Phytochemical Drug Discovery for Central Nervous System Disorders E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Wissenschaft und neue Technologien
- Sprache: Englisch
PHYTOCHEMICAL DRUG DISCOVERY FOR CENTRAL NERVOUS SYSTEM DISORDERS Understand herbal and plant-based treatments for chronic disorders with this groundbreaking work Due in part to the aging of the global population, disorders of the central nervous system have become an increasingly grave public health concern in recent years. Demand for pharmaceutical treatments has been correspondingly high, but there are many barriers to the successful development of effective synthetic drugs. Phytomedicines, or plant-based and herbal medicines, have proven to be an effective alternative, boasting lower toxicity and cost and higher efficacy, and one that demands greater research and broader-based practitioner knowledge. Phytochemical Drug Discovery for Central Nervous System Disorders meets this demand with a timely, clearly-structured guide. It thorough coverage presents a wide range of phytochemicals with potential as candidates for drug discovery, describing their sources, properties, and therapeutic efficacy. The result is a vital contribution to the ongoing fight against central nervous system (CNS) disorders. Phytochemical Drug Discovery for Central Nervous System Disorders readers will also find: * Detailed treatment of CNS-active plant products, neuroprotective chemicals, plant-based nutraceutical products, and more * Up-to-date information on FDA-approved drugs and existing plant-based products used to treat CNS disorders * An authorial team featuring experts from across the globe Phytochemical Drug Discovery for Central Nervous System Disorders is essential for drug discovery scientists, drug developers, medicinal chemists, biochemists, and any researchers and professionals in the health care or pharmaceutical industries.
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Veröffentlichungsjahr: 2023
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Table of Contents
Cover
Title Page
Copyright Page
Contributors
Preface
1 Central Nervous System Disorders and Food and Drug Administration–Approved Drugs
1.1 Incidence and Prevalence of Major Neurologic Disorders
1.2 Etiology
1.3 Pathogenesis
1.4 Central Nervous System Disorders and Drugs Approved by the Food and Drug Administration
1.5 Conclusion
References
2 Drug Discovery from Medicinal Plants against Parkinson's Disease
2.1 Pathogenesis of Parkinson's Disease
2.2 Natural Dopaminergic Neuroprotective Compounds
2.3 Nitrogenated Phytochemicals
2.4 Chinese Herbal Medications and Parkinson's Disease
2.5 Herbal Medicines from India and Parkinson's Disease
2.6 European Plants
2.7 α‐Synuclein as a Potential Therapeutic Target
2.8 Conclusion
References
3 Drug Discovery from Medicinal Plants against Alzheimer's Disease
3.1 Pathogenesis
3.2 Treatment Strategies for Alzheimer's Disease
3.3 Medicinal Plants Having Effects against Alzheimer's Disease
3.4 Natural Products with Proven Anti‐Alzheimer's Activity
3.5 Conclusion
References
4 Effects of Medicinal Plants and Phytochemicals on Schizophrenia
4.1 Mechanisms of Action Related to Schizophrenia
4.2 Ayurvedic Plants Used as Treatment for Schizophrenia and Related Psychoses
4.3 Conclusion
References
5 Drug Discovery from Medicinal Plants and Phytochemicals against Neuropathic Pain
5.1 Mechanisms of Neuropathic Pain
5.2 Animal Models for Studying Neuropathic Pain
5.3 Medicinal Plants and Phytochemicals against Neuropathic Pain
5.4 Role of Plants and Phytochemicals in Different Neuropathic Pain Models
5.5 Future Perspectives
5.6 Conclusion
References
6 Brain Function, Stroke, and Medicinal Herbs
6.1 Brain Function and Stroke
6.2 Strategies for Treatment of Ischemic Stroke
6.3 Medicinal Plants for the Treatment of Stroke
6.4 Natural Products for the Treatment of Stroke
6.5 Recent Applications of Nanomedicine for Treatment of Stroke
6.6 Conclusion
References
7 Plant‐Based Analgesics
7.1 Current Analgesic Drugs and Their Mechanisms of Action
7.2 Plant‐Derived Lead Compounds with Analgesic Activities
7.3 Analgesic Effects of Medicinal Plants Found in Nigeria
7.4 Limitations of Plant‐Based Analgesics
7.5 Future Directions and Perspective for Plant‐Based Analgesics
7.6 Conclusion
References
8 Medicinal Plants and Phytochemicals against Depression
8.1 Causes of Depression
8.2 Symptoms of Depression
8.3 Diagnosis of Depression
8.4 Types of Depression
8.5 Treatment of Depression
8.6 Conclusion
References
9 Anti‐inflammatory Agents from Medicinal Plants
9.1 Role of Neuroinflammation in Neurodegenerative Diseases
9.2 Neuroinflammatory Drugs
9.3 Medicinal Plants as Sources of Anti‐inflammatory Agents
9.4 Bioactive Compounds as Anti‐inflammatory Agents
9.5 Conclusion
References
10 Plant‐Based Products and Phytochemicals against Viral Infections of the Central Nervous System
10.1 Viral Infections of the Central Nervous System
10.2 Plant and Phytochemicals as Antiviral Agents for Central Nervous System Viral Infections
10.3 Controlling Vectors of Viral Diseases of the Central Nervous System
10.4 Future Perspectives
10.5 Conclusion
References
11 Fruits and Nutraceuticals for the Prevention and Treatment of Central Nervous System Disorders
11.1 Fruits for Cognition and Brain Health
11.2 Nutraceuticals in Ameliorating Neurodegeneration
11.3 Nutraceuticals in Alzheimer's Disease
11.4 Nutraceuticals in Parkinson's Disease
11.5 Nutraceuticals in Depression
11.6 Nutraceuticals in Psychotic Disorders
11.7 Conclusion
References
12 Neurorestorative Potential of Medicinal Plants and Their Phytochemicals
12.1 Therapeutic Value of Some Medicinal Plants and their Importance
12.2 Types of Medicinal Plants and Their Uses
12.3 Phytochemicals
12.4 Phytochemical Constituents in Some Medicinal Plants
12.5 The Brain
12.6 Brain Conditions
12.7 Protective Effects of Medicinal Plants on the Brain
12.8 Conclusion
References
13 Neurotransmitter Modulation by Phytochemicals
13.1 Sources, Structures, and Classifications of Phytochemicals
13.2 Neurotransmitters and Their Functions
13.3 Modulation of Cholinergic Signaling by Phytochemicals
13.4 Effect of Phytochemicals on GABAergic Signaling
13.5 Effect of Phytochemicals on Glutamatergic Signaling
13.6 Modulation of Serotonergic and Dopaminergic Signaling by Phytochemicals
13.7 Conclusion
Acknowledgments
References
14 Antipyretic Agents from Plant Origins
14.1 Pyrexia Development, Its Mechanisms, and the Roles of Plant Metabolites as Antipyretics
14.2 Antipyretic Agents of Plant Origin
14.3 Conclusion and Future Perspectives
References
15 Medicinal Herbs against Central Nervous System Disorders
15.1 Medicinal Plants as Interventions for Central Nervous System Disorders
15.2 Some Medicinal Plants with Neuroprotective Action on Central Nervous System Disorders
15.3 Some Central Nervous System Disorders and Medicinal Plant Interventions
15.4 Some Mechanistic Actions of Medicinal Herbs against Central Nervous System Disorders
15.5 Conclusion
References
16 Important Antihistaminic Plants and Their Potential Role in Health
16.1 Antihistaminic Plants
16.2 Bioactive Compounds with Antihistaminic Activities
16.3 Conclusion
References
17 Effect of Plant‐Based Anticonvulsant Products and Phytochemicals
17.1 Types of Epileptic Seizures
17.2 Basic Mechanisms of Epilepsy
17.3 Epilepsy and Oxidative Stress
17.4 Epilepsy and Inflammation
17.5 Tests for Seizure Induction
17.6 Medicinal Plants Used to Treat Epilepsy
17.7 Conclusion
References
18 Application of Nanophytomedicine for the Treatment of Central Nervous System Disorders
18.1 Neurodegenerative Disease and the Blood–Brain Barrier
18.2 Nano Approaches to Central Nervous System Drug Delivery
18.3 Nanophytomedicine for Treatment of Central Nervous System Disorders
18.4 Challenges in Nanophytomedicine
18.5 Conclusion
References
Index
End User License Agreement
List of Tables
Chapter 1
Table 1.1 Recent Food and Drug Administration–approved drugs for central ne...
Chapter 2
Table 2.1 Medicinal plant components, sources, structural model, and effect...
Table 2.2 Medicinal plants used for Parkinson's.
Chapter 3
Table 3.1 Treatment strategies and clinical trials for Alzheimer's disease....
Table 3.2 Medicinal plants targeting the cholinergic system.
Table 3.3 Medicinal plants targeting amyloid beta (Aβ).
Table 3.4 Medicinal plants targeting tau‐related pathways.
Table 3.5 Examples of natural products with anti‐Alzheimer's activity.
Chapter 4
Table 4.1 Phytochemicals and their neurologic mechanisms of action.
Chapter 5
Table 5.1 Medicinal plants effective against neuropathic pain.
Table 5.2 Phytochemicals effective against neuropathic pain.
Chapter 6
Table 6.1 Reported in vitro and in vivo studies on the effects of different...
Chapter 7
Table 7.1 Some analgesics, their mechanisms of action and side effects.
Table 7.2 Plants with analgesic activity found in Nigeria.
Chapter 8
Table 8.1 Phytochemicals against depression.
Table 8.2 Antidepressant activity of herbal plants and their parts.
Chapter 9
Table 9.1 Neuroinflammatory drugs for stroke.
Table 9.2 Neuroinflammatory drugs for traumatic brain injury.
Table 9.3 Neuroinflammatory drugs for neuromyelitis optica (NMO).
Table 9.4 Neuroinflammatory drugs for amyotrophic lateral sclerosis (ALS)....
Table 9.5 Neuroinflammatory drugs for multiple sclerosis (MS).
Table 9.6 Neuroinflammatory drugs for Parkinson's disease (PD).
Chapter 10
Table 10.1 Plant‐based products and phytochemicals against viral infections...
Chapter 11
Table 11.1 Nutraceuticals and their mode of action and specific disease act...
Chapter 12
Table 12.1 List of medicinal plants and their uses.
Table 12.2 Different phytochemicals and their potential benefits.
Chapter 13
Table 13.1 Structure, sources, and biologic actions of major phytochemicals...
Chapter 14
Table 14.1 List of various plant secondary metabolites as antipyretics.
Chapter 15
Table 15.1 Plants used in the management of some central nervous system (CN...
Chapter 16
Table 16.1 Summary of isolated phytoconstituents with reported antihistamin...
Chapter 17
Table 17.1 Antiepileptic properties of medicinal plants and mechanisms of a...
Chapter 18
Table 18.1 Previous studies on central nervous system (CNS)‐related disorde...
Table 18.2 Applications of different nanocarriers.
List of Illustrations
Chapter 2
Figure 2.1 The effect of plants on α‐syn. 6‐OHDA, 6
‐
hydroxydopamine; M...
Chapter 3
Figure 3.1 Acquired risk factors for developing Alzheimer's disease.
Chapter 4
Figure 4.1 Symptoms of schizophrenia.
Figure 4.2 Schematic representation of dopamine synaptic terminals. Dopamine...
Figure 4.3 Schematic representation of 5‐HT synaptic terminals. 5‐HT transpo...
Figure 4.4 Schematic representation of 5‐HT synaptic terminals. Glutaminase ...
Figure 4.5 Schematic representation of GABA (γ‐aminobutyric acid) neurotrans...
Chapter 5
Figure 5.1 Medicinal plants effective in neuropathic pain.
Figure 5.2 Diagrammatic representation of the key mechanisms by which curati...
Chapter 6
Figure 6.1 The structures of active compounds against brain strokes.
Chapter 8
Figure 8.1 Treatment of depression.
Figure 8.2 Importance of medicinal plants in depression.
Chapter 9
Figure 9.1 Role of neuroinflammation in neurodegenerative diseases.
Chapter 10
Figure 10.1 Plant‐based products and phytochemicals against viral infections...
Chapter 11
Figure 11.1 Nutraceuticals that can be utilized as adjunctive therapy in the...
Chapter 13
Figure 13.1 Diagrammatic representation of a typical chemical synapse.
Chapter 14
Figure 14.1 Potential pathogenetic mechanisms in the development of pyrexia....
Figure 14.2 Some common plant compounds with potential antipyretic activitie...
Chapter 15
Figure 15.1 General structure for withanolides.
Figure 15.2 Structures of bacoside A and B.
Figure 15.3 Structures of sapogenin and betulinic acid.
Figure 15.4 Structures of annonacin, α‐asarone, β‐asarone, emblicanin, galli...
Figure 15.5 Structure of quercetin.
Figure 15.6 Structures of bacopaside I, bacopaside II, and bacosaponin C.
Figure 15.7 Structures of ursolic acid, carnosol, and betulinic acid.
Figure 15.8 Structures of 1,8‐cineole, citronellal, geraniol, γ‐terpinene, g...
Figure 15.9 Structures of kavain, dihydrokavain, yangonin, desmethoxyyangoni...
Figure 15.10 Structures of borneol and valeric acid.
Figure 15.11 Structures of ginkgolide A, ginkgolide B, and ginkgolide C.
Figure 15.12 Structures of embelin and epigallocatechin‐3‐gallate.
Chapter 16
Figure 16.1 Chemical structures of isolated phytoconstituents with reported ...
Chapter 17
Figure 17.1 Mechanism of normal synaptic transmission: (a) inhibitory mechan...
Figure 17.2 Role of free radicals in the development of epilepsy through var...
Figure 17.3 Role/mechanism of inflammation or injury in the brain leading to...
Chapter 18
Figure 18.1 Methods of preparation of nanocarriers.
Guide
Cover Page
Title Page
Copyright Page
Contributors
Preface
Table of Contents
Begin Reading
Index
Wiley End User License Agreement
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Phytochemical Drug Discovery for Central Nervous System Disorders
Biochemistry and Therapeutic Effects
Edited by
Chukwuebuka Egbuna
Africa Centre of Excellence for Public Health and Toxicological Research (ACE‐PUTOR)
University of Port Harcourt, Choba, Nigeria
Mithun Rudrapal
Vignan’s Foundation for Science, Technology & Research (Deemed to be University)
Guntur, Andhra Pradesh, India
Copyright © 2023 by John Wiley & Sons, Inc. All rights reserved.
Published by John Wiley & Sons, Inc., Hoboken, New Jersey.Published simultaneously in Canada.
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Library of Congress Cataloging‐in‐Publication DataNames: Egbuna, Chukwuebuka, editor. | Rudrapal, Mithun, editor.Title: Phytochemical drug discovery for central nervous system disorders : biochemistry and therapeutic effects / edited by Chukwuebuka Egbuna, Mithun Rudrapal.Description: Hoboken, NJ : Wiley, 2023. | Includes bibliographical references and index.Identifiers: LCCN 2023002458 (print) | LCCN 2023002459 (ebook) | ISBN 9781119794097 (cloth) | ISBN 9781119794103 (adobe pdf) | ISBN 9781119794110 (epub)Subjects: MESH: Central Nervous System Diseases–drug therapy | Phytochemicals–therapeutic use | Phytotherapy–methods | Drug DiscoveryClassification: LCC RC350.C54 (print) | LCC RC350.C54 (ebook) | NLM WL 301 | DDC 616.8/0461–dc23/eng/20230429LC record available at https://lccn.loc.gov/2023002458LC ebook record available at https://lccn.loc.gov/2023002459
Cover Design: WileyCover Images: © ARTFULLY PHOTOGRAPHER/Shutterstock; picmedical/Shutterstock
Contributors
Raghu Ram AcharDivision of Biochemistry, School of Life SciencesJSS Academy of Higher Education and ResearchMysuru, Karnataka, India
Kamoru A. AdedokunDepartment of ImmunologyRoswell Park Comprehensive Cancer CenterBuffalo, NY, USA
Babatunde O. AdetuyiDepartment of Natural Sciences Faculty of Pure and Applied SciencesPrecious Cornerstone UniversityIbadan, Oyo State, Nigeria
Oluwatosin A. AdetuyiDepartment of BiochemistryOsun State UniversityOsogbo, Osun State, Nigeria
Khawaja S. AhmadDepartment of BotanyUniversity of PoonchRawalakot, Azad Jammu & Kashmir Pakistan
Muhammad AkramDepartment of Eastern Medicine and SurgeryGovernment College University FaisalabadFaisalabad, Punjab, Pakistan
Dunya Al‐DuhaidahawiDepartment of PharmacognosyCollege of PharmacyUniversity of KufaAl‐Najaf, Iraq
Gabriel O. AnyanwuDepartment of BiochemistryFaculty of Science and TechnologyBingham UniversityKaru, Nasarawa State, Nigeria
Godwin AnywarDepartment of Plant SciencesMicrobiology & BiotechnologyCollege of Natural Sciences Makerere UniversityKampala, Uganda
Dorathy O. AnzakuDepartment of BiochemistryCollege of Science and TechnologyCovenant UniversityOta Ogun State, Nigeria
Muhammad M. AslamNuclear Institute of Agriculture (NIA)Tando Jam, Sindh, Pakistan
Salwa BouabdallahEnvironmental Biomonitoring Laboratory LBE (LR01/ES14)Faculty of Sciences Bizerta Carthage UniversityZarzouna, TunisiaFaculty of Sciences TunisUniversity of Tunis El‐ManarTunis, TunisiaPharmacognosy DepartmentFaculty of PharmacyAin Shams UniversityCairo, Egypt
Akeem O. BusariDepartment of Medical Laboratory ScienceLadoke Akintola University of TechnologyOgbomosho, Oyo State, Nigeria
Prachee DubeyGovernment G.I. CollegeMalwan, Fatehpur, India
Chukwuebuka EgbunaAfrica Centre of Excellence for Public Health and Toxicological Research (ACE‐PUTOR)University of Port HarcourtChoba, Rivers State, NigeriaDepartment of BiochemistryChukwuemeka Odumegwu Ojukwu UniversityUli, Anambra State, Nigeria
Omayma A. EldahshanDepartment of Natural SciencesFaculty of Pure and Applied SciencesPrecious Cornerstone UniversityIbadan, Oyo State, Nigeria
Nehal El MahdiDepartment of Pharmaceutics and Industrial Pharmacy, Faculty of PharmacyOctober University for Modern Sciences and Arts (MSA)Giza, Egypt
Abeer M.A. El SayedDepartment of PharmacognosyFaculty of PharmacyCairo UniversityCairo, Egypt
Shahira M. EzzatDepartment of PharmacognosyFaculty of PharmacyCairo UniversityCairo, EgyptDepartment of PharmacognosyFaculty of PharmacyOctober University for Modern Sciences and Arts (MSA)Giza, Egypt
Mai M. FaridDepartment of Phytochemistry and Plant SystematicsNational Research CentreGiza, Egypt
Nilambari GuravPES's Rajaram and Tarabai Bandekar College of Pharmacy, PondaGoa UniversityPanaji, Goa, India
Shailendra GuravDepartment of PharmacognosyGoa College of PharmacyGoa UniversityPanaji, Goa, India
Maria HanifDepartment of BiotechnologyLahore College for Women UniversityLahore, Punjab, Pakistan
Maria HasnainDepartment of BiotechnologyLahore College for Women UniversityLahore, Punjab, Pakistan
Nesrine M. HegaziDepartment of Phytochemistry and Plant SystematicsNational Research CentreGiza, Egypt
Chukwunonso O. IgboekweAfrica Centre of Excellence in Public Health and Toxicological Research (ACE‐PUTOR)University of Port‐HarcourtChoba, Rivers State, Nigeria
Sikiru O. ImodoyeDepartment of Oncological Sciences Huntsman Cancer InstituteUniversity of UtahSalt Lake City, UT, USA
Muhammad A. IshfaqDepartment of ChemistryUniversity of PoonchRawalakot, Azad Jammu & Kashmir Pakistan
Muhammad JahangeerDepartment of BiochemistryGovernment College University FaisalabadFaisalabad, Punjab, Pakistan
Shyam S. KeshDepartment of Veterinary Clinical Complex (Veterinary Biochemistry)Faculty of Veterinary and Animal SciencesWest Bengal University of Animal and Fishery SciencesKolkata, West Bengal, India
M. KishorDepartment of PsychiatryJSS Medical College & HospitalJSS Academy of Higher Education & ResearchMysuru, Karnataka, India
Tran V. LinhVNU University of Medicine and PharmacyVietnam National UniversityHa Noi, Vietnam
Rana MarghanyDepartment of PharmacognosyNational Research CentreGiza, Egypt
Mona M. MarzoukDepartment of Phytochemistry and Plant SystematicsNational Research CentreGiza, Egypt
Akram MuhammadDepartment of Eastern MedicineGovernment College University FaisalabadFaisalabad, Punjab, Pakistan
Naveed MunirDepartment of BiochemistryGovernment College University FaisalabadFaisalabad, Punjab, Pakistan
Neelma MunirDepartment of BiotechnologyLahore College for Women UniversityLahore, Punjab, Pakistan
Shagufta NazDepartment of BiotechnologyLahore College for Women UniversityLahore, Punjab, Pakistan
Diovu E. ObiomaDepartment of Pharmacognosy and Environmental MedicineUniversity of NigeriaNsukka, Enugu State, Nigeria
Kehinde A. OdeladeDepartment of Natural SciencesFaculty of Pure and Applied SciencesPrecious Cornerstone UniversityIbadan, Oyo State, Nigeria
Grace O. OdineDepartment of Natural SciencesFaculty of Pure and Applied SciencesPrecious Cornerstone UniversityIbadan, Oyo State, Nigeria
Estella U. OdohDepartment of Pharmacognosy and Environmental MedicineUniversity of NigeriaNsukka, Enugu State, Nigeria
Olubanke O. OgunlanaDepartment of BiochemistryCovenant UniversityOta, Ogun State, Nigeria
Michael P. OkohDepartment of Medical Biochemistry Faculty of Basic Medical SciencesCollege of Health Sciences, University of AbujaAbuja, Federal Capital Territory, Nigeria
Ahmed OlatundeDepartment of Medical BiochemistryAbubakar Tafawa Balewa UniversityBauchi, Bauchi State, Nigeria
Abdullah OlawuyiDepartment of Medical Laboratory ScienceGeneral HospitalOffa, Kwara State, Nigeria
Semiloore O. OmowumiDepartment of Natural SciencesFaculty of Pure and Applied SciencesPrecious Cornerstone UniversityIbadan, Oyo State, Nigeria
Linda A. OnugwuDepartment of PharmaceuticsUniversity of NigeriaNsukka, Enugu State, Nigeria
Obinna S. OnugwuDepartment of PharmacognosyEnugu State University of Science and TechnologyAgbani, Enugu State, Nigeria
Chukwuma M. OnyegbulamDepartment of Pharmacognosy and Environmental MedicineUniversity of NigeriaNsukka, Enugu State, Nigeria
Maroof G. OyeniyiDepartment of Medical Laboratory ScienceGeneral HospitalOffa, Kwara State, Nigeria
Santwana PalaiDepartment of Veterinary Pharmacology & Toxicology, College of Veterinary Science and Animal HusbandryOdisha University of Agriculture and TechnologyBhubaneswar, Odisha, India
Kanti Bhooshan PandeyCSIR – Central Salt & Marine Chemicals Research InstituteBhavnagar, Gujarat, India
S. PavithraDivision of BiochemistrySchool of Life SciencesJSS Academy of Higher Education and ResearchMysuru, Karnataka, India
David Pérez‐JorgeDepartment of Didactics and Educational ResearchUniversity of La LagunaSan Cristóbal de La LagunaTenerife, Spain
Ayesha QamarDepartment of BiotechnologyLahore College for Women UniversityLahore, Punjab, Pakistan
Nithya Rani RajuDivision of BiochemistrySchool of Life SciencesJSS Academy of Higher Education and ResearchMysuru, Karnataka, India
Nilesh RarokarDepartment of Pharmaceutical SciencesRashtrasant Tukadoji Maharaj Nagpur UniversityNagpur, Maharashtra, India
S.V. RashmithaDivision of BiochemistrySchool of Life SciencesJSS Academy of Higher Education and ResearchMysuru, Karnataka, India
Vanessa de Andrade RoyoDepartment of General BiologyLaboratory of Natural ProductsState University of Montes ClarosMontes Claros, Minas Gerais, Brazil
Muhammad RiazDepartment of Allied Health SciencesGovernment College University FaisalabadFaisalabad, Punjab, Pakistan
Zerfishan RiazDepartment of Eastern Medicine and SurgeryGovernment College University FaisalabadFaisalabad, Punjab, Pakistan
Mithun RudrapalDepartment of Pharmaceutical Sciences School of Biotechnology and Pharmaceutical SciencesVignan’s Foundation for Science Technology & Research (Deemed to be University)Guntur, Andhra Pradesh, India
Mohamed A. SalemDepartment of Pharmacognosy and Natural Products, Faculty of PharmacyMenoufia UniversityMenoufia, Egypt
Malik A. SanusiDepartment of Biochemistry and Molecular BiologyObafemi Awolowo UniversityIle‐Ife, Osun State, Nigeria
Zirwa SarwarDepartment of BiotechnologyLahore College for Women UniversityLahore, Punjab, Pakistan
Barbara SawickaUniversity of Life Sciences in LublinLublin, Poland
Hassan ShahDepartment of Eastern Medicine and SurgeryGovernment College University FaisalabadFaisalabad, Punjab, Pakistan
Hagar A. SobhyDepartment of Natural Sciences Faculty of Pure and Applied SciencesPrecious Cornerstone UniversityIbadan, Oyo State, Nigeria
Imtiaz M. TahirCollege of Allied Health ProfessionalsGovernment College University FaisalabadFaisalabad, Punjab, Pakistan
Trinh P. ThaoVNU University of Medicine and PharmacyVietnam National UniversityHa Noi, Vietnam
Nguyen D. ThuanVNU University of Medicine and PharmacyVietnam National UniversityHa Noi, Vietnam
Habibu TijjaniDepartment of BiochemistryBauchi State UniversityGadau, Bauchi State, Nigeria
Erika Amparo TorresDepartment d’Enginyeria Quimica Universitat Rovira i Virgili Av PaisosCatalans, TarragonaSpain
Bui T. TungVNU University of Medicine and PharmacyVietnam National UniversityHa Noi, Vietnam
Huma WaqifDepartment of BiotechnologyLahore College for Women UniversityLahore, Punjab, Pakistan
Sadia ZafarDepartment of BotanyDivision of Science and TechnologyUniversity of Education LahoreLahore, Punjab, Pakistan
Preface
The growing incidence of central nervous system (CNS) disorders has become a serious public health problem worldwide. This is particularly because of the increased number of people aged over 65, which has led to growing market demand for safe, effective, and affordable medicines for CNS disorders. Though a number of synthetic drugs are available for use, their clinical efficacy, ability to survive the blood–brain barrier, safety, and affordability have been the major bottlenecks.
The effectiveness of phytomedicines against a wide variety of chronic CNS disorders has been documented. This book, Phytochemical Drug Discovery for Central Nervous System Disorders: Biochemistry and Therapeutic Effects, focuses on the use of plants and herbal medicines/products for effectively targeting and treating chronic CNS disorders, including Alzheimer's disease, Parkinson's disease, schizophrenia, convulsions, depression, and viral CNS infections. The chapters offer valuable information on various phytochemicals, their sources, biochemical effects, and therapeutic efficacy, which could help them further develop as lead molecules/candidates for drug discovery against CNS disorders. The exceptional structure and rich contents of this book are timely and the need of the hour.
The book discusses CNS‐active plant products, neuroprotective phytochemicals, plant‐based nutraceutical products, drug discoveries from phytomedicines/medicinal plants, and nanophytomedicines used for the treatment/management of CNS disorders. Some of the key features of the book are as follows:
Presents up‐to‐date information on Food and Drug Administration‐approved drugs, plant‐based products, and phytochemicals used in CNS disorders.
Details drug discovery opportunities from medicinal plants and phytochemicals for CNS disorders.
Highlights the nutraceutical and nanophytomedicine‐based therapeutic management of CNS disorders.
Written by a global team of experts, this book will be useful to drug discovery scientists, drug developers, medicinal chemists, phytochemists, pharmacologists, biochemists, healthcare professionals, researchers, faculty, and students.
1Central Nervous System Disorders and Food and Drug Administration–Approved Drugs
Estella U. Odoh1, Chukwuebuka Egbuna2,3, Chukwuma M. Onyegbulam1, Diovu E. Obioma1, Linda A. Onugwu4, Obinna S. Onugwu5, and Mithun Rudrapal6
1 Department of Pharmacognosy and Environmental Medicine, University of Nigeria, Nsukka, Enugu State, Nigeria
2 Africa Centre of Excellence for Public Health and Toxicological Research (ACE-PUTOR), University of Port Harcourt, Choba, Rivers State, Nigeria
3 Department of Biochemistry, Chukwuemeka Odumegwu Ojukwu University, Uli, Anambra State, Nigeria
4 Department of Pharmaceutics, University of Nigeria, Nsukka, Enugu State, Nigeria
5 Department of Pharmacognosy, Enugu State University of Science and Technology, Agbani, Enugu State, Nigeria
6 Department of Pharmaceutical Sciences, School of Biotechnology and Pharmaceutical Sciences, Vignan’s Foundation for Science, Technology & Research (Deemed to be University), Guntur, Andhra Pradesh, India
The central nervous system (CNS), which is a sophisticated system that regulates and coordinates body activity, consists of nerves in the brain and spinal cord. The brain is a part of the CNS housed inside the skull. The brain controls movement, sleep, hunger, thirst, and practically every other essential activity required for living. The brain logically governs animals' actions. A centralized brain allows groups of muscles to be co‐activated in complicated patterns, allowing stimuli impinging on one region of the body to elicit reactions in another, preventing various body parts from acting in opposition [1].
A CNS disorder is a disease condition in which the brain functions abnormally, with consequent health limitations. CNS disorder could be a result of an inherited metabolic disorder; harmful effects of microbial infection, a degenerative condition, stroke, brain tumor, or other problem; or might arise from unknown or multiple factors. Disorders of the CNS encompass a broad array of maladies, ranging from restless leg syndrome to traumatic brain injury [2].
CNS disorder is indicative of dysfunction of the brain or the spinal cord, or of faulty genes [3]. Stroke, infections such as meningitis, carpal tunnel syndrome, and functional issues such as headache are all causes of nervous system illnesses. A transient ischemic attack (TIA), subarachnoid hemorrhage, subdural hemorrhage, hematoma, and extradural hemorrhage are all vascular disorders that cause a stoppage of the blood flow to the brain. Approximately every 60 seconds in Nigeria, someone has a stroke due to a blocked blood vessel resulting in leakage of blood to the brain. When there is insufficient oxygen to the blood and brain, the brain cell can die and result in permanent damage. In the case of an autoimmune disorder, the immune system attacks and destroys healthy body tissues, which is caused by protein intolerance in the body, making immune cells recognize these as foreign and directing the immune system against them. Infections such as meningitis, encephalitis, polio, and an epidural abscess are often caused by the invasion of a microorganism or virus. Structural disorders include brain or spinal cord damage, Bell's palsy, cervical spondylosis, carpal tunnel syndrome, brain or spinal cord tumors, peripheral neuropathy, and Guillain–Barré syndrome. The functional conditions are headache, epilepsy, dizziness, and neuralgia. A degenerative condition such as Parkinson's disease, a promoting illness of CNS, results in the death of dopamine‐producing brain cells affecting motor skills and speech, multiple sclerosis (MS), damage to the myelin sheath of the neuron, amyotrophic lateral sclerosis (ALS), Huntington's chorea, and Alzheimer's disease [4]. Children born with a structural disorder may have malformed limbs and heart and facial abnormalities.
1.1 Incidence and Prevalence of Major Neurologic Disorders
CNS disorder causes significant morbidity and mortality and often requires neurosurgical intervention for proper diagnosis and treatment. The incidence of CNS disorder is consistently highest in low‐income countries, followed by middle‐ and then high‐income countries. About a million persons are suffering from chronic pain and various forms of sleep disturbance, and approximately 70 million individuals are experiencing vestibular and balance‐associated problems. These CNS disorders constitute five out of the top ten neurologic diseases. In addition, chronic tinnitus, substance‐abuse disorders, blindness, and visual impairment affect about 20 million adults. Of the 1.2 million diagnosed adult‐onset brain disorders, 51.3% and 21% are due to stroke and Alzheimer's disease, respectively. The sum of annual incidences of Parkinson's disease and traumatic brain injury is the same as the number of epilepsy episodes (135 million). In addition, nearly 500 000 cases of brain tumor, MS, and ALS are diagnosed each year. For example, 6.5–7.9% of adults in the United States are affected by a brain impairment [3].
An analysis of FDA‐approved new drugs shows a slow but steady increase in the number of FDA approvals of CNS drugs, with the exception of two bursts of inactivity in the 1950s and 1990s. The average rate of neurologic diseases has almost doubled relative to its baseline since the beginning of the 2000s [2]. Between 2015 and 2021, the FDA approved 323 new drugs (in 2015, 45 novel drugs; in 2016, 22; in 2017, 46; in 2018, 59; in 2019, 48; in 2020, 53; in 2021, 50), of which 31 were for CNS disorders. This listing excludes vaccines, allergenic products, blood and blood products, plasma derivatives, cellular and gene therapy products, and other products approved by the Center for Biologics Evaluation and Research [4–6].
1.2 Etiology
CNS disorders are caused mainly by traumatic brain injury (TBI) or injury to the spinal cord causing a wide range of disabilities in a person [7]. Infectious diseases are one of the causative agents of CNS disease, some of which may directly affect the brain and the spinal cord [8]. In addition, CNS diseases could result from degenerative spinal disorders associated with loss of function in the spine. Brain degeneration also causes the CNS diseases Alzheimer's, Parkinson's, and Huntington's diseases [9]. One of the leading causes of CNS disease is the blockage of a blood vessel by a blood clot or rupture of blood vessels causing hemorrhage in the brain [10]. This condition is medically known as stroke.
1.3 Pathogenesis
The most common pathway for the spread of pathogenic organisms to access the CNS is predominantly hematogenic spread. Viruses usually gain access by colonizing the mucosal surfaces throughout the body and then entering the blood. Therefore, they multiply at different neural sites and then cross the blood–brain barrier (BBB) before destroying the CNS [10]. Although the majority of viruses penetrate the CNS directly through the cerebral capillary endothelial cells, some infect cerebral microvascular endothelial cells, some gain access through the choroid plexus, and some are carried through the barrier by infected leukocytes. Some viruses can also enter through the olfactory nerve [11]. In bacterial infections of the CNS, the first spread is usually mucosal colonization in the nasopharynx to the bloodstream. Once in the bloodstream, bacteria have to survive the host defense mechanism. They achieve that through a polysaccharide capsule that resists phagocytosis by neutrophils and classic complement‐mediated bactericidal activity [12]. The case of bacterial meningitis is cerebral edema caused by a vasogenic, cytotoxic mechanism. It contributes to elevated pressure in the brain and may result in cerebral herniation‐induced deaths. Cerebral blood flow is tampered with and tends to decrease, and relative anoxia follows suit, thus contributing to neuronal damage. The localized purulent spread of bacteria within the CNS originates from adjacent foci of the disease, such as otitis, sinusitis, and septic phlebitis, which arrive through septic emboli from distant sites of infection [13].
1.4 Central Nervous System Disorders and Drugs Approved by the Food and Drug Administration
All medications, including vaccines, have to go through a quality control process to ensure they are safe and effective before being approved for public use. The FDA oversees the process from start to finish – and even after approval. Emergency use authorizations (EUAs) may be granted in some instances. The FDA may also approve drugs before a Phase III clinical trial. This process is called accelerated approval. No medication is entirely safe with 100% effectiveness. Therefore, the drug's side effects and long‐term efficacy will be monitored by the FDA – even after the drug has been approved [14].
The emergence of new drugs for neurologic diseases has almost doubled since the beginning of the year 2000 [2]. Most FDA‐approved CNS drugs are palliatives that provide only symptomatic relief rather than cure the disorders. So this area of drug therapy presents a challenge and an opportunity for the development of new and effective medicines. Unfortunately, the failure rate for the development of new medicinal entities for CNS disorders is higher than for other disorders, and this has been attributed to a lack of understanding of the mechanism of CNS diseases, the possibility of CNS side effects, difficulty identifying and measuring appropriate clinical endpoints, a lack of relevant animal models, and the penetration obstacle posed by the BBB [15–17]. According to a report by the Tufts Center for the Study of Drug Development, the time taken to develop and approve CNS drugs is 20% and 38% longer, respectively, than for non‐CNS drugs. Consequently, many pharmaceutical companies such as Pfizer, GSK, and Eli Lilly have stopped the development of drugs for CNS disorders [18].
Nevertheless, the FDA has approved many drugs for these disorders over the last few decades, and researchers are optimistic about meeting the health needs in this area. In 2021, 17 new drugs and devices were approved for CNS disorders. The approvals were for the management of migraine and pain (5), Parkinson's disease (3), epilepsy/seizure (3), neuromuscular diseases (3), Alzheimer's disease (1), MS (1), and sleep disorder (1). In addition, researchers are looking at drug repurposing as a faster and cheaper way of providing effective medicine. Some of the repurposed drugs are verapamil, amantadine, propranolol, sunitinib, fenfluramine, and minocycline [19]. New disease biomarkers are also being developed to effectively measure the pathophysiologic processes of CNS disorders. New FDA‐approved drugs for some significant CNS disorders – including attention‐deficit/hyperactivity disorder (ADHD), Alzheimer's disease, migraine, MS, Duchenne muscular dystrophy (DMD), and seizure – are shown in Table 1.1.
1.4.1 Attention‐Deficit/Hyperactivity Disorder
ADHD is a chronic neuropsychiatric disorder characterized by attention difficulty, hyperactivity, and impulsiveness [20]. ADHD usually starts in childhood and symptoms can persist into adulthood. It is the most prevalent mental disorder affecting children. Common comorbidities may include anxiety disorder, autism spectrum disorder, specific communication and learning or motor disorders (e.g. reading disability, developmental coordination disorder), and intellectual disability. The specific cause of ADHD is not known, although there is evidence of genes playing an important role in the disorder. Other risk factors implicated in ADHD are brain injury, premature birth and low birth weight, use of tobacco and/or alcohol during pregnancy, and exposure to other harmful substances during pregnancy. Drug therapy and lifestyle changes are employed in the symptomatic management of ADHD as there is no cure yet. Drugs used in the treatment of ADHD are grouped into stimulant and non‐stimulant medications.
Stimulant medications are the first‐line drugs for ADHD and act by elevating the amount of dopamine and norepinephrine in the brain [21]. Dopamine and norepinephrine are neurotransmitters that regulate attention, thinking, pleasure, and movement. Stimulants are primarily of two classes – amphetamine‐based and methylphenidate‐based medications. FDA‐approved amphetamine‐based medications include:
Amphetamine (Adzenys XR‐ODT
®
, Aytu BioPharma, Englewood, CO, USA; Dyanavel XR
®
, Tris Pharma, Monmouth Junction, NJ, USA).
Amphetamine sulfate (Evekeo
®
, Arbor Pharmaceuticals, Woburn, MA, USA).
Dextroamphetamine sulfate (Dexedrine
®
, GSK, Research Triangle Park, NC, USA; ProCentra
®
, Outlook Pharmaceuticals, Cincinnati, OH, USA; Zenzedi
®
, Arbor Pharmaceuticals).
Dextroamphetamine/amphetamine (Adderall
®
, Shire Pharmaceuticals, Wayne, PA, USA; Mydayis
®
, Takeda Pharmaceuticals, Lexington, MA, USA).
Lisdexamfetamine dimesylate (Vyvanse
®
, Takeda Pharmaceuticals) [
22
–
24
].
Methylphenidate hydrochloride, an example of a methylphenidate‐based medication, has been approved for treating ADHD and is available in different dosage forms, including:
Tablets (Ritalin
®
, Novartis, Basel, Switzerland; Methylin
®
, SpecGX, Webster Groves, MO, USA; Metadate
®
ER, UCB, Smyrna, GA, USA; Cotempla XR‐ODT
®
, Aytu BioPharma; Quillichew ER
®
, Tris Pharma; Concerta
®
, Janssen Pharmaceuticals, Beerse, Belgium)
[25]
.
Capsules (Adhansia XR
®
, Purdue Pharma, Stamford, CT, USA; Ritalin LA; Aptensio XR
®
, Rhodes Pharmaceuticals, Coventry, RI, USA; Metadate CD; Jornay PM
®
, Ironshore Pharmaceuticals & Development, Morrisville, NC, USA).
Oral solution (Quillivant XR
®
, Tris Pharma; Methylin).
Skin patch (Daytrana
®
, Noven Pharmaceuticals, Miami, FL, USA).
Table 1.1 Recent Food and Drug Administration–approved drugs for central nervous system disorders.
Drug/dosage form
Indication
Mechanism of action
Approval date
Company
Vyepti (eptinezumab) IV infusion
Prevention of migraine
Humanized IgG1 monoclonal antibody specific for binding to CGRP ligand
February 2020
Lundbeck Seattle BioPharmaceuticals
Nurtec ODT (rimegepant) Oral disintegrating tablet
Treatment of acute migraine with or without aura
CGRP antagonist
February 2020
Biohaven Pharmaceuticals
Zeposia (ozanimod) Capsule
Relapsing forms of MS, CIS, RRMS, and active secondary progressive MS
S1P receptor modulator
March 2020
Bristol‐Myers Squibb
Ongentys (opicapone) Capsule
As an adjunct to levodopa/carbidopa to reduce “off” episodes in patients with Parkinson disease
COMT inhibitor
April 2020
Neurocrine Biosciences
Koselugo (selumetinib) Capsule
Neurofibromatosis type 1 (NF1) in pediatric patients aged 2 years or older who have symptomatic, inoperable plexiform neurofibroma
Inhibitor of mitogen‐activated protein kinases 1 and 2 (MEK1/2)
April 2020
AstraZeneca Pharmaceuticals
Tauvid (flortaucipir F18) IV injection
Diagnostic agent for patients with Alzheimer's disease
Complexes with aggregated tau protein to form neurofibrillary tangles (NFTs), a component required for neuropathologic diagnosis of Alzheimer's disease
May 2020
Avid Radiopharmaceuticals
Bafiertam (monomethylfumarate) Oral capsule
Relapsing forms of MS, CIS, RRMS, and active secondary progressive MS
Not clear. May have antioxidant properties that could be protective against damage to the brain and spinal cord
April 2020
Banner Life Sciences
Fintepla (fenfluramine) Oral solution
For seizures associated with Dravet syndrome in patients aged 2 years or older
Amphetamine derivative
June 2020
Zogenix
Qutenza (capsaicin) Transdermal patch
Treatment of neuropathic pain associated with diabetic peripheral neuropathy of the feet in adults
Reversible inhibition of the TRPV1 (transient receptor potential vanilloid 1) receptor
July 2020
Averitas Pharma
Viltepso (viltolarsen) IV injection
DMD in patients with confirmed alteration of the
DMD
gene responsive to exon 53 skipping
Antisense oligonucleotide that promotes the activity of dystrophin
August 2020
NS Pharma
Kesimpta (ofatumumab) Subcutaneous injection
Relapsing MS, CIA, RRMS, and active secondary progressive disease in adults
B‐cell therapy, anti‐CD20 antibody
August 2020
Novartis
Amondys 45 (casimersen) IV injection
DMD in patients with a confirmed mutation responsive to exon 45 skipping
Antisense oligonucleotide of the phosphorodiamidate morpholino oligomer (PMO) subclass
Feb 2021
Sarepta Therapeutics
Nulibry (fosdenopterin) IV injection
Indicated to decrease mortality rate in patients with molybdenum cofactor deficiency type A (MoCD‐A), a rare disease
Exogenous source of cyclic pyranopterin monophosphate (cPMP)
February 2021
Origin Biosciences
Azstarys (dexmethylphenidate and serdexmethylphenidate) Capsules
ADHD
CNS stimulant
March 2021
KemPharm
Ponvory (ponesimod) Oral tablet
Relapsing forms of MS, CIS, RRMS, and active secondary progressive disease
S1P receptor 1 modulator
March 2021
Janssen Pharmaceuticals
Aduhelm (aducanumab) IV infusion
For patients with mild cognitive impairment or a mild dementia stage of Alzheimer's disease
Monoclonal antibody that targets beta‐amyloid and binds to aggregated forms of beta‐amyloid
June 2021
Biogen
Xywav (oxybate mixed salts) Oral solution
Treatment of idiopathic hypersomnia in adults
CNS depressant
August 2021
Jazz Pharmaceuticals
Qulipta (atogepant) Tablet
Preventive treatment of episodic migraine
CGRP receptor antagonist
September 2021
AbbVie
Vyvgart (efgartigimodalfa) IV injection
Generalized myasthenia gravis in AChR antibody‐positive adult patients
Fc receptor (FcRn) antagonist preventing FcRn from recycling IgG back into the blood
December 2021
Argenx BV
Ztalmy (ganaxolone) Oral suspension
Seizures in cyclin‐dependent kinase‐like 5 (CDKL5) deficiency disorder patients
GABAA receptor‐positive modulator
March 2022
Marinus Pharmaceuticals
AChR, acetylcholine receptor; ADHD, attention‐deficit/hyperactivity disorder; CGRP, calcitonin gene‐related peptide; CIS, clinically isolated syndrome; CNS, central nervous system; COMT, catechol‐O‐methyl transferase; DMD, Duchenne muscular dystrophy; IgG, immunoglobulin G; IV, intravenous; MS, multiple sclerosis; RRMS, relapsing–remitting multiple sclerosis.
Dexmethylphenidate hydrochloride (Focalin XR®, Novartis) is another example in this class of ADHD medications [25]. Azstarys® (KemPharm, Celebration, FL, USA), a combination of serdexmethylphenidate and dexmethylphenidate, was recently approved by the FDA for the management of ADHD in both children and adults [26]. Stimulants have a potential risk for abuse and dependence. Addiction and withdrawal symptoms are possible with amphetamine‐based ADHD medications, which are also associated with increased blood pressure and heart rate.
Non‐stimulant medications may be used if stimulants are not effective or cause unacceptable side effects. Non‐stimulants employed in treating ADHD consist of selective norepinephrine reuptake inhibitors (SNRIs), ɑ‐2 agonists, and antidepressants. SNRIs increase the level of norepinephrine in the brain by preventing its breakdown. The SNRIs approved by the FDA for ADHD are atomoxetine hydrochloride (Strattera®, Eli Lilly, Indianapolis, IN, USA) and viloxazine (Quelbree®, Supernus Pharmaceuticals, Rockville, MD, USA) [27]. Strattera is the first non‐simulant FDA‐approved drug for ADHD. The ɑ‐2 agonists inhibit the release of norepinephrine in the brain, which has sedative and hypotensive effects. They were initially approved for treatment of hypertension, but later approved as monotherapy and as adjunctive therapy to stimulant medications in the management of ADHD. FDA‐approved ɑ‐2 agonists for ADHD include clonidine hydrochloride (Kapvay®, Concordia Pharmaceuticals, Fort Lauderdale, FL, USA; Catapres®, Catapres‐TTS skin patch, Boehringer Ingelheim, Ingelheim am Rhein, Germany) and guanfacine hydrochloride (Intuniv®, Takeda Pharmaceuticals), which is approved for children aged 6–17 years as adjunctive therapy to stimulants [28].
Antidepressants are medications to treat depression that are repurposed to treat ADHD. Most antidepressants for ADHD are long‐acting, with duration of action lasting up to 24 hours, and are typically taken once a day. Tricyclic antidepressants increase the level of serotonin, a hormone that regulates mood, sleep, and digestion. Tricyclic antidepressants utilized in the therapy of ADHD include imipramine hydrochloride (Tofranil®, Mallinckrodt Pharmaceuticals, Staines‐upon‐Thames, UK), desipramine hydrochloride (Norpramin®, Validus Pharmaceuticals, Parsippany, NJ, USA), and nortriptyline hydrochloride (Pamelor®, Mallinckrodt Pharmaceuticals) [29]. Atypical antidepressants employed in treating ADHD include bupropion hydrochloride (Wellbutrin, Bausch Health, Bridgewater, NJ, USA) and venlafaxine hydrochloride (Effexor®, Pfizer, New York, USA) [30, 31]. They elevate dopamine, serotonin, and norepinephrine levels in the brain.
1.4.2 Migraine
Migraine is a complex disorder mostly on one side of the head, characterized by recurrent episodes of headache. It is usually associated with an aura (visual or sensory symptoms) that often occurs before the headache, but can occur during or afterward. Migraine has a strong genetic component. It occurs predominantly in women. Typical migraine symptoms include throbbing or pulsatile headache, nausea and vomiting, and sensitivity to light and sound.
Migraine treatment can be abortive (stop the acute phase) or prophylactic (preventive). Abortive treatment aims to reverse or stop the progression of a headache. It is most effective when given as soon as the headache begins. Abortive medications approved by the FDA include non‐steroidal anti‐inflammatory drugs (NSAIDs), selective serotonin receptor (5‐hydroxytryptamine–1, or 5‐HT1) agonists (triptans), serotonin 5‐HT1F agonists (titans), calcitonin gene‐related peptide (CGRP) receptor antagonists, and ergot alkaloids. FDA‐approved NSAIDs for managing migraine include ibuprofen, diclofenac potassium (Cambia®, Assertio Therapeutics, Lake Forest, IL, USA), and naproxen sodium [32]. They are the most widely used drugs for migraine attacks and first‐line treatment for mild to moderate migraine. Triptans are first‐line acute therapy for moderate to severe migraine attacks. FDA‐approved triptans are sumatriptan (Tosymra®, Upsher‐Smith, Morristown, NJ, USA; Zembrace® SymTouch, Upsher‐Smith; Onzetra® Xsail®, Currax Pharmaceuticals, Brentwood, TN, USA; Imitrex, GSK), eletriptan hydrobromide (Relpax®, Pfizer), frovatriptan (Frova®, Endo Pharmaceuticals, Malvern, PA, USA), and rizatriptan benzoate (Maxalt®, Merck, Rahway, NJ, USA) [33]. Other examples are zolmitriptan, naratriptan, and almotriptan. Titans have fewer vasoconstriction side effects compared to triptans. They have selective activity on the receptor subtype 5‐HT1F. Lasmiditan Reyvow® (Eli Lilly) was the first ditan to be approved for migraine treatment, in 2019.
Other FDA‐approved drugs for acute therapy of migraine are rimegepant (Nurtec® ODT, Biohaven Pharmaceuticals, New Haven, CT, USA), ubrogepant (Ubrelvy®, AbbVie, Chicago, IL, USA), and dihydroergotamine mesylate (Trudhesa®, Impel Pharmaceuticals, Seattle, WA, USA; Migranal®, Bausch Health) [34].
Prophylactic medications for migraine include repurposed drugs initially approved for other diseases such as hypertension, depression, and epilepsy. Antiepileptic drugs acts as channel blockers, thereby preventing the delivery of electrical impulses to nerve, muscle, and brain cells. Additionally, antiepileptic medications potentiate the actions of a neurotransmitter (gamma‐aminobutyric acid, GABA) that modulates motor skills, vision, and anxiety. The mechanism of action of antiepileptic drugs in the management of migraine is not precise. Still, they act on multiple target sites in the brain, modifying the transmission of information through their inhibitory actions on ion channels and metabolism of GABA, as well as their activity on neurotransmitter receptors. The FDA‐approved antiseizure medications for the prophylactic treatment of migraine are divalproex sodium (Depakote®, AbbVie), topiramate (Topamax®, Janssen Pharmaceuticals; Qudexy® XR, Upsher‐Smith; and Trokendi XR®, Supernus Pharmaceuticals), and valproic acid (Stavzor®, Bionpharma, Princeton, NJ, USA) [35]. The FDA approves only two β‐blockers for migraine. These are propranolol (InnoPran XL®, ANI Pharmaceuticals, Baudette, MN, USA) and timolol [36]. β‐Blockers are drugs that were initially developed to treat hypertension (high blood pressure) since they block adrenaline receptors, causing the vessels to relax.
Another FDA‐approved drug for prophylactic management of chronic migraine is botulinum toxin A [37] (Botox®, AbbVie; or Onabotulinum A), a toxin produced by the naturally occurring Clostridium botulinum that causes botulism. Botox decreases the number of migraine headaches in people prone to them who use the drug and was approved in 2010 to treat chronic migraine.
CGRP inhibitors (gepants) are another class of drugs used in migraine prophylaxis. They are monoclonal antibodies and small‐molecule CGRP receptor antagonists that block the activities of CGRP. Six CGRP inhibitors have gained FDA approval for migraine prevention: erenumab (Aimovig®, Amgen, Thousand Oaks, CA, USA), fremanezumab (Ajovy®, Teva Pharmaceuticals, Parsippany, NJ, USA), galcanezumab (Emgality®, Eli Lilly), eptinezumab (Vyepti®, Lundbeck Seattle BioPharmaceuticals, Bothell, WA, USA), rimegepant (Nurtec ODT), and atogepant (Qulipta®, AbbVie) [38].
1.4.3 Parkinson's Disease
Parkinson's disease is among the most common neurologic disorders. It affects approximately 1% of individuals older than 60 years and causes progressive disability. The two significant neuropathologic findings in Parkinson's disease are the depletion of pigmented dopaminergic neurons of the substantia nigra pars compacta and the presence of Lewy bodies and Lewy neuritis [39].
Parkinson's disease is a situation when nerve cells (neurons) in the substantia nigra of the brain become impaired or die, leading to low dopamine production. Dopamine is essential for the operation of basal ganglia, a part of the brain responsible for coordinating body movements. Deficiency of dopamine causes the movement symptoms seen in people with Parkinson's disease. Loss of norepinephrine is also implicated in Parkinson's disease and causes some of the non‐movement‐related symptoms. Common symptoms of this disorder are tremors, slowness of movement, stiff muscles, unsteady walking, balance, and coordination problems. Other symptoms are a subtle decrease in dexterity, soft voice, decreased facial expression, sleep disturbances, decreased sense of smell, constipation, sweating abnormalities, sexual dysfunction, and seborrhea dermatitis. There is no cure for the disease. However, most patients can maintain a good quality of life with medications.
Medical management of Parkinson's disease is to provide control of signs and symptoms for as long as possible while minimizing adverse effects. The gold standard for symptomatic therapy of Parkinson's disease is levodopa, a dopamine precursor. Levodopa is commonly taken with a dopamine decarboxylase inhibitor, carbidopa (Sinemet®, Merck; Parcopa®, UCB; Rytary®, Amneal Pharmaceuticals, Bridgewater, NJ, USA; Duopa®, AbbVie) [40]. Inbrija® (Acorda Therapeutics, New York, USA) is an FDA‐approved levodopa inhalation powder [41]. A combination of carbidopa, levodopa, and entacapone (Stalevo®, Novartis) is also approved [42].
The dopamine agonists approved for treating Parkinson's disease are ropinirole (ReQuip®, GSK), rotigotine (Neupro®, UCB), apomorphine (Apokyn®, Supernus Pharmaceuticals), and pramipexole (Mirapex®, Boehringer Ingelheim) [43]. Neupro is given as a transdermal patch, Apokyn is a short‐acting injectable medication, while Kynmobi®, Sunovion Pharmaceuticals, (Marlborough, MA, USA) is a sublingual film.
The catechol O‐methyltransferase (COMT) inhibitors block the breakdown of dopamine in the brain by inhibiting the activity of COMT. Entacapone (Comtan®, Novartis), tolcapone (Tasmar®, Bausch Health), and opicapone (Ongentys®, Neurocrine Biosciences, San Diego, CA, USA) are the three FDA‐approved COMT inhibitors for Parkinson's disease. Opicapone is the most recent medication in this class, which received FDA approval in 2020 [44].
Monoamine oxidase (MAO) B inhibitors block the monoamine oxidase B (MAO B), another enzyme involved in the breakdown of dopamine in the brain. This allows dopamine to have longer‐lasting effects on the brain. Examples of MAO B inhibitors are selegiline (Eldepryl®, Orion Pharma, Espoo, Finland; Zelapar®, Bausch Health), rasagiline (Azilect®, Teva Pharmaceuticals), and safinamide (Xadago®, Supernus Pharmaceuticals) [45]. Anticholinergic agents, such as benztropine (Cogentin®, Merck) and trihexyphenidyl (Artane®, Teva Pharmaceuticals), help reduce tremor and muscle stiffness. They are the oldest class of drugs to treat Parkinson's disease. Amantadine (Symmetrel®, Endo Pharmaceuticals), an antiviral agent, helps reduce the involuntary movements (dyskinesia) resulting from levodopa medication. There are two extended‐release types of the drug, Gocovri® (Supernus Pharmaceuticals) and Osmolex ER® (Supernus Pharmaceuticals) [46]. Side effects include confusion and memory problems. Another medication, istradefylline (Nourianz®, Kyowa Kirin, Tokyo, Japan), is an adenosine A2A receptor antagonist approved for use in patients taking carbidopa‐levodopa but experiencing off symptoms. Istradefylline is the first non‐dopaminergic drug approved by the FDA for Parkinson's disease in the last two decades. These drugs act to increase the effectiveness of levodopa and also increase its side effects, including involuntary movements (dyskinesia) and hallucinations [47].
Pimavanserin (Nuplazid®, Acadia Pharmaceuticals, San Diego, CA, USA) is an atypical antipsychotic agent and the only drug approved to treat hallucinations and delusions related to Parkinson's disease. In contrast, rivastigmine transdermal system (Exelon® Patch, Novartis) was approved to treat non‐severe dementia associated with Parkinson's disease.
1.4.4 Multiple Sclerosis
MS is an immune‐mediated inflammatory disease. It destroys the myelinated axons in the CNS, producing significant physical disability within 20–25 years in more than one‐third of patients. MS is the most prevalent cause of non‐traumatic disability in young adults. Generally, MS is detected between 20 and 40 years of age, but less than 1% can occur in childhood and approximately 2–10% after 50 years of age. MS affects women more than men. The cause of MS is not yet precise. However, it is considered to be caused by multiple factors, including genetic and environment‐related factors [48, 49].
The treatment of MS is divided into disease‐modifying therapy and symptomatic therapy. The majority of disease‐modifying agents for MS (DMAMS) that have been approved are indicated for treating relapsing forms of MS only. However, siponimod (Mayzent®, Novartis), ocrelizumab (Ocrevus®, Genentech, South San Francisco, CA, USA), ozanimod (Zeposia®, Bristol‐Myers Squibb, New York, USA), ofatumumab (Kesimpta®, Novartis), and cladribine (Mavenclad®, Merck) are also approved for active secondary progressive disease. The FDA‐approved DMAMS include the following:
Interferons (IFNs), e.g. IFN β‐1a (Avonex
®
, Biogen, Cambridge, MA, USA; Rebif
®
, Merck), IFN β‐1b (Extavia
®
, Novartis), and peginterferon β‐1a (Plegridy
®
, Novartis)
[49]
.
Sphingosine 1‐phosphate (S1P) receptor modulators, e.g. siponimod (Mayzent), fingolimod (Gilenya
®
, Novartis), and ozanimod (Zeposia)
[50]
.
Monoclonal antibodies, e.g. natalizumab (Tysabri
®
, Biogen), alemtuzumab (Lemtrada
®
, Genzyme, Cambridge, MA, USA), ocrelizumab (Ocrevus), and ofatumumab (Kesimpta) [
51
,
52
]. Ofatumumab was approved in 2020 for treating relapsing forms of MS in adults. It is the first B‐cell therapy for MS and can be self‐administered once monthly using an autoinjector pen.
Other immunomodulators employed in the therapy of MS are glatiramer (Copaxone
®
, Teva Pharmaceuticals), mitoxantrone, teriflunomide (Aubagio
®
, Genzyme), dimethyl fumarate (Tecfidera
®
, Biogen), and cladribine (Mavenclad)
[53]
.
Diroximel fumarate (Vumerity
®
, Biogen), a fumarate therapy, is also approved for relapsing forms of MS. In addition, diroximel fumarate is indicated for treating clinically isolated syndrome (CIS) and relapsing–remitting MS (RRMS), as well as for the treatment of active secondary progressive disease in adults
[54]
.
Several symptomatic therapies have been licensed specifically for MS. These include nabiximols (Sativex®, GW Pharma, Cambridge, UK) for neuropathic pain and fampridine (Ampyra®, Acorda Therapeutics, Waltham, MA, USA) for walking difficulties.
1.4.5 Alzheimer's Disease
Alzheimer's disease is among the types of dementia that develop gradually with the expression of neuritic plaques and neurofibrillary tangles caused by the buildup of amyloid beta (Aβ) peptide in the brain's most affected area, the medial temporal lobe and neocortical structures [55]. Alzheimer's disease has no cure, although available treatments improve the symptoms [56]. Several physiologic processes in Alzheimer's disease destroy acetylcholine‐producing cells, reducing cholinergic transmission through the brain. Donepezil hydrochloride (Aricept®, Eisai R&D Management, Nutley, NJ, USA), galantamine hydrochloride (Reminyl®, Janssen Pharmaceuticals), and rivastigmine tartrate (Exelon®, Novartis) are acetylcholinesterase inhibitors (AChEIs) and act by blocking cholinesterase enzymes (AChE and butyrylcholinesterase [BChE]) from metabolizing acetylcholine, which results in increasing acetylcholine levels in the synaptic cleft. On the other hand, overactivation of N‐methyl‐D‐aspartate receptor (NMDAR) leads to rising levels of Ca2+, which promotes cell death and synaptic dysfunction. NMDAR antagonists such as memantine HCl (Namenda®, Merz Pharma, Frankfurt, Germany) prevent the overactivation of the NMDAR glutamate receptor, and hence the Ca2+ influx, restoring its regular activity.
Namzaric® (Merz Pharma) combines memantine hydrochloride and donepezil hydrochloride in a fixed dose. It is a medication for moderate to severe dementia of the Alzheimer's type in patients already stabilized on memantine hydrochloride and donepezil hydrochloride.
Aduhelm® (aducanumab‐avwa; Biogen) is a human immunoglobulin gamma 1 (IgG1) monoclonal Aβ‐directed antibody. It was approved in 2021 for treating Alzheimer's disease. Aduhelm reduces Aβ plaques, a pathophysiological feature of Alzheimer's disease [57].
1.4.6 Muscular Dystrophy
Muscular dystrophy is a progressive muscle disorder without a central or peripheral nerve abnormality. The disease causes muscle weakness and degeneration and affects breathing and heart function, which can be life‐threatening. DMD is among the types of muscular dystrophy. Patients with these symptoms are typically diagnosed between 2 and 3 years of age.
DMD is caused by mutations in the DMD gene (encoding dystrophin) that prevents the production of the muscle isoform of dystrophin, resulting from non‐sense or frame‐shifting mutations in the dystrophin gene. Most of these mutations could be resolved by removing an extra exon to generate shorter but in‐frame transcripts and establish partly functional proteins.
Amondys 45® (Sarepta Therapeutics, Cambridge, MA, USA) was approved in 2021 for treating confirmed mutation of the DMD gene responsive to exon 45 skipping. Also, Exondys 51® (Sarepta Therapeutics) and Viltepso® (NS Pharma, Paramus, NJ, USA) are specifically indicated for treating patients with confirmed alterations in the DMD gene responsive to exon 51 and 53 skipping, respectively [58].
Deflazacort (Emflaza®, PTC Therapeutics, South Plainfield, NJ, USA), a corticosteroid that exerts anti‐inflammatory and immunosuppressive effects, is specifically indicated for treating DMD in patients not less than 2 years old.
1.4.7 Epilepsy/Seizure
Epilepsy is a chronic medical disorder, usually resulting in unpredictable, unprovoked recurrent seizures affecting various mental and physical functions. Seizures can be partial, generalized, or unclassified. A shift in the average balance of excitation and inhibition within the CNS and abnormal brain function cause an attack. Causes of epileptic seizures include a genetic predisposition, head trauma, stroke, brain tumors, alcohol or drug withdrawal, repeated episodes of metabolic issues, hypoglycemia, and other conditions.
Many medications have been approved for the management of epilepsy, and the choice of drugs depends on the diagnosis of the epileptic syndrome. Although some anticonvulsants (e.g. lamotrigine, topiramate, valproic acid, zonisamide) have various means of eliciting anticonvulsant action, some (e.g. phenytoin, carbamazepine, ethosuximide) have only one known mechanism of action. FDA‐approved anticonvulsant agents are classified into large groups based on their mechanisms, as follows:
Blockers of repetitive activation of the sodium channel: phenytoin, carbamazepine (Carbatrol
®
, Takeda Pharmaceuticals), oxcarbazepine, lamotrigine, topiramate.
Enhancers of slow inactivation of the sodium channel: lacosamide (Vimpat
®
, UCB), rufinamide (Banzel
®
, Novartis).
GABA(A) receptor enhancers: clobazam (Onfi
®
, Lundbeck Seattle BioPharmaceuticals), diazepam (Valium
®
, Roche, Basel, Switzerland), lorazepam (Ativan
®
, Bausch), clorazepate (Tranxene
®
, Recordati Rare Diseases, Lebanon, NJ, USA), alprazolam (Xanax
®
, Pfizer), gabapentin (Neurontin
®
, Pfizer), phenobarbital (Luminal
®
, Bayer, Leverkusen, Germany), pregabalin (Lyrica
®
, Pfizer), vigabatrin (Sabril
®
, Lundbeck Seattle BioPharmaceuticals), ganaxolone (Ztalmy
®
, Marinus Pharmaceuticals, Radnor, PA, USA).
Glutamate blockers: felbamate, perampanel, topiramate.
Calcium channel blockers: ethosuximide, lamotrigine, topiramate (Trokendi XR; Topamax), zonisamide, valproate (Stavzor).
H‐current modulators: gabapentin (Neurontin
®
, Pfizer), lamotrigine (Lamictal
®
, GSK).
