± 0.03

CSF (μg/ml)

0.43 ± 0.03*#

0.40 ± 0.02*#

0.50 ± 0.08*#

0.30 ± 0.04*#

0.32 ± 0.06*#

0.46 ± 0.04*#

0.84 ± 0.08*

0.26 ± 0.04

0.65 ± 0.12**

0.34 ± 0.08*

0.13 ± 0.05

Values are mean ± SD of six to eight rats at each point. AD Alzheimer’s disease model induced by AβP infusion intracerebroventricularly (i.c.v.) for 4 weeks. SD sleep deprivation AD+SD After 48 h of sleep deprivation, AβP was infused i.c.v. for 4 weeks once daily serotonin was measured using fluorescence spectrophotometer using commercial protocol. For details, see text ANOVA followed by Dunnett’s test for multiple group comparison from one control. *P < 0.05; **P < 0.01

0.56 ± 0.03*#

0.44 ± 0.06*#

III. NWCBL + AD + SD 48 h

IV. NWCBL + mAbAβP + p-tau + TNF-α + SD 48 h

0.96 ± 0.08*#

0.48 ± 0.06*#

I. NWCBL + SD 48 h

II. NWCBL + AD

0.78 ± 0.07*#

0.76 ± 0.10** 1.02 ± 0.07**

0.89 ± 0.12**

1.23 ± 0.14**

I. Control

Nanowired delivery

Hippocampus 0.28 ± 0.05

Cerebral cortex

0.43 ± 0.08

Type of expt.

5-hydroxytryptamine in brain (μg/g)

Table 3 Spectrophotofluorometric determination of serotonin and 5-hydroxytryptamine in sleep deprivation and Alzheimer’s disease

Sleep Deprivation and Alzheimer’s Disease Brain Pathology 25

26

A. Sharma et al.

in myelin basic protein as evidences by reduction in LFB stationing in the brain. Alzheimer’s disease model also showed profound neuronal injury, activation of astrocytes, and reduction in LFB staining across the brain (Fig. 1). Immunohistochemical analysis of albumin exhibited profound spread in neuropil and enhanced AβP immunoreactivity that was further exacerbated in combination with sleep deprivation (Fig. 1).

Fig. 1 Shows neuronal distortions (arrows) in sleep deprivation (SD 48 h, a) and their exacerbation following Alzheimer’s disease (AD, b). Several neurons are shrunken with perineuronal edema in the expanded neuropil in SD. The neuropil exhibits edematous expansion (a). When SD is combined with AD, disintegration of several neurons is seen. Many neurons are dark and distorted with perineuronal edema (arrows). Treatment with nanowired cerebrolysin (NWCBL) in SD (c) markedly attenuated neuronal damages as several neurons look normal in appearance among few damaged or distorted nerve cells (arrows) within the neuropil (c). On the other hand, when the combined treatment with nanowired delivery of NWCBL together with monoclonal antibodies (mAb) to amyloid beta peptide (AβP), phosphorylated tau (p-tau) and tumor necrosis factor alpha (TNF-α) in SD with AD profound neuroprotection is seen (d). This is clearly evident with several normal looking neurons and only few damaged nerve cells (arrows) are apparent. Paraffin sections (3-μm thick), Toluidine blue stain, Bar = 30 μn

Sleep Deprivation and Alzheimer’s Disease Brain Pathology

27

Fig. 2 Shows sleep deprivation (SD, a) induced amyloid beta peptide (AβP, arrows) upregulation using immunohistochemistry within the parietal cerebral cortex and their exacerbation following Alzheimer’s disease (AD) pathology in combination with SD (arrows, b). Treatment with nanowired delivery of cerebrolysin (NWCBL, c) markedly reduced AβP positive cells (arrows, c) whereas the combined administration of NWCBL together with monoclonal antibodies (mAb) to AβP, p-tau, and TNF-α markedly reduced the AβP positive nerve cells in both SD+AD (d). Paraffin sections (3-μm), Bar = 30 μm

Profound increases in immunohistochemistry of NMDAR1, S-100, and Iba1 were observed in cerebral cortex in rats of sleep deprivation that was further exacerbated following Alzheimer’s disease (Fig. 1). At the ultrastructural level, sleep deprivation showed membrane vacuolation, myelin vesiculation, edema, and synaptic damage that were further exacerbated by combination with Alzheimer’s disease. Alzheimer’s alone also induces widespread changes in neuropil as seen using TEM analysis (Fig. 2).

7.7

Nanowired Delivery of Agents in Sleep Deprivation and Alzheimer’s Disease

We used nanowired delivery of cerebrolysin together with mAbs of AβP, p-tau, and TNF-α to induce possible superior neuroprotection in combined sleep deprivation with Alzheimer’s disease model. These combined treatments significantly attenuated

28

A. Sharma et al.

sleep deprivation associated with Alzheimer’s disease model induced physiological variables, biochemical markers, pathological markers, serotonin increase, and morphological alterations in the brain (Tables 3, 4 and 5). Nanodelivery of combined administration of cerebrolysin with mAbs against AβP, p-tau, and TNF-α significantly attenuated BBB breakdown to EBA as well as radioiodine together with edema and volume swelling following sleep deprivation 48 h or Alzheimer’s disease model as well as the sleep deprivation and Alzheimer’s disease group (Table 4). Although nanodelivery of cerebrolysin alone was also able to thwart brain edema and volume swelling together with BBB disruption in all three experimental groups (Table 4), combination with mAbs against AβP, p-tau, and TNF-α resulted superior neuroprotection in sleep deprivation as well as in Alzheimer’s disease or their combination. This combination of nanowired delivery also significantly attenuated alterations in the physiological variables in all experimental groups (Table 4). Further investigations show that the triple mAbs together with cerebrolysin nanodelivery also successfully attenuated CSF and plasma levels of AβP, p-tau, and TNF-α in sleep deprivation, Alzheimer’s disease, or their combination (Table 5). The levels of albumin, GFAP, and MBP in CSF following sleep deprivation, Alzheimer’s disease, or their combination was also thwarted significantly by combination of cerebrolysin with AβP, p-tau, and TNF-α mAbs when delivered using nanowired technology (Table 5). However, nanowired delivery of cerebrolysin significantly attenuated alone these parameters in sleep deprivation, Alzheimer’s disease, or a combination of both; however, combination of mAbs of AβP, p-tau, and TNF-α induced superior neuroprotection on these parameters (Table 5). On similar lines of observations, nanodelivery of cerebrolysin combined with mAbs of AβP, p-tau, and TNF-α induced superior reductions in regional brain serotonin as well as plasma and CSF levels in sleep deprivation, Alzheimer’s disease, or a combination of them (Table 3). However, nanodelivery of cerebrolysin alone also induced significant reductions in serotonin levels in plasma, CSF and brain areas following sleep deprivation, Alzheimer’s disease or their combination (Table 3). Addition of mAbs to cerebrolysin appears much more superior in reducing serotonin levels in brain, CSF and plasma in sleep deprivation, Alzheimer’s disease, and their combination groups (Table 3). Morphological alterations of nerve cells following sleep deprivation, Alzheimer’s disease, or their combination is also attenuated markedly following nanodelivery of cerebrolysin with mAbs of AβP, p-tau, and TNF-α (Fig. 1). This combined treatment through nanowired delivery has also reduced the expression of AβP (Fig. 2), NMDAR1 (Fig. 3), Iba1 (Fig. 4), S-100 (Fig. 5), as well as albumin, GFAP upregulation, and restored MBP immunostaining (results not shown). The histological alterations in nerve cells and degradation of LFB in sleep deprivation, Alzheimer’s disease, or their combination is profoundly attenuated by nanodelivery of cerebrolysin with mAbs of AβP, p-tau, and TNF-α in sleep deprivation or Alzheimer’s disease and their combination (unpublished observation). Nanowired delivery of cerebrolysin also markedly reduced these morphological changes in sleep deprivation, Alzheimer’s disease, and their combination with regard to albumin,

5±3

5±3

6±4

35.87 ± 0.08*

35.80 ± 0.04*

35.21 ± 0.11*

II. SD 48 h

III. AD

IV. AD+SD 48 h

36.06 ± 0.12

36.21 ± 0.13

36.35 ± 0.25

36.43 ± 0.21

II. NWCBL + AD

III. NWCBL + AD + SD 48 h

IV. NWCBL + mAbAβP + p-tau + TNF-α + SD 48 h

V. NWCBL + mAbAβP + p-tau + TNF-α + AD

VI. NWCBL + mAbAβP + p-tau+TNF-α + AD+SD 48 h

6±3

5±4

5±3

6±2

4±2

118 ± 8

124 ± 8

122 ± 6

125 ± 8

124 ± 9

120 ± 8

130 ± 6*

134 ± 8**

128 ± 6*

119 ± 6

MABP torr

7.33 ± 0.06

7.31 ± 0.06

7.32 ± 0.08

7.30 + 0.07

7.32 ± 0.06

7.33 ± 0.04

7.30 ± 0.07

7.32 ± 0.08

7.34 ± 0.06

7.38 ± 0.04

Arterial pH

Physiological variables

80.87 ± 0.21

80.89 ± 0.14

81.09 ± 0.15

81.18 ± 0.14

81.10 ± 0.12

81.05 ± 0.11

81.22 ± 0.10

81.19 ± 0.13

81.25 ± 0.17

80.34 ± 0.23

PaO2 torr

34.89 ± 0.31

34.97 ± 0.21

35.10 ± 0.18

35.14 ± 0.10

35.16 ± 0.11

35.30 ± 0.14

35.18 ± 0.23

35.24 ± 0.13

35.37 ± 0.12

34.56 ± 0.34

PaCO2 torr

0.74 ± 0.09

0.62 ± 0.08

0.67 ± 0.15

1.14 ± 0.16

0.98 ± 0.06*

1.01 ± 0.15*

2.36 ± 0.18**

1.94 ± 0.21**

1.98 ± 0.14**

0.20 ± 0.08

EBA mg %

-I-Na %

0.98 ± 0.14

0.74 ± 0.14

0.77 ± 0.4

1.34 ± 0.15

1.78 ± 0.12*

1.23 ± 0.18*

3.28 ± 0.32**

2.83 ± 0.21**

2.76 ± 0.18**

0.34 ± 0.06

[131]

BBB permeability

75.26 ± 0.16

75.11 ± 0.23

75.28 ± 0.25

76.03 ± 0.23

75.90 ± 0.21*

75.98 ± 0.23*

77.10 ± 0.21**

76.58 ± 0.18**

76.73 ± 0.15**

75.21 ± 0.32

0.20

0.40

0.28

+3

+2

+2

+8

+5

+6

Nil

Swelling % ƒ

Brain edema formation Brain water %

Values are mean ± SD of six to eight rats at each point. AD Alzheimer’s disease model induced by AβP infusion intracerebroventricularly (i.c.v.) for 4 weeks. SD sleep deprivation AD+SD After 48 h of sleep deprivation, AβP was infused i.c.v. for 4 weeks once daily. Rectal temperature was recorded using thermal probe inserted into rectum (about 5–6 cm deep) and data recorded on a 12-channel telethermometer. Volume swelling (%ƒ) was calculated from differences between control and experimental group brain water according to formula of Elliott and Jasper [201]. About 1% increase in brain water leads to roughly 4% increase in volume swellings. Tail flick response was obtained by placing animal’s tail on a thermal plate (52 °C) and the duration of withdrawal of tail from the hotplate was recorded manually. For details, see text ANOVA followed by Dunnett’s test for multiple group comparison from one control. *P < 0.05; **P < 0.01

36.05 ± 0.13

36.12 ± 0.09

I. NWCBL + SD 48 h

5±3

5±1

36.80 ± 0.21

I. Control

Nanowired delivery

Tail flick (Sec)

Rectal temp (°C)

Type of expt.

Table 4 Effect of nanowired delivery of cerebrolysin with monoclonal antibodies (mAb) of AβP, p-tau, and TNF-α on body temperature, physiological variables, blood– brain barrier permeability, and brain edema formation in sleep deprivation and Alzheimer’s disease

22 ± 6#

28 ± 6#

7 ± 43

8 ± 3#

289 ± 19#

257 ± 21#

312 ± 18£ 254 ± 22#

28 ± 8# 23 ± 5#

10 ± 4# 8 ± 2#

7 ± 3#

5±2

6±2 4±3

5±2

235 ± 12#

20 ± 6#

8 ± 4#

12 ± 6#

10 ± 4#

25.7 ± 8.4# 11.3 ± 1.8#

14.3 ± 3.2#

14.7 ± 7.8#

16.6 ± 4.8

23.5 ± 6.7# 15.7 ± 5.4#

17.6 ± 3.5#

TNF-α (pg/ml) CSF Plasma 7.5 ± 0.6 12.4 ± 2.3 23.4 ± 3.6* 31.7 ± 2.8* 89.6 ± 3.5* 63.9 ± 4.6* 96.8 ± 3.4* 74.7 ± 6.3*

14.7 ± 3.4#

14.3 ± 3.4#

19.8 ± 7.3# 13.3 ± 5.4#

14.7 ± 4.3#

Albumin (ng/ml) CSF 0.14 ± 0.06 28.34 ± 3.45* 50.68 ± 3.24* 67.43 ± 5.29*

13.2 ± 2.5#

11.5 ± 4.7#

21.8 ± 6.3# 12.6 ± 3.8#

12.8 ± 4.7#

GFAP (ng/ml) CSF 9.8 ± 2.3 23.6 ± 3.2* 63.8 ± 4.6* 72.6 ± 5.3*

7.6 ± 2.2#

6.3 ± 3.5#

13.7 ± 6.5# 7.4 ± 2.6#

8.5 ± 3.6#

MBP (ng/ml) CSF 5.6 ± 1.2 12.8 ± 3.1* 19.3 ± 2.4* 26.7 ± 3.6*

Values are mean ± SD of six to eight rats at each point. AD Alzheimer’s disease model induced by AβP infusion intracerebroventricularly (i.c.v.) for 4 weeks. SD sleep deprivation AD+SD After 48 h of sleep deprivation, AβP was infused i.c.v. for 4 weeks once daily. TNF-α tumor necrosis factor-alpha, GFAP glial fibrillary acidic protein, MBP myelin basic protein. For details, see text ANOVA followed by Dunnett’s test for multiple group comparison from one control. *P < 0.05

Type of expt. I. Control II. SD 48 h III. AD IV. AD+SD 48 h Nanowired delivery I. NWCBL + SD 48 h II. NWCBL + AD III. NWCBL + AD + SD 48 h IV. NWCBL + mAbAβP + p-tau+TNF-α+SD 48 h V. NWCBL+mAbAβP+ p-tau+TNF-α+AD VI. NWCBL+mAbAβP+ p-tau+TNF-α+AD+SD 48 h

p-tau (pg/ml) CSF Plasma 248 ± 24 5±1 345 ± 13* 6 ± 2 623 ± 15* 7 ± 2 734 ± 18* 9 ± 3*

AβP (pg/ml) CSF Plasma 7±2 27 ± 5 11 ± 3* 32 ± 4* 18 ± 3* 38 ± 7* 28 ± 6* 46 ± 8*

Table 5 Effect of nanowired delivery of cerebrolysin with monoclonal antibodies (mAb) of AβP, p-tau, and TNF-α on enzyme-linked immunosorbent assay (ELISA) of AβP, p-tau, TNF-α, albumin, GFAP, and MBP in sleep deprivation and Alzheimer’s disease

30 A. Sharma et al.

Sleep Deprivation and Alzheimer’s Disease Brain Pathology

31

Fig. 3 Shows NMDA receptor1 (NMDAR1) upregulation using immunohistochemistry in sleep deprivation (SD, a) and their exacerbation in combination with Alzheimer’s disease (AD) brain pathology with SD (b). NMDAR1 overactivation (arrows) induces brain pathology, and cell death is evident in SD and in combination with SD+AD. Treatment with nanodelivery of cerebrolysin (NWCBL) markedly reduces NMDAR1 upregulation (c), and this was further attenuated when the combined administration of NWCBL together with monoclonal antibodies (mAb) to AβP, p-tau, and TNF-α was administration in SD+AD group (arrows, d). Paraffin section (3 μm), Bar = 30 μn

GFAP, AβP immunoreactivity, nerve cell changes, and restores MBP or LFB degradation (results not shown). Treatment strategies with cerebrolysin in combination of mAbs of AβP, p-tau, and TNF-α markedly attenuated AβP, Iba1, NMDAR1, and S-100 immunohistochemistry in sleep deprivation associated with Alzheimer’s disease (Figs. 2, 3, 4 and 5). Ultrastructural changes showing membrane vacuolation, synaptic damages, myelin vesiculation, and perivascular edema are considerable reduced by nanowired delivery of cerebrolysin with mAbs against AβP, p-tau, and TNF-α (Fig. 6) in sleep deprivation, Alzheimer’s disease, or their combination. Cerebrolysin alone is able to attenuate ultrastructural changes as well in sleep deprivation and Alzheimer’s disease or their combination (results not shown).

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Fig. 4 Sleep deprivation (SD) induces activation of microglia as evident with upregulation of Iba1 immunohistochemistry (a, arrows) that is further exacerbated by a combination of SD and Alzheimer’s disease (AD) brain pathology (b, arrows). Treatment with nanowired cerebrolysin (NWCBL) markedly attenuated Iba1 upregulation in SD (c, arrows) and combined treatment with NWCBL together with monoclonal antibodies (mAb) to AβP, p-tau, and TNF-α further attenuated Iba1 upregulation in SD+AD group (d, arrow). Paraffin section (3-μm), Bar = 30 μn

These observations clearly suggests that combined therapy of cerebrolysin with antibodies against AβP, p-tau, and TNF-α is needed to restore neuroprotection at the cellular level and biochemical level in sleep deprivation or Alzheimer’s disease and their combination, not reported earlier.

7.8

Possible Mechanism of Superior Neuroprotection by Nanodelivery of Agents

Our observations clearly show that sleep deprivation further exacerbates Alzheimer’s disease brain pathology. This observation is in line with the ideas that sleep deprivation alone even for short period leads to development of Alzheimer’s disease [40–42, 118–121]. Several studies show that there is a strong correlation between lack of sleep and development of Alzheimer’s disease [40–42, 214,

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Fig. 5 Shows upregulation of S-100 immunohistochemistry, a marker of neuroinflammation in sleep deprivation (SD 48 h, a, arrows) and their exacerbation in SD with Alzheimer’s disease (AD) brain pathology (b, arrows). Treatment with nanodelivery of cerebrolysin (NWCBL) markedly attenuated neuroinflammation as evident with reduction in S-100 upregulation (c, arrows) and this was further attenuated when combined administration of NWCBL was done together with monoclonal antibodies (mAb) to AβP, p-tau with TNF-α in SD+AD group (d, arrow). Paraffin section (3-μm), Bar = 30 μm

215]. This suggests that lack of sleep is responsible for AβP and p-tau accumulation in the brain fluid compartments [40, 119, 216–218]. Accumulation of AβP and p-tau in sleep deprivation seen in our investigation further supports this hypothesis. Likewise, Alzheimer’s disease model in our experiments also shows increased AβP and p-tau in the CSF and plasma indicating that brain pathology induced by these agents are primarily responsible for cell injury and altered brain functions. When sleep deprivation and Alzheimer’s disease models are combined, exacerbation of brain pathology occurs together with exacerbation of AβP and p-tau levels in the CSF and in plasma. Since the BBB breakdown occurs in both sleep deprivation and in Alzheimer’s disease models, it is quite likely that some of the AβP and p-tau could enter into the brain fluid compartments from the plasma. However, possibility of AβP and p-tau produced in brain are equally responsible for the high levels seen in our experiments in sleep deprivation and Alzheimer’s disease models.

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Fig. 6 High power transmission electron microscopic (TEM) images of ultrastructural damage to neuropil showing synaptic damage, vacuolation, and axonal swellings (arrows) in sleep deprivation (SD, a) that are further exacerbated by combination with Alzheimer’s disease (AD) brain pathology (b, arrows). Treatment with nanodelivery of cerebrolysin (NWCBL) reduces ultrastructural damages in the neuropil (c, arrow) whereas combined administration of NWCBL with monoclonal antibodies (mAb) to AβP, p-tau, and TNF-α further induced neuroprotection of neuropil in SD+AD group (d). Ultrathin section contrasted with lead citrate and uranyl acetate, Bar = 1 μm

In Alzheimer’s disease, excess release of glutamate results in cell death that is clearly seen by upregulation of NMDA immunohistochemistry in the cerebral cortex. An enhanced expression of Iba1 denoted activation of microglia and increase immunostaining of S-100 suggests that neuroinflammation influencing upregulation of several Alzheimer’s disease related proteins causing brain pathology. These expressions of Iba1, NMDA, and S-100 are considerable reduced following the combined treatments with cerebrolysin, mAbs of AβP, p-tau, and TNF-α markedly reduced the upregulation of Iba1, S-100, and NMDA expression in the cerebral cortex in sleep deprivation associated with Alzheimer’s diseases [133, 150, 182, 202, 230]. The factors responsible for increased AβP and p-tau in sleep deprivation or Alzheimer’s disease are not clear from our experiments. However, an increase in inflammatory cytokines such as TNF-α in both conditions appears to play key roles [155, 219]. Inflammatory cytokines are responsible to enhance oxidative stress and

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alter molecular mechanisms of brain in inducing AβP and p-tau release [220, 221, 223]. Oxidative stress is one of the key factors in inducing brain pathology in sleep deprivation and Alzheimer’s disease [222–224]. Thus, this is quite likely that inflammatory reactions caused by TNF-α play important roles in the pathophysiology of sleep deprivation and Alzheimer’s disease. This hypothesis is further supported from our observations showing marked increase in TNF-α levels in plasma and CSF following sleep deprivation and Alzheimer’s disease. When sleep deprivation is combined with Alzheimer’s disease model, exacerbation of TNF-α levels in plasma and in CSF is seen. This indicates the synergistic effects of sleep deprivation and Alzheimer’s disease in our model, a feature not reported earlier. Several lines of evidences suggest that oxidative stress is crucial for BBB breakdown, brain edema formation, and brain pathology [225–228]. These observations suggest that oxidative stress induced by sleep deprivation or Alzheimer’s disease is responsible for brain pathology precipitated by neuroinflammation through activation of TNF-α related mechanisms. In our studies, we have used nanowired cerebrolysin that induces significant neuroprotection in both sleep deprivation and Alzheimer’s disease models. This suggests that nanowired cerebrolysin induces profound antioxidant and antiinflammatory activity in sleep deprivation or Alzheimer’s disease leading to marked reduction in brain pathology (Tables 4 and 5). This is evident from the fact that nanowired cerebrolysin is able to reduce AβP, p-tau, and TNF-α levels in sleep deprivation or Alzheimer’s disease and their combination effectively. The antioxidant effects of cerebrolysin are supported from our earlier studies as well as in other investigations [229–232]. These results support the idea that reduction in oxidative stress attenuated neuroinflammation, BBB breakdown, edema formation, and brain pathology. However, when nanowired cerebrolysin is administered with monoclonal antibodies of AβP, p-tau, and TNF-α, these combined agents induce much more superior neuroprotection in sleep deprivation or Alzheimer’s disease models and in combination of them. This suggests that apart from antioxidative and anti-inflammatory effects of cerebrolysin, blockade of AβP, p-tau, and TNF-α could all induce synergistic beneficial effects in sleep deprivation or Alzheimer’s disease model and in their combination. As a result, with combined treatment with cerebrolysin and three mAbs resulted in pronounced reduction in the BBB breakdown, edema formation, and brain pathology together with pronounced reduction in the biochemical changes in AβP, p-tau, and TNF-α. Treatment with monoclonal antibodies to thwart the respective antigens action in vivo is well documented from our laboratory [188, 189, 233]. This indicates that adding mAbs of AβP, p-tau, and TNF-α together with cerebrolysin attenuated their effects in vivo resulting in their quick metabolism in sleep deprivation or Alzheimer’s disease and their combination. When AβP, p-tau, and TNF-α are not able to bind to their targets, they would be quickly metabolized as evident with their low levels seen in plasma or CSF in sleep deprivation or Alzheimer’s disease and their combination. These factors are important for superior neuroprotection with combined mAbs and cerebrolysin in sleep deprivation or Alzheimer disease either separately or in combination.

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This is further evident with the measurement of pathological markers albumin, GFAP, and MBP levels in the CSF as well as using light and electron microscope for visualization of structural changes. These pathological markers and images were markedly attenuated with cerebrolysin and triple mAbs treatment together suggests that reduction in oxidative stress plays key roles in reducing brain pathology in association with BBB breakdown and edema formation. When BBB breakdown to large molecules such endogenous proteins occur then the serum proteins enter into the brain fluid environment together edema fluid leading to cellular damage. Vasogenic edema-induced BBB disruption may lead to cytotoxic damage as well depending on the magnitude and spread of edema fluid. Ultrastructural studies showing membrane vacuolation, cell swelling, damage, and distortion together with myelin vesiculation suggest both vasogenic and cytotoxic edema occur in sleep deprivation and/or Alzheimer’s disease probably caused by synergistic actions of AβP, p-tau, and TNF-α. Both sleep deprivation and Alzheimer’s disease represent severe stressful situations that perturb serotoninergic metabolism in the central nervous system as well as in blood plasma. Our observations are in line with this hypothesis. The regional changes in brain serotonin along with plasma and CSF suggest that serotonin is also contributing to the BBB breakdown and edema formation associated with brain pathology [26, 28, 30–33]. Weather alterations in brain or plasma and CSF serotonin reflect oxidative stress or neuroinflammation is not well known and requires further investigation. Earlier, experiments carried out in our laboratory clearly show that ondansetron- a serotonin 5-HT3 receptors when blocked in sleep deprivation resulted in neuroprotection [21]. Similarly Alzheimer’s disease brain pathology was significantly reduced when 5-HT6 receptor antagonists were administered (Sharma HS, unpublished observations). These observations clearly indicate involvement of serotonin in sleep deprivation or Alzheimer’s diseases either alone or in combination. It appears that increased levels of serotonin in regional brain areas as well as in plasma and CSF could reflect the pathological process of oxidative stress and neuroinflammation. As a result, nanodelivery of cerebrolysin together with mAbs of AβP, p-tau, and TNF-α reduced the alterations in serotonin in brain areas along with plasma and CSF. These observations suggest that in pathological situations of sleep deprivation and Alzheimer’s disease, several endogenous factors including AβP, p-tau, TNF-α, and serotonin actively participate in a complex manner. However, there are reasons to believe that oxidative stress and neuroinflammation are the key factors in causing brain pathology in sleep deprivation and Alzheimer disease either alone or in combination. It would be interesting to see whether nanodelivery of serotonin receptors could also reduce brain pathology and attenuate biochemical and pathological markers in sleep deprivation and Alzheimer’s disease. This is a feature currently being investigated in our laboratory.

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8 Conclusion and Future Perspectives In conclusion, our results show that sleep deprivations is able to induce Alzheimer’s disease and a combination of sleep deprivation and Alzheimer’s disease induces exacerbation of brain pathology. Under these co-morbidity conditions, nanodelivery of cerebrolysin together with mAbs against AβP, p-tau, and TNF-α is needed to induce superior neuroprotection. Furthermore, whether addition of serotonin antagonists would further enhance neuroprotective ability in combined sleep deprivation and Alzheimer’s disease induced brain pathology requires additional investigation in future.

9 Functional Significance of Our Findings The military personnel, emergency health care professionals, service providers, fire fighters who require continuous attention, and security personnel are prone to sleep deprivation thus vulnerable to Alzheimer’s disease and related problems in life. In addition, military personnel in combat operations are often subjected to long-term sleep deprivation. Thus, they are likely to develop Alzheimer’s-like diseases that make them difficult to make them vulnerable in decision-making. In such cases, routine testing of their health is needed to avoid abnormal brain functions. Timely intervention with neuroprotective agents is needed to thwart brain dysfunction in such professionals. Reduction in stress levels, mental fitness, and decision-making ability requires sound sleep that is crucial to mind and body relationship for optimal performance. How this could be achieved in present circumstances requires additional investigation. Acknowledgments This investigation is supported by grants from the Air Force Office of Scientific Research (EOARD, London, UK), and Air Force Material Command, USAF, under grant number FA8655-05-1-3065; Grants from the Alzheimer’s Association (IIRG-09-132087), the National Institutes of Health (R01 AG028679) and the Dr. Robert M. Kohrman Memorial Fund (RJC); Swedish Medical Research Council (Nr 2710-HSS), Göran Gustafsson Foundation, Stockholm, Sweden (HSS), Astra Zeneca, Mölndal, Sweden (HSS/AS), The University Grants Commission, New Delhi, India (HSS/AS), Ministry of Science & Technology, Govt. of India (HSS/AS), Indian Medical Research Council, New Delhi, India (HSS/AS) and India-EU Co-operation Program (AS/HSS) and IT-901/16 (JVL), Government of Basque Country and PPG 17/51 (JVL), JVL thanks to the support of the University of the Basque Country (UPV/EHU) PPG 17/51 and 14/08, the Basque Government (IT-901/16 and CS-2203) Basque Country, Spain; and Foundation for Nanoneuroscience and Nanoneuroprotection (FSNN), Romania. Thanks to expert reviewers for constructive suggestions to the manuscript for improvement in quality with regard to immunohistochemistry data is highly appreciated. Technical and human support provided by Dr. Ricardo Andrade from SGIker (UPV/EHU) is gratefully acknowledged. We thank Suraj Sharma, Blekinge Inst. Technology, Karlskrona, Sweden for computer and graphic support. The U.S. Government is authorized to reproduce and distribute reprints for Government purpose notwithstanding any copyright notation thereon. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of the Air Force Office of Scientific Research or the US government.

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Conflict of Interest The authors declare no conflict of interest with any entity mentioned here.

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225. Panickar KS, Anderson RA. Effect of polyphenols on oxidative stress and mitochondrial dysfunction in neuronal death and brain edema in cerebral ischemia. Int J Mol Sci. 2011;12 (11):8181–207. https://doi.org/10.3390/ijms12118181. Epub 2011 Nov 18. 226. Candelario-Jalil E, Dijkhuizen RM, Magnus T. Neuroinflammation, stroke, blood-brain barrier dysfunction, and imaging modalities. Stroke. 2022;53(5):1473–86. https://doi.org/10. 1161/STROKEAHA.122.036946. Epub 2022 Apr 7. 227. Yang C, Hawkins KE, Doré S, Candelario-Jalil E. Neuroinflammatory mechanisms of bloodbrain barrier damage in ischemic stroke. Am J Phys Cell Phys. 2019;316(2):C135–53. https:// doi.org/10.1152/ajpcell.00136.2018. Epub 2018 Oct 31. 228. Welcome MO, Mastorakis NE. Stress-induced blood brain barrier disruption: molecular mechanisms and signaling pathways. Pharmacol Res. 2020;157:104769. https://doi.org/10. 1016/j.phrs.2020.104769. Epub 2020 Apr 8. 229. Sharma HS, Muresanu DF, Ozkizilcik A, Sahib S, Tian ZR, Lafuente JV, Castellani RJ, Nozari A, Feng L, Buzoianu AD, Menon PK, Patnaik R, Wiklund L, Sharma A. Superior antioxidant and anti-ischemic neuroprotective effects of cerebrolysin in heat stroke following intoxication of engineered metal Ag and Cu nanoparticles: a comparative biochemical and physiological study with other stroke therapies. Prog Brain Res. 2021;266:301–48. https://doi. org/10.1016/bs.pbr.2021.06.014. Epub 2021 Oct 6. 230. Avci S, Gunaydin S, Ari NS, Karaca Sulukoglu E, Polat OE, Gecili I, Yeni Y, Yilmaz A, Genc S, Hacimuftuoglu A, Yildirim S, Mokresh MY, Findik DG, Tsatsakis A, Margina D, Tsarouhas K, Wallace DR, Taghizadehghalehjoughi A. Cerebrolysin alleviating effect on glutamate-mediated neuroinflammation via glutamate transporters and oxidative stress. J Mol Neurosci. 2022;72(11):2292–302. https://doi.org/10.1007/s12031-022-02078-8. Epub 2022 Nov 4. 231. González ME, Francis L, Castellano O. Antioxidant systemic effect of short-term Cerebrolysin administration. J Neural Transm Suppl. 1998;53:333–41. https://doi.org/10.1007/978-3-70916467-9_29. 232. Boshra V, Atwa A. Effect of cerebrolysin on oxidative stress-induced apoptosis in an experimental rat model of myocardial ischemia. Physiol Int. 2016;103(3):310–20. https:// doi.org/10.1556/2060.103.2016.3.2. 233. Sharma HS, Olsson Y, Nyberg F. Influence of dynorphin A antibodies on the formation of edema and cell changes in spinal cord trauma. Prog Brain Res. 1995;104:401–16. https://doi. org/10.1016/s0079-6123(08)61803-8.

Nanodelivery of Histamine H3/H4 Receptor Modulators BF-2649 and Clobenpropit with Antibodies to Amyloid Beta Peptide in Combination with Alpha Synuclein Reduces Brain Pathology in Parkinson’s Disease Anca D. Buzoianu, Aruna Sharma, Dafin F. Muresanu, Lianyuan Feng, Hongyun Huang, Lin Chen, Z. Ryan Tian, Ala Nozari, José Vicente Lafuente, Lars Wiklund, and Hari Shanker Sharma

Abstract Parkinson’s disease (PD) in military personnel engaged in combat operations is likely to develop in their later lives. In order to enhance the quality of lives of PD patients, exploration of novel therapy based on new research strategies is

A. D. Buzoianu Department of Clinical Pharmacology and Toxicology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania A. Sharma · L. Wiklund · H. S. Sharma (✉) International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden e-mail: [email protected]; [email protected] D. F. Muresanu Department of Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania ”RoNeuro” Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania L. Feng Department of Neurology, Bethune International Peace Hospital, Zhongshan, Hebei Province, China H. Huang Beijing Hongtianji Neuroscience Academy, Beijing, China L. Chen Department of Neurosurgery, Dongzhimen Hospital, Beijing University of Traditional Chinese Medicine, Beijing, China Z. R. Tian Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. S. Sharma, A. Sharma (eds.), Progress in Nanomedicine in Neurologic Diseases, Advances in Neurobiology 32, https://doi.org/10.1007/978-3-031-32997-5_2

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highly warranted. The hallmarks of PD include increased alpha synuclein (ASNC) and phosphorylated tau (p-tau) in the cerebrospinal fluid (CSF) leading to brain pathology. In addition, there are evidences showing increased histaminergic nerve fibers in substantia niagra pars compacta (SNpc), striatum (STr), and caudate putamen (CP) associated with upregulation of histamine H3 receptors and downregulation of H4 receptors in human brain. Previous studies from our group showed that modulation of potent histaminergic H3 receptor inverse agonist BF-2549 or clobenpropit (CLBPT) partial histamine H4 agonist with H3 receptor antagonist induces neuroprotection in PD brain pathology. Recent studies show that PD also enhances amyloid beta peptide (AβP) depositions in brain. Keeping these views in consideration in this review, nanowired delivery of monoclonal antibodies to AβP together with ASNC and H3/H4 modulator drugs on PD brain pathology is discussed based on our own observations. Our investigation shows that TiO2 nanowired BF-2649 (1 mg/kg, i.p.) or CLBPT (1 mg/kg, i.p.) once daily for 1 week together with nanowired delivery of monoclonal antibodies (mAb) to AβP and ASNC induced superior neuroprotection in PD-induced brain pathology. These observations are the first to show the modulation of histaminergic receptors together with antibodies to AβP and ASNC induces superior neuroprotection in PD. These observations open new avenues for the development of novel drug therapies for clinical strategies in PD. Keywords Parkinson’s disease · Histamine · Amyloid beta peptide · Alpha synuclein · Phosphorylated tau · BF-2549 · Clobenpropit · Dopamine · Brain pathology · Neuroprotection

1 Introduction Histamine is an endogenous biogenic amine affecting brain functions and involved in neurodegenerative diseases as one of the potent inflammatory mediators [1–6]. Various stimuli including stress, brain injury, inflammation as well as day– night cycle modulate histamine endogenous release and production [2, 5, 7]. Hista-

A. Nozari Anesthesiology & Intensive Care, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA J. V. Lafuente LaNCE, Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain

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mine is synthesized from the amino acid L-histidine-by-L-histidine decarboxylase and catabolized by histamine N-methyltransferase, oxidation or by diamine oxidase in various species and specific tissues [8–11]. In the brain most histamine is catabolized by histamine N-methylhistamine and is further oxidized by monoamine oxidase-B (MAO-B) that is expressed in histaminergic neurons as well as in the astrocytes [11–13]. These pathways appear important for involvement of histamine in Parkinson’s disease as inhibitors of MAO-B are used as therapy in neurodegenerative diseases including Parkinson’s disease in clinic [13, 14]. MAO-B inhibitors are used clinically to treat depression and Parkinson’s disease since 1980 [15– 18]. MAO-B inhibitors are one of the major therapeutic options for Parkinson’s disease either alone or co-administered with levodopa (L-DOPA) [16, 19–21]. The most common use of MAO-B inhibitors approved for Parkinson’s disease includes rasagiline and selegiline either alone or in combination therapy [22, 23]. Recently, safinamide, another MAO-B inhibitor with an additional inhibition of pathological release of glutamate, is approved for combination therapy in Parkinson’s disease [24–26]. Histamine H3 receptors are heterodimers with dopamine receptors D1 and D2 and are known to influence dopaminergic transmission as well [27–30]. Histamine H3 receptors are also involved in nociception, cognition and sleep–wake cycles [31– 38]. The histamine H4 receptors are largely involved in immune reactions and activate mitogen-activated protein kinase (MAPK) signaling and also induce increase in intracellular calcium concentration [39–45]. Histamine H4 receptors are mainly involved in inflammation or injury-induced signals and thus participate in neurodegenerative processes including Parkinson’s disease [45–48]. These observations suggest a prominent role of histamine in Parkinson’s disease. Histamine has H1 to H4 receptors that are mediated through G-protein-coupled receptors [49, 50]. Histamine H1 and H2 receptors are low-affinity receptors located within the central nervous system (CNS) as well as in periphery have mainly excitatory actions [51–54]. While H3 and H4 receptors are high affinity receptors located within the CNS and in periphery that are largely inhibitory in nature [55, 56]. Histamine H3 receptor is a presynaptic receptor that inhibits the release of histamine and several other neurotransmitters including dopamine, noradrenaline, serotonin, glutamate, GABA or acetylcholine [57–62]. Histamine is produced in mast cells present in the choroid plexus, area postrema, parenchymal border of the blood–brain barrier, meninges and hippocampus, thalamus and hypothalamus in brain [63–68]. Histaminergic neurons are emanated from the tuberomamillary nucleus neurons located within the hypothalamus projecting into several areas in brain and spinal cord [69–75]. Wide ramification of histaminergic neurons in brain suggests that the amine is involved in several physiological conditions such as emotions, learning and memory, neuronal survival and neurogenesis [71–75]. In pathological conditions, histamine levels in the blood or cerebrospinal fluid (CSF) are altered in a variety of neurological diseases. Increased histaminergic innervations in substantia nigra pars compacta (SNpC) in patients of Parkinson’s disease and elevated levels of histamine in the CSF is seen multiple sclerosis patients [76–82].

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These observations show that histamine is actively involved in that pathophysiology of Parkinson’s disease. This is further evident with postmortem studies in human subjects of Parkinson’s disease exhibiting increased histaminergic nerve fibers in substantia nigra pars compacta (SNpc), striatum (STr) and caudate putamen (CP) [77]. These changes are coupled with histamine H3 receptors upregulation and downregulation of H4 receptors in human cases of Parkinson’s disease [77–80]. It appears that modulation of histamine H3 and H4 receptors may be neuroprotective in Parkinson’s disease-induced brain pathology. Our previous results show that nanodelivery of a potent histaminergic H3 receptor inverse agonist BF-2549 or partial histamine H4 agonist with H3 receptor antagonist clobenpropit (CLBPT), together with monoclonal antibodies (mAb) to histamine markedly reduced brain pathology in Parkinson’s disease rodent model [46, 83, 84]. In Parkinson’s disease, elevation of amyloid beta peptide (AβP) occurs together with alpha-synuclein (ASNC) precipitating in brain pathology [85]. Thus, in this review, we examined combined nanodelivery of mAb to AβP and ASNC together with histaminergic H3 and H4 modulators drugs in Parkinson’s diseaseinduced brain pathology. Our results showed that combined administration of drugs and antibodies induced superior neuroprotection in Parkinson’s disease brain pathology, not reported earlier. These results are discussed in the light of preset literature with aim to develop suitable strategies in clinics for Parkinson’s disease.

1.1

Amyloid Beta Peptide Is Elevated in Parkinson’s Disease

The deposition of AβP and amyloid plaques are the hallmark of Alzheimer’s disease first discovered in 1984 [86–90]. AβP is also associated with p-tau and development of neurofibrillary tangles (NFTs) that are collectively responsible for brain pathology in Alzheimer’s disease [91–98]. However, the development of brain pathology in Parkinson’s disease is also associated with AβP deposition together with p-tau and alpha synuclein (ASNC) [99–104]. Thus, the pathological overlap exists between Alzheimer’s disease and Parkinson’s disease. Alzheimer’s disease patients exhibit Lewy bodies’ depositions in more than 50% of cases together with AβP [105–107]. Interestingly, patients with Lewy bodies’ depositions together with AβP in Parkinson’s disease are associated with dementia [108–111]. In animal models, it appears that in Parkinson’s disease, there is a strong synergy between AβP and ASNC deposition where one promotes the aggregation of the other and vice versa [112–114]. Using CSF, analysis in patients of Parkinson’s disease showed AβP1-42 decrease that correlates well with gait disturbances in patients [115–117]. This indicates that AβP is also involved in locomotor functions apart from cognition. Decrease in AβP levels in CSF is associated with high levels of p-tau in patients that could be a predictor value in Parkinson’s disease progression and impairment of motor functions [118–120].

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AβP is formed from its precursor amyloid precursor protein (APP) through the enzyme alpha, beta and gamma secretase among which beta and gamma secretase are important for cleavage of APP in forming amyloid plaques [121, 122]. AβP then released into the CSF, plasma and within interstitial fluid. In the CSF, AβP40 accounts for about 50% followed by AβP38 to 16% and AβP42 about 10%. Out of which AβP42 has the ability to aggregate and forming amyloid plaques leading to neurotoxicity [85, 118]. The AβP could cross the BBB using bidirectional transport through diffusion [123, 124]. In pathological conditions, the efflux transport of AβP is reduced resulting in decreased clearance from brain parenchyma. As a result, AβP deposition occurs into the brain or CSF. There are reasons to believe that decrease clearance of AβP is due to dysfunctional glia-lymphatic system that uses active transport probably through aquaporin-4 channels in Parkinson’s disease [125–130]. This idea gets support from the findings of a negative correlation between ASNC deposition and aquaporin-4 channels expression in the temporal cortex of patients of Parkinson’s disease [131, 132]. These results suggest that reduced glia-lymphatic system is involved in decreased ASNC clearance [133, 134]. In rodent models, studies show that absence of aquaporin-4 channels increases AβP deposition in the brain [135– 137]. These observations indicate a possible relationship between AβP and glialymphatic system. However, further research is needed to prove this point. The AβP, other neuropeptides and polypeptides in vivo are also degraded by two enzymes neprilysin and insulysin [138–141]. These enzymes are responsible for AβP degradation leading to reduction in AβP levels both intra- and extracellularly accumulation in the brain. These enzymes are decreased in normal aging and this reduction is pronounced in the areas involved in cognition including hippocampus, cerebral cortex and cerebellum [142–144]. In early Alzheimer’s disease cases, neprilysin is shown to be reduced in the CSF [138, 139]. In Parkinson’s disease, ASNC is linked to insulysin enzyme [145–147]. However, additional research is needed to see if exogenous administration of insulysin may attenuate brain pathology of ANC clearance in Parkinson’s disease.

1.2

Alpha-Synuclein and Parkinson’s Disease

Parkinson’s disease is a progressive neurodegenerative phenomena associated with los or degeneration of dopaminergic neurons in SNpC. Apart from this, accumulation of cytoplasmic protein Lewy bodies and ASNC aggregation plays significant role in Parkinson’s disease-induced brain pathology [147–154]. Lewy bodies or Lewy neurites are accumulating within the neurons in Parkinson’s disease and other neurodegenerative diseases [155–157]. Postmortem studies of brain from patients of Parkinson’s disease exhibited Lewy bodies or Lewy neurites in the SNpC and neurons in the striatum and amygdala. ASNC is one of the major components of Lewy bodies in Parkinson’s disease [158–160]. These Lewy bodies interfere with axonal transport and other cellular activities leading to

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compromise neuronal functions or their survival [161–164]. Lewy neurites could be seen in Parkinson’s disease much earlier than the formation of Lewy bodies indicating greater brain damages at the late stages of the progression of brain pathology [165, 166]. ASNC the major component of Lewy bodies is neurotoxic and is responsible for development of neurodegeneration in Parkinson’s disease [167– 169]. ASNC is largely located within the presynaptic terminals and releasing synaptic vesicles into the synapses affecting synaptic plasticity by regulating neurotransmitters function [170–174]. Phosphorylated ASNC is also located within the cell nucleus and nitrated forms of ASNC are seen in dopaminergic neurons [175]. Interestingly, both phosphorylated and nitrated ASNC are found in the brains of Parkinson’s disease patients [175–177]. This indicates that ASNC is one of the important agents in brain pathology in Parkinson’s disease. The ubiquitin–proteasome system and autophagy lysosomal pathways are responsible for degradation of ASNC [178–180]. Either failure or malfunctioning of these systems leads to accumulation of ASNC contributing to Parkinson’s disease brain pathology [177, 178]. These observations suggest that therapies directed to neutralize or block the functions of ASNC may induce neuroprotection in Parkinson’ disease. This is a subject that is currently under investigation in our laboratory.

1.3

p-Tau Pathology in Parkinson’s Disease

The microtubule-associated protein (MAP) tau when hyperphosphorylated (p-tau) becomes neurotoxic and contributes to neurodegeneration in Alzheimer’s or Parkinson’s disease [181–185]. Similar changes in tau are also seen in multiple system atrophy (MSA) [186]. Studies indicate that total tau (t-tau) levels are higher in the CSF in MSA patients, whereas p-tau and AβP1-42 levels are lower in MSA than in Parkinson’s disease patients [187–193]. Accumulations of p-tau in neurons and glia cells are the primary contributing factors in neurodegeneration seen in Alzheimer’s and Parkinson’s diseases [189–192]. More than 50–60% of patients in Alzheimer’s disease with NFTs exhibited ASNC in Lewy bodies and exhibited extensive neuropathology in SNpC with p-tau [193–197]. In Parkinson’s disease, patients associated with dementia Lewy bodies show p-tau in more than 40% of cases. Extensive overlap between ASNC and p-tau is seen in basalis nucleus, locus coeruleus and medulla in Parkinson’s disease patients associated with dementia [186–190]. In animal models of Parkinson’s disease, increased ASNC initiates tau phosphorylation [112, 198, 199]. During oxidative stress in Parkinson’s disease models, ASNC initiates p-tau formation through activation of glycogen synthase kinase-3β (GSK-3β) phosphorylation. GSK-3β is one of the major kinases involved in tau phosphorylation [200–203]. This is further evident from the findings of increased state of taupathies associated with ASNC and phosphorylated-GSK-3β in SNpC of postmortem brains in Parkinson’s disease patients [192, 193, 200–206].

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Similar findings are also seen in animal models of Parkinson’s disease [207, 208]. Observation of p-tau is well correlated with neurodegenerative changes in Parkinson’s disease patients as well as in animal models [209–211]. p-Tau induces destabilization of microtubules leading to collapse of cytoskeleton causing neurodegeneration [212–214]. These p-tau-induced degenerated changes are seen in dopaminergic neurons innervating the SNpC area in Parkinson’s disease [215, 216]. Hyperphosphorylation of tau by GSK-3β is also responsible for inhibiting proteasomal activity [217–219]. These observations suggest that targeting GSK-3β by drugs or monoclonal antibodies in Parkinson’s disease may have novel therapeutic strategies for neuroprotection. This is a subject that is currently being investigated in or laboratory.

2 Histaminergic Receptors in Parkinson’s Disease There are reasons to believe that interaction of histaminergic neurons and dopaminergic system within the basal ganglia has a prominent role in Parkinson’s disease [77–79, 220, 221]. This was further emphasized by studies using lack of endogenous histamine results in dopaminergic denervation [222–224]. Genetic lack of histamine is associated with motor behavior and altered pre- and postsynaptic neurotransmitter function [221]. Endogenous lacking of histamine induces dyskinetic behavior in mice models of Parkinson’s disease [225–227]. These observations suggest histaminergic system could influence dopaminergic system-induced behaviors within the nigrostriatal pathways. Loss of nigrostriatal dopaminergic neurons in Parkinson’s disease patients is evident in association with ASNC and Lewy bodies and exhibits increased density of histaminergic fibers in SNpC at postmortem studies [13, 77–80]. Increased levels of histamine also occur in basal ganglia in Parkinson’s disease patients [79]. The increased histamine level induces pro-inflammatory activity in microglia resulting in degeneration of dopaminergic neurons in SNpC [227, 228]. These neuroinflammatory signals and microglial inflammation are one of the major factors in degeneration of dopaminergic neurons in the Parkinson’s disease. Decrease in brain histamine levels prevents the loss of dopaminergic neurons in the SNpC and behavioral impairments in animal models of Parkinson’s disease [77–80, 224]. These observations clearly indicate involvement of histamine in Parkinson’s disease brain pathology. There are four types of histamine receptors identified in the central nervous system (CNS), namely histamine H1 to H4 receptors [2, 39, 229]. Histamine H4 receptors appear to be main mediator of histamine-induced microglial activation [230]. Antagonists of histamine H4 receptors reduce the levels of pro-inflammatory cytokine including TNF-α and IL-6 within the microglia [230, 231]. Furthermore, intracerebroventricular (i.c.v.) administration of histamine significantly increases the ionized calcium binding adapter molecule 1 (Iba-1) in microglia associated with brain inflammation within the striatum in animal models [230–232]. Histamine H4

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receptor antagonists block this effect of histamine on microglia. Systemic administration of histamine H4 receptor antagonist improves sensory motor deficits and reduces the expression of Iba-1 in microglia in animal model of stroke-induced brain inflammation [230–234]. When histamine H4 receptor antagonist was administered through i.c.v., route reduction in dopamine levels and dopaminergic neuronal degeneration are prevented in animal models of Parkinson’s disease [235]. The protective effects of histamine H4 receptor antagonist appear to be due to downregulation of pro-inflammatory cytokines including IL-1β, TNF-α and clusters of differentiation 86 (CD86) expression [230–234]. These observations suggest that histamine regulates brain inflammation through microglia modulation involving histamine H4 receptors. Thus, drugs modulating histamine receptors could be beneficial in attenuating Parkinson’s disease brain pathology and behavioral symptoms. Further evidence of histamine involvement in Parkinson’s disease is apparent from anatomical studies showing histaminergic innervation emanating from tuberomamillary nucleus (TMN) to SNpC that produces neuronal histamine [236]. Dense histaminergic innervation with enlarged axonal varicosities as well as increased levels of histamine is seen in SNpC of Parkinson’s disease patients [13, 77, 78, 80]. Administration of histamine H3 receptor agonist in animal models is associated with locomotor defects probably by inhibiting GABA release from SNpC neurons into the basal ganglia [237]. Data also show that histamine methyltransferase (HMT), the enzyme responsible for catabolism of histamine, is altered in Parkinson’s disease [238, 239]. These observations show that alterations in histamine homeostasis in CNS are associated with Parkinson’s disease. Histamine H3 receptor is an autoreceptor located on TMN nerve cell bodies, dendrites and axons and expressed constitutively and suppressed cell firing and histamine production and release [235, 240]. Histamine H3 receptor is also presynaptic heteroreceptor regulating release of several other neurotransmitters as well [241, 242]. In several neuronal populations, histamine H3 receptor is located on the perikarya as postsynaptic receptor. Apart from neuronal populations, histamine H3 receptor is also found located on glial cells as well [235, 240–242]. In Parkinson’s disease patients, significant decrease in histamine H3 receptormRNA and markedly increased HMT-mRNA are seen within the SNpC [77– 80]. The histamine H3 receptor immunoreactivity is seen in neuromelanincontaining neurons within the SNpC of same patients [77]. In SNpC, decreased expression of histamine H3 receptor in SNpC and increased expression of HMT-mRNA are present in putamen [77, 78]. Also, histamine H4 receptor-mRNA is present into the SNpC, caudate nucleus and putamen in Parkinson’s disease patients [77–79]. An increased density of histaminergic fibers occurs in SNpC with enhanced levels of histamine in SNpC and putamen in Parkinson’s disease patients [77]. On the other hand, increased HMT-mRNA is seen in SNpC and putamen in patients of Parkinson’s disease [78, 80]. The HMT-mRNA is also expressed in the glial cells besides neuron in Parkinson’s disease patients [78]. In Parkinson’s disease, both astrocytes and microglia are activated in SNpC, and it appears that activated glial cell populations contribute to increase HMT-mRNA

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expression in patients of Parkinson’s disease [13, 77–80]. It may be that increased HMT-mRNA has some neuroprotective effects in Parkinson’s disease by metabolizing histamine level. This is apparent from the findings that increased histamine levels in SNpC lead to degeneration of dopaminergic neurons in SNpC [see 78]. These data suggest that histamine is actively involved in the physiology and pathology of neurodegenerative diseases including Parkinson’s disease.

3 Our Observations on Histamine Modulation in Parkinson’s Disease Keeping these views in consideration, our laboratory has initiated several investigations on nanowired delivery of histamine receptor modulation together with monoclonal antibodies (mAbs) to key elements of Parkinson’ disease such in order to neutralize them in vivo for superior neuroprotection. In this review, we discuss our findings using mAbs to AβP and ASNC together with histamine H3 and H4 receptor modulation in a rodent model of Parkinson’s disease. The salient features of our observations are discussed in this review.

3.1

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) Mouse Model of Parkinson’s Disease

Parkinson’s disease-like symptoms were induced in mice using MPTP administration intraperitoneally [46, 198, 208]. MPTP was administered 20 mg/kg, i.p. twice daily with interval of 5 h for 5 days. This dose and treatment schedule induces Parkinson’s disease-like symptoms on the eighth day as described earlier [46]. This is further evident from the findings on various parameters as described below. The control groups were administered 0.9% saline in identical manner [46].

3.2

Novel Treatment Strategy

To explore suitable therapeutic measures for Parkinson’s disease, we used TiO2 nanowired delivery of histaminergic receptor modulators along with monoclonal antibodies against AβP and ASNC alone or together and examined various physiological, biochemical and morphological parameters as described earlier [46, 83, 84]. We have chosen histamine H3 receptor inverse agonist BF-2649 and H3 receptor antagonist with partial H4 receptor agonist clobenpropit [46] delivered through nanowired technology [46, 83, 84] either alone or in combination with monoclonal antibody (mAb) against AβP and ASNC in Parkinson’s disease model.

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Administration of drugs was commenced after the onset of MPTP administration once daily for 1 week. The water-soluble selective histamine H3 receptor inverse agonist BF-2649 hydrochloride (1-[3-[3-(4-chlorophenyl)propoxy]propyl]-piperidine hydrochloride, Cat. Nr. 3743, CAS Nr. 903576-44-3, Batch Nr. 2, Tocris, Bristol, UK) was administered in a dose of 1 mg/kg, i.p. once daily for 7 days after the onset of MPTP administration on the first day [46]. Likewise, the extremely potent water-soluble histamine H3 receptor antagonist with partial H4 receptor agonist clobenpropit dihydrobromide (N-(4-Chlorobenzyl)-S-[3-(4(5)-imidazolyl) propyl]isothiourea dihydrobromide Cat. Nr. 0752, CAS Nr. 145231-35-2, Batch Nr. 3, Tocris, Bristol, UK) was given in a dose of 1 mg/kg, i.p. once daily for 7 days after the onset of MPTP administration on the first day [46, 83, 84]. Monoclonal mouse antiamyloid beta peptide antibody-42 (MBS592412; MyBioSource, San Diego, CA, USA) was administered 50 μl (dilution 1:20 in phosphate buffer saline, PBS, pH 7.0) into the left lateral cerebral ventricle using once daily for 1 week from the start of MPTP administration in Parkinson’s disease model. Likewise, monoclonal mouse antibody antialpha synuclein (Cat # 32-8100, Thermo Fisher Scientific, Waltham, MA USA) was administered intracerebroventricularly 50 μl (1:20 in PBS) once daily for 1 week [46, 83, 84]. In control groups, 0.9% saline or PBS was administered in identical manner instead of monoclonal antibodies against AβP or ASNC. On the eighth day in control or experimental groups, all the parameters were examined using standard protocol described below [46, 83, 84].

3.3

Physiological Variables

Measurement of body weight, rectal temperature and thermal or mechanical pain stimulus in control or MPTP treated mice on the eighth day did not show any significant differences except a slight increased body temperature in MPTP treated mice seen on the eighth day (Table 1). Other physiological variables including mean arterial blood pressure (MABP) and arterial pH between the control and MPTP group did not differ on the eighth day. MPTP-treated mice, however, showed a significant increase in PaO2 and PaCO2 as compared to the control group (Table 1). Treatment with NWBF2649, NWCLBPT either alone or together with monoclonal antibodies to AβP and ASNC in MPTP mice showed significant decrease in MABP (Table 1) and significant increase in body temperature except NWBF2649 as compared to the control group (Table 1). There were no significant differences among control with untreated MPTP group or following treatment with histaminergic receptor-modulating agents together with monoclonal antibodies to AβP and ASNC on heart rate or reparation rate (Table 1).

37.14 ± 0.04*

37.06 ± 0.12

37.23 ± 0.09*

37.26 ± 0.06*

28 ± 4

30 ± 4

28 ± 3

30 ± 4

PD (MPTP 8th day)

NWBF2649 + PD

NWCLBPT + PD

NWBF2649 + CLBPT + AβPmAb + ASNC + PD

5±2

6±3

5±2

6±2

6±2

5±4

6±3

7±3

6±3

Sec

Sec 5±2

Pain stimulus

Mechanical

Pain stimulus

Thermal

94 ± 5*

97 ± 4*

93 ± 8*

110 ± 4

112 ± 6

Torr

MABP

7.36 ± 0.08

7.37 ± 0.10

7.36 ± 0.06

7.41 ± 0.08

7.36 ± 0.04

Arterial pH

Physiological variables PaCO2

34.36 ± 0.14

34.56 ± 0.13

34.34 ± 0.07

35.78 ± 0.08*

34.23 ± 0.08

Torr

PaO2

79.34 ± 0.12

79.08 ± 0.07

78.94 ± 0.13

78.38 ± 0.12*

79.32 ± 0.07

Torr

384 ± 8

379 ± 4

375 ± 8

385 ± 10

380 ± 12

bpm

Heart rate

65 ± 4

66 ± 7

65 ± 6

68 ± 6

65 ± 8

cpm

Respiration

Values are mean ± SD of six to eight mice at each point. MPTP was administered 20 mg/kg, i.p. twice daily with interval of 5 h for 5 days. NWBF2649 were administered once daily in a dose of 1 mg/kg, i.p. for 1 week. NWCLBPT were administered separately (1 mg/kg, i.p.) for 1 week one injection daily. AbPmAb and ASNCmAb were administered with NWBF2640 and NWCLBPT daily once for week. AβP or ASNCmAb was administered into the i.c.v. route 50 μl once daily for 1 week. For details see text. NW TiO2 nanowired, CLBPT Clobenpropit, mAb monoclonal antibody, AβP amyloid beta peptide (1–40), ASNC alpha synuclein; *P < 0.05 from saline control, ANOVA followed by Dunnett’s test for multiple group comparison from one control

36.81 ± 0.25

30 ± 3

Rectal T°C

Saline control

Types of experiment

g

Body weight

Table 1 Physiological parameters following MPTP administration in mice and their modification with histaminergic receptors H3 and H4 modulating agents with monoclonal antibodies against amyloid beta peptide and alpha synuclein. For details, see text

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A. D. Buzoianu et al.

Blood–Brain Barrier Permeability

The BBB permeability was measured using Evans blue albumin (EBA) and radioiodine tracers as described earlier [46]. In MPTP mice on the eighth day, BBB breakdown to EBA and [131]-I was significantly increased from the control group (Table 2). Treatment with NWBF2649 or NWCLBPT given alone significantly reduced MPTP-induced BBB breakdown of EBA and radioiodine tracers within the brain (Table 1). When combined treatment with histaminergic receptor modulators together with monoclonal antibodies to AβP and ASNC was given MPTP mouse, the reduction in BBB permeability to EBA and radioiodine was further reduced indicating a superior BBB protection against MPTP (Table 2). In general, blue staining was seen on the dorsal surface in cingulate, frontal, occipital and parietal cortices exhibiting mild-to-moderate blue coloration. Cerebellar vermis and lateral cerebellar cortices also showed faint to mild blue staining. On the central surface, piriform cortex stained mild blue. When a mid-sagittal section was made, the cerebral ventricular walls of lateral ventricles and fourth ventricles were madly stained. Striatum, substantia nigra, caudate putamen, hippocampus and thalamus showed mild-to-moderate blue staining indicating breakdown of the blood–cerebrospinal fluid barrier (BCSFB) was also broken down in MPTP mice. This suggests that breakdown of the BBB and BCSFB pays important roles in neurotoxicity in Parkinson’s disease. Treatment with NWBF2649 or NWCLBPT alone and in combination with monoclonal antibodies to AβP and ASNC in MPTP mice reduced this blue coloration over the dorsal, ventral and in cerebral ventricles and underlying tissue to faint staining as seen with reduction of EBA measurement studies (Table 2).

3.5

Cerebral Blood Flow

Cerebral blood flow (CBF) was measured using carbonized microsphere (15 ± 0.6 μm) using a peripheral reference blood flow as discussed earlier [46, 83, 84]. The results of CBF measurement showed a significant reduction in MPTP mice on the eighth day as compared to control group (Table 2). Treatment with either NWBF2649 or NWCLBPT significantly enhanced cerebral blood flow in MPTP mice as compared to the untreated group. However, most pronounced increase in the cerebral blood flow in MPTP mice was observed when these histaminergic receptor modulators together with monoclonal antibodies to AβP and ASNC was administered as compared to the untreated MPTP group (Table 2).

3.6

Brain Edema Formation

Brain edema was measured in control and experimental groups using differences in wet and dry weight of the brain samples as described earlier [46, 83, 84]. A percentage

0.39 ± 0.06*#

0.28 ± 0.09*#

NWBF2649 + CLBPT + AβPmAb + ASNC + PD

Cerebral blood flow

1.65 ± 0.06*#

1.38 ± 0.06*#

1.21 ± 0.05*#

0.76 ± 0.08*

1.78 ± 0.04

ml/g/min

75.48 ± 0.19#

75.98 ± 0.10*#

76.04 ± 0.08*#

77.34 ± 0.13*

75.23 ± 0.08

Brain water %

0

+1

+3

+8

nil

%ƒ

Brain edema formation

8.87 ± 1.04*#

12.34 ± 1.32*#

10.09 ± 1.21*#

18.64 ± 1.43*

8.43 ± 0.23

Iba1 pg/g

0.38 ± 0.06*#

0.51 ± 0.04*#

0.44 ± 0.08*#

0.98 ± 0.21*

0.23 ± 0.02

GSK-3β ng/g

SNpC pathology ELISA*

0.10 ± 0.03*#

0.17 ± 0.06*#

0.14 ± 0.03*#

0.26 ± 0.04*

0.08 ± 0.02

Caspase-3 ng/g

Values are mean ± SD of six to eight mice at each point. MPTP was administered 20 mg/kg, i.p. twice daily with interval of 5 h for 5 days. NWBF2649 were administered once daily in a dose of 1 mg/kg, i.p. for 1 week. NWCLBPT were administered separately (1 mg/kg, i.p.) for 1 week one injection daily. AbPmAb and ASNCmAb were administered with NWBF2640 and NWCLBPT daily once for week. AβP or ASNCmAb was administered into the i.c.v. route 50 μl once daily for 1 week. For details, see text. NW TiO2 nanowired, CLBPT Clobenpropit, mAb monoclonal antibody, AβP Amyloid beta peptide (1–40), ASNC alpha synuclein; *P < 0.05 from saline control, ANOVA followed by Dunnett’s test for multiple group comparison from one control

0.76 ± 0.09*#

0.65 ± 0.08*#

0.68 ± 0.08*#

0.59 ± 0.07*#

NWBF2649 + PD

2.04 ± 0.10*

1.58 ± 0.09*

PD (MPTP 8th day)

NWCLBPT + PD

0.28 ± 0.04

0.18 ± 0.02

Saline control

-Iodine %

EBA mg %

Types of experiment

[131]

Blood-brain barrier permeability

Table 2 Blood–brain barrier, cerebral blood flow, brain edema and substantia nigra ELISA following MPTP administration induced PD in mice and their modification with histaminergic receptors H3 and H4 modulating agents together with monoclonal antibodies against amyloid beta peptide and alpha synuclein. For details, see text

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volume swelling (%ƒ) was calculated from the differences between control and experimental brain water content using formula of Elliott and Jasper (1949) [46, 243]. Roughly, about 1% increase in brain water results in about 4% in volume swelling. Our results showed a significant increase in brain edema was significantly increased in MPTP mice on the eighth day as compared to control group (Table 2). In MPTP mice, about 8% volume swelling was seen. Treatment with NWBF2649 or NWCLBPT was able to significantly reduce brain edema resulting in volume swelling of 3% and 1%, respectively (Table 2). However, when these histaminergic receptor modulators were administered together with monoclonal antibody to AβP and ASNC, the brain edema formation was almost completely abolished (Table 2).

3.7

Pathological Markers in Substantia Nigra

Parkinson’s disease induces activation of microglia [244–247] and activates neuronal death pathways via modulating glycogen synthase kinase-3β (GSK-3β) [248– 250] and caspase 3 activity [251–254] in the brain areas associated with dopaminergic neurons. The microglia activation was used to determine ionized calciumbinding adapter molecule 1 (Iba1) in substantia nigra using ELISA (Mouse AIF1/ IBA1 ELISA Kit – LS-F7666, Seattle WA, USA) according to commercial protocol. GSK-3β ELISA (Mouse GSK-3β ELISA kit, MyBioSource MBS2122221, San Diego, CA, USA) and mouse caspase 3ELISA kit (Mouse Caspase-3 ELISA Kit, MyBioSource MBS733100, San Diego, CA, USA) in substantia nigra was measured using commercial protocol. Iba1 Measurement Our results show that Iba1 enhanced significantly by more than 120% in MPTP mice as compared to control group (Table 2). Treatment with NWBF2649 or NWCLBPT reduced Iba1 upregulation in SNpC of MPTP mice by 19% and 46%, respectively, as compared to the untreated MPTP group. Whereas when these histamine receptorsmodulating agents were administered together with monoclonal antibodies to AβP and ASNC resulted in superior reduction in Iba1 in SNpC of MPTP mice as compared to the untreated MPTP group (Table 2). GSK-3β Measurement In SNpC, measurement of GSK-3β showed significant profound increase in MPTP mice by more than 326% from the control group (Table 2). Treatment with NWBF2649 or NWCLBPT in MPTP mice resulted in significant reduction of GSK-3β in SNpC by 91% and 121% from the untreated MPTP group. When these histamine receptors-modulating agents were administered together with monoclonal antibodies to AβP and ASNC, the reduction in SNpC of GSK-3β was much more exacerbated leading to only 65% as compared to the control group (Table 2).

Histamine H3 and H4 Receptor Modulators in Parkinson’s Disease

69

Caspase 3 Measurement of caspase 3 in SNpC of MPTP mice showed significant increase by massive 225% from the control group. Treatment with NWBF2649 or NWCLBPT in SNpC of MPTP group showed significant considerable reduction in caspase 3 by 75% and 112%, respectively, from MPTP group. However, when these histaminergic receptors-modulating agents were administered with monoclonal antibodies to AβP and ASNC in MPTP mice, superior reduction in caspase 3 was observed by about 25% as comate to the untreated MPTP group (Table 2).

3.8

Synaptophysin in SNpC and STr

In view of altered synaptic activity in Parkinson’s disease [32, 33, 52, 53, 57], synaptophysin is measured in SNpC and STr in MPTP mouse using ELISA (Mouse Synaptophysin (SYP) ELISA Kit, MBS2701787, MyBioSource, San Diego, CA, USA) according to commercial protocol. Measurement of synaptophysin showed significant decrease in SNpC and STr in MPTP group as compared to the controls (Table 3). Treatment with NWNBF2649 or NWCLBPT significantly enhanced synaptophysin levels in SNpC and STr in MPTP mice. When these histaminergic receptor-modulating agents were administered together with monoclonal antibodies to AβP and ASNC, synaptophysin levels in SNpC and STr are most restored near control values (Table 3).

3.9

Biochemical Determination of Dopamine and Related Enzymes

Using electrochemical detection, and ELISA, we measured tyrosine hydroxylase enzyme (mouse tyrosine hydroxylase ELISA Kit, MBS2019774, MyBioSource, San Diego, CA, USA). In addition, tyrosine hydroxylase was visualized using mouse monoclonal antityrosine hydroxylase antibody (MAB7566 R&D System, Minneapolis, MN, USA) immunohistochemistry on paraffin sections according to the commercial protocol [46]. Dopamine, 3,4-Dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured in SNpC and STr using HPLC and electrochemical detection [46]. Our observations show that tyrosine hydroxylase is significantly decreased in MPTP mouse as compared to the control group (Table 3). The number of tyrosine hydroxylase positive cells showed significant reduction in both SNpC and STr (Table 4). Treatment with NWBF2649 or NWCLBPT significantly enhanced tyrosine hydroxylase positive cells (Table 4) and the content was also significantly elevated in SNpC and STr (Table 3). Both the increase in tyrosine hydroxylase content and the number of positive sells were further enhanced when the histaminergic receptor-modulating agents were administered in MPTP group together with monoclonal antibodies to AβP and ASNC in SNpC and STr (Tables 3 and 4).

SNpC 2.32 ± 0.12* 8.76 ± 0.09*# 9.23 ± 0.12*# 13.34 ± 0.10*#

STr

0.74 ± 0.14

0.18 ± 0.06*

SNpC

0.86 ± 0.12

0.24 ± 0.08*

0.60 ± 0.12*# 0.62 ± 0.08*#

0.67 ± 0.09*# 0.70 ± 0.08*#

Types of experiment

Saline control

PD (MPTP 8th day)

NWBF2649 + PD

NWCLBPT + PD

NWBF2649 + CLBPT + 0.78 ± 0.14*# 0.69 ± 0.12*# AβPmAb + ASNC + PD

10.28 ± 0.11*#

5.64 ± 0.08*#

4.02 ± 0.14*#

3.89 ± 0.14*#

7.80 ± 012*# 8.21 ± 0.18*#

0.68 ± 0.07*

6.10 ± 0.12

SNpC

DOPAC ng/g

1.86 ± 0.08*

12.13 ± 0.15

STr

4.89 ± 0.13*#

3.86 ± 0.08*#

3.46 ± 0.13*#

0.56 ± 0.04*

5.41 ± 0.16

STr

1.86 ± 0.05*#

1.67 ± 0.13*#

1.56 ± 0.08*#

0.21 ± 0.06*

2.10 ± 0.10

SNpC

HVA ng/g

1.42 ± 0.07*#

1.23 ± 0.09*#

1.15 ± 0.06*#

0.14 ± 0.08*

1.86 ± 0.09

STr

1.01 ± 0.04#

0.90 ± 0.06*#

0.96 ± 0.04*#

0.78 ± 0.09*

1.02 ± 0.08

SNpC

0.90 ± 0.02#

0.80 ± 0.03*#

0.83 ± 0.04*#

0.67 ± 0.05*

0.89 ± 0.07

STr

Synaptophysin ng/g

Values are mean ± SD of six to eight mice at each point. MPTP was administered 20 mg/kg, i.p. twice daily with interval of 5 h for 5 days. NWBF2649 were administered once daily in a dose of 1 mg/kg, i.p. for 1 week. NWCLBPT were administered separately (1 mg/kg, i.p.) for 1 week one injection daily. AbPmAb and ASNCmAb were administered with NWBF2640 and NWCLBPT daily once for week. AβP or ASNCmAb was administered into the i.c.v. route 50 μl once daily for 1 week. For details, see text. NW TiO2 nanowired, CLBPT Clobenpropit, mAb monoclonal antibody, AβP Amyloid beta peptide (1–40), ASNC alpha synuclein; *P < 0.05 from saline control, ANOVA followed by Dunnett’s test for multiple group comparison from one control

15.24 ± 0.18

Dopamine ng/g

Tyrosine hydroxylase ng/μg protein

Biochemical analysis

Table 3 Biochemical analysis following MPTP administration induced PD in mice and their modification with histaminergic with histaminergic receptors H3 and H4 modulating agents together with monoclonal antibodies against amyloid beta peptide and alpha synuclein. For details, see text

2.14 ± 0.08*# 1.87 ± 0.10*#

28 ± 6*

12 ± 4*#

10 ± 6*#

61 ± 4*

85 ± 6*#

89 ± 8*#

102 ± 9*# 7 ± 6*#

Saline control

PD (MPTP 8th day)

NWBF2649 + PD

NWCLBPT + PD

NWBF2649 + CLBPT + AβPmAb + ASNC + PD

STr

0.97 ± 0.04*#

1.26 ± 0.08*#

1.54 ± 0.09*#

2.89 ± 0.06*

0.89 ± 0.03

4.38 ± 0.12*#

6.98 ± 0.08*#

7.12 ± 0.08*#

12.34 ± 0.12*

3.48 ± 0.08

SNpC

ASNC ng/μg

STr

5.13 ± 0.14*#

8.23 ± 0.12*#

9.34 ± 0.13*#

18.53 ± 0.15*

4.38 ± 0.06

24.12 ± 0.16*#

32.48 ± 0.13*#

34.51 ± 0.17*#

42.56 ± 0.13*

22.34 ± 0.08

SNpC

p-tau ng/μg

STr

30.12 ± 0.11*#

34.52 ± 0.16*#

36.18 ± 0.21*#

45.43 ± 0.21*

28.28 ± 0.07

8634 ± 54*#

7032 ± 134*#

6503 ± 123*#

4157 ± 93*

9456 ± 49

SNpC

TH+ cells Nrs.

STr

6638 ± 68*#

6032 ± 101*#

5945 ± 108*#

4236 ± 79*

7534 ± 87

Values are mean ± SD of six to eight mice at each point. MPTP was administered 20 mg/kg, i.p. twice daily with interval of 5 h for 5 days. NWBF2649 were administered once daily in a dose of 1 mg/kg, i.p. for 1 week. NWCLBPT were administered separately (1 mg/kg, i.p.) for 1 week one injection daily. AbPmAb and ASNCmAb were administered with NWBF2640 and NWCLBPT daily once for week. AβP or ASNCmAb was administered into the i.c.v. route 50 μl once daily for 1 week. For details see text. NW TiO2 nanowired, CLBPT Clobenpropit, mAb monoclonal antibody, AβP Amyloid beta peptide (1–40), ASNC alpha synuclein; *P < 0.05 from saline control, ANOVA followed by Dunnett’s test for multiple group comparison from one control

1.12 ± 0.08*#

4.23 ± 0.08*

0.96 ± 0.04

6±2

118 ± 4

Types of experiment

AβP pg/μg

FS Immobility Sec SNpC

Rota-Rod Treadmill Sec

Behavioral analysis

Table 4 Behavioral analysis following MPTP administration induced PD biomarkers in mice and their modification with histaminergic receptors H3 and H4 modulating agents together with monoclonal antibodies against amyloid beta peptide and alpha synuclein. For details, see text

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Likewise, dopamine, DOPAC and HVA levels were significantly decreased in MPTP group as compared to controls in SNpC and STr (Table 3). Treatment with NWBF2649 or NWCLBPT significantly enhanced the levels of dopamine, DOPAC and HVA in SNpC and STr in MPTP mice (Table 3). Administration of these histaminergic receptor-modulating agents together with monoclonal antibodies to AβP and ASNC further enhanced the levels of dopamine, DOPAC and HVA in MPTP group (Table 3).

3.10

Amyloid Beta Peptide, Phosphorylated Tau and Alpha Synuclein in Brain

To further confirm that MPTP induces Parkinson’s disease-like symptoms, we measured AβP, p-tau and ASNC in SNpC and STr using commercial ELISA kit according to standard protocol [46, 83, 84]. In SNpC and STr, AβP was measured using Mouse Amyloid Beta Peptide 40 Monoclonal Antibody, MBS592378, MyBioSource (San Diego, CA, USA) ELISA according to commercial protocol. The results showed that MPTP mice on the eighth day exhibited pronounced increase in AβP in SNpC and STr by 340% and 224%, respectively, from the control group (Table 4). Treatment with NWBF2649 or NWCLBPT in MPTP mice resulted in significant reduction in AβP in SNpC and STr by 85% and 73% (BF-2649) and 94% and 42% (NWCLBPT), respectively, from the untreated MPTP group. When these histaminergic receptor-modulating agents were administered with monoclonal antibodies to AβP and ASNC, the reduction in AβP in SNpC and STr was further exacerbated to 17% and 9%, respectively, from the untreated MPTP group (Table 4). Measurement of ASNC by ELISA kit (Mouse alpha Synuclein Monoclonal Antibody, MBS500025, MyBioSource (San Diego, CA, USA) was done according to commercial protocol in SNpC and STr as described earlier [46]. Our results show a profound increase in MPTP mice from control value in SNpC and STr by 255% and 323%, respectively (Table 4). When NWBF2649 or NWCLBPT was administered in MPTP mice, the ASNC values were significantly reduced by 105% and 113% (BF-2649) and 101% and 89% (CLBPT), respectively, as compared to untreated MPTP group (Table 4). Administration of monoclonal antibodies to AβP and ASNC in combination with the histamine receptor-modulating agents in MPTP mice further reduced the ASNC values in SNpC and STr by 26% and 17%, respectively, from the untreated MPTP group (Table 4). In SNpC and STr, measurement of p-tau was dome using ELISA kit (Mouse Phospho Tau Protein ELISA Kit, MBS2087944, MyBioSource (San Diego, CA, USA) according to commercial protocol [46]. The results show significant increase in p-tau in MPTP mice on the eighth day in SNpC and STr by 91% and 61%, respectively, from the control group (Table 4). Treatment with NWBF2649 or NWCLBPT in MPTP group resulted in significant reductions in p-tau in SNpC and STr by 54% and 28% (BF-2649) or 28% and 22% (CLBPT), respectively, as

compared from the untreated MPTP group. Combined administration of monoclonal antibodies to AβP and ASNC with these histaminergic receptor-modulating agents resulted in superior reduction in p-tau in MPTP mice in SNpC and STr by 8% and 7%, respectively, from the untreated MPTP group (Table 4).

3.11

Motor, Cognitive and Depression in MPTP Mice

We evaluated cognitive and motor functions in MPTP mice using Rota-Rod Treadmill as described earlier [46, 83, 84]. Since Parkinson’s disease induces synaptic dysfunctions and neuronal loss impairing depressive behavior [32, 37, 161–163], we used immobility test [83] to explore depression in MPTP mice using standard protocol [see 83]. When MPTP mice were subjected to Rota-Rod treadmill test at 16 rotations per minute (rpm), they were unable to stand more than 60 s as compared to control group where mice can stand on Rota-Rod for more than 115 s (Table 4). When NWBF2649 or NWCLBPT was administered in MPTP mice, they were able to maintain their posture on Rota-Rod for 85 and 89 s, respectively, as compared to the MPTP mice (Table 4). When monoclonal antibodies to AβP and ASNC were administered in combination with these histaminergic receptor-modulating agents, the ability of mice to stay on Rota-Rod treadmill was further enhanced to 102 s in MPTP group as compared to the untreated MPTP mice (Table 4). During immobility test when mice became floating and do not try to swim in pool of water at 30 °C for some time this could be recorded for the duration. Control mice showed about 6 s of immobility during a 30-min swimming session in pool (Table 4), whereas in the MPTP-treated mice, the duration of immobility was enhanced to 28 s in a 30-min swimming session (Table 4). Administration of NWBF2649 or NWCLBPT resulted in significantly reduced immobility duration by 13 and 10 s, respectively. However, when the monoclonal antibodies to AβP and ASNC were administered in combination with these histaminergic receptormodulating agents, the immobility duration in MPTP mice is further reduced to only 7 s in a 30-min swimming session as compared to untreated MPTP mice (Table 4). These behavioral observations suggest that MPTP mice model is a quite good model to evaluate anti-Parkinson’s disease drug trials accurately.

3.12

Morphological Neuroprotection in Parkinson’s Disease Model

Morphological analysis of structural changes in MPTP mice and their reductions with histaminergic receptor-modulating agents are clearly seen in several brain areas [46]. Treatment with NWBF2549 or NWCLBPT markedly attenuated the

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Fig. 1 Shows MPTP neurotoxicity (arrows) in mice parietal cerebral cortex (a) and marked neuroprotection seen by combined administration of nanowired BF-2649 with clobenpropit (CLBPT) together with monoclonal antibodies (mAb) to amyloid beta peptide (AβP9 and alphasynuclein (ASNC) (b). In treated group, several neurons show normal appearance and only a few nerve cells exhibited dark and distorted appearance (arrows, b) as compared to MPTP toxicity alone where several neurons are damaged and distorted (arrows, a). Paraffin section (3 μm), Bar = 25 μm

neuronal, glial and axonal changes in the neuropil of MPTP mice group as compared to untreated MPTP mice. An example of morphological neuroprotection by NWBF2649 and NWCLBPT is shown in Fig. 1. In addition, when monoclonal antibodies to AβP and ASNC were administered in combination with MPTP mice, superior neuroprotection is seen (Fig. 1). At the ultrastructural level, marked reduction in synaptic damage, membrane vacuolation, edema formation and axonal damage is seen when monoclonal antibodies to AβP and ASNC were combined with histaminergic receptor-modulating agents in MPTP mice as compared to the untreated MPTP group (Fig. 2). These observations further confirm that structural preservation of neuropil appears to play the important key roles in attenuating behavioral, biochemical and physiological parameters using these combined treatments with monoclonal antibodies against AβP and ASNC together with histaminergic receptor-modulating agents in MPTP mice, not reported earlier.

4 Possible Mechanisms of Neuroprotection in Parkinson’s Disease Model The salient points of this investigation show that histamine plays one of the key roles in Parkinson’s disease brain pathology. Thus, blockade of histamine effects by histamine antibodies [46] or modulating histamine H3 and histamine H4 receptor agonists/antagonists could induce neuroprotection in Parkinson’s disease. These observations suggest that histamine H3 and H4 receptors participate in Parkinson’s disease-induced brain pathology [83, 84].

Histamine H3 and H4 Receptor Modulators in Parkinson’s Disease

75

Fig. 2 Low-power transmission electron micrograph (TEM) showing ultrastructural changes in the neuropil of parietal cerebral cortex in MPTP neurotoxicity (a) and neuroprotection by nanodelivery of BF-2649 (NWBE2649) together with clobenpropit (CLBPT) and monoclonal antibodies (mAb) to amyloid beta peptide (AβP) and alpha-synuclein (ASNC) (b). In MPTP toxicity synaptic damage, vacuolation (*) and axonal swellings (arrows) together with myelin vesiculation is clearly seen (a). Treatment strategies with mAb to AβP and ASNC together with BF2639 and CLBPT nanodelivery markedly reduced these alterations in cellular structures caused by MPTP neurotoxicity (b). As a result synaptic damage, membrane vacuolation (*) and axonal swellings are much less frequent (b) in MPTP intoxication (b). Ultrathin sections contrasted with lead citrate and uranyl acetate, Bar = 2 μm

Histamine is a neurotransmitter/neuromodulator in the central nervous system [1–3]. Histamine has the capacity to influence other neurotransmitters in the brain [10–13]. Histamine is also actively involved in various brain disorders [4–7]. There are reasons to believe that histamine is one of the important mediators of BBB and brain edema [255, 256]. There are enough evidences that histamine is involved in Parkinson’s disease [48–50]. Thus, it is quite likely that histamine induces breakdown of the BBB and induces edema formation [256]. This would allow toxic elements to enter into the brain and degenerate dopaminergic nearness leading to Parkinson’s disease. Increased BBB permeability to protein racers and subsequent edema formation seen in this investigation in MPTP treated mice are in line with this hypothesis. In MPTP model, Parkinson’s disease in mice further shows significant increase in AβP and ASNC in SNpC and STr in this investigation. These findings are in line with our previous investigation of increased AβP and ASNC in CSF of MPTP mice and in rat models [46, 84, 257]. These findings suggest that breakdown of the BBB or BCSFB leads to increase in CSF AβP and ASNC from the peripheral sources in Parkinson’s disease [46, 257]. Similar increase in CSF AβP is seen in Alzheimer’s disease model [see 84]. Our current observations further show an increased level of p-tau in SNpC and STr in MPTP mice [258]. This suggests that ASNC increase in Parkinson’s disease is responsible for tau phosphorylation and increased levels in the CSF or in MPTP brains [85, 91–93, 215]. Tau phosphorylation is also cussed by

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GSK-3β [249]. GSK-3β is also responsible for neuronal death in Parkinson’s disease [248–250]. Increased tau phosphorylation in SNpC and STr in MPTP mice is also associated with microglial activation or vice versa that needs to be further clarified. In our study, activation of microglia is supported by the findings of increased Iba1 in SNpC and STr of MPTP mice [246–248]. Phosphorylation of ASNC is also responsible for increased microglial activation and expression of Iba1 [245–247]. Parkinson’s disease like symptoms is induced in MPTP mice is further evident by increased caspase 3 activity in SNpC and STr in present study [251–254]. Reduction in caspase 3 activities by pharmacological manipulation reduces Parkinson’s disease brain pathology [252, 253]. Phosphorylation of ASNC also affects synaptic plasticity and degradation of synaptophysin in Parkinson’s disease [259]. Thus, alterations in synaptic plasticity, synaptic damage and loss of neurons are frequent in Parkinson’s disease. In MPTP mice, our observations of a significant reduction of synaptophysin in SNpC and STr are in line of this idea. Increased ASNC, p-tau and AβP levels in SNpC and STr all could be responsible for synaptic damages and reduction in synaptophysin [34, 35, 54, 55, 59). The present results further confirm that increase in AβP, p-tau and ASNC in Parkinson’s disease are the major causes of brain pathology and behavioral disturbances similar to Alzheimer’s disease [104–106, 115]. Cortical atrophy, cognitive changes and depressive behaviors could result from interactions between ANSC and AβP [113]. Mice treated with MPTP showed significant reduction in their Rota-Rod performances and depressive-like behaviors on immobility in swimming sessions further confirm this idea. To further investigate memory impairment and associated other behavioral alterations like sleep disturbances, additional investigation is required in MPTP mice, a feature that is currently being investigated in our laboratory. Another important observation in MPTP-induced Parkinson’s disease-like symptoms is evident from the decrease in cerebral blood flow at the time of increased BBB and BCSFB permeability in this investigation [260, 261]. Reduction in cerebral blood flow in Parkinson’s disease patients is responsible for freezing of gate and related motor disturbances [262]. In our investigations, decreased cerebral blood flow is also associated with immobility and Rota-Rod decreased performances support this idea. A decrease in cerebral blood flow causing ischemia in brain areas associated with BBB and BCSFB disruption allows endogenous protein extravasation in the neuropil leading to brain edema and volume swelling [255, 256]. Increased tissue pressure within the brain further compresses the cerebral blood vessels causing compression-induced ischemia [263]. Thus, a vicious cycle after opening of the BBB and BCSFB results in reduction in the cerebral blood flow, and induction of brain edema and volume swelling results in increased tissue pressure on internal organs of the brain [263] that will lead to structural changes in the brain tissues [83, 84]. This is clearly evident from the morphological changes seen in the brain in MPTP-induced Parkinson’s disease-like symptoms in rodents [46, 83, 84, 257]. There are reasons to believe that the BBB or BCSFB breakdown following MPTP chronic administration is associated with histaminergic mechanisms [47, 230–234,

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236, 237, 255, 256]. Thus, it would be interesting to measure histamine levels in the brain following chronic administration of MPTP in rodents [76–79]. This is a feature that requires additional investigation. However, it appears that histamine from activated microglia plays important role in the pathology of Parkinson’s disease [230–234, 236, 237]. This is further evident from our study in this investigation showing significant reduction in Iba1 denoting activated microglia in SNpC and STr when histaminergic receptors H3 and H4 modulating agents were administered using nanowired technology in MPTP mice model. However, when monoclonal antibodies against AβP and ASNC were also co-administered together with NWBF2649 and NWCLBPT, the superior reduction in Iba1 in MPTP mice is observed. This suggests that AβP and ASNC are involved in microglial activation or vice versa in Parkinson’s disease. Administration of histamine H3 and H4 receptors-modulating agents together with monoclonal antibodies to AβP and ASNC also results in superior refection in GSK-3β and caspase 3 in SNpC and STr in MPTP mice. This observation clearly supports the involvement of histaminergic mechanisms in Parkinson’s disease [47, 238, 239, 248–254]. Activation of Iba1, GSK-3β or caspase 3 is responsible for neuronal damage and cell death [244–246, 248–254]. Cell death and neuronal loss in Parkinson’s disease are associated with synaptic damage and loss of synaptic function [32–38]. Loss of synapse and synaptic network affects synaptophysin degeneration within the synapse [259]. Reduction in synaptophysin in MPTP mice in this investigation further supports this idea. When NWBF2649 and NWCLBPT were given in association with monoclonal antibodies to AβP and ASNC, this reduction in synaptophysin is almost restored to normal levels in MPTP mice. This suggests that histaminergic mechanisms are involved in synaptophysin degradation via AβP and ASNC phosphorylation [22, 114, 198, 264]. Histaminergic receptors H3 and H4 modulating agents together with monoclonal antibodies to AβP and ASNC are able to induce superior performances on swimming sessions and on Rota-Rod performances in MPTP mice indicating the histamine is involved in behavioral disturbances in Parkinson’s disease model as seen in our investigation as well [46, 76–79]. Our observations further show that structural abnormalities, neuronal damages and axonal contacts were disturbed in MPTP mice. Treatment with NWBF2649 and NWCLBPT together with monoclonal antibodies to AβP and ASNC when administered in combination in MPTP mice induced superior neuroprotection and improved synaptic contacts within the neuropil. This suggests that histaminergic receptors H3 and H4 modulating agents are able to thwart brain pathology in Parkinson’s disease together with blockade of AβP and ASNC in MPTP mice [46, 83, 84]. Development of brain edema and expansion of neuropil due to deposition of edematous fluid within extracellular compartments is the key for pathological damage of the brain cells [84, 96, 111, 112]. Treatment with histaminergic receptor H3 and H4 modulating agents is able to reduce brain edema formation in MPTP mice resulting in neuroprotection that was further enhanced when combined administration of monoclonal antibodies to AβP and ASNC was done together with NWBF2649 and NWCLBPT. These observations suggest that histamine is actively playing key roles in Parkinson’s disease brain pathology [76–82].

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We have used nanowired delivery of histaminergic agents to modulate histamine H3 and H4 receptors that induce superior neuroprotection in Parkinson’s disease induced by MPTP in mace model. Nanodelivery of compounds induces widespread superior neuroprotection in several models of neurodegeneration or trauma as compared to the conventional delivery of the same compounds [46, 83, 84]. The possible reasons of superior neuroprotection by nanodelivered compounds include widespread penetration, resistance to catabolism from endogenous enzymes and deep penetration within brain tissues [46, 83, 233, 265, 266]. It would be interesting to use other nanoformulations of nanowires such as silver nanowires or K-TiO2 nanowires instead of Na-TiO2 nanowires to see weather the therapeutic efficacy of these compounds are further enhanced in Parkinson’s disease [267]. Based on our observation of nanodelivery of histaminergic compound-induced superior neuroprotection, it would be interesting to examine whether nanoformulations of rasagiline may further enhance therapeutic values in Parkinson’s disease in clinic. Likewise, selection of other potential drugs and their nanodelivery in Parkinson’s disease may be examined in future strategies for effective therapy in Parkinson’s disease.

4.1

Conclusion and Future Perspectives

In conclusion, histamine receptor H3 inverse agonist BF-2649 and histamine receptor H4 agonist and H3 receptor antagonist clobenpropit are quite effective in reducing brain pathology in Parkinson’s disease either alone or in combination with monoclonal antibodies to AβP and ASNC. Thus, it would be interesting to explore other receptor modulation of histamine, such as H2 receptors antagonists together with H3 and H4 modulating agents in Parkinson’s disease for effective therapy in future. Furthermore, we have sued Na-TiO2 nanowires to deliver drugs and antibodies in this investigation. It would be worthwhile to investigate use of K-TiO2 nanowired labeled drugs in Parkinson’s disease to see whether their efficacy is further enhanced as seen in our investigations in oxiracetam treatment in brain trauma [267]. Acknowledgments This investigation is supported by grants from the Air Force Office of Scientific Research (EOARD, London, UK), and Air Force Material Command, USAF, under grant number FA8655-05-1-3065; Ministry of Science & Technology, People Republic of China; Grants from the Alzheimer’s Association (IIRG-09- 132087), the National Institutes of Health (R01 AG028679) and the Dr. Robert M. Kohrman Memorial Fund (RJC); Swedish Medical Research Council (Nr 2710-HSS), Göran Gustafsson Foundation, Stockholm, Sweden (HSS), Astra Zeneca, Mölndal, Sweden (HSS/AS), The University Grants Commission, New Delhi, India (HSS/AS), Ministry of Science & Technology, Govt. of India (HSS/AS), Indian Medical Research Council, New Delhi, India (HSS/AS) and India-EU Co-operation Program (AS/HSS) and IT-901/16 (JVL), Government of Basque Country and PPG 17/51 (JVL), JVL thanks to the support of the University of the Basque Country (UPV/EHU) PPG 17/51 and 14/08, the Basque Government (IT-901/16 and CS-2203), Basque Country, Spain; and Foundation for Nanoneuroscience and Nanoneuroprotection (FSNN), Romania. Technical and human support provided by Dr. Ricardo

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Andrade from SGIker (UPV/EHU) is gratefully acknowledged. We thank Suraj Sharma, Blekinge Inst. Technology, Karlskrona, Sweden, for computer and graphic support. The US government is authorized to reproduce and distribute reprints for Government purpose notwithstanding any copyright notation thereon. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of the Air Force Office of Scientific Research or the US government. Conflict of Interest The authors declare no conflict of interest with any entity mentioned here.

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Co-administration of Nanowired DL-3-n-Butylphthalide (DL-NBP) Together with Mesenchymal Stem Cells, Monoclonal Antibodies to Alpha Synuclein and TDP-43 (TAR DNA-Binding Protein 43) Enhance Superior Neuroprotection in Parkinson’s Disease Following Concussive Head Injury Lianyuan Feng, Aruna Sharma, Zhenguo Wang, Dafin F. Muresanu, Z. Ryan Tian, José Vicente Lafuente, Anca D. Buzoianu, Ala Nozari, Lars Wiklund, and Hari Shanker Sharma

Abstract dl-3-n-butylphthalide (dl-NBP) is one of the potent antioxidant compounds that induces profound neuroprotection in stroke and traumatic brain injury. Our previous studies show that dl-NBP reduces brain pathology in Parkinson’s disease (PD) following its nanowired delivery together with mesenchymal stem cells (MSCs) exacerbated by concussive head injury (CHI). CHI alone elevates

L. Feng Department of Neurology, Bethune International Peace Hospital, Zhongshan Road (West), Shijiazhuang, Hebei Province, China A. Sharma · L. Wiklund · H. S. Sharma (✉) International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden e-mail: [email protected]; [email protected] Z. Wang Shijiazhuang Pharma Group NBP Pharmaceutical Co., Ltd., Shijiazhuang, Hebei Province, China D. F. Muresanu Department of Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania ”RoNeuro” Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania Z. R. Tian Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA J. V. Lafuente LaNCE, Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. S. Sharma, A. Sharma (eds.), Progress in Nanomedicine in Neurologic Diseases, Advances in Neurobiology 32, https://doi.org/10.1007/978-3-031-32997-5_3

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alpha synuclein (ASNC) in brain or cerebrospinal fluid (CSF) associated with elevated TAR DNA-binding protein 43 (TDP-43). TDP-43 protein is also responsible for the pathologies of PD. Thus, it is likely that exacerbation of brain pathology in PD following brain injury may be thwarted using nanowired delivery of monoclonal antibodies (mAb) to ASNC and/or TDP-43. In this review, the co-administration of dl-NBP with MSCs and mAb to ASNC and/or TDP-43 using nanowired delivery in PD and CHI-induced brain pathology is discussed based on our own investigations. Our observations show that co-administration of TiO2 nanowired dl-NBP with MSCs and mAb to ASNC with TDP-43 induced superior neuroprotection in CHI induced exacerbation of brain pathology in PD, not reported earlier. Keywords Parkinson’s disease · Alpha synuclein · Phosphorylated tau · TDP-43 · Mesenchymal stem cells · Nanowired delivery · Dopamine · Brain pathology · Neuroprotection

1 Introduction Parkinson’s disease (PD) is a worldwide problem of populations above 50–60 years of age [1–6]. PD involves brain areas of dopaminergic system degeneration causing motor function impairment, rigidity, imbalance and other related disorders that progress with time [3–7]. At the moment, there is no cure available for PD patients. The nonmotor functions that are affected in PD include cognitive impairments, sleep disturbances, mental health dysfunctions associated with involuntary muscle contractions (dystonia) affecting speech, writing and impairment of many different areas in normal life of the patients [6, 7]. In the past 25 years, the PD cases have increased to more than double in 2019 and about more than nine million are living with PD currently [8, 9]. This resulted in over 330 k deaths since the year 2000 [8]. In China, the populations are aging and thus, PD cases are also increasing dramatically [3]. A rough estimate indicates that by 2030, more than five million cases of PD may occur alone in China [3]. Thus, there is an urgent need to explore suitable treatment strategies to treat PD cases or slowing the progression of the disease in patients. However, none of the available drugs are at

A. D. Buzoianu Department of Clinical Pharmacology and Toxicology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania A. Nozari Anesthesiology & Intensive Care, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA

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the moment showing great progress in relieving symptoms of PD or enhancing the quality of life during patient care [see Ref. 3]. Previously, we have shown that dl-3-n-butylphthalide (dl-NBP), a synthetic compound that is potent potent neuroprotective against stroke and brain injury [10–15]. This effect of dl-NBP is further enhanced in concussive head injury (CHI) when administered through nanowired delivery [13, 14]. CHI is one of the key risk factors in precipitating PD in military personnel who are prone to central nervous system (CNS) injury during combat operations [16, 17]. When dl-NBP was administered through nanowired delivery together with mesenchymal stem cells (MSCs), the combined administration induces profound and superior neuroprotection in PD after CHI in rodent model [15]. This suggests that nanowired delivery of dl-NBP either alone or with MSCs enhanced superior neuroprotection in CHI or PD cases [14, 15]. The combined nanowired delivery of dl-NBP and MSCs also resulted in reduction of a-synuclein (ASNC) levels in the cerebrospinal fluid (CSF) in PD with CHI [15]. ASNC together with elevated TAR DNA-binding protein 43 (TDP-43) is also increased in brain or CSF after CHI or traumatic brain injury without PD pathology [18–21]. TDP-43 elevation is involved in several neurodegenerative diseases including PD [19]. Thus, it would be interesting to include monoclonal antibodies (mAb) to ASNC and TDP-43 in treating PD-induced brain pathology following CHI using nanowired delivery. In present investigation, we have added mAb to ASNC and/or TDP-43 together with dl-NBP and MSCs in PD associated with CHI in rodent model [15]. Our observations clearly showed a significant enhanced neuroprotection in PD exacerbated by CHI. This suggests that the combination of dl-NBP with MSCs and mAb to ASNC and/or TDP-43 is needed to thwart PD-induced brain pathology aggravated by CHI. The possible mechanisms and functional significance of our findings are discussed in this review.

1.1

Parkinson’s Disease

Parkinson’s disease (PD) is recognized in the early 1817 by James Parkinson as “Paralysis agitans” as a chronic progressive disorder of neurodegeneration affecting both motor and nonmotor system mainly in older people over 60 years of age [22– 24]. However, younger people may also develop this disease [25, 26]. PD is one of the second most neurodegenerative diseases affecting more than ten million people across the globe [27]. Men are prone to 1.5 times greater than women in developing PD. The pathophysiology of PD includes loss of dopaminergic neurons mainly in the substantia nigra associated with precipitation of Lewy bodies or other intracellular deposits in the brain [28–33]. These pathologic changes may occur during more than 20 years of life [34]. At this time, deposition of alpha synuclein and/or ubiquitin further impairs the neuronal functions affecting motor system [35, 36]. Loss of dopaminergic neurons or degeneration by more than 50–70% in locus coeruleus

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and substantia nigra pars compacta (SNpC) are the main manifestations of PD [37–39]. These pathophysiological events may possibly occur due to some viral pathogens enter into the brain through the olfactory route affecting olfaction in PD patients [40, 41]. It is likely that nasal secretions when enters into the gut or vagus nerves, it may reach the brain [42, 43]. In PD patients, Lewy bodies are present in the vagus nerve, intestine as well as in the brain [44, 45].

1.1.1

Clinical Symptoms of PD

Clinical symptoms of PD include both motor and nonmotor dysfunction. The motor dysfunction in PD includes tremor, bradykinesia, rigidity, altered gait and postural inability [6, 7, 46]. These symptoms are progressive in nature in PD. Other motor symptoms include facial expression, blurred vision, decrease in eye blink, impaired gaze, freeze movement, speech impairment and/or repetition of words or phrases [47–50]. The nonmotor symptoms include cognitive, behavioral, psychiatric or autonomic impairments affecting sensory and sleep disturbances. These nonmotor symptoms in PD affect quality of life and represent major challenges to deal with for the patients. Almost 90% of PD patients experience nonmotor symptoms during the process of the disease manifestations [51–53]. In addition, decision-making abilities, memory retrieval, multitasking and dementia are other key features of PD cases. Normally, PD patients develop dementia with 10–12 years of PD diagnosis. These changes will further develop in mood disorders, depression, apathy and anxiety that are very common in PD patients [see Refs. 4, 54–56].

1.2

Brain Injury Is a Major Risk Factor in PD

Traumatic brain injuries (TBI) including concussive head injury (CHI) or mild traumatic brain injury (mTBI) are one of the greatest risk factors in developing PD especially in military personnel [15–17, 21]. This is evident from the findings that Veterans who sustained mTBI are more than 60% greater risk of developing PD in the later years of their life [57, 58]. This risk of TBI on PD further aggravates based on the initial magnitude and severity of earlier brain injury. A rough estimate suggests that more than 20% of returning service members is affected with some form of TBI amounting to more than 330 k Veterans in number since 2000 [59– 62]. Men are mostly accounted for TBI and they are vulnerable to PD almost twice as compared to women [63]. It is likely that women are protected from developing PD due to estrogen that is neuroprotective [64]. This could be one of the reasons that

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showing only mild symptoms at the onset of PD in women [65]. However, the exact reasons are not well clear at the moment. At the moment, about 950 k are diagnosed with PD in the US population, but this number may further increase to 1250 k by 2030 [66, 67]. Thus, exploration of novel strategies of drugs and their delivery are needed to improve quality of life in PD patients with or without TBI urgently.

1.2.1

Brain Pathology in TBI and PD Are Very Similar

There are many similarities in brain pathology caused by TBI or PD [68, 69]. Thus, in both TBI and PD, neuronal damages and degeneration associated with breakdown of the blood–brain barrier (BBB), infiltration of microglia in damaged brain areas, activation of astrocytes or gliosis, loss of myelinated or nonmyelinated axons are quite common [13, 27]. Inflammation of the central nervous system (CNS), metabolic disturbances and/or protein aggregation are some key factors that suggest that TBI and PD have many things in common with regard to brain pathology [68–70]. Inflammation Inflammation of the brain is one of the most important pathologies after TBI that persist even after several years of primary impact [71, 72]. Such inflammation of the brain is also present in PD patients [73]. Using positron emission tomography (PET) exhibited activated microglia markers in the areas of brain soon after TBI and persisted up to 17 years after the primary injury [74, 75]. This activated microglia disrupts information processing in the brain [76]. Similar activation of microglia in substantia nigra pars compacta (SNpC) was seen in PD patients [77–79]. These activated microglia increase in numbers and spread in other brain regions in PD patients with time affecting distortion of the information processing system within the brain [78, 79]. Due to this similarity in inflammation between TBI and PD, this is quite understandable that TBI is a major risk factor in precipitating PD in later years of life [16, 80]. Metabolic Disturbances Alterations in neurovascular units comprising astrocytes, endothelial cells and pericytes associated with microvessels are primarily responsible for supplying nutrients to neurons and maintain homeostasis within the nervous system [81– 83]. However, TBI damages the neurovascular unit results in disruption of homeostasis causing energy crisis within the nervous tissues [83–85]. This leads to production of excitotoxicity, generation of free radicals and inflammation within the nervous system [85]. Reactive oxygen species generation and further damage due to oxygen radicals are responsible for neuroinflammatory signals, resulting in cascade of tissue damage [85–87]. These events spread beyond the injury site and result in further development of nucleation in PD-like symptoms [88–90].

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In PD, nucleation is caused by decreased supply of metabolic nutrients and oxygen due to damage to BBB and neurovascular unit [91, 92]. BBB breakdown results in selective transport of Ca++ across mitochondria, alters intracellular catabolic processes and induces increased production of reactive oxygen species (ROS) within the brain [93–95]. Likewise, altered mitochondrial function and transport in TBI similarly induces increased ROS production within the nerve cells resulting in brain damage [83–85]. Several lines of evidences suggest that ASNC interacts with disrupted mitochondrial functions resulting in impeding axonal transport functions. Loss or decrease in energy production leads to ASNC production or phosphorylation. Degenerating neurons following ASNC neurotoxicity further leads to Lewy bodies in PD pathology [95–97]. Repeated TBI or CHI over the years may further accelerate the existing brain pathology cussed by trauma leading to late onset of PD [98–100]. These findings clearly show that TBI and PD are associated in inducing neurodegeneration. Aggregation of Proteins Protein aggregation in PD and TBI are the common features leading to neurodegeneration indicating similarities in the process of brain pathology in these conditions [69, 101, 102]. Several proteins like ASNC, amyloid beta peptide (AβP), tau phosphorylation or TAR DNA-binding protein 43 (TDP-43) are elevated in several neurodegenerative diseases including TBI and PD [103–108]. In normal conditions, ASNC in the brain is not phosphorylated; however, in PD, hyperphosphorylation occurs [109–111]. Although ASNC is a highly abundant protein in the neurons in the nucleus and in synapses, its conversion into phosphorylated ASNC in disease process is not yet well known. It is believed that production of ROS and lipid peroxidation may lead to phosphorylation of ASNC in PD [112, 113]. Exposure to pesticides or metal may enhance ASNC phosphorylation causing PD brain pathology [114–116]. ASNC level is elevated in the CSF following TBI that is proportional to the severity of trauma [117, 118]. In TBI, elevated ASNC causes enhanced ROS production and promotes PD brain pathology [108, 111]. Thus, it is quite likely that higher concentration of ASNC in TBI together with mitochondrial damage and increased ROS production are responsible for development of PD pathology. Another important protein in neurodegenerative disease is amyloid beta protein (AβP) that is normally associated with Alzheimer’s disease (AD) [119–121]. When the brain amyloid plaques or senile plaques are formed they are highly toxic and one of the main causes of neurodegeneration [122, 123]. Aggregation of AβP is both intracellular and extracellular causing neurotoxicity of hippocampus, frontal cortex and subcortical cell nuclei [124, 125]. Extracellular AβP interacts with N-methyl-Daspartate (NMDA) receptors resulting in synaptic dysfunction and neuronal damage [126]. Intracellular AβP is present in mitochondrial membranes leading to cytotoxicity of endoplasmic reticulum and lysosomal membranes with disruption of other intracellular organelles [127, 128].

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Following TBI, levels of AβP and/or senile plaque increase in various parts of the brain even after a single insult [59, 129–131]. These data suggest that TBI is one of the instrumental insults in causing development of AD or PD brain pathology. There are reasons to believe that AβP enhances ASNC aggregation into Lewy bodies and in turn accelerate AβP aggregation [132–135]. Thus, these protein aggregates are common in both AD and PD leading to neurodegeneration that are triggered by TBI. Another protein tau from microtubule-associated proteins (MAP) family responsible for maintaining the microtubule networks in healthy condition is phosphorylated in PD, AD and TBI cases leading to brain pathology [136–138]. Like ASNC and AβP, phosphorylated tau (p-tau) is associated with brain pathology in PD. The pathological involvement of p-tau in PD is also seen in TBI cases [139, 140]. Development of neurofibrillary tangles (NFTs) largely results from hyperphosphorylation of tau. Hyperphosphorylated tau leads to toxicity of microtubule networks causing structural damages to microtubules and impaired transport functions throughout the cellular system [141–143]. In PD cases, tau and ASNC are often co-localized in Lewy bodies [144–146]. Tau is also associated with TBI-induced brain pathology [147, 148]. In case of repetitive brain trauma in athletes causing degenerative changes, p-tau deposits are often seen around microvessels within cortical sulci [149–151]. Although, so far Lewy bodies are not so frequent in TBI, deposition of protein aggregates including ASNC, AβP and p-tau is likely to cause Lewy bodies pathology in TBI as well [152, 153]. However, further research in this area is needed to confirm this assumption in TBI.

1.2.2

TAR DNA-Binding Protein 43 (TDP-43) in Neurodegeneration

TDP-43 is first discovered in association with amyotrophic lateral sclerosis [154, 155]. TDP-43 is largely located within the cell nucleus of most cells where several genes are regulated by TDP-43 [156, 157]. In repetitive brain trauma and frontotemporal lobes degeneration, TDP-43 is found in the cytoplasm of several cells [158–160]. In PD cases, TDP-43 inclusions are also seen associated with ASNC [19, 161–163]. In TBI cases either with single impact or repetitive insults, TDP-43 fractions are present into the cell cytoplasm with phosphorylation causing memory loss, impaired cognition as well as neuronal death [19, 161, 162]. Following repetitive mild-to-moderate blast brain injury, TDP-43 proteinopathy is seen in the injured brain regions [19, 163]. TDP-43 inclusions are often seen with ASNC pathology, and recently, its association with Lewy bodies is seen in human cases [164, 165]. It would be interesting to explore further relationship between TDP-43 following TBI in association with PD cases, a feature that is currently being examined in our laboratory.

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2 dl-3-n-Butylphthalide (dl-NBP) and PD dl-NBP was first isolated from the seeds of Apium graveolens in 1978 and synthesized in 1980 at the Chinese Academy of Medical Sciences as anticonvulsion and sedative activities [10, 166, 167]. The Food and Drug Administration of China approved dl-NBP in 2005 for the treatment of ischemic stroke [11, 12, 168]. After that due its antioxidative properties, dl-NBP was used to treat TBI and associated neurodegenerative diseases such as PD or AD [169–172]. dl-NBP is able to prevent mitochondrial dysfunction in cellular model of PD induced by 1-methyl-4-phenylpyridinium (+)- and rescued dopaminergic neurons in rotenone-induced PD model [169, 173, 174]. In lipopolysaccharide (LPS)-induced PD model, dl-NBP improves dyskinesia, reduces microglial activation, decreases nuclear ASNC deposition and increases survival of tyrosine hydroxylase-positive cells in the SNpC [174, 175]. Based on this information, dl-NBP was used in patients with PD between 2014 and 2016 in China [176]. For brain infarction and vascular stroke patients, dl-NBP using multicenter study of phase 2 and 3 randomized controlled clinical trials showed improved neurologic function with good safety and tolerability [177–183]. In PD clinical trials, dl-NBP was given 200 mg three times for 24 weeks similarly to that dose regimen approved for stroke treatment. The drug was well tolerated without any potential side effects [184]. The dl-NBP-treated PD patients showed significant decrease in bradykinesia and rigidity or tremor scores at 12, 24 and 48 weeks after medication [184]. The sleep quality in PD patients on dl-NBP treatment also improved significantly at 12 and 24 weeks. In addition, the quality of life in dl-NBP-treated PD patients was also increased significantly at 12 and 24 weeks that was maintained after 48 weeks [184]. These observations suggest that dl-NBP could be the effective treatment in reducing bradykinesia with rigidity or tremor in PD patients [176–184]. It appears that dl-NBP in PD is affecting multiple targets in the pathogenesis of PD [184]. The dl-NBP is likely to protect dopaminergic neurons by reducing ROS production and/or free radicals [176–184]. The dl-NBP may enhance synaptogenesis and attenuate neural inflammation by reducing oxidative stress, decreasing nuclear fragmentation, maintaining mitochondrial membrane potential and activating ASNC degradation [11, 12, 168–174]. Further research on dl-NBP in PD patients is needed to clarify these points.

2.1

dl-3-n-Butylphthalide (dl-NBP) and TBI

dl-NBP exerts powerful neuroprotection in TBI or CHI. Using a weight drop model of CHI in mice, dl-NBP when given in a dose of 100 mg/kg, i.p. 1 h after insult was able to protect brain damage following 24-h injury [185, 186]. The brain water content is significantly reduced together with functional deficits and cortical

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neuronal apoptosis. dl-NBP also reduced the oxidative stress parameters as seen by restoring the levels of malondialdehyde, superoxide dismutase and glutathione peroxidase after CHI [186]. Apart from CHI, controlled cortical impact (CCI) in mice was delivered after opening the skull in mice that were given dl-NBP (100 mg/kg, i.p.) 5 min after trauma and the parameters were measured 24 h after CCI. In the same setup, dl-NBP (100 mg/kg) was delivered through intranasal route after CCI for 3 or 21 days [185, 186]. When dl-NBP was delivered intraperitoneally 5 min after CCI, caspase-3/9 activation, cytochrome c release from the mitochondria, and apoptosis-inducing factor (AIF) in the pericontused areas are significantly attenuated in NBP-treated mice [186]. This indicates that dl-NBP reduced apoptotic events after TBI. In addition, dl-NBP also significantly reduced p65 expression and nuclear factor κB pathway suggesting amelioration of brain inflammation [186]. This is further evident from the findings that dl-NBP decreases upregulation of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β) after TBI. When dl-NBP is delivered intranasally for 3 days, the contusion volume and cell death in the perifocal regions are considerably reduced [185, 186]. After dl-NBP treatment for 21 days, post-TBI though intranasal route upregulation of brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), endothelial-nitric oxide synthase (eNOS) and matrix metallopeptidase-9 (MMP-9) is seen [185–189]. This indicates that dl-NBP elevates several regenerating neuronal and vascular factors after brain injury. Apart from brain injury, dl-NBP also protects spinal cord pathology after trauma. When spinal cord injury is inflicted in rats with a vascular clip and dl-NBP (80 mg/ kg) is given by oral gavage 2 h before injury and then once daily for 28 days neurological recovery as seen using locomotion rating scale, inclined plane angle test or footprint analysis is significantly improved [185, 187–189]. Furthermore, dl-NBP significantly attenuated spinal cord cavity area and cell death in the injured cord. NBP also decreased neuronal apoptosis and inhibited activation of the caspase 3 cascade. These results suggest that dl-NBP is neuroprotective in spinal cord injury as well [187, 189].

3 Nanowired Delivery of dl-3-n-Butylphthalide (dl-NBP) for Superior Neuroprotection In brain injury or neurodegenerative diseases such PD or AD, vascular reactions, breakdown of the BBB, edema formation and cell injury are the common features [27, 106]. For clinical therapy, drug treatments are always given after the injury or neurodegenerative diseases processes are already developed in patients. Under such circumstances, conventional drugs do not reach brain targets for effective treatment strategies [191]. Edema formation and vascular injury alter normal permeability properties of the drugs across the BBB [190, 191]. Thus, effective delivery system for drug is needed following brain injury or neurodegenerative diseases.

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Recently, nanodrug delivery has shown the capability to penetrate into the brain in wide areas and presents within the neural compartment for long time maintaining their pharmacological activity for longer durations [192]. Keeping these views in mind, we developed nanowire drug delivery to treat TBI and PD or AD effectively for superior neuroprotective effects [192–196]. Our results clearly suggest that nanowired delivery of neuroprotective compounds in TBI, AD or PD induce superior neuroprotection as compared to the same drugs given as conventional therapy [190–196]. This suggests that suitable neuroprotective agents may be given using nanowired delivery for enhanced neuroprotection in chronic ailments or TBI in patients for effective management of the diseases.

3.1

Nanowired Delivery of dl-3-n-Butylphthalide in Concussive Head Injury

Using CHI model in rats inflicted by dropping a weight of 114.6 g from a height of 20 cm on the exposed right parietal bone produces an impact of 0.224 N is given dl-NBP was (40 or 60 mg/kg, i.p.) 2 and 4 h after injury in 8-h survival group and 8 and 12 h after trauma in 24-h survival group. In separate group of rats, TiO2nanowired delivery of dl-NBP (20 or 40 mg/kg, i.p.) in 8- and 24-h CHI rats was also examined [see Ref. 14]. Treatment with dl-NBP significantly reduced BBB damage, brain edema formation and brain pathology in CHI following 8–12 h at 40-mg dose whereas, 60-mg dose is required to thwart brain pathology at 24 h following CHI. When TiO2–dl-NBP only 20-mg dose is able in reducing brain pathology in CHI up to 8 or 12 h and 40-mg dose is able to effectively induce neuroprotection at 24-h CHI [14]. These observations are in line to suggest that nanowired delivery of dl-NBP has far more superior effects in CHI in almost half doses from the conventional dl-NBP dose. The reasons of 50% less dl-NBP dose given through nanowired delivery in CHI because of its slow release inside the brain compartments for longer time periods after penetrating the damaged brain tissues [192–196]. In addition, binding of drug to nanowires makes them less degradable by brain enzymes as compared to the conventional drugs [195, 196]. These factors could play important role in pharmacokinetics of nanowired delivery of drugs for effective neuroprotection.

3.2

Nanowired Delivery of dl-3-n-Butylphthalide in Parkinson’s Disease

Nanowired delivery of drugs not only induces superior neuroprotection following CHI, AD or PD but also exerts significant reduction in brain pathology associated with co-morbidity factors [13, 14, 197]. Thus, when AD is complicated with brain injury, nanowired delivery of drugs is able to thwart brain pathology and exerts

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powerful neuroprotection in such combined injury process with neurodegeneration [198–200]. This is further evident from our findings of nanowired delivery of dl-NBP in PD associated with CHI cases [13, 14, 197]. We used nanowired delivery of dl-NBP with mesenchymal stem cells (MSCs) in PD with CHI [13, 14, 197]. CHI exacerbates PD pathophysiology by enhancing the magnitude of elevated p-tau, α-synuclein (ASNC) levels in the CSF [13]. The loss of tyrosine hydroxylase (TH) immunoreactivity in substantia niagra pars compacta (SNpc) and striatum (STr) with dopamine (DA), dopamine decarboxylase (DOPAC and homovanillic acid (HVA) are significantly greater in PD with CHI as compared to PD or CHI alone [13, 14]. When nanowired delivery of dl-NBP in combination with MSCs is given to PD with CHI cases, superior neuroprotective effects in PD brain pathology exacerbated by CHI are seen [13]. This indicates that nanowired delivery of drugs alone or in combination exerts superior neuroprotective effects in neurodegenerative diseases complicated with co-morbidity or associated risk factors [13, 14, 192–200].

4 Mesenchymal Stem Cells and PD Mesenchymal stem cells (MSCs) are one of the potent agents to treat PD-induced loss of dopaminergic neurons [201–203]. Pharmacological agents are able to reduce PD symptoms in clinic at an early stage but at a later stage, these agents miserably fail to provide any benefit to the patients [204–208]. In this regard, MSCs could be one of the promising agents to treat PD cases successfully and may prevent further damage of dopaminergic neurons [209–211]. MSCs are able to induce regeneration in brain injury cases and have anti-inflammatory properties suitable for PD treatment safely [212–214]. MSCs when transplanted secrete several anti-inflammatory factors such as interlukin-6 (IL-6) and IL-10 associated with hepatocyte growth factor (HGF), macrophage colony-stimulating factor (MCSF) and prostaglandin-2 (PGE2) [215– 218]. These factors secreted by MSCs promote tissue repair, stimulate proliferation, decrease inflammation and enhance immune system. With trophic factors, secretion MSCs are able to induce regeneration and with differentiation effects, MSCs could repair or replenish lost cells. These properties of MSCs are used in PD to restore or regenerate dopaminergic neurons in the brain [219]. Studies of MSCs transplantation in PD patients are performed and followed up to 36 months indicated marked amelioration of D symptoms without any tumor formation [220]. In some cases, genetically modified MSCs were transplanted that produce L-DOPA or neurotrophins such as glia cell line-derived neurotrophic factor (GDNF) that was found to significantly reduce PD symptoms in patients [221, 222]. When MSCs engineered with dopamine neurons (1 × 105 cells) from rodent or humans are transplanted into the SNpC of a rat PD model, these cells migrated across the injected site and only 30% remained in the striatum after 10 weeks of transplantation showing TH positive neurons [220]. MSCs enhance neuronal plasticity and cell survival due to increased striatal dopamine levees [220]. These observations

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suggest that dopamine neurons induced from MSCs are capable in enhancing TH positive neurons and increase dopamine levels in SNpC without forming any tumors. Thus, MSCs have potential capacity in PD treatment. This is because of the fact that MSCs have neurotrophic effects and protect damaged brain tissues and differentiate into dopamine neurons, as well as contribute to replenish the degenerated/or lost cells in PD [209–216].

4.1

Mesenchymal Stem Cells in Brain Injury

The excellent regenerating properties of MSCs including secretion of neurotrophic factors together with antiapoptotic proteins and enhancing immune responses are quite effective for the treatment in TBI or other insults to brain [223–226]. The differentiation ability of MSCs is also remarkable into both the neuronal and gliallike cells in experimental conditions [227, 228]. This is likely to be achieved by release of chemokines in the cellular environment or through activation of astrocytes. The MSCs also regulate the growth and differentiation of cells through secretion of inflammatory cytokines and inhibit proliferation of T cells and microglia [229, 230]. There are reasons to believe that MSCs migrate to the damaged tissues and enhance cell survival by releasing anti-inflammatory cytokines. MSCs transfusion after brain damage is shown to reduce microglia-induced release of TNF-α and enhance anti-inflammatory cytokine IL-10 [231, 232]. MSCs also elevate antiapoptotic gene bcl2 in the damaged tissue and periphery along with decrease protein bax and caspase 3 levels in the injured tissues [233–235]. TNF-α receptor (TNFR) is known to induce several survival complexes in the plasma membrane in healthy conditions but activates caspase 8 in pathological situations [236, 237]. MSCs are able to modify the TNFR distributions in the injured tissues in order to enhance survival signals though TNFR activity [238, 239]. In addition, MSCs may produce Wnt3a protein that has neurogenic effects and increases neuronal survival [240]. However, the details of MSCs-induced cell survival are not well characterized and require additional investigations. Following brain injury, MSCs enhance learning and long-term memory function associated with improvement of motor function [241–243]. This could be due to MSCs-induced increased BDNF secretion and enhance phosphorylation of extracellular signal-related kinase (ERK) and cAMP-response element-binding (CREB) proteins in the hippocampus [244–246]. Administration of MSCs after brain injury enhances vascular endothelial growth factor (VEGF) and induces angiogenesis in damaged tissues for improved survival [247, 248]. MSCs after injection or transplant following TBI migrate to the injury site within 1 week and promote release of adhesion molecule such as vascular cell adhesion molecule-1 (VCAM-1), resulting in adhesion of MSCs to endothelial cells of the damaged tissue initiating repair and cell survival [225]. As a result, reduction in brain edema, inflammatory cytokines and decrease in the number of microglia, macrophages or neutrophils are seen in the

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damaged cortex following TBI [see Ref. 225]. After MSCs transplantation in TBI, neurological scores improved and reduction in the BBB breakdown and upregulation of tissue inhibitor metalloproteinase 3 (TIMP3) occurs [225]. Furthermore, MSCs administration induces expression of anti-inflammatory TNF-stimulated gene-6 (TSG-6), an inhibitor of NFκB signaling pathway and reduces the pro-inflammatory cytokines production within 12–72 h in TBI [224– 226]. MSCs induce better recovery from neuronal inflammation after TBI through activation of cyclooxygenase 2 (COX II) and the production of prostaglandin E2 that was directly related to the inhibition of TNF-α expression and the activation of COX II pathway [225, 228]. Recent research shows that the exosomes derived from MSCs significantly improve neurological functions following TBI and reduce the secondary injury processes by reducing the inflammatory signaling and pathways. These include significant reduction in brain lesion volume and expression of inflammatory cytokines TNF-α and IL-1β in addition to BAX preapoptotic protein [249, 250]. These MSCs-derived exosomes elevate anti-apoptotic BCL-2 expression together with anti-inflammatory functions of microglia in TBI [250]. These observations suggest that MSCs administration induces superior neuronal survival after TBI or neurodegeneration following PD or AD [13, 190, 251].

4.2

TDP 43 and Parkinson’s Disease

Accumulation of TAR DNA-binding protein 43 (TDP-43) and its aggregation is commonly seen in neurodegenerative diseases including Parkinson’s disease, Alzheimer’s disease as well as following traumatic brain injury [19, 20, 163, 252]. Age-related TDP-43 proteinopathy and accumulation result in aggregation comprising tau, amyloid beta and alpha synuclein, resulting in the development of Parkinson’s or Alzheimer’s disease [253]. Thus, targeting TDP-43 using drugs and monoclonal antibodies in Parkinson’s disease could lead to novel therapeutic approaches in clinics.

5 Our Investigations in PD with CHI We have undertaken a series of studies using dl-3-n-butylphthalide nanowired delivery in brain injury associated with chronic neurodegenerative diseases such as PD or AD in enhancing neuroprotection together with monoclonal antibodies to various agents involved in the signaling pathways of brain pathology under these conditions. In this investigation, we used nanowired dl-3-n-butylphthalide with MSCs together with monoclonal antibodies to ASNC and TDP-43 in order to achieve superior neuroprotection in PD associated with CHI. Brief description of our investigation is discussed below.

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Methodological Consideration

Experiments were done on 20–23-week-old inbred C57BL/6 male mice (body weight 30–35 g) housed at controlled room temperature (21 ± 1 °C) with 12-h light and 12-h dark schedule. The commercial mouse food and tap water were supplied ad libitum. All experiments were conducted according to the National Institutes of Health (NIH) Guide for the Care and Use of Laboratory Animals and approved by the Local Institutional Ethics Committee (Guide for the Care and Use of Laboratory Animals, 8th edition, National Institute of Health, The National Academies Press, Washington DC, USA, 2011, https://www.nap.edu).

5.1.1

Mouse Model of Parkinson’s Disease

We used MPTP (1-metyl-4-fenyl-1,2,3,6-tetrahydropyridin) model in mice to simulate PD-like symptoms as described earlier. In brief, MPTP (20 mg/kg, i.p.) was administered in mice twice daily within 2-hour intervals for 5 days using standard protocol. This treatment causes PD-like symptoms at the eighth day. Several physiological, behavioral or pathological parameters were examined on the eighth day. Control group of animals receives 0.9% physiological saline instead of MPTP in identical manner.

5.1.2

Concussive Head Injury

In MPTP-treated mice on the eighth day, CHI was inflicted using a weight drop technique on the right side exposure skull as described in details earlier [251]. In brief, a weight of 28.6 g was dropped over 20 cm height on mouse right parietal skull inflicting an impact injury of 0.56 N without perforation [251]. The MPTP mouse with CHI was allowed to survive 48 h after the traumatic insult.

5.1.3

Nanowired Treatments Strategies

In MPTP mouse model, nanowired NBP was administered in a dose of 40 mg/kg (i.p.) combined with intravenous nanowired MSCs (1 × 106, Cyagen Biosciences Inc., Santa Clara, CA 95050, USA; Cat # RASMX-01001) together with monoclonal antibodies (mAb) to ASNC (alpha Synuclein Monoclonal Antibody, Catalog # AHB0261, Thermo Fisher Scientific, Waltham, MA USA) and Recombinant Anti-TDP-43 antibody (ab254166, Waltham, MA, USA), diluted 1:20 in PBS, 20 μl each, i.c.v. through a constant infusion pump at the rate of 4 μl/min (Harvard Apparatus, Holliston, MA, USA). Nanowired delivery of NBP, MSCs together with mAbs to ASNC and TDP-43 is prepared as discussed earlier [13, 14,

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198–200, 251]. Nanowired delivery of NBP, MSCs and mAb to ASNC and TDP-43 was done 4 h after CHI and repeated 24 h after trauma, and various parameters are examined 48 h after CHI in MPTP-treated mice [251].

6 Observations in PD and CHI The following observations were made in MPTP mice with CHI 48 h using standard protocol as described earlier [13, 14, 198, 199, 208].

6.1

Blood–Brain Barrier Breakdown in MPTP Mice

Blood–brain barrier was examined in MPTP mice associated with CHI using Evans blue albumin (EBA) and radioiodine [131]-I-Na tracers as described earlier [13, 14]. The results are shown in Table 1. MPTP-induced Parkinson’s-like behavior in mice is associated with BBB breakdown to EVA and radioiodine tracers as shown earlier [13]. When CHI was inflicted in MPTP mice, the magnitude and severity of BBB breakdown was further enhanced (Table 1). Leakage of EVA was much deeper and spread all over the brain in dorsal and in ventral surfaces of the cerebral cortex and cerebellum as well. Cerebral ventricles were also stained moderately in CHI with MPTP mice staining moderately blue the brain regions including SNpC, striatum, caudate nucleus, hippocampus, thalamus, hypothalamus, follicular regions and brain stem. In MPTP mice alone, the brain areas were also stained moderately blue in similar areas with less intensity (results not shown). Extravasation of radioiodine was significantly higher in both MPTP alone and CHI inflicted in MPTP mice (Table 1). Treatment with nanowired NBP together with MSCs and mAbs to ASNC, TDP-43 significantly reduced the BBB breakdown in MPTP mice. This effect was also seen in CHI in MPTP mice after 48-h trauma (Table 1). Thus, nanowired treatment with NBP, MSCs and mAbs to ASNC and TDP-43 significantly reduced the BBB breakdown in MPTP mice with CHI that was significantly exacerbated in the untreated group (Table 1).

6.2

Brain Edema Formation in MPTP Mice

Brain edema was measured using water content as described earlier [13, 14]. In MPTP mice, there was a significant increase in brain water content from the control group representing about 5% increase in volume swelling. Whereas when CHI was inflicted in MPTP mice, the brain water content showed further exacerbation amounting to enhance volume swelling to about 13% from the control group (Table 1).

0.92 ± 0.07#

0.73 ± 0.06#

PD+CHI

75.89 ± 0.15#

75.67 ± 0.14#

75.34 ± 0.25

78.67 ± 0.25*#

76.54 ± 0.21*

75.32 ± 0.14

1.19 ± 0.05#

1.18 ± 0.04#

1.67 ± 0.09

0.78 ± 0.09*#

0.98 ± 0.08*

1.63 ± 0.08

ml/g/min

Cerebral blood flow

82 ± 4#

89 ± 6#

108 ± 4

33 ± 6*#

43 ± 6*

105 ± 4

Sec

Rota-rod

45 ± 53

50 ± 6#

63 ± 6

30 ± 8*#

40 ± 5*

60 ± 6

Inclined

Inclined plane

8 ± 3#

6 ± 4#

2±3

24 ± 7*#

18 ± 6*

1±2

Error Nr

Placement

2.96 ± 0.08#

2.89 ± 0.06#

2.28 ± 0.08

4.38 ± 0.12*#

3.54 ± 0.07*

2.25 ± 0.06

Stride width cm

Foot print analyses

5.94 ± 0.12#

5.79 ± 0.13#

6.24 ± 0.12

3.52 ± 0.11*#

4.33 ± 0.15*

6.20 ± 0.13

Stride length cm

Values are mean ± SD of six to eight mice at each point. MPTP was administered 20 mg/kg, i.p. twice daily with interval of 5 h for 5 days. Concussive head injury (CHI) was inflicted on the eight day in MPTP mice on the right parietal skull (0.56 N) and allowed to survive 48 hours after trauma. Nanowired NBP was administered in a dose of 40 mg/kg (i.p.) combined with intravenous nanowired MSCs (1 × 106) together with monoclonal antibodies (mAb) to ASNC (alpha synuclein) and TDP-43 diluted 1:20 in PBS, 20 μl each, i.c.v. at the rate of 4 μl/min. Nanowired NBP (dl-3-n-butylphthalide), MSCs and mAb to ASNC and TDP-43 was delivered in MPTP mice 4 h after CHI and repeated 24 h after trauma and parameters are examined 48 h after CHI [251] * P < 0.05 from saline control, # P < 0.05 from MPTP-PD cases; ANOVA followed by Dunnett’s test for multiple group comparison from one control

0.26 ± 0.07

0.63 ± 0.10#

0.19 ± 0.08

0.45 ± 0.08#

Control

PD

C. Nanowired NBP+MSC+mAb ASNC+TDP-43

1.58 ± 0.89*

3.14 ± 0.27*#

1.17 ± 0.12*

2.45 ± 0.29*#

PD

0.31 ± 0.04

Water content %

0.23 ± 0.02

Brain edema

EBA mg %

[131]-I-Na %

BBB breakdown

PD+CHI

B. MPTP-PD

Saline

A. Control

Type of expt.

Table 1 Concussive brain injury exacerbates Parkinson’s disease blood–brain barrier (BBB) disruption, brain edema formation, cerebral blood flow reduction and behavioral function and gait abnormalities in MPTP mice

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Treatment with NWNBP, NWMSCs and NWmAbs to ASNC and TDP-43 significantly attenuated brain edema in MPTP alone, resulting in much less volume swelling to about 1% from the control group (Table 1). Treatment with combined NBP, MSCs and mAbs to ASNC and TDP-43 given through nanodelivery resulted in profound reduction in brain edema and volume swelling. Thus, only 2% volume swelling is seen after CHI in MPTP mice after combined with NBP, stem cell and antibodies to ASNC and TDP-43 (Table 1).

6.3

Cerebral Blood Flow Reduction in MPTP Mice

Brain edema and volume swelling often results in reduction in cerebral blood flow and vice versa [13, 14]. We measured cerebra blood flow using radiolabelled carbonized microspheres (15 ± 0.6 μm OD) as described earlier [13, 14]. Our results showed a significant reduction in the cerebral blood flow in MPTP mice alone by more than 40% as compared to the controls (Table 1). This reduction in the cerebral blood flow was further exacerbated following CHI in MPTP mice. Thus, about 52% reduction in cerebral blood flow was seen in MPTP mice after CHI as compared to the control group (Table 1). When nanowired delivery of NBP together with NWMSCs and NWmAbs to ASNC and TDP-43 was done in MPTP mice with CHI, the reduction in cerebral blood flow was significantly minimized to only 26% from the control group. However, this nanowired delivery of NBP, MSCs and mAbs to ASNC and TDP-43 was also able to reduce cerebral blood flow changes in MPTP mice alone by 27% from the control values (Table 1).

6.4

Behavioral Symptoms in MPTP Mice

We examined behavioral functions in mice PD model using a variety of parameters on Rota-Rod performances, inclined plane angle test, walking on mesh grid for paw placements and or foot print analysis [198]. Our observations show that MPTP mice exhibited significantly reduced duration on Rota-Rod treadmill (16 r.p.m.) by 59% as compared to the control group (Table 1). On the other hand, CHI inflicted on MPTP mice further decreased their time on Rota-Rod treadmill compared to the controls (Table 1). Thus, MPTP mice with CHI showed 68% reduction in time to maintain on Rota-Rod treadmill (Table 1). Treatment with NWNBP together with NWMSCs and NWmAbs to ASNC and TDP-43 significantly enhanced the maintenance time on Rota-Rod treadmill to MPTP mice with CHI. Thus, the combined treatment strategies in MPTP mice with CHI were able to reduce their time on Rota-Rod treadmill to 21% only, whereas this identical treatment in MPTP mice alone reduced their time on Rota-Rod treadmill to 15% from the control value (Table 1).

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During inclined plane angle test, the MPTP mice alone are able to maintain on the inclined plane at an angle of 40° as compared to the control values of 60° (Table 1). When CHI was inflicted in MPTP mice, the inclined plane angle was further lowered down to 30° (Table 1). However, treatment with NWNBP together with NWMSCs and NAmAbs to ASNC and TDP-43 significantly improved the inclined plane angle for MPTP mice with CHI to 45° and to MPTP alone to 50° as compared to the co-troll value of 60° (Table 1). In walking on a mesh grid at 45°, MPTP mice showed significant placement error of their hind paw on the grid and this placement error was exacerbated when these MPTP mice were inflicted with CHI (Table 1). On the other hand, treatment with NWNBP together with NWMSCs and NWmAbs to ASNC and TDP-43 significantly attenuated these placement errors on mesh grid in CHI-inflicted MPTP mice as well as MPTP mice alone (Table 1). When gait abnormalities were examined in MPTP mice using foot print analyses, it appears that both the stride width and stride length were significantly affected as compared to the controls (Table 1). Thus, MPTP mice alone showed significant increase in stride width and significant decrease in stride length as compared to the controls (Table 1). The stride width is further exacerbated in CHI-inflicted MPTP mice as compared to the control and stride length was also further decreased as compared to the controls (Table 1). Treatment with NWNBP together with NWMSCs and NWmAbs to ASNC and TDP-43 significantly reduced the stride width and significantly increased the stride length in CHI-inflicted MPTP mice or MPTP alone group as compared to the controls (Table 1).

6.5

Biochemical Measurements in MPTP Mice

In order to understand the biochemical changes in MPTP mice with or without CHI, we measured dopamine, = 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and tyrosine hydroxylase (TH) activity in SNpC. In MPTP mice alone, there was a significant reduction in dopamine, DOPAC, HVA and tyrosine hydroxylase activity in SNpC as compared to the controls (Table 2). In CHI-inflicted MPTP mice, this decrease was further exacerbated in dopamine, DOPAC, HVA and tyrosine hydroxylase activity in SNpC as compared to the control group (Table 1). Treatment with NWNBP together with NWMSCs and NWmAbs to ASNC and TDP-43 significantly enhanced the levels of dopamine, DOPAC, HVA and tyrosine hydroxylase activity in SNpC in MPTP mica with CHI and also in MPTP alone group (Table 2).

6.6

Molecular Pathology Markers in MPTP Mice

We also measured molecular pathology markers such as p-tau, ASNC, TDP-43, Iba1 and synaptophysin in SNpC of MPTP mice with or without CHI (Table 2). Our results showed a significant increase in p-tau, ASNC, TDP-43 and Iba1 levels in

1.17 ± 0.23*#

1.38 ± 0.23*#

5.23 ± 0.22#

4.89 ± 0.27#

12.56 ± 0.38#

10.28 ± 0.31#

PD

PD+CHI

HVA

1.21 ± 0.06#

1.56 ± 0.09#

2.48 ± 0.12

0.26 ± 0.06*#

0.34 ± 0.08*

2.15 ± 0.14

ng/mg

TH

0.79 ± 0.10#

0.88 ± 0.07#

0.97 ± 0.09

0.24 ± 0.09*#

0.38 ± 0.08*

0.87 ± 0.16

ng/μg protein

p-tau

16.47 ± 0.21#

18.39 ± 0.16#

22.46 ± 0.12

54.38 ± 0.27*#

43.34 ± 0.16*

20.45 ± 0.13

ng/μg

ASNC

5.37 ± 0.16#

4.24 ± 0.13#

3.67 ± 0.08

16.76 ± 0.31*#

12.86 ± 0.23*

3.45 ± 0.09

ng/μg

TDP-43

6.28 ± 0.22#

4.37 ± 0.14#

1.18 ± 0.07

10.18 ± 0.16*#

8.48 ± 0.23*

1.24 ± 0.04

ng/g

Iba1

18.36 ± 0.08#

16.19 ± 0.26#

12.28 ± 0.18

27.38 ± 0.32*#

23.14 ± 0.27*

10.24 ± 0.06

pg/g

Synaptophysin

1.98 ± 0.14#

1.72 ± 0.12#

2.24 ± 0.10

0.62 ± 0.14*#

1.03 ± 0.15*

2.34 ± 0.12

ng/g

Values are mean ± SD of six to eight mice at each point. MPTP was administered 20 mg/kg, i.p. twice daily with interval of 5 h for 5 days. Concussive head injury (CHI) was inflicted on the eight day in MPTP mice on the right parietal skull (0.56 N) and allowed to survive 48 h after trauma. Nanowired NBP was administered in a dose of 40 mg/kg (i.p.) combined with intravenous nanowired MSCs (1 × 106) together with monoclonal antibodies (mAb) to ASNC (alpha synuclein) and TDP-43 diluted 1:20 in PBS, 20 μl each, i.c.v. at the rate of 4 μl/min. Nanowired NBP, MSCs and mAb to ASNC and TDP-43 was delivered in MPTP mice 4 h after CHI and repeated 24 h after trauma and parameters are examined 48 h after CHI [251] NBP dl-3-n-butylphthalide, TH Tyrosine hydroxylase, ASNC alpha synuclein, p-tau phospho tau, DOPAC 3,4-dihydroxyphenylacetic acid, HVA homovanillic acid * P < 0.05 from saline control, # P < 0.05 from MPTP-PD cases; ANOVA followed by Dunnett’s test for multiple group comparison from one control

6.26 ± 0.17

16.18 ± 0.31

Control

C. Nanowired NBP+MSC+mAb ASNC+TDP-43

2.18 ± 0.29*

2.31 ± 0.12*

6.18 ± 0.13

PD+CHI

15.76 ± 0.24

DOPAC

ng/mg

Dopamine

ng/mg

PD

B. MPTP-PD

Saline

A. Control

Type of expt.

Table 2 Concussive brain injury exacerbates Parkinson’s biochemical parameters in substantia nigra pars compacta (SNpC) in MPTP mice

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SNpC of MPTP mice that was further exacerbated when additional CHI was inflicted in MPTP mice (Table 2). On the other hand, the synaptic protein synaptophysin exhibited significant decrease in SNpC of MPTP mice that was further exacerbated in MPTP mice inflicted with CHI (Table 2). Treatment strategies with the combined administration of NWNBP together with NWMSCs and NWmAba to ASNC and TDP-43 were able to significantly decrease the levels of p-tau, ASNC, TDP-43 and Iba1 in SNpC of MPTP mice with or without CHI (Table 2). The level of synaptophysin also restored near-normal values in SNpC of MPTP mice with or without CHI following NWNBP, NWMSCs and NWmAbs to ASNC and TDP-43 combined administration (Table 2).

6.7

Morphological Alterations in MPTP Mice

Morphological examinations in MPTP mice with or without CHI were done using light and transmission electron microscopy using standard protocol as described earlier [13, 14]. MPTP mice show severe neuronal damages, edema formation, expansion of the neuropil and sponginess together with damage to myelin, astrocytes and neurons in several brain areas. A representative example of neuronal damages in the cerebral cortex in MPTP mice with CHI and without is shown in Fig. 1. Treatment strategy with NWNBP together with NWMSCs and NAmAbs to ASNC and TDP-43 in MPTP mice with CHI is shown in Figs. 2 and 3. The combined treatment in MPTP mice inflicted with CHI showed profound neuroprotection as compared to the untreated group (Fig. 2).

Fig. 1 Shows MPTP neurotoxicity (arrows) in parietal cerebral cortex (a) and its exacerbation following concussive head injury (CHI) in Parkinson’s disease model (b). Several dark and distorted neurons (arrows) are seen in the neuropil with edematous expansion and sponginess is clearly evident. Paraffin section 3 μm, Nissl staining, Bar = 30 μm

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Fig. 2 Shows MPTP neurotoxicity after concussive head injury (b) exhibiting several dark and distorted neurons in the parietal cerebral cortex (arrows, b). Treatment with nanowired delivery of NBP (NWNBP) together with mesenchymal stem cells (MSC) markedly attenuated neurotoxicity in MPTP mice with CHI (a). Several healthy looking neurons are present in treated mice parietal cerebral cortex (a) while only a few dark and distorted neurons could be seen (arrows, a). Paraffin section 3 μm, Nissl Staining, Bar = 30 μm

Fig. 3 Shows marked neuroprotection in MPTP mice with concussive head injury (CHI) treated with nanowired NBP (NWNBP) together with mesenchymal stem cell (MSC) and monoclonal antibodies (mAb) to alpha synuclein (ASNC) (a) and further superior neuroprotection seen when monoclonal antibodies (mAb) to TDP-43 is also added together with NWNBP, MSC and mAb to ASNC (b). Only a few dark and distorted nerve cells are present in the neuropil (arrows). Paraffin section 3 μm, Nissl staining, Bar = 30 μm

Using ultrastructural changes in the cerebral cortex of mice with MPTP and CHI, cellular damage, loss of synapse, vacuolation and membrane damage together with myelin vesiculation are seen, and these changes were markedly attenuated following nanowired delivery of NBP, MSCs and mAbs to ASNC and TDP-43 (Fig. 4).

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Fig. 4 High-power transmission electron micrograph (TEM) showing axonal swelling (A) with vacuolation (*) and edema (arrow, a) in saline treated MPTP mice with concussive head injury (CHI) (a). Treatment with nanowired NBP (NWNBP) together with mesenchymal stem cell (MSC) together with monoclonal antibodies (mAb) to alpha synuclein (ASNC) and TDP-43 induced superior neuroprotection in MPTP mice with CHI (b). The axonal (A) swelling is not seen and incidences of vacuolation (*) and edema are much less frequent (b). Ultrathin section contrasted with lead citrate and uranyl acetate, Bar = 2 μm

7 Possible Mechanisms of Neuroprotection in MPTP Mice The present results show that MPTP mice when subjected to additional CHI exhibit exacerbation of brain pathology associated with blood–brain barrier breakdown, edema formation and ischemic reductions in the cerebral blood flow. These observations are in line with our findings on MPTP-induced Parkinson’s disease with CHI in mice and rats shown earlier [13, 27]. The occurrence of exacerbation of Parkinson’s disease following brain injury is well supported in clinical situations [16, 21]. One of the main reasons of such exacerbations in MPTP-induced Parkinson’s disease and CHI is related to the proteinopathy caused by aggregation of TDP-43 within the brain regions [18–20, 145, 154–156, 158–162]. TDP-43 accumulations occur after traumatic brain injury and also seen in several neurodegenerative diseases including Alzheimer’s and Parkinson’s disease [154–156, 158– 162]. TDP-43 proteinopathy is also associated with increased ASNC proteins within the brain that is seen in Parkinson’s disease as hallmark of the disease [18, 21, 32, 33, 44, 78, 79, 104, 109–111, 117, 118]. These observations show that ASNC and TSP-43 proteins work in synergy to induce neurodegenerative diseases following trauma as well as in Parkinson’s disease [118, 132–135, 144–146, 161]. This further confirms our findings of increased TDP-43 and ASNC levels in the SNpC of mice following MPTP alone or in combination with MPTP and CHI. Exacerbation of ASNC and TDP-43 levels seen in SNpC in MPTP mice after CHI in present study further supports this hypothesis.

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That ASNC and TDP-43 are crucial for brain pathology in Parkinson’s disease alone or after the infliction of CHI is further observed in our investigations when nanowired monoclonal antibodies to ASNC and TDP-43 were added in the treatment strategies with nanowired NBP and MSCs in this investigation. Our results showed that combined administration of NWNBP together with NWMSCs and NWmAbs to ASNC and TDP-43 enhanced superior neuroprotection in MPTP nice with CHI. Interestingly, treatment with NWNBP and NWMSCs without NWmAbs ASNC and TDP-43 also attenuated brain pathology in rodents using MPTP model and CHI shown earlier [13, 27]; however, adding NWmAbs induced superior neuroprotection, a feature not seen in earlier studies. This suggests that blockade of ASNC and TDP-43 is one of the effective therapeutic approaches in reducing brain pathology following Parkinson’s disease and CHI together. Both CHI alone and MPTP-induced Parkinson’s disease induce breakdown of the BBB [13, 14]. Thus, when MPTP alone is able to BBB disruption, then additional CHI will further exacerbate breakdown of the BBB as found earlier [13–15, 71, 139, 140, 192, 200, 232]. Breakdown of the BBB to protein tracers such as EBA and radioiodine used in this investigation together with reduction in the cerebral blood flow leads to edema formation [14, 188, 195, 196, 254–258]. Treatment with NWNBP significantly reduces edema formation and BBB disruption following CHI, in Parkinson’s disease and other neuronal diseases [10–14, 186]. When NWMSCs are added with NWNBP, their combined efficacy in neurological disorders is significantly enhanced including CHI and in Parkinson’s disease [13, 14, 198, 201, 203, 209–212, 215–218, 223–227, 232–235]. This suggests that mesenchymal stem cells are quite potent in reducing BBB damage and induce neuroprotection. In our investigations, we combined NWNBP together with NWMSCs together with NWmAbs to ASNC and TDP-43 that appears to be the most effective combination in reducing the brain pathology in MPTP-induced Parkinson’s disease in mice with or without additional CHI. This is further evident with the findings that structural changes in the neuropil together with synaptic damage, membrane vacuolation, myelin vesiculation and axonal damages seen at ultrastructural level were also prevented by the combined strategies of monoclonal antibodies to ASNC with RDP-43 and NWNBP together with NWMSCs. That synaptic damage is also minimized with this combined treatment is further evident with the findings with synaptophysin measurement in MPTP with or without CHI in mice. Our observations clearly show that synaptophysin, the synaptic protein [108, 126, 160], significantly decreased in MPTP mice with or without CHI and the treatment strategies with combined NWNBP, NWMSCs and NWmAbs to ASNC and TDP-43 significantly retire the synaptophysin levels. This suggests that these treatment strategies in combination are quite effective in restoring synaptic function following Parkinson’s disease associated with CHI, not reported earlier. The other salient features of this investigation further suggest that treatment with NWNBP in combination with NWMSCs and NWmAbs to ASNC and TDP-43 is also able to reduce activation of microglia in Parkinson’s disease that was exacerbated following additional CHI [88, 175, 187, 230] as evident from the measurement of Iba1 level in SNpC. These observations suggest that activation of microglia is one of the key features in Parkinson’s disease and CHI-induced brain pathology.

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There are reasons to believe that when NWNBP, NWMSCs and mAbs to ASNC and TDP-43 significantly reduce the structural changes and molecular markers of neuropathology in Parkinson’s disease that means the destruction of dopaminergic fibers in MPTP mice is also reduced or neuroprotected. This assumption appears to be valid in view of the biochemical measurements in MPTP mice with or without CHI following the combined treatment strategies. Thus, measurement of dopamine, DOPAC, HVA and tyrosine hydroxylase suggests a significant restoration of their levels in SNpC in MPTP mice with or without CHI. The value of dopamine, DOPAC, HVA and tyrosine hydroxylase is significantly reduced in MPTP mice, and this was further exacerbated following additional CHI in MPTP mice groups. This suggests that treatment strategies with NWNBP, NWMSCs and NWmAbs to ASNC and TDP-43 also protect the dopaminergic fibers in Parkinson’s disease and its further destruction by additional CHI, not reported earlier. When the dopaminergic neurotransmission is restored together with molecular markers of brain pathology and enhanced neuroprotection due to combined administration of NWNBP, NWMSCs and NWmAbs to ASNC and TDP-43, then obviously the behavioral parameters will further improve in MPTP mice with or without CHI. This is further supported by our observation of behavioral parameters examined in MPTP mice with or without additional CHI. Our results clearly show that the performance of MPTP mice is significantly reduced on Rota-Rod, inclined plane angle, walking on mesh grid and their gait disturbances as even using foot print analyses. Interestingly, these behavioral parameters are exacerbated when MPTP mice were inflicted with additional CHI. Interestingly, when the combined treatment strategies with NWNBP, NWMSCs and NWmAbs to ASNC and TDP-43 were administered in MPTP mice with or without CHI, their performances on these behavioral parameters significantly restored. These observations clearly support the idea that addition of monoclonal antibodies to ASNC and TDP-34 together with MSC and NBP administered through nanowired technology-enhanced neuroprotection is achieved in MPTP mice with or without additional CHI, not described before. Nanowired delivery of drugs or antibodies is better effective in inducing superior neuroprotection as compared to their conventional administration [190–195, 197– 199, 251]. When nanowired-labeled drugs administered systemically, they are able to penetrate the brain quickly in widespread areas where they could release their drug content from their scaffold for long time without being catabolized quickly [192– 195]. Thus, their pharmacokinetics in the brain is far more superior to the conventional delivery. These are some of the key factors that are responsible for superior neuroprotection in brain disease [13, 14]. In conclusion, our observations are the first to show that nanowired delivery of monoclonal antibodies to ASNC and TDP-43 together with NWNBP and NWMSCs is quite effective in reducing brain damage in Parkinson’s disease in association with additional brain injury. It remains to be seen what will happen when CHI was delivered long before MPTP administration and whether this combined treatment strategies are able to induce superior neuroprotection or to prevent or delay the development of Parkinson’s disease, a feature that is currently being investigated in our laboratory.

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Acknowledgments This investigation is supported by grants from the Ministry of Science & Technology, People Republic of China, the Air Force Office of Scientific Research (EOARD, London, UK), and Air Force Material Command, USAF, under grant number FA8655-05-1-3065; Grants from the Alzheimer’s Association (IIRG-09-132087), the National Institutes of Health (R01 AG028679) and the Dr. Robert M. Kohrman Memorial Fund (RJC); Swedish Medical Research Council (Nr 2710-HSS), Göran Gustafsson Foundation, Stockholm, Sweden (HSS), Astra Zeneca, Mölndal, Sweden (HSS/AS), The University Grants Commission, New Delhi, India (HSS/AS), Ministry of Science & Technology, Govt. of India (HSS/AS), Indian Medical Research Council, New Delhi, India (HSS/AS) and India-EU Co-operation Program (AS/HSS) and IT-901/16 (JVL), Government of Basque Country and PPG 17/51 (JVL), JVL thanks to the support of the University of the Basque Country (UPV/EHU) PPG 17/51 and 14/08, the Basque Government (IT-901/16 and CS-2203) Basque Country, Spain; and Foundation for Nanoneuroscience and Nanoneuroprotection (FSNN), Romania. Technical and human support provided by Dr. Ricardo Andrade from SGIker (UPV/EHU) is gratefully acknowledged. We thank Suraj Sharma, Blekinge Inst. Technology, Karlskrona, Sweden for computer and graphic support. The U.S. Government is authorized to reproduce and distribute reprints for Government purpose notwithstanding any copyright notation thereon. The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of the Air Force Office of Scientific Research or the U.S. Government. Conflict of Interest The authors declare no conflict of interest with any entity mentioned here.

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Neuroprotective Effects of Nanowired Delivery of Cerebrolysin with Mesenchymal Stem Cells and Monoclonal Antibodies to Neuronal Nitric Oxide Synthase in Brain Pathology Following Alzheimer’s Disease Exacerbated by Concussive Head Injury Hari Shanker Sharma, Dafin F. Muresanu, Ala Nozari, José Vicente Lafuente, Anca D. Buzoianu, Z. Ryan Tian, Hongyun Huang, Lianyuan Feng, Igor Bryukhovetskiy, Igor Manzhulo, Lars Wiklund, and Aruna Sharma

Abstract Concussive head injury (CHI) is one of the major risk factors in developing Alzheimer’s disease (AD) in military personnel at later stages of life. Breakdown of the blood–brain barrier (BBB) in CHI leads to extravasation of plasma amyloid beta protein (ΑβP) into the brain fluid compartments precipitating AD brain H. S. Sharma (✉) · L. Wiklund · A. Sharma International Experimental Central Nervous System Injury & Repair (IECNSIR), Department of Surgical Sciences, Anesthesiology & Intensive Care Medicine, Uppsala University Hospital, Uppsala University, Uppsala, Sweden e-mail: [email protected]; [email protected] D. F. Muresanu Department of Clinical Neurosciences, University of Medicine & Pharmacy, Cluj-Napoca, Romania ”RoNeuro” Institute for Neurological Research and Diagnostic, Cluj-Napoca, Romania A. Nozari Anesthesiology & Intensive Care, Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA J. V. Lafuente LaNCE, Department of Neuroscience, University of the Basque Country (UPV/EHU), Leioa, Bizkaia, Spain A. D. Buzoianu Department of Clinical Pharmacology and Toxicology, “Iuliu Hatieganu” University of Medicine and Pharmacy, Cluj-Napoca, Romania Z. R. Tian Department of Chemistry & Biochemistry, University of Arkansas, Fayetteville, AR, USA H. Huang Beijing Hongtianji Neuroscience Academy, Beijing, China © The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 H. S. Sharma, A. Sharma (eds.), Progress in Nanomedicine in Neurologic Diseases, Advances in Neurobiology 32, https://doi.org/10.1007/978-3-031-32997-5_4

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pathology. Oxidative stress in CHI or AD is likely to enhance production of nitric oxide indicating a role of its synthesizing enzyme neuronal nitric oxide synthase (NOS) in brain pathology. Thus, exploration of the novel roles of nanomedicine in AD or CHI reducing NOS upregulation for neuroprotection are emerging. Recent research shows that stem cells and neurotrophic factors play key roles in CHI-induced aggravation of AD brain pathologies. Previous studies in our laboratory demonstrated that CHI exacerbates AD brain pathology in model experiments. Accordingly, it is quite likely that nanodelivery of NOS antibodies together with cerebrolysin and mesenchymal stem cells (MSCs) will induce superior neuroprotection in AD associated with CHI. In this review, co-administration of TiO2 nanowired cerebrolysin – a balanced composition of several neurotrophic factors and active peptide fragments, together with MSCs and monoclonal antibodies (mAb) to neuronal NOS is investigated for superior neuroprotection following exacerbation of brain pathology in AD exacerbated by CHI based on our own investigations. Our observations show that nanowired delivery of cerebrolysin, MSCs and neuronal NOS in combination induces superior neuroprotective in brain pathology in AD exacerbated by CHI, not reported earlier. Keywords Alzheimer’s disease · Traumatic brain injury · Brain pathology · Mesenchymal stem cells · Cerebrolysin · Nanowired delivery · Nanomedicine blood–brain barrier · Brain edema · Oxidative stress · Nitric oxide synthaseneuroprotection

1 Introduction Military personnel are vulnerable to traumatic brain or head injury during their combat-related operations worldwide [1–5]. Head or brain injury is one of the major risk factors for developing Alzheimer’s disease [6–12]. Thus, in several veterans, AD pathology develops within 8–15 years after the initial trauma [13– 18]. However, the magnitude and intensity of brain trauma results in early

L. Feng Department of Neurology, Bethune International Peace Hospital, Shijiazhuang, Hebei Province, China I. Bryukhovetskiy Department of Fundamental Medicine, School of Biomedicine, Far Eastern Federal University, Vladivostok, Russia I. Manzhulo Laboratory of Pharmacology, National Scientific Center of Marine Biology, Far East Branch of the Russian Academy of Sciences, Vladivostok, Russia

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development of AD-like pathology [14, 19–21]. A link between head injury from mild to moderate leading to loss of consciousness is already established and found an increased risk of 15–45% greater in developing AD brain pathology within decades [22–24]. Thus, efforts are needed to explore suitable therapeutic strategies in central nervous system (CNS) trauma to minimize the risk burden of developing AD brain pathology. Increased understanding the secondary injury mechanisms initiated following CNS trauma and in order to neutralize those agents in time is likely to reduce the neurodegenerative mechanisms leading to AD brain pathology [25–27]. In animal models, traumatic brain injury (TBI) induces neurodegeneration leading to progressive brain atrophy up to 1 year after the initial trauma [28–30]. In these neurodegenerative processes after TBI, several proteins are involved after TBI in animals that are similar to human cases of brain trauma. Upregulation of amyloid precursor protein (APP) occurs immediately after TBI and amyloid beta peptide (AβP) accumulates in brain over weeks or months following injury [30–32]. Other proteins such as beta secretase, persenilin 1 and caspase 3 accumulate within the brain after 6 months of TBI [33–38]. Phosphorylation of tau-protein occurs within 1 week after TBI [39–41]. These observations clearly suggest that AβP and p-tau are one of the important events after TBI that lead to the development of Alzheimer’s disease brain pathology. Postmortem studies in patients that died after TBI exhibited AβP accumulation with amyloid plaques in 30% cases [42, 43]. Accumulation of AβP appears to be rapid in human cases of TBI that is evident from the tissues removed surgically within hours after TBI [43]. Autopsy finding in patients who survived 1–47 years after a single episode of TBI amyloid plaques and neurofibrillary tangles (NFTs) are present in more than 30% of cases [44–47]. In retired athlete who received multiple concussions and developed dementia exhibit astrocytic tangles together with NFTs that were immunoreactive to tau in several brain regions [47]. About 50% of cases also showed AβP pathology in different brain areas [43–47]. These observations show similar brain pathology following TBI as seen in Alzheimer’s disease brain pathology in humans. Imaging studies further shoed close molecular connections between TBI and Alzheimer’s disease brain pathology. In both TBI and in Alzheimer’s disease, brain atrophy is seen in selective regions including hippocampus, amygdala with parietal and frontal cortices that closely overlap with AβP depositions and decreased glucose metabolism [48]. These findings show that the molecular pathological mechanisms in TBI and Alzheimer’s disease are similar leading to neurodegeneration. Previous studies from our laboratory show that brain pathology in Alzheimer’s disease is exacerbated after concussive head injury (CHI) and enhance AβP and p-tau levels in the brain [25–27]. There are reasons to believe that TBI or CHI upregulates nitric oxide synthase (NOS), the synthesizing enzymes of nitric oxide (NO) [49–53]. Upregulation of NO after brain injury generates oxidative stress, lipid peroxidation and peroxynitrite damaging the brain tissues [54–56]. Thus, it would be possible to attenuate the upregulation of NO in CHI using drugs or antibodies generated against NOS that may help in achieving neuroprotection. Our

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earlier studies in spinal cord injury show that monoclonal antibodies (mAb) against neuronal NOS (nNOS) when applied topically over a longitudinal lesion of the spinal cord at T10-11 segments 5 min after infliction of trauma prevented NOS upregulation and cord pathology [50–56]. This suggests that NOS antibodies could be used as powerful tool to thwart NO upregulation in CHI as well [56–59]. Keeping these views in mind in present investigation, we used nanodelivery of mAb nNOS together with mesenchymal stem cells (MSCs) and cerebrolysin for enhancing neuroprotective ability in Alzheimer’s disease associated with CHI. Nanodelivery of cerebrolysin together with MSCs is able to attenuate brain pathology in AD following CHI in our earlier investigations [25–27]. Thus, it is interesting to see whether adding mAb of nNOS together with cerebrolysin and MSCs induces superior neuroprotection in Alzheimer’s disease associated with CHI. In present investigation, our observations clearly show that adding mAb against nNOS with cerebrolysin and MSCs significantly enhanced neuroprotection in Alzheimer’s disease after CHI. This indicates that nNOS plays key role in Alzheimer’ disease and CHI-induced brain pathology. The possible mechanisms and clinical significance of our findings are discussed based on current scientific literature in the field.

1.1

Nitric Oxide in Alzheimer’s Disease

Although the brain constitutes only 2% of the body mass, it consumes almost 20% of oxygen out of which 15% oxygen in the brain is reduced to superoxide, the major constituent of oxidative stress [60]. Also, the brain produces the highest amount of NO that could react with superoxide – the peroxynitrite the neurotoxic agent and powerful oxidant [60–63]. Thus, the brain is highly vulnerable to oxidative stress. The NO is synthesized from oxygen and L-arginine by the enzyme nNOS in the brain [64]. There are three isoforms of NOS, namely, nNOS and endothelial NOS (eNOS) that are constitutively express within the neurons and endothelial cells, respectively, and one inducible NOS (iNOS) [54]. The iNOS expression is stimulated by oxidative stress and inflammatory signals within the brain, whereas nNOS and eNOS are activated by calcium–calmodulin complex [65]. Activation of iNOS could occur within astrocytes, microglia, macrophages, vascular smooth muscles, endothelial cells as well as in mesenglial cells and last for longer duration of several hours. On the other hand, nNOS is cytosolic and eNOS is membrane bound producing NO for short durations in seconds [66, 67]. NO-soluble guanylase cyclase-cGMP signal transduction plays key role in synaptic transmission and neuronal plasticity within the cerebral cortex and hippocampus involved in learning and memory functions [66–68]. nNOS produced by NO in the brain works as integrated synaptic messenger [54, 66]. Inhibition of nNOS

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impairs memory functions, whereas soluble guanylase cyclase in hippocampus blocks long-term potentiation [66–68]. The duration of NO produced by nNOS is short ranging from 1 to 3 s but is more intense generation of about 57 molecules per second [54, 66–69]. NO is implicated in the pathology of Alzheimer’s disease because of its neurotoxicity [61, 70]. The toxic effects of NO in brain are largely due to production of peroxynitrite [54, 61, 66]. The pathology of Alzheimer’s disease is mainly due to deposition of amyloid plaques and intracellular NFTs resulting in cell death [25– 27]. The neurotoxicity of amyloid plaques is mediated by oxidative stress [61, 70, 71]. AβP1-42 is one of the key factors in generating oxidative stress and neurotoxicity in Alzheimer’s disease [71]. AβP induces NO production from neuronal and endothelial cells in the microvessels of brain and increases the concentration of nitrotyrosine residue—a marker of peroxynitrite [61, 70, 71]. AβP damages neuronal cells either directly or through activation of microglia by producing neurotoxic cytokines and/or oxygen and nitrogen species [61–67]. Activation of microglia also generates production of peroxynitrite [69–71]. The cytotoxicity of AβP1-42 is blocked by inhibition of NO synthesis or catalytic decomposition of peroxynitrite using metalloporphyrines [70, 71]. Thus, activated microglia plays a major role in AβP1-42 neurotoxicity though peroxynitrite generation in Alzheimer’s disease [70, 71]. Apart from microglia, AβP1-42 stimulates astrocytes as well and induces iNOSmediated NO generation [71–73]. Production of iNOS-induced NO increases the levels of peroxynitrite leading to neurotoxicity [70–73]. The peroxynitrite level generation depends on the NO level produced by both the neuronal and glial nNOS [54, 66–68]. In Alzheimer’s disease brain, the levels of nitrosylated proteins are very high in hippocampus and cerebral cortex as compared to non-Alzheimer’s disease brains [61, 70–72]. Thus, novel therapeutic strategies in AD include addition of NO synthesis inhibitors or neutralization of nNOS production in brain with mAb against nNOS. Our previous studies using nNOS mAb neutralizes nNOS induction in brain and spinal cord after trauma indicates that mAb application [54]. This is likely that nanowired mAb administration may be one of the effective approaches in neutralizing nNOS production in CHI or in Alzheimer’s disease in vivo [25–27].

1.2

Nitric Oxide in Brain Injury

Traumatic brain injury or concussive head injury is one of the most prominent causes of disability in military populations as well as in civilians worldwide [2, 3, 74]. The epidemiological data suggest that more than 1.5 million individuals are affected with brain injury annually in the United States of America and more than 50k death and disability occurs in almost 90k victims per year [75–77]. In European Union, similar data show that more than 1.6 million are affected with brain trauma annually leading to death in over 70k people and about 100k individuals become disable after brain

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injury every year. In this group of brain-injured victims, children and young adults occupy more than 70% of cases [78–80]. Brain injury victims are at greater risk of secondary infections leading to weaken immune system followed by cellular abnormalities and inflammatory responses contributing to brain pathology and functional disabilities [81– 85]. With regard to inflammatory mediators, NO is one of the key mediators of inflammations in TBI [9, 86]. Brain injury activates upregulation of nNOS and iNOS and induces release of NO for longer duration within the damaged tissues [50–54]. The secondary injury mechanisms after brain trauma lead to greater upregulation of iNOS through endogenous or exogenous pro-inflammatory and pathophysiological stimuli [55, 56]. These include Damage-Associated Molecular Pattern Molecules (DAMPs) and Pathogens Associated Molecular Pattern Molecules (PAMPs) [49, 86, 87]. DAMPs in brain tissues following TBI induce neuronal inflammatory responses in the absence of pathogens and activate signaling pathways inducing upregulation of nNOS, eNOS and iNOS enzymes [88– 90]. DAMPs induce release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) that binds to TNF-receptor1 (TNFR1) and activates signaling that upregulates nNOS and iNOS in microglia, astrocytes and in neurons affecting brain dysfunction [49, 87–91]. TNFR1 signaling also induces release of glutamate into the intracellular fluid in microglia and astrocytes activating glutamate exocytosis [91–95]. High levels of glutamate ranging up to 1 mM in the extracellular fluid in TBI patients are seen using microdialysis system [96–98]. Glutamate further activates NMDA receptors that are known to stimulate NO production or release from NOS containing neurons [99–101]. Increased activity of all different kinds of NOS in both ipsilateral and in contralateral hemispheres after brain injury indicates widespread of cytotoxicity within the CNS [102, 103]. Activation of nNOS after brain trauma induces hyperemia in the whole brain and induces neuronal death predominantly within the injured area [49–55, 86– 88]. Upregulation of iNOS produces high concentration of NO leading to cytotoxicity and apoptotic neuronal death [49–55]. With regard to iNOS activation in the injured areas of brain during the first 4 h is largely due to activation of microglia and macrophages and the second phase is activated after 72 h of traumatic insults that reaches its peak level around seventh day of injury [49–52, 86–88]. TBI-induced oxidative stress also contributes to increased NO levels in the brain [104–106]. Simultaneous generation of superoxide and NO leads to formation of peroxynitrite, a highly neurotoxic molecule causing cell death, microvascular damage and modification of post-translational proteins following brain injury [49–55]. Peroxynitrite induces DNA damage and activates constitutive nuclear and mitochondrial enzyme poly- (ADP-ribose) polymerase (PARP1) that leads to neurotoxicity [107, 108]. These observations strongly suggest that NO-mediated neurotoxic mechanisms play key roles in neurodegeneration in brain injury or Alzheimer’s disease. Thus, it

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is quite likely that blockade of NO mechanisms or neutralization of NOS activity with mAb may reduce the brain pathology and induce neuroprotection [49–53].

1.3

Mesenchymal Stem Cells in Alzheimer’s Disease

Alzheimer’s disease is a slowly progressive neurodegenerative disease leading to cognitive impairments and loss of memory functions at the initial stages and later results in dementia [13, 16, 17]. These symptoms are caused by loss of neurons within the hippocampus and cerebral cortex that are involved in learning and memory processes [13]. Eventually, the brain size showed severe shrinkage due to major loss of neurons. It is estimated that about more than 5.5 million Americans above the age of 65 are suffering from various stages of Alzheimer’ disease and about 50 million people suffer from dementia as seen in 2019 [13, 16, 17]. It is estimated that about 152 million people will suffer from dementia or Alzheimer’s disease worldwide by 2050 [1–5]. Thus, exploration of suitable therapeutic measures in neurodegenerative diseases including Alzheimer’s disease is urgently needed in clinical practices. The etiology of Alzheimer’s disease is still not well known in all its details. However, ageing, genetics, life style and stressors associated with environmental factors and other risk factors such as brain trauma play important determining role in development of Alzheimer’s disease [11, 14, 15, 48]. The well-known factors in Alzheimer’s disease show that amyloid plaques together with neurofibrillary tangles (NFTs) and phosphorylated tau (p-tau) are the leading neurotoxic agents in Alzheimer’s disease populations [25–28]. In spite of knowledge in Alzheimer’s disease brain pathology for decades, no suitable therapeutic measures are developed in reducing the symptoms or brain degeneration in patients so far. Due to lack of successful pharmacological agents in Alzheimer’s disease therapy, treatment with mesenchymal stem cells-based novel therapeutic strategies are developed using animal models and in human cases [109–115]. MSCs are one of the most potent stem cells for Alzheimer’s disease or other neurodegenerative diseases [109, 110]. MSCs have great advantages for therapy because they could be obtained from several sources such as bone marrow, adipose tissues, umbilical cord blood or dental pulp. MSCs could easily differentiate into neuronal cells, chondrocytes adipocytes or osteocytes after stimulation with suitable growth factors [109]. Other benefits to use MSCs include in the fact that their use is rather safe than other forms of stem cells due to very low risk of differentiating them into cancer cells [109–111]. Also, MSCs are very rare to be immunogenic. These qualities of MSCs make them the most widely used therapeutic stem cells in several neurodegenerative diseases [109, 110].

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The pathological mechanisms of Alzheimer’s disease to induce inflammatory reactions that are ameliorated by MSCs transplantation due its suppressive effects on pro-inflammatory cytokines including IL-1β, IL-6, iNOS and hemeoxugenesae-1 (HO-1) together with increasing the levels of transforming growth factor-beta (TGF-β) that reduces inflammation, oxidative stress and enhance cognitive functions [109–114]. MSCs also reduce microglia cell numbers in cortex, reduce microglia sizes together with TNF-α and IL-6 harmful cytokines and increase beneficial cytokine IL-10 in animal model of Alzheimer’s disease [113, 116–118]. MSCs secrete TGF-β and further block the nuclear factor NF-κB pathways [115]. MSCs increase proteasome activity and reduce amyloid plaques in the Alzheimer’s disease brain probably through activation of neprilysin, a AβP degrading enzyme together with growth differentiation factor-15 (GDF-15) that promote hippocampal neurogenesis and reduce AβP levels in Alzheimer’s disease models [26, 27, 119]. Secretion of thrombospondin-1 (TSP-1) from MSCs restores neuronal synaptic density impairments by AβP and ameliorates memory deficits [120–122]. MSCs are also able to reduce NFTs together with levels of phosphorylated tau in Alzheimer’s disease model experiments [123, 124]. MSCs are also able to increase proteasome activity and decreased the ubiquitin in conjugated protein accumulation in Alzheimer’s disease brain in animal models [125, 126]. MSCs can be differentiated into endothelial cells and enhance vascular endothelial growth factors (VEGF) expression that restores endothelial dysfunction and blood–brain barrier (BBB) breakdown [127, 128] that is responsible for AβP deposition in brain from plasma. All these beneficial effects of MSCs in Alzheimer’s disease suggest an important therapeutic tool to reduce brain pathology together with other agents such as mAb raised against NOS in Alzheimer’s disease associated with brain trauma.

1.4

Mesenchymal Stem Cells in Brain Injury

Traumatic brain injury (TBI) and concussive head injury (CHI) are very common in military populations during combat or peacekeeping operations across the globe [1– 5]. Missile injury, blast trauma, gun violence as well as motor vehicle accidents result in brain and spinal cord injury resulting in functional deficits, paralysis and even death in severe cases. No suitable regenerative therapeutic approaches are available at the moment that could reduce functional deficit or paralysis and improve quality of life of trauma victims [2, 3, 74–77]. Thus, apart from pharmacological management of TBI, stem cell therapy is gradually emerging that appears to be promising in reducing TBI-induced pathophysiology and sensory motor disturbances in patients. Use of stem cells may repair and regenerate neurons in the traumatized area improving functional parameters and reduce brain pathology [129–132]. MSCs are able to reduce brain edema, pro-inflammatory cytokines, microglia and macrophages and restore BBB function together with functional deficits [133, 134]. MSCs transplantation in TBI result in enhanced neuronal survival and

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improved neurological functions in animal models due to their migration into the traumatized tissues and secretion of growth factors together with neurotrophins that are responsible for neurorestoration in brain injury [135–137]. MSCs have the ability to improve neurological functions after TBI when injected into the cranial compartment following trauma and associated with reduction in neuroinflammation, gliosis and myelin damages [138, 139]. MSCs in brain injury also inhibited pro-inflammatory cytokines and pro-apoptotic caspase-3 and increased antiapoptotic Bcl2 expression together with anti-inflammatory cytokines following 7–14 days of administration [2, 3, 33–133, 140]. In TBI, MSCs administration inhibits levels of mRNA of NF-κB in 12–48 after transplantation and reduces the production of reactive oxygen species [117–120]. These observations are in line with MSCs-induced neuroprotection in Alzheimer’s disease and similar mechanism of reducing brain pathology in TBI. Thus, it seems probable that adding the MSCs together with neurotrophins and mAb of NOS could have superior neuroprotective effects in Alzheimer’s disease aggravated with CHI cases.

1.5

Neurotrophic Factors in Alzheimer’s Disease

Neurotrophins belong to the family of growth factors that are essentials for the survival of neurons and development of dendrites during brain development periods [141–146]. These neurotrophic factors also protect ageing in the hippocampus that is responsible for memory and learning process [142, 143]. Neurotrophins prevent axonal degeneration and neuronal death within the central nervous system (CNS) [142–146]. The family of neurotrophins includes nerve growth factor (NGF), brainderived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4) [146]. BDNF enhances learning and memory functions by maintaining excitatory hippocampal synapses as well as improve their functions [147]. During age-related decrease in BDNF function increases the risk of developing Alzheimer’ disease leading to memory impairments [13–16]. The mild cognitive impairments further progresses to Alzheimer’s disease during the period of accelerated brain atrophy as compared to slowly developing brain atrophy in normal ageing [148–151]. After 65 years of age, the cognitive decline is prominent in hippocampus that is more vulnerable as compared to other brain regions resulting and memory and cognitive dysfunctions in normal ageing [149, 150]. However, accelerated decline and brain atrophy in brain regions including hippocampus lead to Alzheimer’s diseases associated with brain pathology [151]. There are reasons to believe that early synapse loss or degeneration in Alzheimer’s disease is caused by AβP-induced synaptic dysfunction [152– 154]. Postmortem studies of Alzheimer’s disease brain show significant reductions in synaptic protein, decrease in the density of dendritic spines as well as severe loss of synapses are in line with this idea [153, 154].

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These age-related impairments in brain function are largely due to BDNF transcription that is significantly decreased in aged hippocampus and cortex in rodents [155–157]. This is further supported by the fact that in aged rodents brain-reduced phosphorylated cAMP (Adenosine 3′ 5′ Cyclic Monophosphate)-Response Element Binding protein (pCREB), pTrkB and PKCε expressions are seen [156, 157]. BDNF transcription is reduced in hippocampal CA1 pyramidal neurons during cognitive impairment followed by neuritic plaques development in pyramidal neurons in human cases [153–157]. There are strong positive correlations between serum BDNF and CSF AβP42 levels in human cases [158]. In elderly people less than 65 years of age, a reduction in BDNF serum level exhibited worsening of cognitive and memory functions as compared to healthy people of similar ages [155– 158]. This suggests that low-serum BDNF levels are one of the major risk factors in developing Alzheimer’s disease in humans. Thus, reducing the imbalances in neurotrophic factors could be one of the important strategies in reducing or halting the Alzheimer’s disease progression.

1.5.1

Cerebrolysin Therapy in Alzheimer’s Disease

Cerebrolysin is well-balanced composition of several neurotrophic factors and active peptide fragment for neural regeneration in several diseases from stroke to traumatic brain injury and neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease [159–161]. Our previous experiments using cerebrolysin showed profound neuroprotection in diverse animal models from heat stroke, spinal cord injury, traumatic brain injury, concussive head injury, chronic nerve lesion, morphine dependence, drugs of abuse induced by methamphetamine, blast brain injury as well as disease models in rodents of Alzheimer’s and Parkinson diseases [162–174]. In clinical situations, neurodegenerative diseases are often associated with several co-morbidity factors prevalent in human populations and other disease modifying factors such as brain injury, emotional stress, substance abuse and similar other factors. Thus, our laboratory is using disease models associated with major risk factors in modifying the disease pathology that usually aggravated immensely. Under these conditions, standard treatment with one compound may not be sufficient and thus, other molecules or factors need to be incorporated for the treatment strategies that could significantly reduce brain pathology and induce neural repair. Keeping these views in mind, we identify several key agents who may contribute actively to disease processes with co-morbidity factors to thwart brain pathology. In this regard, we use nanowired delivery of cerebrolysin in small doses that appear to be far superior in reducing brain pathology as compared to conventional cerebrolysin in high doses [162–166]. Accordingly, nanowired delivery of cerebrolysin with MSCs and antibodies to key agents causing brain pathology in Alzheimer’s disease like AβP or tau when used in combination exerted far superior effect on neuroprotection as compared to any one of the compound alone [166–174].

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Several clinical trials of cerebrolysin in the last 30 years are commenced in Alzheimer’s disease patients [175–177]. During therapy with cerebrolysin, profound beneficial effects on brain function and marked improvement in patient’s cognitive ability are seen [176, 177]. Available data show that cerebrolysin reduce AβP production and stimulate its clearance from the brain and reduce tau phosphorylation in clinical cases [175]. Cerebrolysin is also able to attenuate neuroinflammation and prevents upregulation of pro-inflammatory cytokines such as TNF-α and IL-1β and related agents [175–177]. In addition, cerebrolysin enhances expression and cell signaling of NGF, BDNF and IGF-1 and exerts neurotrophic factors like effects in Alzheimer’s brain [175]. These effects of cerebrolysin enhance synaptogenesis, neuroplasticity, neurogenesis and protecting synaptic loss and dendrites [175– 177]. Due to these molecular cellular effects of cerebrolysin, neurons are well protected from death and cognition and memory functions are improved [175, 178, 179]. The long-lasting effects of cerebrolysin induce neurotrophic factors like influence in brain that is one of the crucial beneficial effects in slowing the development of Alzheimer’s disease [175–177]. It is likely that when nanodelivery of cerebrolysin for clinical therapy is approved further enhancement of cerebrolysin beneficial effects may be seen in Alzheimer’s disease patients. This is a feature that requires further investigation.

1.6

Neurotrophic Factors in Traumatic Brain Injury

Traumatic brain Injury (TBI) is the leading cause of dementia and lifetime paralysis associated with impaired cognitive functions and deposition of neurotoxic proteins including AβP and p-tau [180–182]. There are many similarities between TBI and Alzheimer’s disease with regard to functional deficit and pathological changes within the brain [183–185]. Pharmacological manipulation of TBI with drugs did not provide sufficient improvements in their mental or cognitive functional behavior or in brain pathology. On the other hand, treatment with neurotrophic factors shows promising results in TBI patients [186, 187]. Neurotrophic factors are proteins that are important for neural cell growth, stability, plasticity and regeneration [188– 191]. The neurotrophic factors family includes NGF, BDNF, granulocyte colony stimulating factor (G-CSF), glia-derived neurotrophic factor (GDNF), NT-3 and NT-4 [142, 192–195]. After TBI, dysregulation of neurotrophic factors are primarily responsible for exacerbation of functional impairment in victims [196–199]. Administration of exogenous neurotrophic factors after TBI not only improves immediate potential benefit but also prevents long-term cognitive impairment and alleviates the risk of later development of dementia [200, 201]. Exogenous supplement of either BDNF alone or associated with GDNF given topically over the injured spinal cord reduces spinal cord pathology, edema formation and restores breakdown of the blood–spinal cord barrier (BSCB)

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[51, 202–208]. Likewise, topical application of insulin-like growth factor-1 (IGF-1) applied over the lesion spinal cord 2–5 min after trauma attenuates pathophysiology of cord injury in terms of BSCB leakage, edema formation and cell pathology. Interestingly, topical application of BDNF or IGF-1 significantly reduced spinal cord trauma-induced upregulation of nNOS and also downregulated hemeoxygenease-2 (HO-2), the constitutive isoforms of carbon monoxide that is responsible to cell damage [51, 202–210]. In this series of experiments, when cerebrolysin that is a balanced composition of several neurotrophic factors and active peptide fragments when applied either topically over the injured spinal cord segment or administered intravenously attenuated spinal cord pathology, BSCB disturbances and edema formation effectively [164, 211]. Likewise, cerebrolysin-treated CHI or TBI group also exhibited profound neuroprotection on brain pathology in rodent models [164, 212]. This observation clearly suggests the role of neurotrophic factors as major neuroprotective therapy in various forms of CNS injury.

1.6.1

Cerebrolysin in Clinical Brain Injury

Clinical trials using cerebrolysin in severe TBI after standard medical protocol of decompression were undertaken in large number of patients from 2010 to 2015 [213–216]. These TBI patients were not operated and were in Glasgow Coma Scale 5–7. About 42 patients were given cerebrolysin 30 ml/day intravenously for 14 days followed by 10 ml/day for another 14 days. The results of this study show that cerebrolysin is beneficial in severe TBI patients that were not operated for brain injury lesions. Meta-analysis show that functional and neurological outcomes were considerable improved on day 10 and 30 in cerebrolysin-treated patients [213, 214]. Cerebrolysin treatment also improved consciousness and cognitive functions in another TBI trial associated with motor functions as early as 7–10 days after treatment [215–217]. In the present study, more than 50% patients showed improvement from severe TBI to mild or moderate TBI after 14 days [213, 216, 217]. The exact cellular and molecular mechanisms of cerebrolysin treatment-induced beneficial effects are not well understood yet. However, available evidences suggest that cerebrolysin reduces excessive nitric oxide production, oxidative stress formation, microglial activation, inflammatory responses and BBB disturbances [213, 216, 217]. Cerebrolysin also reduces secondary injury mechanisms by targeting free radical formation, lipid peroxidation and apoptotic pathways in the brain [218]. These clinical trials using cerebrolysin in severe TBI patients clearly demonstrate a positive role of neurotrophins in attenuating secondary injury cascades following TBI in achieving long-term neuroprotection and improving patients’ well-being.

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2 Our Observations in Alzheimer’s Disease and Concussive Head Injury In different groups of animals, CHI and/or Alzheimer’s disease model was used as described before [25, 26, 163, 172], and nanowired delivery of neuroprotective agents was examined [25–27]. A summary of experimental procedures and results obtained are described below. Animals Experiments were carried out on inbred male Wistar rats (300–400 g body wt, age 16–18 weeks old) housed at controlled ambient temperature (21 ± 1 °C) with 12-h light and 12-h dark schedule. The rat food and tap water were supplied ad libitum before the experiment. All experiments were commenced between 8:00 and 9:00 AM in order to avoid diurnal variations in the data obtained. All experiments and handling of animals were carried out according National Institute of Health (NIH) guidelines for the care and use of laboratory animals [219] and approved by Local Ethics committee (National Research Council 2011). Closed Head Injury (CHI) Closed head injury (CHI) in Equithesin anesthesia (3 ml/kg, i.p.) was performed as described earlier [25–27]. In brief, a sterile steel rod tapered at one end (outer diameter 4 mm) weighing 114.6 g was dropped on exposed skull from a height of 20 cm through a guide tube. This weight and height adjustment yields an impact force of 0.224 N over the right parietal skull. The rat head is fixed in a stereotaxic apparatus (Harvard Apparatus, Holliston, MA, USA) with cushion so that weight drop on skull does not induce rebound movement of the head [25]. The impact of head injury did not cause skull perforation. After injury, the rats were allowed to survive up to 48 h after the primary injury. The animals are placed in individual cages with skin sutured and taken appropriate care during the experiment duration [25–27]. Sham group was similarly fixed in the stereotaxic apparatus with exposed parietal bone except no weight was dropped over the skull. Control group consists of intact animals of similar age and weight group. Alzheimer’s Disease Model In rats, Alzheimer’s disease-like symptoms are induced by intracerebroventricular administration of amyloid beta peptide [AβP1-40] in the left lateral ventricle once daily for 4 weeks through a chronic cannula implanted aseptically 1 week ago as described earlier [25–27]. The AβP (1-40 Rat, Tocris, Madrid, Spain; 200 ng/30 μl in sterile saline (0.9% NaCl) was administered into the lateral cerebral ventricle of normal or CHI rats using a constant infusion pump slowly (6 μl/min) for 5 min [26, 27]. This dose and speed delivers AβP to the whole ventricular system without raising the intracranial pressure in the rat (Sharma HS, unpublished observations). Control group of rats received sterile saline (30 μl) in identical manner once daily for 4 weeks.

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Parameters Measured The following parameters are measured as follows. Physiological Variables The mean arterial blood pressure (MABP) was measured using an indwelling left carotid artery cannulation (PE 10) toward heart aseptically implanted 1 week before experiments connected to a strain gauge (Statham P23, Kennewick, WA, USA) pressure transducer connected to a chart recorder (Electromed, UK). At the time of connecting carotid artery cannula to pressure transducer, about 1 ml arterial whole blood was collected for later determination of blood gases (PaO2 and PaCO2) and arterial pH using a radiometer apparatus (Copenhagen, Denmark). During MABP recording, additional leads were placed to record heart rate and respiration rate recorded on the chart recorder. The data are analyzed manually [172]. Body Temperature Measurement Using 12-channel telethermometer (Harvard Apparatus, Holliston, MA, USA), rectal temperature was measured using rat thermistor probes (Yellow Springfield, USA) to record deep visceral temperature. The animals were adapted for at least one time daily for 1 week before the experiments so that handling stress did not modify the rectal temperature measurements [54]. Blood–Brain Barrier Permeability The blood–brain barrier (BBB) permeability was measured using intravenous protein tracers, for example, Evans blue albumin (EBA) (2% sterile solution 3 ml/kg) and radioiodine ([131]-I, 100 μCi/kg) administered together through a venous cannula implanted into the right jugular vein 1 week before aseptically [25–27, 50]. After circulation of the tracers for about 10 min, the animals were anesthetized and the intravascular tracers were washed out by 0.9% saline perfusion (50 ml) through heart at 90 torr perfusion pressure. Immediately before cardiac puncture and cutting of right auricle, about 1 ml of whole blood from the left ventricle was taken out after cardiac puncture for later determination of whole blood radioactivity in a 3-in Gamma counter (Packard, USA). After saline perfusion, the brains were dissected out and examined for blue coloration of dorsal and ventral surfaces of the brains by visual inspection. After that, a mid-sagittal section was done and the brain ventricles and underlying structures of hippocampus, caudate putamen, colliculi, cerebellum and brain stem were examined for dye penetration [25–27, 50]. After recording the due penetration into the brain, small tissue samples were cut from the different anatomical areas of the brain (sample size 65–120 mg) were measured for brain radioactivity in 3-in Gamma counter as described earlier. Extravasation of radioactivity was determined as percentage of the whole blood radioactivity. After measurement of the radioactivity, the bran samples were homogenized in a mixture of 0.5% sodium sulfate and ultrapure analytical grade of acetone to extract Evans blue dye entered into the brain. The samples were centrifuged at 900× g and the supernatant was measured for the dye entered into the sample in spectrophotometer at 620 nm. The value of EBA entered into the brain was calculated from the standard curve obtained with different dye concentration [25–27, 50, 52].

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Brain Edema and Volume Swelling Brain edema is measured from the differences between wet weight and dry weight of the brain samples as described earlier. For this purpose, after saline perfusion, the brain samples were dissected (sample size 60–120 mg) weighed immediately on a preweighed filter paper and placed in an oven at 90 °C for 72 h. When the dry weight of the samples in three determinations became constant, the water content of the samples was calculated from the differences between dry and wet weight. The volume swelling (% ƒ) was calculated from the differences between water content of the control and experimental groups using formula of Elliott & Jasper as described earlier. In general, about 1% difference between water content of the control and experimental samples approximately equal to 4% increase in volume swelling [25– 27, 54–60]. Morphological Analysis For histological, immunocytochemical and ultrastructural investigation, after the end of the experiments, animals were perfused in situ through transcardiac perfusion with 0.1 M phosphate buffer saline (pH 7.0) to washout the remaining blood into microvessels at 90 torr followed by 4% buffered paraformaldehyde with 0.25% picric acid for better preservation of cellular structures. On the next day, brains were taken out and multiple coronal sections were cut and embedded in paraffin using tissue processer. About 3-μm thick sections were cut and stained with hematoxylin and eosin (H&E), Nissl staining or Luxol Fast Blue (LFB) for histological examination. Some sections were immunostained with albumin, AβP, GFAP or MBP using standard protocol as described earlier [25–27]. In addition, immunohistochemistry was performed on paraffin sections for CD86 (Anti-CD86 antibody [EP1158-37] abcam, ab 269587, Cambridge, MA, USA), Vimentin (Anti-Vimentin antibody [EPR3776] abcam, ab92547, Cambridge, MA, USA and Iba1 (Anti-Iba1 antibody [EPR16589] abcam, ab 283319, Cambridge, MA, USA) using standard commercial protocol. For ultrastructural investigation, small tissue pieces were postfixed in osmimum tetraocide (OsO4) and embedded in palstik (Epon 801). About 1-μm thick sections were cut using diamond knife and stained with toluidine blue for examining the areas for ultrathin sections. About 50-nm thick ultrathin sections were cut using an LKB Ultramicrotome (Stockholm, Sweden) using a diamond knife. Serial sections were collected on a one hole copper grid (600 μm) and some of them were stained with lead citrate and uranyl acetate to contrast these sections and examined under a Phillips 400 transmission electron microscope (TEM) and photographed using attached digital camera system (Gatan K3 IS camera, Pleasanton, CA, USA). Some of the sections were examined unstained for comparison [25–27]. Biochemical Measurements The following biochemical measurements are done using commercial ELISA protocol.

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Neuronal Nitric Oxide Measurement Commercial Rat nNOS (NOS1) ELISA Kit (Abbexa Ltd., Cambridge, UK, Item Nr. abx155900, sensitivity