List of Contributors ........................................... xv
Dedication .................................................... xix
Preface ....................................................... xxi
Editor Biography .............................................. xxv
1 Neuroprotective Natural Products: Clinical Aspects and
Modes of Action-An Overview ................................ 1
Goutam Brahmachari
1.1 Introduction ............................................... 1
1.2 An Overview of the Book .................................... 1
1.2.1 Chapter 2 ........................................... 1
1.2.2 Chapter 3 ........................................... 2
1.2.3 Chapter 4 ........................................... 2
1.2.4 Chapter 5 ........................................... 3
1.2.5 Chapter 6 ........................................... 3
1.2.6 Chapter 7 ........................................... 3
1.2.7 Chapter 8 ........................................... 4
1.2.8 Chapter 9 ........................................... 4
1.2.9 Chapter 10 .......................................... 4
1.2.10 Chapter 11 .......................................... 5
1.2.11 Chapter 12 .......................................... 5
1.2.12 Chapter 13 .......................................... 5
1.3 Concluding Remarks ......................................... 6
2 Neuroprotective Agents: An Overview on the General Modes
of Action .................................................. 7
Christina Volsko and Ranjan Dutta
2.1 Introduction ............................................... 7
2.2 Neuroprotective Agents ..................................... 7
2.2.1 Pituitary Adenylate Cyclase-Activating Polypeptide
(PACAP) ............................................. 7
2.2.2 Hepatocyte Growth Factor (HGF) ...................... 8
2.2.3 Trophic Factors ..................................... 9
2.2.4 Apolipoprotein E (apoE)-Containing Lipoproteins ..... 9
2.2.5 Prothymosin a (PTMA) ............................... 10
2.2.6 Erythropoietin (EPO) ............................... 11
2.2.7 Neuregulin-1 (NRG1) ................................ 11
2.3 Neurodegenerative Diseases ................................ 12
2.4 Neuroprotection in Common Neurodegenerative Diseases ...... 13
2.5 Concluding Remarks ........................................ 16
Acknowledgments ........................................... 17
Abbreviations ............................................. 17
References ................................................ 17
3 Beneficial Upshots of Naturally Occurring Antioxidant
Compounds against Neurological Disorders .................. 23
Sukanya Saha, Pritam Sadhukhan, and Parames С. Sil
3.1 Introduction .............................................. 23
3.2 Oxidative Stress .......................................... 25
3.2.1 Oxidants and Its Types ............................. 25
3.2.2 Oxidants: Its Production, Consumption, and Way to
Oxidative Stress ................................... 25
3.2.3 Oxidative Stress Affecting Various Organs Leads
to Different Diseases .............................. 27
3.3 Neurological Disorders .................................... 28
3.3.1 ROS and Its Way to Oxidative Stress Results in
Neurotoxicity ...................................... 28
3.3.2 Why Is the Brain Particularly Prone to Oxidative
Stress? ............................................ 29
3.3.3 The Different Types of Neurological Diseases ....... 30
3.3.4 Cognitive Diseases ................................. 31
3.3.5 Movement Diseases .................................. 32
3.4 Beneficial Effects of Different Antioxidants against
Various Neurological Disorders ............................ 34
3.4.1 Role of Natural Antioxidants in the Amelioration
of Different Cognitive Disorders ................... 36
3.4.2 Role of Natural Antioxidants in the Amelioration
of Different Movement Disorders .................... 38
3.5 Concluding Remarks ........................................ 40
Abbreviations ............................................. 41
References ................................................ 42
4 Natural Neuroprotectives for the Management of
Parkinson's Disease ....................................... 57
Bharti Gaba, Shobhit Kumar, Shadab Md, Sanjula Baboota,
Jasjeet K. Narang, and Javed Ali
4.1 Introduction .............................................. 57
4.2 Role of Antioxidants/Natural Neuroprotectives in PD ....... 58
4.2.1 Vitamin E (α-Tocopherol) ........................... 59
4.2.1.1 Animal Studies with Vitamin E .................. 60
4.2.1.2 Human Studies with Vitamin E ................... 61
4.2.2 Naringenin ......................................... 62
4.2.2.1 Animal Studies with Naringenin ................. 63
4.2.3 Curcumin ........................................... 64
4.2.3.1 Animal Studies with Curcumin ................... 65
4.2.4 Resveratrol ........................................ 66
4.2.4.1 Animal Studies with Resveratrol ................ 67
4.2.5 Coenzyme Q10 ....................................... 68
4.2.5.1 Animal Studies with Coenzyme Q10 ............... 69
4.2.5.2 Human Studies with Coenzyme Q10 ................ 69
4.2.6 Vitamin С .......................................... 70
4.2.6.1 In Vitro Studies with Vitamin С ................ 71
4.2.6.2 Animal Studies with Vitamin С .................. 71
4.2.6.3 Human Studies with Vitamin С ................... 71
4.2.7 Melatonin .......................................... 72
4.2.7.1 Animal Studies with Melatonin .................. 73
4.3 Concluding Remarks ........................................ 74
Abbreviations ............................................. 75
References ................................................ 75
5 Neuroprotective Effect of Ayurvedic Preparations and
Natural Products on Parkinson's Disease ................... 91
Anupom Borah, Amarendranath Choudhury, Rajib Paul,
Muhammed K. Mazumder, and Swapnali Chetia
5.1 Introduction .............................................. 91
5.1.1 Therapy for Parkinson's Disease .................... 91
5.2 Parkinsonian Symptoms and Ayurveda ........................ 92
5.2.1 Equivalent Parkinsonian Symptoms in Ayurveda ....... 92
5.2.2 Treating Parkinsonian Symptoms with Ayurvedic
Preparations ....................................... 93
5.3 Medicinal Plants in the Ayurvedic Formulation for
Parkinson's Disease Therapy ............................... 94
5.3.1 Mechanism of Action of Ayurvedic Preparation in
PD ................................................. 96
5.3.1.1 Mucuna pruriens ................................ 96
5.3.1.2 Hyoscyamus niger ............................... 96
5.3.1.3 Withania somnifera ............................. 96
5.3.1.4 Sida cordifolia ................................ 97
5.4 Concluding Remarks ........................................ 97
Abbreviations ............................................. 97
References ................................................ 98
6 Lipid Peroxidation and Mitochondrial Dysfunction in
Alzheimer's and Parkinson's Diseases: Role of Natural
Products as Cytoprotective Agents ........................ 107
Carlos Fernández-Moriano, Elena González-Burgos, and
Maria Pilar Gómez-Serranillos
6.1 Introduction ............................................. 107
6.1.1 Oxidative Stress .................................. 707
6.1.2 Lipid Peroxidation ................................ 111
6.1.3 Mitochondrial Dysfunction ......................... 114
6.1.4 Lipid Peroxidation and Mitochondrial Dysfunction
in PD ............................................. 115
6.1.4.1 Lipid Peroxidation ............................ 116
6.1.4.2 Mitochondrial Dysfunction ..................... 116
6.1.5 Lipid Peroxidation and Mitochondrial Dysfunction
in AD .................................................. 776
6.1.5.1 Lipid Peroxidation ............................ 117
6.1.5.2 Mitochondrial Dysfunction ..................... 117
6.2 History and Context ...................................... 117
6.3 Potential Therapeutic Agents with Natural Origin:
Current Knowledge on the Discovery of Newer Drugs ........ 119
6.3.1 Flavonoids ........................................ 119
6.3.2 Vitamins .......................................... 121
6.3.3 Carotenoids ....................................... 123
6.3.4 Alkaloids ......................................... 125
6.3.5 Non-flavonoid Phenolic Compounds .................. 726
6.3.6 Terpenes .......................................... 129
6.3.7 Other Compounds ................................... 130
6.3.8 Plant Extracts .................................... 132
6.4 Future Trends in Research ................................ 132
6.5 Concluding Remarks ....................................... 133
Abbreviations ............................................ 134
References ............................................... 135
7 Marine-Derived Anti-Alzheimer's Agents of Promise ........ 153
Kapil Dev and Rakesh Maurya
7.1 Introduction ............................................. 153
7.2 Identification of Potent Anti-Alzheimer's Agents from
Marine Sources ........................................... 154
7.2.1 Cholinergic Hypothesis in Treatment of
Alzheimer's Disease .................................... 154
7.2.1.1 Cholinesterase Inhibitors ..................... 154
7.2.1.2 Nicotinic Acetylcholine Receptor Agonists ..... 760
7.2.2 Amyloid Cascade Hypothesis in the Treatment of
Alzheimer's Disease .................................... 767
7.2.2.1 Secretase Inhibitors .......................... 767
7.2.2.2 Anti-aggregation and Clearance Promoters ...... 766
7.2.3 Kinase Modulators in the Treatment of Alzheimer's
Disease (Tau Hypothesis) ............................... 767
7.2.4 Antioxidant Natural Products ...................... 777
7.3 Molecules in Clinical Trials for Alzheimer's Disease
from Marine Sources ...................................... 777
7.4 Concluding Remarks ....................................... 772
Acknowledgments .......................................... 772
Abbreviations ............................................ 772
References ............................................... 773
8 Natural Products against Huntington's Disease (HD):
Implications of Neurotoxic Animal Models and
Transgenics in Preclinical Studies ....................... 785
Abhijit Dey
8.1 Introduction ............................................. 785
8.2 Methodology .............................................. 786
8.3 Neurotoxic In Vitro and In Vivo Anti-HD Models ........... 188
8.3.1 Excitotoxic Lesion Models ......................... 194
8.3.1.1 Kainic Acid ................................... 194
8.3.1.2 Quinolinic Acid ............................... 195
8.3.2 Metabolie Toxin Models ............................ 195
8.3.3 3-Nitropropionic Acid ............................. 196
8.3.4 Transgenic Mouse Models ........................... 197
8.3.4.1 Knock-In and Knockout Mouse Models ............ 198
8.3.4.2 Virus-Mediated Mutated polyQ Tracts and mHtt
Models ............................................ 198
8.3.4.3 Transgenic Primate Models ..................... 198
8.3.5 Fly (Drosophila) Models ........................... 199
8.3.6 Caenorhabditis elegans Model ...................... 199
8.3.7 Yeast HD Models ................................... 200
8.3.8 Cellular Models of HD ............................. 200
8.4 Anti-HD Natural Products and Implications of HD Models ... 200
8.4.1 Anti-HD Properties of Medicinal Plants ............ 200
8.4.1.1 Bacopa monnieri (L.) Wettst.
(Plantaginaceae) .............................. 200
8.4.1.2 Boerhaavia diffusa L. (Nyctaginaceae) ......... 201
8.4.1.3 Calendula officinalis L. (Asteraceae) ......... 201
8.4.1.4 Cannabis sativa L. (Cannabaceae) .............. 201
8.4.1.5 Centella asiatica (L.) Urb. (Apiaceae) ........ 202
8.4.1.6 Convolvulus pluricaulis Choisy
(Convolvulaceae) .............................. 202
8.4.1.7 Garcinia kola Heckel (Clusiaceae) ............. 203
8.4.1.8 Gastrodia elata Blume (Orchidaceae) ........... 203
8.4.1.9 Ginkgo biloba L. (Ginkgoaceae) ................ 203
8.4.1.10 Luehea divaricata Mart. (Malvaceae) ........... 204
8.4.1.11 Olea europaea L. (Oleaceae) ................... 204
8.4.1.12 Panax ginseng C.A. Mey. and Panax
quinquefolius L. (Araliaceae) ................. 204
8.4.1.13 Psoralea corylifolia L. (Fabaceae) ............ 204
8.4.1.14 Punica granatum L. (Lythraceae) ............... 205
8.4.1.15 Valeriana officinalis L. (Caprifoliaceae) ..... 205
8.4.1.16 Withania somnifera L. (Dunal) (Solanaceae) .... 205
8.4.2 Anti-HD Activity of Phytochemicals ................ 205
8.4.2.1 α-Mangostin ................................... 205
8.4.2.2 Astragalan .................................... 206
8.4.2.3 Berberine ..................................... 206
8.4.2.4 Celastrol ..................................... 206
8.4.2.5 Curcumin ...................................... 206
8.4.2.6 (-)-Epigallocatechin-gallate .................. 206
8.4.2.7 Ferulic Acid .................................. 207
8.4.2.8 Fisetin ....................................... 207
8.4.2.9 Galantamine ................................... 207
8.4.2.10 Genistein ..................................... 207
8.4.2.11 Ginsenosides .................................. 207
8.4.2.12 Hesperidin .................................... 207
8.4.2.13 Kaempferol .................................... 208
8.4.2.14 L-Theanine .................................... 208
8.4.2.15 Lutein ........................................ 208
8.4.2.16 Lycopene ...................................... 208
8.4.2.17 Melatonin ..................................... 208
8.4.2.18 Naringin ...................................... 209
8.4.2.19 Nicotine ...................................... 209
8.4.2.20 Onjisaponin B ................................. 209
8.4.2.21 Protopanaxatriol .............................. 209
8.4.2.22 Puerarin ...................................... 209
8.4.2.23 Quercetin ..................................... 210
8.4.2.24 Resveratrol ................................... 210
8.4.2.25 S-Allylcysteine ............................... 210
8.4.2.26 (-)Schisandrin В .............................. 210
8.4.2.27 Sesamol ....................................... 210
8.4.2.28 Spermidine .................................... 210
8.4.2.29 Sulforaphane .................................. 277
8.4.2.30 Trehalose ..................................... 277
8.4.2.31 Vanillin ...................................... 277
8.4.3 Herbal Formulations with Anti-HD Properties ....... 277
8.5 Synergism: A Novel Approach against Neurological
Disorders ................................................ 272
8.6 Discussion ............................................... 273
8.7 Concluding Remarks ....................................... 275
Abbreviations ............................................ 275
References ............................................... 278
9 Possible Role of Neuroprotectants and Natural Products in
Epilepsy: Clinical Aspects and Mode of Action ............ 247
Anil Kumar, Manveen Bhardwaj, and Harshpreet Kaur
9.1 Introduction ............................................. 247
9.2 Global Prevalence of Natural Products in Epilepsy ........ 248
9.3 Pathophysiology of Epilepsy .............................. 248
9.3.1 Oxidative Stress .................................. 249
9.3.2 Mitochondrial Electron Transport Chain ............ 249
9.3.3 Brain Inflammatory Pathways ....................... 249
9.3.4 Apoptosis ......................................... 250
9.4 Role of Neurotransmitters in Neuronal Excitation ......... 250
9.4.1 γ-Aminobutyric Acid (GABA) ........................ 250
9.4.2 Glutamate ......................................... 251
9.4.3 Serotonin ......................................... 252
9.4.4 Acetylcholine (ACh) ............................... 252
9.5 Role of Neuroprotectants in Seizures ..................... 252
9.5.1 Alkaloids ......................................... 253
9.5.2 Flavonoids ........................................ 254
9.5.3 Terpenoids ........................................ 254
9.5.4 Saponins .......................................... 255
9.5.5 Coumarins ......................................... 255
9.5.6 Antioxidants ...................................... 255
9.6 Natural Plants against Epilepsy .......................... 256
9.6.1 Nardostachys jatamansi (Jatamansi) ................ 256
9.6.2 Cotyledon orbiculata (Seredile, Plakkie,
Imphewula) ........................................ 256
9.6.3 Lauras nobilis .................................... 256
9.6.4 Bacopa monnieri (Brahmi) .......................... 256
9.6.5 Rhizoma pinelliae ................................. 257
9.6.6 Taxus wallichiana (Himalayan Yew) ................. 257
9.6.7 Sutherlandia frutescens (Umwele, Cancerbush) ...... 257
9.6.8 Ficus platyphylla (Dell-Holl) ..................... 257
9.6.9 Scutellaria baicalensis (Skullcaps) ............... 257
9.6.10 Harpagophytum procumbens (Devil's Claw) ........... 258
9.6.11 Delphinium denudatum (Jadwar) ..................... 258
9.6.12 Withania somnifera (Ashwagandha): ................. 258
9.6.13 Magnolia grandiflora (Him-Champa): ................ 258
9.7 Natural Plants Examined in Epilepsy ...................... 259
9.7.1 Capsaicin ......................................... 259
9.7.2 Curcumin .......................................... 259
9.7.3 Piperine .......................................... 259
9.7.4 Quercetin ......................................... 260
9.7.5 Cod Liver Oil ..................................... 260
9.7.6 Vitamin С ......................................... 260
9.7.7 Lycopene .......................................... 261
9.7.8 Coenzyme Q10 ...................................... 261
9.7.9 Resveratrol ....................................... 267
9.8 German Herbs in Epilepsy ................................. 262
9.9 Complement and Alternative Medicine ...................... 263
9.9.1 Psychological Therapies and Mind-Body Techniques .. 263
9.9.2 Homeopathy ........................................ 263
9.9.3 Acupuncture ....................................... 263
9.10 Marketed Formulation of Natural Products in India ........ 264
9.11 Herbs That Induce Seizures ............................... 264
9.12 Interaction of Natural Products with Antiepileptic
Drugs (AEDs) ............................................. 264
9.13 Concluding Remarks ....................................... 267
References ............................................... 268
10 Neuroprotective Effects of Flavonoids in Epilepsy ........ 279
Hossein Hosseinzadeh and Marjan Nassiri-Asl
10.1 Introduction ............................................. 279
10.2 Natural Flavonoids with Antiepileptic Potential .......... 287
10.2.1 Rutin ............................................. 287
10.2.2 Quercetin ......................................... 287
10.2.3 Vitexin ........................................... 287
10.2.4 Hesperidin ........................................ 284
10.2.5 Apigenin .......................................... 284
10.2.6 Oroxylin A ........................................ 284
10.2.7 Wogonin ........................................... 284
10.2.8 Baicalein ......................................... 284
10.2.9 Luteolin .......................................... 285
10.2.10 Hispidulin ....................................... 285
10.2.11 Naringin ......................................... 285
10.3 Discovery and Development of Newer Agents ................ 285
10.4 Concluding Remarks ....................................... 286
Abbreviations ............................................ 286
References ............................................... 287
11 The Role of Noncompetitive Antagonists of the
N-Methyl-D-aspartate (NMDA) Receptors in Treatment-
Resistant Depression ..................................... 293
Gianluca Serafini, Shawn Hayley, Mehdi Ghasemi, and
Mario Amore
11.1 Introduction ............................................. 293
11.2 Noncompetitive Antagonists of the NMDA Receptors:
Ketamine and Its Mechanism of Action ..................... 294
11.2.1 The Antidepressant Efficacy of Ketamine ........... 295
11.2.2 Safety and Tolerability of Ketamine ............... 296
11.3 Other Noncompetitive NMDA Antagonists: Selective GluN2B
Subunit NMDA Antagonists ................................. 297
11.4 Other Noncompetitive NMDA Antagonists: Glycine Binding
Site Modulators .......................................... 298
11.5 AMPA Receptor Activation: A Possible Adjunctive
Antidepressant Role? ..................................... 299
11.6 Discussion and Future Directions ......................... 300
11.7 Concluding Remarks ....................................... 301
Abbreviations ............................................ 302
References ............................................... 302
12 Safety and Efficacy of Ashwagandha [Withania somnifera) .. 313
Shri K. Mishra, Bharathi A. Venkatachalapathy, and Hadi M.
Khanli
12.1 Introduction ............................................. 313
12.2 Ashwagandha .............................................. 374
12.2.1 The Plant ......................................... 374
12.2.2 Safety and Toxicological Evaluation of Withania
somnifera ......................................... 315
12.2.3 Effects of Ashwagandha on Muscle Sarcopenia ....... 376
12.3 Discussion ............................................... 377
12.4 Concluding Remarks ....................................... 377
Abbreviations ............................................ 378
References ............................................... 378
13 Cannabinoids: A Group of Promising Neuroprotective
Agents ................................................... 327
Laura R. Caltana and Alicia Brusco
13.1 Introduction ............................................. 327
13.1.1 The History of Marijuana .......................... 327
13.1.2 Current Context ................................... 322
13.2 The Cannabinoid System ................................... 322
13.3 Cannabinoids and Neuroprotection ......................... 325
13.3.1 Cannabinoids in Hypoxia/Ischemia .................. 325
13.2 Cannabinoids in Parkinson's Disease ...................... 326
13.3.3 Cannabinoids in Alzheimer's Disease ............... 327
13.3.4 Cannabinoids in Epilepsy .......................... 327
13.3.5 Cannabinoids in Multiple Sclerosis ................ 328
13.3.6 Cannabinoids in Psychiatric Disorders ............. 328
13.3.7 Cannabinoids in Retinal Diseases .................. 329
13.4 Concluding Remarks ....................................... 329
Abbreviations ............................................ 330
References ............................................... 330
Index ......................................................... 341
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