Phytochemical Drug Discovery for Central Nervous System Disorders

Chukwuebuka Egbuna, PhD, is Research Biochemist in the Africa Centre of Excellence in Public Health and Toxicological Research (ACE-PUTOR), University of Port-Harcourt, Rivers State, Nigeria. He has published extensively on phytochemistry and serves on the editorial boards of several leading journals. Muthun Rudrapal, PhD, FIC, FICS, CChem, is Associate Professor of the 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. He has published very widely on pharmaceuticals and related subjects and is the holder of numerous patents.

• Contributors xvPreface xxi1 Central Nervous System Disorders and Food and Drug Administration–Approved Drugs 1Estella U. Odoh, Chukwuebuka Egbuna, Chukwuma M. Onyegbulam, Diovu E. Obioma, Linda A. Onugwu, Obinna S. Onugwu, and Mithun Rudrapal1.1 Incidence and Prevalence of Major Neurologic Disorders 21.2 Etiology 21.3 Pathogenesis 31.4 Central Nervous System Disorders and Drugs Approved by the Food and Drug Administration 31.4.1 Attention-Deficit/Hyperactivity Disorder 41.4.2 Migraine 81.4.3 Parkinson’s Disease 91.4.4 Multiple Sclerosis 111.4.5 Alzheimer’s Disease 111.4.6 Muscular Dystrophy 121.4.7 Epilepsy/Seizure 121.5 Conclusion 13References 132 Drug Discovery from Medicinal Plants against Parkinson’s Disease 17Dunya Al-Duhaidahawi2.1 Pathogenesis of Parkinson’s Disease 172.1.1 Misfolding and Aggregation of Proteins 172.1.2 Mitochondrial Dysfunction 182.1.3 Neuroinflammation 182.1.4 Metal Ion Imbalance in the Brain 182.1.5 Protease-Mediated Degradation Inhibition 182.1.6 Oxidative Stress 192.2 Natural Dopaminergic Neuroprotective Compounds 192.2.1 Polyphenols 192.2.1.1 Resveratrol 192.2.1.2 Sesamin 192.2.1.3 Curcumin 192.2.1.4 6-Shogaol 202.2.1.5 Fustin 202.2.1.6 Biochanin A 202.2.1.7 Acacetin 202.2.1.8 Baicalein 202.3 Nitrogenated Phytochemicals 212.3.1 Alkaloids 212.3.1.1 Tetrahydro Berberine 212.3.1.2 Berberine 212.3.1.3 Celastrol 212.3.2 Saponins 212.3.2.1 Astragaloside IV 212.3.2.2 Ginseng 212.4 Chinese Herbal Medications and Parkinson’s Disease 222.4.1 Acanthopanax 222.4.2 Alpinia 222.4.3 Camellia 222.4.4 Cassia 232.4.5 Chrysanthemum 232.4.6 Cistanche 232.4.7 Gastrodia 232.4.8 Ginkgo 242.4.9 Gynostemma 242.4.10 Paeonia 242.4.11 Panax 252.4.12 Polygala 252.4.13 Polygonum 252.4.14 Psoralea 262.5 Herbal Medicines from India and Parkinson’s Disease 262.5.1 Withania somnifera 262.5.2 Tinospora cordifolia 262.5.3 Mucuna pruriens 262.6 European Plants 272.7 α-Synuclein as a Potential Therapeutic Target 272.7.1 Phytochemicals Targeting the α-Synuclein Cascade 272.8 Conclusion 28References 393 Drug Discovery from Medicinal Plants against Alzheimer’s Disease 43Mona M. Marzouk, Mai M. Farid, Nesrine M. Hegazi, and Shahira M. Ezzat3.1 Pathogenesis 443.1.1 Amyloid Plaques 443.1.2 Neurofibrillary Tangles 453.1.3 Synaptic Damage 453.1.4 Cholinergic Functions 453.1.5 Oxidative Stress 453.1.6 Neuroinflammation 453.2 Treatment Strategies for Alzheimer’s Disease 463.2.1 Amyloid Hypothesis 463.2.2 Tau Proteins Hypothesis 463.2.3 Dendritic Hypothesis 543.2.4 Cholinergic Hypothesis 553.2.5 Strategies for 5-HT 6 Obstruction 553.2.6 Metabolic Hypothesis 553.3 Medicinal Plants Having Effects against Alzheimer’s Disease 563.3.1 Medicinal Plants Targeting the Cholinergic System 563.3.2 Medicinal Plants Targeting Amyloid Beta 613.3.3 Medicinal Plants Targeting Tau-Related Pathways 653.4 Natural Products with Proven Anti-Alzheimer’s Activity 663.5 Conclusion 66References 704 Effects of Medicinal Plants and Phytochemicals on Schizophrenia 81Nithya Rani Raju, S.V. Rashmitha, S. Pavithra, Erika Amparo Torres, M. Kishor, and Raghu Ram Achar4.1 Mechanisms of Action Related to Schizophrenia 814.1.1 Vesicular Monoamine Transporters 824.1.2 Dopamine Receptors/Transporters 824.1.3 Serotonin Receptors/Transporters 834.1.4 Glutamate Transporters 844.1.5 Gamma-Aminobutyric Acid Level/Receptors 844.1.6 Genes Related to Schizophrenia 874.2 Ayurvedic Plants Used as Treatment for Schizophrenia and Related Psychoses 884.2.1 Allium cepa 884.2.2 Acorus calamus. Linn 884.2.3 Bacopa monnieri 894.2.4 Carum carvi 894.2.5 Celastrus panicutalus 904.2.6 Centella asiatica 904.2.7 Convolvulus pluricaulis 914.2.8 Coriandrum sativum 914.2.9 Cuminum cyminum L. 914.2.10 Cyperus Rotundus Linn. 924.2.11 Eclipta alba 924.2.12 Ficus religiosa 924.2.13 Glycyrrhiza glabra 934.2.14 Moringa oleifera 934.2.15 Nigella sativa 934.2.16 Piper longum 944.2.17 Rauwolfia serpentina 944.2.18 Sesbania grandiflora 954.2.19 Sphaeranthus indicus 954.2.20 Tinospora cordifolia 964.2.21 Valeriana wallichii 964.2.22 Withania somnifera 974.2.23 Ziziphus mauritiana 974.3 Conclusion 97References 1225 Drug Discovery from Medicinal Plants and Phytochemicals against Neuropathic Pain 137Santwana Palai, Shyam S. Kesh, and Mithun Rudrapal5.1 Mechanisms of Neuropathic Pain 1385.2 Animal Models for Studying Neuropathic Pain 1395.2.1 Streptozotocin-Induced Diabetes 1395.2.2 High-Fat Diet 1395.2.3 Sciatic Nerve Injury 1395.2.4 Chemotherapy-Induced Peripheral Neuropathy 1395.3 Medicinal Plants and Phytochemicals against Neuropathic Pain 1395.4 Role of Plants and Phytochemicals in Different Neuropathic Pain Models 1405.4.1 Diabetic Neuropathy 1405.4.2 Chemotherapy-Induced Peripheral Neuropathy 1535.4.3 Sciatic Nerve Chronic Constriction Injury 1545.4.4 Other Neuropathic Pain Signaling Pathways 1545.5 Future Perspectives 1555.6 Conclusion 155References 1556 Brain Function, Stroke, and Medicinal Herbs 161Shahira M. Ezzat, Rana Marghany, Nehal El Mahdi, and Mohamed A. Salem6.1 Brain Function and Stroke 1616.2 Strategies for Treatment of Ischemic Stroke 1626.2.1 Neuroprotective Strategy 1626.2.1.1 Oxidative Stress Targeting 1626.2.1.2 Excitotoxicity Targeting 1626.2.1.3 Apoptosis Targeting 1626.2.2 Neurorestorative Strategy 1626.2.2.1 Angiogenesis Targeting 1626.2.2.2 Neurogenesis Targeting 1636.3 Medicinal Plants for the Treatment of Stroke 1636.4 Natural Products for the Treatment of Stroke 1656.5 Recent Applications of Nanomedicine for Treatment of Stroke 1656.6 Conclusion 174References 1747 Plant-Based Analgesics 181Gabriel O. Anyanwu and Dorathy O. Anzaku7.1 Current Analgesic Drugs and Their Mechanisms of Action 1827.2 Plant-Derived Lead Compounds with Analgesic Activities 1827.2.1 Saponins and Terpenoids 1847.2.2 Flavonoids 1847.2.3 Alkaloids 1847.2.4 Glycosides 1857.3 Analgesic Effects of Medicinal Plants Found in Nigeria 1857.4 Limitations of Plant-Based Analgesics 1947.5 Future Directions and Perspective for Plant-Based Analgesics 1947.6 Conclusion 194References 1958 Medicinal Plants and Phytochemicals against Depression 203Neelma Munir, Ayesha Qamar, Maria Hasnain, Huma Waqif, Maria Hanif, Zirwa Sarwar, and Shagufta Naz8.1 Causes of Depression 2038.1.1 Genetic Factors 2048.1.2 Environmental Factors 2048.1.3 Risk Factors for Depression 2048.2 Symptoms of Depression 2048.2.1 Symptoms of Depression in Men 2048.2.2 Symptoms of Depression in Women 2058.2.3 Symptoms of Depression in Children 2058.3 Diagnosis of Depression 2058.4 Types of Depression 2058.4.1 Major Depressive Disorder 2068.4.2 Persistent Depressive Disorder 2068.4.3 Depression with Psychosis 2068.4.4 Depression in Pregnancy 2078.5 Treatment of Depression 2078.5.1 Natural Treatment for Depression 2088.5.2 Medicinal Plants as Antidepressants 2088.5.2.1 Lavandula officinalis 2098.5.2.2 Kaempferia parviflora 2108.5.2.3 Asparagus racemosus 2118.5.2.4 Passiflora foetida 2118.5.2.5 Momordica charantia 2128.5.2.6 Bacopa monniera 2128.5.2.7 Valeriana officinalis 2128.5.2.8 Rhodiola rosea 2128.5.2.9 Withania somnifera 2128.5.2.10 Matricaria recutita 2138.5.2.11 Ginkgo biloba 2138.6 Conclusion 213References 2149 Anti-inflammatory Agents from Medicinal Plants 219Bui T. Tung, Tran V. Linh, Trinh P. Thao, and Nguyen D. Thuan9.1 Role of Neuroinflammation in Neurodegenerative Diseases 2209.2 Neuroinflammatory Drugs 2229.3 Medicinal Plants as Sources of Anti-inflammatory Agents 2319.3.1 Allium sativum 2329.3.2 Azadirachta indica 2339.3.3 Cassia tora 2339.3.4 Euphorbia hirta 2339.3.5 Garcinia mangostana 2349.3.6 Punica granatum 2359.3.7 Ricinus communis 2359.3.8 Scutellaria baicalensis 2369.3.9 Solanum melongena 2379.4 Bioactive Compounds as Anti-inflammatory Agents 2379.4.1 Curcumin 2389.4.2 Eugenol 2389.4.3 Epigallocatechin 3-Gallate 2399.4.4 Guggulsterone 2409.4.5 Resveratrol 2409.4.6 Thymoquinone 2419.5 Conclusion 241References 24210 Plant-Based Products and Phytochemicals against Viral Infections of the Central Nervous System 251Santwana Palai, Shyam S. Kesh, and Mithun Rudrapal10.1 Viral Infections of the Central Nervous System 25210.2 Plant and Phytochemicals as Antiviral Agents for Central Nervous System Viral Infections 25210.2.1 SARS Cov-2 Virus 25210.2.2 Japanese Encephalitis Virus 26210.2.3 West Nile Virus 26310.2.4 Tick-Borne Encephalitis Virus 26410.2.5 Herpes Simplex Virus 26410.2.6 Rabies Virus 26510.2.7 Varicella Zoster Virus 26610.2.8 Poliomyelitis Virus 26610.2.9 Human Immunodeficiency Virus 26710.3 Controlling Vectors of Viral Diseases of the Central Nervous System 26810.4 Future Perspectives 26910.5 Conclusion 269References 27011 Fruits and Nutraceuticals for the Prevention and Treatment of Central Nervous System Disorders 273Abeer M. A. El Sayed and Chukwuebuka Egbuna11.1 Fruits for Cognition and Brain Health 27411.1.1 Aegle marmelos 27411.1.2 Citrullus lanatus 27411.1.3 Citrus grandis 27411.1.4 Phoenix sylvestris 27411.1.5 Phyllanthus emblica 27411.1.6 Emblica officinalis 27511.1.7 Solanum torvum 27511.1.8 Terminalia chebula 27511.1.9 Blackberries 27511.1.10 Blueberries 27611.1.11 Strawberries 27611.1.12 Raspberries 27611.1.13 Cherries 27611.1.14 Oranges 27711.1.15 Plums 27711.1.16 Prunes 27711.1.17 Red Grapes 27711.1.18 Pomegranates 27811.2 Nutraceuticals in Ameliorating Neurodegeneration 27811.2.1 Quercetin and Kaempferol 27811.2.2 Withanine 27811.2.3 Asiatic Acid 27911.2.4 Bhilavanol A and B 27911.3 Nutraceuticals in Alzheimer’s Disease 27911.3.1 Flavonoids 27911.3.2 Apigenin 28011.3.3 Genistein, Daidzein, Glycitin 28011.3.4 Resveratrol 28011.3.5 Curcumin 28011.3.6 Carotenoids 28011.3.7 Crocin 28111.3.8 Carnosic Acid and Rosmarinic Acid 28111.3.9 Alkaloids 28111.4 Nutraceuticals in Parkinson’s Disease 28111.4.1 Vitamins: Folate, Cobalamin, Pyridoxin 28111.5 Nutraceuticals in Depression 28311.6 Nutraceuticals in Psychotic Disorders 28311.7 Conclusion 283References 28412 Neurorestorative Potential of Medicinal Plants and Their hytochemicals 291Babatunde O. Adetuyi, Kehinde A. Odelade, Grace O. Odine, Oluwatosin A. Adetuyi, Semiloore O. Omowumi, Olubanke O. Ogunlana, and Chukwuebuka Egbuna12.1 Therapeutic Value of Some Medicinal Plants and their Importance 29212.2 Types of Medicinal Plants and Their Uses 29312.3 Phytochemicals 29312.4 Phytochemical Constituents in Some Medicinal Plants 29512.4.1 Onions 29512.4.1.1 Phytochemical Constituents in Onions 29512.4.2 Turmeric 29612.4.2.1 Phytochemical Constituents in Turmeric 29612.4.3 Ginger 29712.4.3.1 Phytochemical Constituents in Ginger 29712.4.4 Garlic 29712.4.4.1 Phytochemical Constituents in Garlic 29812.5 The Brain 29812.5.1 Brain Physiology 29912.5.1.1 Neurotransmitters and Receptors 29912.5.1.2 Electrical Activity 30012.5.1.3 Metabolism 30012.5.2 Functions of the Brain 30012.5.2.1 Perception 30012.5.3 Motor Control 30012.5.4 Homeostasis 30112.5.5 Motivation 30112.5.6 Learning and Memory 30212.6 Brain Conditions 30212.7 Protective Effects of Medicinal Plants on the Brain 30312.7.1 Crocus sativus 30312.7.1.1 Medicinal Properties of Crocus sativus 30312.7.2 Nigella sativa 30412.7.2.1 Medicinal Properties of Nigella sativa 30412.7.3 Coriandrum sativum 30412.7.3.1 Medicinal Properties of Coriandrum sativum 30412.7.4 Ferula assafoetida 30412.7.4.1 Medicinal Properties of Ferula assafoetida 30412.7.5 Thymus vulgaris 30512.7.5.1 Medicinal Properties of Thymus vulgaris 30512.7.6 Curcuma longa 30512.7.6.1 Medicinal Properties of Curcuma longa 30512.8 Conclusion 305References 30613 Neurotransmitter Modulation by Phytochemicals 311Prachee Dubey and Kanti Bhooshan Pandey13.1 Sources, Structures, and Classifications of Phytochemicals 31113.2 Neurotransmitters and Their Functions 31613.3 Modulation of Cholinergic Signaling by Phytochemicals 31713.3.1 Effect of Phytochemicals on Acetylcholinesterase 31813.4 Effect of Phytochemicals on GABAergic Signaling 31813.5 Effect of Phytochemicals on Glutamatergic Signaling 31913.6 Modulation of Serotonergic and Dopaminergic Signaling by Phytochemicals 32013.7 Conclusion 321Acknowledgments 321References 32114 Antipyretic Agents from Plant Origins 327Kamoru A. Adedokun, Sikiru O. Imodoye, Akeem O. Busari, Malik A. Sanusi, Abdullah Olawuyi, and Maroof G. Oyeniyi14.1 Pyrexia Development, Its Mechanisms, and the Roles of Plant Metabolites as Antipyretics 32814.1.1 Fever Development 32814.1.2 Mechanisms of Fever Development 32814.1.2.1 Humoral Pathway 32814.1.2.2 Neural Pathway 33014.1.3 Roles of Plant Metabolites as Antipyretics 33114.2 Antipyretic Agents of Plant Origin 34114.2.1 Arbutus andrachne (Family Ericaceae) 34114.2.2 Berberis spp. (Family Berberidaceae) 34314.2.3 Cassia fistula Linn. (Family Caesalpiniaceae) 34314.2.4 Crataeva magma (Family Capparidaceae) 34414.2.5 Echinops kebericho M. (Family Asteraceae) 34514.2.6 Enicostema littorale (Family Gentianaceae) 34614.2.7 Piper nigrum (Family Piperaceae) 34614.2.8 Viola betonicifolia (Family Violaceace) 34714.3 Conclusion and Future Perspectives 348References 34915 Medicinal Herbs against Central Nervous System Disorders 359Ahmed Olatunde, Neelma Munir, Godwin Anywar, Maria Hanif, Huma Waqif, Habibu Tijjani, Barbara Sawicka, and Akram Muhammad15.1 Medicinal Plants as Interventions for Central Nervous System Disorders 36015.2 Some Medicinal Plants with Neuroprotective Action on Central Nervous System Disorders 36215.2.1 Desmodium adscendens, Cleome rutidosperma, Withania somnifera, and Panax ginseng 36215.2.2 Baccopa monnieri and Rauvolfia serpentina 36315.2.3 Avena sativa and Annona squamosa 36415.2.4 Acorus calamus, Emblica officinalis, and Strychnos nux-vomica 36515.3 Some Central Nervous System Disorders and Medicinal Plant Interventions 36615.3.1 Depression 36615.3.1.1 Family Amaryllidaceae – Allium cepa 36615.3.1.2 Family Plantaginaceae – Bacopa monnieri 36715.3.1.3 Family Fabaceae – Glycyrrhiza glabra 36815.3.1.4 Family Lamiaceae – Rosmarinus officinalis 36815.3.1.5 Family Zingiberaceae – Zingiber officinale 36915.3.2 Epilepsy 36915.3.2.1 Family Hypoxidaceae – Hypoxis hemerocallidea 37015.3.2.2 Family Piperaceae – Piper methysticum 37115.3.2.3 Family Caprifoliaceae – Valeriana officinalis 37215.3.2.4 Family Phyllanthaceae – Bridelia micrantha 37215.3.2.5 Family Rubiaceae – Sarcocephalus latifolius 37215.3.3 Huntington’s Disease 37215.3.3.1 Family Ginkgoaceae – Ginkgo biloba 37315.3.3.2 Family Araliaceae – Panax ginseng 37315.3.3.3 Family Asteraceae – Calendula officinalis 37315.3.3.4 Family Primulaceae – Embelia ribes 37415.3.3.5 Family Theaceae – Camellia sinensis 37415.4 Some Mechanistic Actions of Medicinal Herbs against Central Nervous System Disorders 37415.4.1 In Vitro Studies 37515.4.2 In Vivo Studies 37515.5 Conclusion 376References 37616 Important Antihistaminic Plants and Their Potential Role in Health 385Salwa Bouabdallah, Hagar A. Sobhy, Babatunde O. Adetuyi, Omayma A. Eldahshan, and Chukwuebuka Egbuna16.1 Antihistaminic Plants 38616.1.1 Family Acanthaceae 38616.1.2 Family Amaranthaceae 38616.1.3 Family Amaryllidaceae 38716.1.4 Family Asclepiadaceae 38716.1.5 Family Asteraceae 38716.1.6 Family Caesalpiniaceae 38716.1.7 Family Casuarinaceae 38716.1.8 Family Cruciferae 38816.1.9 Family Cucurbitacea 38816.1.10 Family Euphorbiaceae 38816.1.11 Family Fabaceae 38816.1.12 Family Lamiaceae 38816.1.13 Family Moraceae 38816.1.14 Family Myricaceae 38816.1.15 Family Myrtaceae 38916.1.16 Family Olacaceae 38916.1.17 Family Piperaceae 38916.1.18 Family Poaceae 38916.1.19 Family Polygalaceae 39016.1.20 Family Scrophulariaceae 39016.1.21 Family Verbenaceae 39016.1.22 Family Zygophylaceae 39016.2 Bioactive Compounds with Antihistaminic Activities 39016.3 Conclusion 394References 39417 Effect of Plant-Based Anticonvulsant Products and Phytochemicals 397Muhammad Akram, Sadia Zafar, Hassan Shah, Zerfishan Riaz, Khawaja S. Ahmad, Muhammad Riaz, Naveed Munir, Muhammad Jahangeer, Imtiaz M. Tahir, Michael P. Okoh, Muhammad A. Ishfaq, David Pérez-Jorge, Vanessa de Andrade Royo, Muhammad M. Aslam, Chukwuebuka Egbuna, and Chukwunonso O. Igboekwe17.1 Types of Epileptic Seizures 39817.2 Basic Mechanisms of Epilepsy 39817.3 Epilepsy and Oxidative Stress 40017.4 Epilepsy and Inflammation 40117.5 Tests for Seizure Induction 40217.6 Medicinal Plants Used to Treat Epilepsy 40217.7 Conclusion 403References 40718 Application of Nanophytomedicine for the Treatment of Central Nervous System Disorders 413Nilesh Rarokar, Nilambari Gurav, and Shailendra Gurav18.1 Neurodegenerative Disease and the Blood–Brain Barrier 41418.1.1 Problems Associated with Treatment of Central Nervous System Disorders 41418.1.2 Role of the Blood–Brain Barrier 41518.1.3 Blood–Brain Barrier Crossing Mechanism 41518.1.4 Phytomedicine/Neuroprotective Drugs Reported for Central Nervous System Disorders 41618.2 Nano Approaches to Central Nervous System Drug Delivery 41818.2.1 Types of Nanocarriers 41818.2.1.1 Liposomes 41818.2.1.2 Micelles 41818.2.1.3 Solid Lipid Nanoparticles 41818.2.1.4 Phytosomes 41918.2.1.5 Nanosponges 41918.2.1.6 Nanoemulsions 41918.2.1.7 Dendrimers 42018.2.1.8 Nanoparticles 42018.2.2 Techniques/Preparation/Methods 42018.2.3 Mechanism of Action of Drug Release 42118.3 Nanophytomedicine for Treatment of Central Nervous System Disorders 42218.3.1 Alzheimer’s Disease 42218.3.2 Parkinson’s Disease 42218.3.3 Epilepsy 42318.3.4 Stroke 42318.3.5 Huntington’s Disease 42418.3.6 Multiple Necrosis 42518.3.7 Tumors/Gliomas/Glioblastomas 42518.4 Challenges in Nanophytomedicine 42518.5 Conclusion 426References 426Index 431