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- Herausgeber: Wiley-VCH Verlag GmbH & Co. KGaA
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
Focusing on the molecular mechanisms of powerful naturally occurring agents and their implication for drug discovery, this timely book presents an overview of the most recent research advances in the field of bioactive natural products and natural drug formulations to combat today's destructive diseases.
To this extent, the authors discuss the most severe neurological disorders in our modern civilization, such as Alzheimer's, Parkinson's and Huntington's disease, as well as ischemic brain stroke and depression. The emerging diversity of active compounds is covered in detail, including flavonoids, cannabinoids and oleanolic acid, while experts in the field explain the chemistry, mode of action and clinical aspects of novel neuroprotective natural products. In each case, the benefits of treatments using natural products are addressed from the perspective of modern as well as traditional medicine.
With its multidisciplinary viewpoint, this is the ideal companion for medicinal and natural products chemists as well as neuroscientists, biochemists, pharmacologists, neurobiologists, and phytotherapists.
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Veröffentlichungsjahr: 2017
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Table of Contents
Cover
Title Page
Copyright
List of Contributors
Dedication
Preface
Editor Biography
Chapter 1: Neuroprotective Natural Products: Clinical Aspects and Modes of Action – An Overview
1.1 Introduction
1.2 An Overview of the Book
1.3 Concluding Remarks
Chapter 2: Neuroprotective Agents: An Overview on the General Modes of Action
2.1 Introduction
2.2 Neuroprotective Agents
2.3 Neurodegenerative Diseases
2.4 Neuroprotection in Common Neurodegenerative Diseases
2.5 Concluding Remarks
Acknowledgments
References
Chapter 3: Beneficial Upshots of Naturally Occurring Antioxidant Compounds against Neurological Disorders
3.1 Introduction
3.2 Oxidative Stress
3.3 Neurological Disorders
3.4 Beneficial Effects of Different Antioxidants against Various Neurological Disorders
3.5 Concluding Remarks
References
Chapter 4: Natural Neuroprotectives for the Management of Parkinson's Disease
4.1 Introduction
4.2 Role of Antioxidants/Natural Neuroprotectives in PD
4.3 Concluding Remarks
References
Chapter 5: Neuroprotective Effect of Ayurvedic Preparations and Natural Products on Parkinson’s Disease
5.1 Introduction
5.2 Parkinsonian Symptoms and Ayurveda
5.3 Medicinal Plants in the Ayurvedic Formulation for Parkinson’s Disease Therapy
5.4 Concluding Remarks
References
Chapter 6: Lipid Peroxidation and Mitochondrial Dysfunction in Alzheimer’s and Parkinson’s Diseases: Role of Natural Products as Cytoprotective Agents
6.1 Introduction
6.2 History and Context
6.3 Potential Therapeutic Agents with Natural Origin: Current Knowledge on the Discovery of Newer Drugs
6.4 Future Trends in Research
6.5 Concluding Remarks
References
Chapter 7: Marine-Derived Anti-Alzheimer’s Agents of Promise
7.1 Introduction
7.2 Identification of Potent Anti-Alzheimer’s Agents from Marine Sources
7.3 Molecules in Clinical Trials for Alzheimer’s Disease from Marine Sources
7.4 Concluding Remarks
Acknowledgments
References
Chapter 8: Natural Products against Huntington’s Disease (HD): Implications of Neurotoxic Animal Models and Transgenics in Preclinical Studies
8.1 Introduction
8.2 Methodology
8.3 Neurotoxic
In Vitro
and
In Vivo
Anti-HD Models
8.4 Anti-HD Natural Products and Implications of HD Models
8.5 Synergism: A Novel Approach against Neurological Disorders
8.6 Discussion
8.7 Concluding Remarks
References
Chapter 9: Possible Role of Neuroprotectants and Natural Products in Epilepsy: Clinical Aspects and Mode of Action
9.1 Introduction
9.2 Global Prevalence of Natural Products in Epilepsy
9.3 Pathophysiology of Epilepsy
9.4 Role of Neurotransmitters in Neuronal Excitation
9.5 Role of Neuroprotectants in Seizures
9.6 Natural Plants against Epilepsy
9.7 Natural Plants Examined in Epilepsy
9.8 German Herbs in Epilepsy
9.9 Complement and Alternative Medicine
9.10 Marketed Formulation of Natural Products in India
9.11 Herbs That Induce Seizures
9.12 Interaction of Natural Products with Antiepileptic Drugs (AEDs)
9.13 Concluding Remarks
References
Chapter 10: Neuroprotective Effects of Flavonoids in Epilepsy
10.1 Introduction
10.2 Natural Flavonoids with Antiepileptic Potential
10.3 Discovery and Development of Newer Agents
10.4 Concluding Remarks
References
Chapter 11: The Role of Noncompetitive Antagonists of the N-Methyl- d-aspartate (NMDA) Receptors in Treatment-Resistant Depression
11.1 Introduction
11.2 Noncompetitive Antagonists of the NMDA Receptors: Ketamine and Its Mechanism of Action
11.3 Other Noncompetitive NMDA Antagonists: Selective GluN2B Subunit NMDA Antagonists
11.4 Other Noncompetitive NMDA Antagonists: Glycine Binding Site Modulators
11.5 AMPA Receptor Activation: A Possible Adjunctive Antidepressant Role?
11.6 Discussion and Future Directions
11.7 Concluding Remarks
References
Chapter 12: Safety and Efficacy of Ashwagandha (Withania somnifera)
12.1 Introduction
12.2 Ashwagandha
12.3 Discussion
12.4 Concluding Remarks
References
Chapter 13: Cannabinoids: A Group of Promising Neuroprotective Agents
13.1 Introduction
13.2 The Cannabinoid System
13.3 Cannabinoids and Neuroprotection
13.4 Concluding Remarks
References
Index
End User License Agreement
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Guide
Cover
Table of Contents
Preface
Begin Reading
List of Illustrations
Chapter 3: Beneficial Upshots of Naturally Occurring Antioxidant Compounds against Neurological Disorders
Figure 3.1 Causes and downstream phenomenon associated with different neurodegenerative diseases.
Figure 3.2 Various molecular events leading to the Alzheimer’s disease neurodegeneration.
Figure 3.3 Schematic representation of a common signaling mechanism stimulated by different naturally occurring antioxidants against neurodegenerative disorders.
Chapter 6: Lipid Peroxidation and Mitochondrial Dysfunction in Alzheimer’s and Parkinson’s Diseases: Role of Natural Products as Cytoprotective Agents
Figure 6.1 Oxidative stress induces modifications to biomolecules including proteins, lipids, DNA, and RNA.
Figure 6.2 Antioxidant defense system.
Figure 6.3 Chemical structure of 4-hydroxynonenal.
Figure 6.4 Chemical structure of acrolein.
Figure 6.5 Chemical structure of malondialdehyde.
Figure 6.6 Chemical structures of flavonoid compounds quercetin (a), kaempferol (b), epigallocatechin gallate (c), hesperidin (d), and baicalein (e).
Figure 6.7 Chemical structures of vitamin E as alpha-tocopherol (a), vitamin C (b), and vitamin A as retinol (c).
Figure 6.8 Chemical structures of carotenoid compounds lycopene (a), crocin (b), crocetin (c), and astaxanthin (d).
Figure 6.9 Chemical structures of alkaloid compounds berberine (a), huperzine A (b), huperzine B (c), caffeine (d), and piperine (e).
Figure 6.10 Chemical structures of phenolic compounds resveratrol (a), curcumin (b), rosmarinic acid (c), caffeic acid (d), and gallic acid (e).
Figure 6.11 Chemical structures of phenolic compounds xyloketal b (a), bilobalide (b), gypenoside XVII (c), and ginsenoside Re (d).
Figure 6.12 Chemical structures of acteoside (a), nolinospiroside F (b), genistein (c), and puerarin (d).
Chapter 7: Marine-Derived Anti-Alzheimer’s Agents of Promise
Figure 7.1 Clinically approved anti-Alzheimer’s disease agents (
1–8
).
Figure 7.2 Chemical structure of cholinesterase inhibitors (
9–29
).
Figure 7.3 Chemical structure (
30–57
) of cholinesterase inhibitors.
Figure 7.4 Chemical structure (
58–72
) of cholinesterase enzyme inhibitors.
Figure 7.6 Chemical structure of secretase inhibitors (
79–86
).
Figure 7.7 Chemical structure of BACE inhibitors (
87–106
).
Figure 7.8 Chemical structure of BACE inhibitors (
107–131
).
Figure 7.9 Chemical structure of BACE inhibitors (
132–134
).
Figure 7.10 Chemical structure of anti-aggregation and clearance promoters (
135–138
).
Figure 7.11 Chemical structure of glycogen synthase kinase 3 (GSK3β) inhibitors (
139–158
).
Figure 7.12 Chemical structure of glycogen synthase kinase 3 (GSK3β) inhibitors (
159–165
).
Figure 7.13 Chemical structures of gracilins (
166–171
) as antioxidants.
Chapter 8: Natural Products against Huntington’s Disease (HD): Implications of Neurotoxic Animal Models and Transgenics in Preclinical Studies
Figure 8.1 Medicinal plants as source of anti-HD botanicals and/or phytochemicals. (a)
Allium sativum
L.; (b)
Bacopa monnieri
(L.) Wettst.; (c)
Boerhaavia diffusa
L.; (d)
Camellia sinensis
(L.) Kuntze; (e)
Centella asiatica
(L.) Urb. (f)
Citrus
sp.; (g,h)
Curcuma longa
L. (habit and roots); (i)
Ginkgo biloba
L.; (j)
Lycopersicon
sp.; (k)
Punica granatum
L.; and (l)
Withania somnifera
L. (Dunal).
Figure 8.2 Chemical structures of anti-HD phytochemicals
1
, berberine;
2
, cannabidiol;
3
, celastrol;
4
, curcumin;
5
, (−)-epigallocatechin-gallate;
6
, ferulic acid;
7
, fisetin;
8
, galantamine;
9
, genistein;
10
, ginsenoside Rb1;
11
, hesperidin;
12
, kaempferol;
13
, l-theanine;
14
, lutein;
15
, lycopene;
16
, melatonin;
17
, naringin;
18
, nicotine;
19
, puerarin;
20
, quercetin;
21
, resveratrol;
22
, S-allylcysteine;
23
, schisandrin B;
24
, sesamol;
25
, spermidine;
26
, trehalose; and
27
, vanillin.
Figure 8.3 A schematic presentation of anti-HD models.
Chapter 9: Possible Role of Neuroprotectants and Natural Products in Epilepsy: Clinical Aspects and Mode of Action
Figure 9.1 Pathophysiology of epilepsy.
Figure 9.2 Diagram showing the cascade of seizure induction, which causes cognitive deficiency.
Figure 9.3 A list of German herbs.
Figure 9.4 Divisions of the complementary and alternative medicines.
Chapter 10: Neuroprotective Effects of Flavonoids in Epilepsy
Figure 10.1 Chemical structure of some important natural flavonoids.
List of Tables
Chapter 3: Beneficial Upshots of Naturally Occurring Antioxidant Compounds against Neurological Disorders
Table 3.1 Neurodegenerative diseases: proteins and associated pathology.
Table 3.2 Some biologically relevant polyphenolic compounds with their natural sources and major metabolites.
Chapter 5: Neuroprotective Effect of Ayurvedic Preparations and Natural Products on Parkinson’s Disease
Table 5.1 Active ingredients present in the plants used in antiparkinsonian Ayurvedic formulation.
Chapter 6: Lipid Peroxidation and Mitochondrial Dysfunction in Alzheimer’s and Parkinson’s Diseases: Role of Natural Products as Cytoprotective Agents
Table 6.1 Types of reactive oxygen species (ROS).
Chapter 8: Natural Products against Huntington’s Disease (HD): Implications of Neurotoxic Animal Models and Transgenics in Preclinical Studies
Table 8.1 Anti-HD activity of some of the medicinal plants.
Table 8.2 Anti-HD activity of phytochemicals.
Chapter 9: Possible Role of Neuroprotectants and Natural Products in Epilepsy: Clinical Aspects and Mode of Action
Table 9.1 List of marketed formulations.
Table 9.2 List of herbal drugs that show epileptic behavior.
Table 9.3 Interaction of herbal drugs with antiepileptic drugs (AEDs).
Chapter 10: Neuroprotective Effects of Flavonoids in Epilepsy
Table 10.1 Anticonvulsant effects of some flavonoids in animals.
Neuroprotective Natural Products
Clinical Aspects and Mode of Action
Edited by Goutam Brahmachari
Editor
Dr. Goutam Brahmachari
Visva-Bharati (a Central University)
Department of Chemistry, Laboratory of Natural Products and Organic Synthesis, Santiniketan
West Bengal 731 235
India
Cover
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List of Contributors
Javed Ali
Jamia Hamdard
Department of Pharmaceutics
Hamdard Nagar
New Delhi 110062
India
Mario Amore
University of Genoa
Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health
Section of Psychiatry
IRCCS San Martino
Largo Rosanna Benzi 10
16132 Genoa
Italy
Sanjula Baboota
Jamia Hamdard
Department of Pharmaceutics
Hamdard Nagar
New Delhi 110062
India
Manveen Bhardwaj
Panjab University
UGC Centre of Advanced Study
University Institute of Pharmaceutical Sciences
Department of Pharmacology
Pharmacology Division
Chandigarh 160014
India
Anupom Borah
Assam University
Department of Life Science and Bioinformatics
Cellular and Molecular Neurobiology Laboratory
Silchar 788011
Assam
India
Goutam Brahmachari
Visva-Bharati (a Central University)
Department of ChemistryLaboratory of Natural Products and Organic Synthesis
Santiniketan
West Bengal 731 235
India
Alicia Brusco
Universidad de Buenos Aires
Consejo Nacional de lnvestigaciones Científicas y Técnicas
Instituto de Biología Celular
y Neurociencia (IBCN)
Facultad de Medicina
Paraguay 2155
Ciudad Autónoma de Buenos Aires
Buenos Aires 1114
Argentina
Laura R. Caltana
Universidad de Buenos Aires
Consejo Nacional de lnvestigaciones Científicas y Técnicas
Instituto de Biología Celular
y Neurociencia (IBCN)
Facultad de Medicina
Paraguay 2155Ciudad Autónoma de Buenos Aires
Buenos Aires, 1114
Argentina
Swapnali Chetia
Assam University
Department of Life Science and Bioinformatics
Cellular and Molecular Neurobiology Laboratory
Silchar 788011
Assam
India
Amarendranath Choudhury
Assam University
Department of Life Science and Bioinformatics
Cellular and Molecular Neurobiology Laboratory
Silchar 788011
Assam
India
Kapil Dev
Academy of Scientific and Innovative Research
CSIR-Central Drug Research Institute
Medicinal and Process Chemistry Division
Sector 10
Jankipuram Extension
Sitapur Road
Lucknow 226031
India
Abhijit Dey
Presidency University
Department of Life Sciences
Ethnopharmacology and Natural Products Research Laboratory
86/1 College Street
Kolkata 700073
India
Ranjan Dutta
Department of Neurosciences
Lerner Research Institute
Cleveland Clinic 9500 Euclid Avenue, NC-30
Cleveland, OH 44195
USA
Carlos Fernández-Moriano
University Complutense of Madrid School of Pharmacy
Department of Pharmacology
Plaza Ramón y Cajal s/n
28040 Madrid
Spain
Bharti Gaba
Jamia Hamdard
Department of Pharmaceutics
Hamdard Nagar
New Delhi 110062
India
Mehdi Ghasemi
University of Massachusetts Medical Center
Department of Neurology
55 Lake Avenue North Worcester, MA 01655
USA
Maria Pilar Gómez-Serranillos
University Complutense of Madrid School of Pharmacy
Department of Pharmacology
Plaza Ramón y Cajal s/n
28040 Madrid
Spain
Elena González-Burgos
University Complutense of Madrid School of Pharmacy
Department of Pharmacology
Plaza Ramón y Cajal s/n
28040 Madrid
Spain
Shawn Hayley
Carleton University
Department of Neuroscience
1125 Colonel By Drive
Ottawa, K1S 5B6 ON
Canada
Hossein Hosseinzadeh
Mashhad University of Medical Sciences
Pharmaceutical Research Center School of Pharmacy
Department of Pharmacodynamics and Toxicology
Vakilabad Blvd.Mashhad 1365-91775
Iran
Harshpreet Kaur
Panjab University
UGC Centre of Advanced Study
University Institute of Pharmaceutical Sciences
Department of Pharmacology
Pharmacology Division
Chandigarh 160014
India
Hadi M. Khanli
Olive View UCLA Medical Center Department of Neurology
14445 Olive View Drive
Sylmar, CA 91342
USA
Anil Kumar
Panjab University
UGC Centre of Advanced Study
University Institute of Pharmaceutical Sciences
Department of Pharmacology
Pharmacology Division
Chandigarh 160014
India
Shobhit Kumar
Jamia Hamdard
Department of Pharmaceutics
Hamdard Nagar
New Delhi 110062
India
Rakesh Maurya
Academy of Scientific and Innovative Research
CSIR-Central Drug Research Institute
Medicinal and Process Chemistry Division
Sector 10
Jankipuram Extension
Sitapur Road
Lucknow 226031
India
Muhammed K. Mazumder
Assam University
Department of Life Science and Bioinformatics
Cellular and Molecular Neurobiology Laboratory
Silchar 788011
Assam
India
Shadab Md
International Medical University (IMU)
School of PharmacyDepartment of Pharmaceutical Technology
Kuala Lumpur 57000
Malaysia
Shri K. Mishra
University of Southern California
Keck School of Medicine
1100 North State Street
Clinic Tower
Los Angeles, CA 90033
USA
Jasjeet. K. Narang
Khalsa College of Pharmacy Department of Pharmaceutics
Amritsar
India
Marjan Nassiri-Asl
Qazvin University of Medical Sciences
Cellular and Molecular Research CentreSchool of MedicineDepartment of Pharmacology
Bahonar Blvd.Qazvin 341197-598
Iran
Rajib Paul
Assam University
Department of Life Science and Bioinformatics
Cellular and Molecular Neurobiology Laboratory
Silchar 788011
Assam
India
Pritam Sadhukhan
Bose InstituteDivision of Molecular Medicine
P-1/12, CIT Scheme VII M
Kolkata 700054
India
Sukanya Saha
Bose InstituteDivision of Molecular Medicine
P-1/12, CIT Scheme VII M
Kolkata 700054
India
Gianluca Serafini
University of Genoa
Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health Section of Psychiatry
IRCCS San Martino
Largo Rosanna Benzi 10
16132 Genoa
Italy
Parames C. Sil
Bose InstituteDivision of Molecular Medicine
P-1/12, CIT Scheme VII M
Kolkata 700054
India
Bharathi A. Venkatachalapathy
Medical Ayurveda Rejuvenation Center
Newport Beach, CA 92660
USA
Christina Volsko
Department of Neurosciences Lerner Research Institute Cleveland Clinic
9500 Euclid Avenue, NC-30
Cleveland, OH 44195
USA
Dedication
Dr. Arnold L. Demain (Drew University, USA).
Preface
Neuroprotective Natural Products: Clinical Aspects and Mode of Action is an endeavor to offer an account on the recent cutting-edge research advances in the field of bioactive natural products with neuroprotective potential against various neurological diseases and disorders, particularly focusing on their clinical aspects and mode of action, and also to underline how natural product research continues to make significant contributions in the domain of discovery and development of new medicinal entities. This book consists of a total of 13 chapters contributed by eminent researchers from several countries in response to my personal invitation. I am most grateful to the contributors for their generous and timely response in spite of their busy and tight schedules with academics, research, and other responsibilities.
The term neuroprotection refers to strategies able to defend the nervous system against neuronal injury and/or death when exposed to trauma and surgery and that developed due to both acute and chronic neurodegenerative disorders. Among central nervous system (CNS) disorders, neurodegenerative disorders affect majority of population worldwide and are a major health problem in the twenty-first century. Neurodegenerative disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS) are currently incurable pathologies with huge social and economic impacts closely related to the increasing of life expectancy in modern times. In the course of time, a number of neurotransmitters and signaling molecules have been identified, which have been considered as therapeutic targets against these devastating disorders, and conventional and newer molecules have been tried against these targets. Still the progress is too limited. Neuroprotection is, thus, an important part of care for all types of neurological disorders. Treatment of neurological disorders should not be merely symptomatic, but an effort should be made to prevent the progression of the underlying disease and to develop therapies for regeneration.
The history of neuroprotection dates back to ancient Greek physicians who used hypothermia as treatment of head injury. Neuroprotection has been used in medical practice for more than the past half century. The earliest agents were barbiturates and nonpharmacological approaches such as hypothermia and hyperbaric oxygen. Neuroprotection has now been placed on a firm scientific basis due to an improved understanding of the molecular basis of neurological diseases. The concept of neuroprotection has found increased acceptance in neurology during the past decade and is linked initially to the role of free radicals in the etiology of neurological disorders, particularly stroke and degenerative neurological symptoms. Considerable work has been performed to elucidate the pathomechanism of various neurological disorders; consequently, a number of neurotoxic phenomena have been identified.
Nature stands as an inexhaustible source of novel chemotypes and pharmacophores; natural products present in the plant and animal kingdoms offer a huge diversity of chemical structures, which are the result of biosynthetic processes that have been modulated over the millennia through genetic efforts. Natural products continue to provide useful drugs in their own right and also provide templates for the development of other useful compounds. A major advantage of natural products approach to drug delivery is that it is capable of providing complex molecules that are not accessible by other routes. Many of such bioactive molecules are found to play a vital role in maintaining the brain’s chemical balance by influencing the function of receptors for the major inhibitory neurotransmitters. In traditional medicinal practice, several plants have been reported to treat cognitive disorders. Plant secondary metabolites include an array of bioactive constituents from both medicinal and food plants that are able to improve human health. The exposure to these phytochemicals, including phenylpropanoids, isoprenoids, and alkaloids, through proper dietary habits may promote health benefits, protecting against chronic degenerative disorders. Recently, it has been suggested that drug discovery should not always be limited to the discovery of a single molecule, and the current belief is that rationally designed polyherbal formulation could also be investigated as an alternative in multitargeted therapeutics and prophylaxis. Development of standardized, safe, and effective herbal formulation with proven scientific evidence can also provide an economical alternative in several disease areas.
It is regarded that herbal medicine may represent a valuable resource in prevention rather than in therapy of some CNS diseases, in association with a healthy lifestyle including beneficial dietary habits and moderate physical activities. Nutritional therapy is a healing system using functional foods and nutraceuticals as therapeutics. This complementary therapy is based on the assumption that food not only is a source of nutrients and energy but also can provide health benefits. In particular, the reported health-promoting effects of plant foods and beverages can be ascribed to the numerous bioactive chemicals present in plant tissues and, consequently, occurring in foods. Consumed as part of a normal diet, plant foods are thus a source of nutrients and energy. It may additionally provide health benefits beyond basic nutritional functions by virtue of their dietary therapeutics. Thus, neuroprevention appears to be an important target and strategy in overcoming neurodegenerative disorders! Prevention coupled with curing therapy for various neurodegenerative diseases is of demanding importance in modern medicinal chemistry.
This book, which comprises 13 chapters written by active researchers and leading experts working in the field of neuroprotective natural products, brings together an overview of current discoveries and trends in this remarkable field. Chapter 1 presents an overview of the book and summarizes the contents of other chapters so as to offer glimpses of the subject matter covered to the readers before they go in for a detailed study. Chapters 2–13 are devoted to exploring the ongoing chemical, biological, and pharmacological advances in naturally occurring neuroprotective agents with a focus on their clinical aspects and mode of action. This timely volume encourages interdisciplinary work among chemists, biologists, pharmacologists, botanists, and agronomists with an interest in bioactive natural products. It is also an outstanding source of information with regard to the industrial application of natural products for medicinal purposes. The broad interdisciplinary approach dealt with in this book would surely make the work much more interesting for scientists deeply engaged in the research and/or use of neuroprotective natural products.
Representation of facts and their discussions in each chapter are exhaustive, authoritative, and deeply informative; hence, the book would serve as a key reference for recent developments in the frontier research on neuroprotective natural products at the interface of chemistry and biology and would also be of much utility to scientists working in this area. I would like to express my sincere thanks once again to all the contributors for their excellent reviews on the chemistry, biology, and pharmacology of these medicinally promising agents. It is their participation that makes my effort to organize such a book possible. Their masterly accounts will surely provide the readers with a strong awareness of current cutting-edge research approaches being followed in some of the promising fields of biologically active natural products.
Finally, I would like to express my deep sense of appreciation to all of the editorial and publishing staff–members associated with Wiley-VCH, Weinheim, Germany, for their keen interest in publishing the work and also for their all-round help so as to ensure that the highest standards of publication are maintained in bringing out this book.
Goutam Brahmachari Visva-Bharati University, Chemistry Department, Santiniketan, India November 2016
Editor Biography
Professor (Dr) Goutam Brahmachari currently holds the position of full professor of chemistry at the Department of Chemistry, Visva-Bharati University, Santiniketan, India. He was born at Barala in the district of Murshidabad (West Bengal, India) in 1969. He received B.Sc. (Honours) in Chemistry and M.Sc. with specialization in organic chemistry from Visva-Bharati University, India, in 1990 and 1992, respectively. Thereafter, he received his Ph.D. in organic chemistry in 1997 from the same university. In 1998, he joined his alma mater as an assistant professor. He became an associate professor in 2008 and was promoted to full professor in 2011. At present, he is responsible for teaching courses in organic chemistry, natural products chemistry, and physical methods in organic chemistry. Several students received their Ph.D. degree under the supervision of Prof. Brahmachari during this period, and couples of research fellows are presently working with him in the fields of both natural products and synthetic organic chemistry. Prof. Brahmachari’s research is supported by several funding organizations including SERB-DST (New Delhi), CSIR (New Delhi), DBT (New Delhi), and UGC (New Delhi). He is a 2015 and 2016 Who’s Who in the World listee and also a recipient of the 2015 Academic Brilliance Award (Excellence in Research). He is the series editor of the book series Natural Product Drug Discovery.
Prof. Brahmachari’s research interests include (i) isolation, structural determination, and/or detailed NMR study of new natural products from medicinal plants; (ii) synthetic organic chemistry with special emphasis on green chemistry; (iii) semisynthetic studies with natural products; and (iv) evaluation of biological activities and pharmacological potential of natural and synthetic compounds. With more than eighteen years of teaching experience, he has also produced so far nearly 160 publications including original research papers, review articles, and invited book chapters in edited books in the field of natural products and organic synthesis from internationally reputed presses. Prof. Brahmachari has authored/edited a number of textbooks and reference books, including Organic Name Reactions: A Unified Approach (Narosa Publishing House, New Delhi; copublished by Alpha Science International, Oxford, 2006), Chemistry of Natural Products: Recent Trends & Developments (Research Signpost, 2006), Organic Chemistry Through Solved Problems (Narosa Publishing House, New Delhi; copublished by Alpha Science International, Oxford, 2007), Natural Products: Chemistry, Biochemistry and Pharmacology (Narosa Publishing House, New Delhi; copublished by Alpha Science International, Oxford, 2009), Handbook of Pharmaceutical Natural Products—2-Volume Set (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2010), Bioactive Natural Products: Opportunities & Challenges in Medicinal Chemistry (World Scientific Publishing Co. Pte. Ltd, Singapore, 2011), Chemistry and Pharmacology of Naturally Occurring Bioactive Compounds (CRC Press, Taylor & Francis group, USA, 2013), Natural Bioactive Molecules: Impacts & Prospects (Narosa Publishing House, New Delhi; copublished by Alpha Science International, Oxford, 2014), Green Synthetic Approaches for Biologically Relevant Heterocycles (Elsevier Inc., USA, 2014), Bioactive Natural Products—Chemistry & Biology (Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2015), Room Temperature Organic Synthesis (Elsevier Inc., USA, 2015), Biotechnology of Microbial Enzymes: Production, Biocatalysis and Industrial Applications (Academic Press, London, 2016), and Discovery and Development of Antidiabetic Agents from Natural products (Natural Product Drug Discovery Series; Elsevier Inc., USA, 2016), and few are forthcoming.
Prof. Brahmachari serves as a member of the Indian Association for the Cultivation of Science (IACS) and Indian Science Congress Association (ISCA), Kolkata, and as an editor-in-chief of Signpost Open Access Journal of Organic and Biomolecular Chemistry. He also serves as an editorial advisory board member for several international journals. He is regularly consulted as a referee by leading international journals including Elsevier, Royal Society of Chemistry, American Chemical Society, Wiley, Taylor & Francis, Springer, Bentham Science, Indian Chemical Society, Indian Journal of Chemistry (Sec. B), Korean Chemical Society, Pakistan Chemical Society, Brazilian Chemical Society, Bulgarian Academy of Sciences, and so on and also by various financial commissions.
Goutam Brahmachari enjoys songs of Rabindranath Tagore and finds interests in literature as well!
Chapter 1Neuroprotective Natural Products: Clinical Aspects and Modes of Action – An Overview
Goutam Brahmachari
Visva-Bharati (a Central University), Department of Chemistry, Laboratory of Natural Products and Organic Synthesis, Santiniketan, West Bengal, 731 235, India
1.1 Introduction
The book titled Neuroprotective Natural Products: Clinical Aspects and Modes of Action is an endeavor to the present cutting-edge research in the neuroprotective natural products and helps the reader understand how natural product research continues to make significant contributions in the discovery and development of new medicinal entities. The reference is meant for phytochemists, synthetic chemists, combinatorial chemists, biologists, pharmacologists, clinicians, as well as other practitioners and advanced students in related fields. This book, comprising 12 technical chapters, highlights the clinical aspects and modes of action of potential neuroprotective natural products with an intention to unravel their pharmaceutical applicability in modern drug discovery processes in the field of neurodegenerative diseases.
This introductory chapter presents an overview of the book and summarizes the contents and subject matter of each chapter so as to offer certain glimpses of the coverage of discussion to the readers before they go for detailed study.
1.2 An Overview of the Book
This book contains a total of 12 technical chapters – Chapters 2–13; this section summarizes the contents and subject matter of each of these chapters.
1.2.1 Chapter 2
In Chapter 2, Volsko and Dutta have offered an overview on the general modes of action of neuroprotective agents in several neurodegenerative disorders as studied in various animal models. The results suggest that administration of such therapeutic candidates postpones disease progression and increases survival rate. Neuroprotective agents act through certain key pathways associated with development, maturation, and repair in abnormal pathological environments during neurodegenerative diseases, thereby resulting in the reduction of cellular distress and slowing disease development in the nervous system. Specific trophic factors, polypeptides, and heterodimers activate or block the receptors during pathogenesis to slow disease progression. Natural neuroprotective agents that are effective in humans and suppress symptoms and delay disease progression are regarded as promising lead candidates in the drug discovery process in treating neurodegenerative diseases. Modifying treatments based on neuropathology of each such disease is essential, and this chapter boosts the ongoing research in this remarkable field.
1.2.2 Chapter 3
Sil and his group have furnished a thorough discussion on the beneficial effects of different classes of naturally occurring antioxidant compounds against various neurological disorders in Chapter 3. Oxidative stress (elevation of intracellular reactive oxygen species level) is a major cause in the development and progression of neurological diseases such as neurodegenerative diseases, movement disorders, and so on. The brain in particular is prone to this oxidative stress phenomenon, and impairment in memory and cognition are hallmarks of progressive neurodegenerative diseases. Therefore, targeting these diseases with antioxidants may be expected to be a fruitful solution. Antioxidant molecules combat oxidative stress by neutralizing excessively produced free radicals and inhibiting them from initiating the signaling cascades and chain reactions that result in various diseases and premature aging. Several natural compounds with antioxidant property have been found to be greatly effective in treating these diseases as they effectively scavenged free radicals and inhibited their generation. This chapter covers the sources of such antioxidants and the general mechanism by which they play a protective role in different cognitive and movement-related neurological disorders. This illuminating review on natural antioxidants would obviously enrich the readers and would motivate them in undertaking in-depth further research.
1.2.3 Chapter 4
Chapter 4 is dedicated to natural neuroprotectives for the management of Parkinson’s disease (PD) by Ali and his group. PD is regarded as the second most general neurodegenerative disorder that involves a decreased nigrostriatal availability of dopamine, resulting in motor impairment including bradykinesia, rigidity, and tremor. Currently, the exact cause of this devastating disease is unclear with no single factor accountable for neurodegeneration. It shows that several factors may contribute to its development, such as formation of reactive oxygen species (ROS), protein misfolding, and neuroinflammation. The deficiency of dopamine occurs due to loss of dopaminergic neurons and degradation of dopamine. It has been evidenced that oxidative stress is critically involved in the pathogenesis of PD, and thus antioxidants may find beneficial role in treating the disease. This chapter deals with the literature covering the use of various natural antioxidative neuroprotective agents including naringenin, curcumin, vitamin E, vitamin C, resveratrol, coenzyme Q10, and melatonin, which may find application in PD. In addition, the authors have discussed on the mechanism of actions and in vitro and in vivo application of natural neuroprotectives in experimental animal models and in patients with PD. This chapter offers an up-to-date development in this field.
1.2.4 Chapter 5
In Chapter 5, Borah and his group have discussed the role and therapeutic efficacy of Ayurvedic preparations in treating Parkinson’s disease (PD). A prospective clinical trial on the effectiveness of an Ayurvedic formulation, composed of Mucuna pruriens, Withania somnifera, Hyoscyamus niger, and Sida cordifolia, on PD patients demonstrated significant improvement of the symptoms. The authors have elaborated the potentials of such natural products used in Ayurvedic formulations as alternative/adjuvant to the dopamine replenishment therapy for PD and also highlighted their molecular mechanisms of action.
1.2.5 Chapter 6
Chapter 6 deals with the role of natural products as cytoprotective agents against lipid peroxidation and mitochondrial dysfunction in Alzheimer’s and Parkinson’s diseases by Gómez-Serranillos and her group. Among their pathological hallmarks, increased lipid peroxidation and mitochondrial dysfunction appear to be relevant from the early events of these age-related disorders. Neurodegenerative diseases in humans are strongly associated with oxidative stress generated by ROS, which can cause oxidative damage to cell structures, including alterations in membrane lipids, proteins, and DNA. In turn, it may trigger cellular organelle dysfunction that finally leads to cell death. Lipid peroxidation is a process that takes place along the cell membrane by effect of free radical oxidation of polyunsaturated fatty acids, and as a consequence of this chain reaction, it results in the formation of reactive products with toxic effects. Mitochondria are cytoplasmic organelles that regulate both metabolic and apoptotic signaling pathways, including energy generation; thus, they exhibit special susceptibility to oxidative stress, which eventually provokes the mitochondrial dysregulation. Herein, the authors have provided a detailed overview of the involvement of lipid peroxidation and mitochondrial dysfunction in Parkinson’s and Alzheimer’s diseases, with special consideration to natural products exerting beneficial effects on neurodegeneration models through an amelioration of these molecular disorders.
1.2.6 Chapter 7
Dev and Maurya have presented an exhaustive review on potential marine-derived anti-Alzheimer’s agents in Chapter 7. Marine secondary metabolites develop under very adverse conditions and, thus, may contain very unusual structural skeletons; such chemical entities with new and varying scaffolds and interesting biological activity have created a new hope of drug discovery and development for various disease areas including neurodegenerative disorders. The main hurdle in drug discovery for Alzheimer’s disease is associated with the permeability of blood–brain barrier (BBB) to exhibit drug’s effective activity. A number of marine natural products and their synthetic analogs showed efficacy with good bioavailability against Alzheimer’s disease. This chapter includes 163 compounds and some extracts from different marine sources such as algae, sponges, coelenterates, bryozoans, molluscs, tunicates, and echinoderms together with their pharmacological activity in the treatment of Alzheimer’s disease. This informative review would act as a stimulus in this direction.
1.2.7 Chapter 8
Huntington’s disease (HD) is a neurological disorder characterized by abnormal body movements (chorea) associated with cognitive and motor dysfunctions, neuropsychiatric disturbances, and striatal damage. Therapeutic advancement in screening of natural products against HD suffers from constraints such as limited animal models and giving maximum emphasis on cellular models during experimentations. However, recent progress in animal HD transgenic models expressing mutant proteins may reveal the therapeutic efficacy of natural products against HD, a disease with less elucidated pathogenesis and inadequate treatment strategies. In Chapter 8, Dey has offered an illuminating and comprehensive account on the anti-HD efficacy of a number of plant extracts, fractions, and isolated compounds investigated in various neurotoxic animal models and transgenics highlighting their ability to influence signaling pathways, leading to neuromodulation and probable neuroprotection.
1.2.8 Chapter 9
Chapter 9 by Kumar and his group deals with the possible role of neuroprotectants and natural products in epilepsy, a common neurological problem with complex pathology and uncured treatment. The roles of oxidative stress, mitochondrial dysfunction, and neuroinflammation have been well suggested to explain its pathophysiology and related complications, particularly cognitive dysfunction. Several antiepileptic drugs have been in use for the treatment and management of epilepsy, but majority of them are often associated with the problems due to either side effects, drug interactions, or treatment resistance. Different neuroprotectants of diverse nature are being tried with limited success. In search of new and more efficacious drugs, researchers have been engaged to explore therapeutic potentials of plant-based bioactive molecules, particularly belonging to the alkaloid, flavonoid, terpenoid, saponin, and coumarin skeletons, which have been found responsible for their anticonvulsants properties. In this chapter, the authors have made a significant attempt to highlight the potential role of various natural neuroprotectants, their modes of action, and clinical aspects/status for the treatment of epilepsy and related problems.
1.2.9 Chapter 10
Hosseinzadeh and Nassiri-Asl have presented an account on the neuroprotective effects of flavonoids in epilepsy in Chapter 10. Flavonoids are present in foods such as fruits and vegetables, and these natural polyphenolics are reported to possess beneficial effects against many neurological disorders including epilepsy, a serious but common problem in our society. It seems that many of these compounds are ligands for γ-aminobutyric acid type A (GABA-A) receptors in the central nervous system. Furthermore, flavonoids have well-established antioxidants and free radical scavenging activities. The authors have discussed such effects in their presentation.
1.2.10 Chapter 11
Chapter 11 is devoted to the role of noncompetitive antagonists of the N-methyl-d-aspartate (NMDA) receptors in treatment-resistant depression by Serafini and coauthors. The authors have discussed the pros and cons of using NMDA antagonists in treating the disease manifestation. As mentioned, ketamine (an NMDA antagonist) exhibits good response as a useful clinical agent in cases of severe intractable depression and suicidal risk; the drug works rapidly in many such patients but is not devoid of adverse effects. Hence, it is of critical importance to develop alternate NMDA or other novel antidepressants as well as possible combinatorial drug approaches to treat depression. For instance, novel agents that target AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors are currently being explored; it has been found that compounds able to exert neurotrophic effects and anti-inflammatory drugs might be useful as add-on (or adjuvants) with traditional antidepressants. The authors are in opinion that more personalized approaches will be the way of the future.
1.2.11 Chapter 12
Mishra and coauthors have presented an overview of the safety and efficacy of Ashwagandha (Withania somnifera), an important medicinal plant used in Ayurvedic preparations to treat various diseases including neurological disorders, in Chapter 12. Medicinal herbs in Ayurveda have been widely used for thousands of years to promote health and treat diseases. However, limited evidence is available to testify the safety and efficacy of Ayurvedic herbs. An integrated approach for safety assessment focused on the hazard identification is imperative. Under this purview, this chapter highlighting the safety and efficacy of Ashwagandha plant is of interest.
1.2.12 Chapter 13
Chapter 13 deals with the neuroprotective properties of cannabinoids by Laura and Alicia. The cannabinoid system is well characterized, and abundant research supports their role in ameliorating neuropathologies such as ischemia, Alzheimer’s diseases (AD), Parkinson’s disease (PD), multiple sclerosis, retinal diseases, and psychiatric disorders. Hence, the manipulation of the endocannabinoid system, using phytocannabinoids or synthetic cannabinoids, could lighten the processing in the treatment and evolution of cerebral diseases. Certain clinical trials have also demonstrated promising results; however, cannabinoid adverse effects still remain to be elucidated. The authors have discussed all such considerations in this chapter.
1.3 Concluding Remarks
This introductory chapter summarizes each technical chapter of the book for which representation of facts and their discussions are exhaustive, authoritative, and deeply informative. The readers would find interest in each of the chapters, which practically cover a wide area of neuroprotective natural product research, particularly on their clinical aspects and modes of action. The reference encourages interdisciplinary works among chemists, pharmacologists, clinicians, biologists, botanists, and agronomists with an interest in these bioactive natural products. Hence, this book would surely serve as a key reference for recent developments in the frontier research on neuroprotective natural products and also would find much utility to the scientists working in this area.
Chapter 2Neuroprotective Agents: An Overview on the General Modes of Action
Christina Volsko and Ranjan Dutta
Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, NC-30, Cleveland, OH, 44195, USA
2.1 Introduction
Neuroprotection is defined as the protection of neurons from principle mechanisms that results due to cell loss within the central nervous system (CNS) or peripheral nervous system (PNS). Common mechanisms that have been linked to neurodegeneration within the CNS include neurotoxicity, inflammation, oxidative stress, accumulation of iron, excitotoxicity, and dysregulation of gene expression. While a considerable amount of research has been conducted into the mechanisms underlying neurodegeneration, the majority of diseases, there are no treatment options that can either stop or reverse the degenerative process. Researchers are turning to neuroprotective agents such as hepatocyte growth factor (HGF) and/or trophic factors that increase cell and neuron survival [1, 2] as a possible therapeutic treatment to relieve symptoms and delay progression of these diseases. In this chapter, we discuss some of the available neuroprotective agents, their mechanisms of action, and clinically derived neuroprotective treatment for some common neurodegenerative diseases.
2.2 Neuroprotective Agents
2.2.1 Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP)
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuroprotective peptide that is abundant and present in the nervous system during development to adulthood [3]. Within the CNS, PACAP is located in the hippocampus, amygdala, substantia nigra, and cerebellar granule. PACAP can also be found in PNS structures including sensory neurons in the dorsal root ganglia, sympathetic and parasympathetic nervous system, and some somatomotor neurons [4]. PACAP is derived from 38 amino acid hypothalamic neuropeptides and a derivative of vasoactive intestinal peptide/secretin/glucagon peptide superfamily. There are two forms, PACAP27 (PAC1) and PACAP38 (PAC2), that are dependent on binding to three different G-protein-coupled receptors [2, 5]. VPAC1 and VCAP2 are vasoactive intestinal polypeptide receptors, yet they have around 70% homology with PACAP. Once activated, these receptors do not yield high intensity for stimulation unlike PAC1 [2]. When activated, PACAP receptors play a significant role in synaptic plasticity, memory, hippocampal neurogenesis, and neuroprotection. Similar to BDNF, PACAP acts as a neurotransmitter, neuromodulator, and neurotrophic factor [3]. The functional mechanism of PACAP binding to G-protein-coupled receptors activates cAMP-dependent protein kinase A (PKA) pathway. This pathway modulates ion channel properties, neuronal excitability, and synaptic strength.
PAC1 has been found to be an endogenous ligand that is a treatment target for neurodegenerative and neuropathic diseases [5]. PACAP promotes cortical neurogenesis, protects from necrosis, and inhibits neuronal death by the induction of excitotoxin N-methyl-d-aspartate (NMDA) [2]. NMDA receptors are glutamate receptors that have the ability to prevent degeneration from occurring when glutamate and kainate are receptor bound. NMDAR has been found to prevent the commonly occurring degradations such as excitotoxic and ischemic injuries, degeneration from UV-A, optic nerve transection, and streptozotocin-induced diabetic retinopathy [5]. Studies suggest that the NMDA receptors and PAC1 receptors can control the nociception signal being sent through ERK phosphorylation and JNK pathway [6], leading to increased neuroprotection. Recent studies are investigating the effects of administrating PACAP to wild-type mice after middle cerebral artery occlusion (MCAO). These mice became PACAP deficient but revealed a lower lesion volume and improvement of neurological deficiencies after PACAP treatments in striatal lesions [2]. In addition to the examples mentioned earlier, the role of PACAP is also under investigation in improving neurological deficits in models of stroke, traumatic brain injury, and Parkinson’s disease (PD) [7].
2.2.2 Hepatocyte Growth Factor (HGF)
HGF is a heterodimer that induces favorable protective responses within the brain, especially following a stroke, and could have an impact in the pathogenesis of PD [1, 8]. The heterodimer consists of 728 amino acids forming 69 kDa α-chains and 34 β-sheets [8, 9]. HGF is secreted from stromal cells and activates a signal transduction cascade through tyrosine phosphorylating proto-oncogenic c-Met receptors. This pathway generates differentiation, proliferation, and regeneration of multiple different cell types [1, 8]. Activation of the c-Met tyrosine causes survival and proliferation not only in the brain but also in the kidneys and lungs while playing a critical role in embryonic development [1, 2]. Within the brain, HGF is believed to be a key factor for motor and sensory neuron survival [1]. Neuroprotective characteristics include preventing nuclear translocation of apoptosis-inducing factors [2]. Ongoing clinical studies involve the administration of HGF into the brain. The treatment has been determined to delay neuronal death within the hippocampus following ischemia. Accumulation of HGF blocks additional pathways preventing oxidative DNA damage and stimulates polymerase/p53/apoptosis-inducing factors. This results in protection within the CA1 region of the hippocampus and transient forebrain of ischemic rats [2]. HGF administration has shown to improve motor coordination in 3 days’ post-stroke-induced rat models. HGF induces neuroprotective responses up to 28 days after induced-stroke model in both rat and mouse; it has the ability to initiate regeneration within PD cell models by regulating intracellular Ca2+ levels through gene expression of CaBP-D28k. This treatment also improves axotomized retinal ganglion cells, but postischemic proliferation of NPCs has not been researched [1, 8]. Further investigations are underway to decipher the downstream pathways that regulate HGF-mediated protection.
2.2.3 Trophic Factors
Within the CNS, trophic factors are characterized as neurotrophin clusters entailing BDNF, neurotrophin-3, neurotrophin-4, and nerve growth factor (NGF). These proteins stimulate axonal growth, synaptic plasticity, and neurotransmitter synthesis and release [2, 10]. In addition, two other neurotrophic factors that have been widely studied include ciliary neurotrophic factor (CNTF) and glial cell line-derived neurotrophic factor (GDNF) [2].
Each trophic factor molecule is activated by many different molecular pathways, ultimately leading to neuroprotection. BDNF and NGF are stimulated through the phosphatidylinositol-3-kinase Akt pathway by Trk receptors [2]. Signaling through these receptors has been shown to protect hippocampal progenitor cells from staurosporine-induced apoptosis [2]. BDNF and NGF, when used to treat cultured hippocampal neurons, protects neurons from glutamate-induced neurotoxicity [2] through enhanced antioxidant enzyme activation and blockage of intracellular calcium. Similar to BDNF and NGF, CNTF also shows neuroprotection potential by protecting retinal ganglion cells when activated through Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway [2]. Lastly, mesenchymal stem cells have been shown to release NT3, NT4, and BDNF, which bind to specific Trk receptors on sensory neurons located on dorsal root ganglia, leading to increased cell survival following spinal cord injury [11]. In an attempt to use these trophic factors in a clinical settings, experimentations have been conducted with the administration of CNTF and BDNF with some success in promoting neuroprotective functions in Huntington’s disease [2]. Treatments involving CNTF conclude survival of striatal output neurons, whereas BDNF and neurotrophin-3 administration results in survival of immature neurons within the cerebellum in neurotrophin-deficient models. Researchers recently discovered that Alzheimer’s disease (AD) mouse models treated with a TrkB agonist, 7,8-dihydroxyflavone, showed improvement in hippocampus-dependent learning and memory [2]. Transplantation of mesenchymal stem cells that express trophic factors has shown initial promise. When these stem cells express GDNF, it has been shown to improve motor performance as well as protects dopaminergic neurons in the striatum [2] and lower expression of apoptotic markers in Friedreich’s ataxia (FRDA) mouse models [11].
2.2.4 Apolipoprotein E (apoE)–Containing Lipoproteins
This 35 kDa protein is primarily found in the liver but is also highly expressed in the brain [2, 12] by the glial cells [13]. Apolipoprotein E (apoE)-containing lipoproteins have endocytosis receptors known to interact with members of a low-density lipoprotein receptor-related protein 1 (LRP1) [2]. It is an important component in the cerebrospinal fluid (CSF) and acts as a ligand for LDL receptor. This receptor is expressed on the outer membrane of glia and neurons and stimulates the transportation of cholesterol and phospholipids [12]. LRP1 mediates the accumulation of apoE-containing lipoprotein. The expression of apoE controls the regulation of lipid metabolism and transport. Once the LRP1 receptor is activated, it initiates intracellular signaling pathway involving phospholipase Cγ1, protein kinase Cδ, and glycogen synthase kinase 3β. If LRP1 is bound to an NMDA receptor, activation from apoE blocks intracellular calcium from entering and allows calcium to accumulate within the intracellular membrane [2]. The buildup of intracellular calcium inhibits calcineurin and the dephosphorylation of BAD and caspase-3, which blocks apoptosis from occurring. ApoE must therefore be bound to lipoproteins in order to execute its antiapoptotic properties. This molecule also has the ability to prevent retinal ganglion cells from degeneration in the retina of glutamate/aspartate transporter-deficient mice [2, 14].
Neuroprotective research has focused on the role of LRP1 ligands due to its involvement in neuritic outgrowth, neuronal development, and survival. Structurally, LRP1, embedded into the membrane, are attached to the NMDA receptor. ApoE lipoprotein binds to LRP1 to activate phospholipase Cγ1, resulting in the production of diacylglycerol and triphosphate from PIP2 [2]. Protein kinase Cγ activation signals proapoptotic kinase and glycogen synthase kinase to be phosphorylated, causing them to be deactivated. Based on these findings, glycogen synthase kinase inhibitors are currently undergoing clinical research as a potential therapeutic treatment for neurodegeneration [14].
2.2.5 Prothymosin α (PTMA)
Prothymosin α (PTMA) is a nuclear protein with acidic and hydrophilic characteristics highly expressed in mammalian cells [2, 15]. PTMA was formally extracted from a thymosin α1 precursor; however, it could also be isolated from cultured cortical neurons. While the function of PTMA is not well understood, it is considered to contain hormone-like factors [2], which may be important in its involvement in several key biological processes such as cell proliferation, cell survival, regulating antioxidative stress genes, stimulating immune response, stimulation or inhibition of specific pathways, and activation of receptor or transcription factors [16].
PTMA induces cell proliferation through inhibition of estrogen receptor stimulation. This action is linked to the proliferation of cancer cells if PTMA is highly expressed in the intracellular membrane [16]. Additionally, through interaction of PTMA with Keap1, anti-necrosis factors are also stimulated [15]. Mechanistically, PTMA binding to Keap1 inhibits formation of the Keap1-Nrf2 (nuclear factor erythroid 2-related factor 2) complex, leading to Nrf2-mediated increase of antioxidative stress genes, resulting in protection from apoptosis-mediated cell death [16]. Lastly, PTMA has also been shown to alter inflammation due to increased signaling through Toll-like receptors on monocytes [15]. This mechanism can protect neurons from necrosis during ischemic stress once PTMA is mediated by S100A13, a cargo protein, in order to block caspase-3 activation [16].
PTMA is considered to be a promising candidate for the treatment of stroke and Huntington’s disease. In stroke-induced models and cultured cortical neurons, PTMA expressed the downregulation of necrosis at the ischemic core damage [2, 16]. In treated culture cells expressing mutant huntingtin protein (mHtt), PTMA suppressed mHtt-caused cytotoxicity by binding to the mutated protein with its central acidic domain [17]. Research is still evaluating the tendencies of this nuclear protein for future therapeutic treatments.
2.2.6 Erythropoietin (EPO)
Erythropoietin (EPO) (a 34 kDa glycoprotein composed of 165 amino acids) is known as humoral regulator of erythropoiesis during maturation and proliferation of erythroid progenitor cells and synthesized from the fetal liver, kidney, and brain after birth [2, 18]. EPO is a multifunctional molecule for enhancing neuroprotective mechanisms. Through different molecular pathways, EPO stimulates cytoprotective, antiapoptotic, antioxidant, anti-inflammatory behaviors, improves tissue oxygenation, and stimulates neurogenesis and angiogenesis [18]. During the activation of neurogenesis, histological functions are improved after hypoxic ischemia episodes [19]. Two EPO molecules form a dimer in order to activate JAK-2 pathway through autophosphorylation, which ultimately leads to suppression of apoptosis. This also triggers a cascade of signaling to branch out, creating a domino effect and stimulating multiple intracellular transductions factors [2]. In addition, using paracrine and autocrine mechanism within the brain, EPO produces antiapoptotic signals to protect neurons against ischemic damages and inflammation [2, 15, 20].
EPO administration is becoming highly used in treating hypothermia. Research has also shown that EPO administration improves long-term motor and cognitive responses along with cerebellar growth. Administration of EPO also protects cultured hippocampal and cortical neurons from glutamate-induced neurotoxicity and nitric oxide-induced neuronal death [2]. Administration of EPO in conjunction with other neuroprotective agents could therefore help neurogenesis and lower long-term neurological deficits [19].
2.2.7 Neuregulin-1 (NRG1)
Neuregulin-1 (NRG1) is a complex growth factor that transcribes more than 20 different transmembrane proteins with a single membrane-spanning domain. This molecule belongs to a multipotential neuroprotective and anti-inflammatory growth factor family and generates large numbers of isoforms in tissue- and cell-type-specific patterns. There are different types of NRG1 (type I, II, or III) based on the molecules of amino acid sequence. Type I NRG1 are secreted immunoglobulin-like antigens with carbohydrate-spacer regions along the extracellular regions. Type II NRG1 are similar isoforms as type I but lack a carbohydrate-spacer region. Lastly, type III NRG1 are membrane-bound isoforms with cysteine-rich domains. Each NGR1 type consists of similar epidermal growth factor (EGF) domains. These domains entail formations of alpha units and beta sheets. The beta domain contains a higher potential of activity compared with alpha domains, which defines their functional contribution [21].
NRG1 binds to a simple extracellular amino terminus with two cysteine-rich domains of the ErbB receptor protein tyrosine kinases. NGR1 bound to the selected receptor leads to suppression of specific genes through selected canonical pathways including immune cell trafficking, hepatic fibrosis/hepatic stellate cell activation, acute phase responses, and IL-6 signaling [21, 22]. Functional implication of this inhibition leads to beneficial outcomes toward neurons, astrocytes, oligodendrocyte precursor cells, endothelial cells, and microglia. The structure of NGR1 receptors include transmembrane and intracellular tyrosine kinase domain with a carboxyl-terminal tail. When attaching to ligands, signaling cascades activate for neuronal migration, dendritic spine maturation, cellular differentiation and proliferation, and inhibitory synapses onto excitatory pyramidal neurons [21]. Studies have provided information of NGR1 stimulation signals for blocking microglia activation and increasing permeability of endothelial cells and blood–brain barrier after traumatic brain injury [22, 23]. NGR1, however, does not contain neuroprotective characteristics to completely inactivate microglia in amygdala, medial dorsal thalamus, reunion of thalamus or piriform cortex within neurotoxic diisopropylfluorophosphate rat model [22]. Ongoing studies are looking into how NRG1 can be used as a neuroprotective therapy.
2.3 Neurodegenerative Diseases
Neurodegeneration is the progressive and irreversible loss of structure or function in neurons within the CNS [24] culminating in some form of neurological disorder. In a recent epidemiological study, statistics revealed that 1 in every 400 individuals develops some form of neurological disorder [25]. Individuals diagnosed with these diseases experience a range of motor or sensory deficits to cognitive impairment [24]. Such plethora of neurological deficits are derived from multifactorial mechanisms that are caused by neuronal death. Intense research activity is directed toward exposing new possible causes for neurodegenerative disease development. Among these, major focus has been on factors that control gene regulation and protein expression, which cause major disturbances in cellular homeostasis.
Tight regulation of gene expression is needed to control the amount of transcribed RNA and translated proteins. Duplication of a gene in the genetic sequence causes disruption in genetic splicing, which determines gene expression. Proximal spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease in infants. It is derived by the duplication of chromosome 5p13 within the survival motor neuron (SMN) gene locus. This duplication causes a disruption in exon 7 which splices SMN1 and SMN2; the second copy of SMN gene remains in the genetic coding. The number of copies of SMN2 defines disease severity due to the production of unstable proteins that lack functional aspects needed for survival [26]. Looking at a different angle, genes can also form a mutation within its sequence. This phenomenon has been seen in a number of diseases such as FRDA and amyotrophic lateral sclerosis (ALS). For example, in ALS, the repeated G4C2 sequence in the chromosome 9 open reading frame 72 (C9orf72) gene can be translated into toxic dipeptide repeat proteins. This mechanism is detrimental to the nucleocytoplasmic transport. C9orf72 proteins are able to self-bind to nuclear pore complexes in order to relocate from the nuclear membrane to the plasma membrane in neurons [27].
