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Neuroprotection

Part I: Methods & Drugs

By

Prof. K. K. Jain MD, FRACS, FFPM

Jain PharmaBiotech

Basel, Switzerland

March 2020

A Jain PharmaBiotech Report

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A U T H O R ' S B I O G R A P H Y

Professor K. K. Jain is a neurologist/neurosurgeon with specialist qualifications including Fellowships of the Royal Colleges of Surgeons in Australia and Canada. He has trained, practiced and held academic positions in several countries including Switzerland, India, Iran, Germany Canada and USA. After retirement from neurosurgery, Prof. Jain remains a consultant in neurology. He is also working in the biotechnology/biopharmaceuticals industry and is a Fellow of the Faculty of Pharmaceutical Medicine of the Royal College of Physicians of UK. Currently, he is the CEO of Jain PharmaBiotech.

Prof. Jain’s 484 publications include 32 books (6 as editor+ 26 as author) and 50 special reports, which have covered biotechnology and biopharmaceuticals topics; e.g., molecular diagnostics, biomarkers, proteomics, cell therapy, gene therapy, drug delivery nanobiotechnology, and personalized medicine. Recent books include “Handbook of Nanomedicine” (Springer 2008, Chinese edition by Peking University Press 2011, 3rd ed 2017), “Textbook of Personalized Medicine” (Springer 2009; Japanese ed 2012; 2nd ed Springer 2015, 3rd ed 2020, in preparation), "Handbook of Biomarkers" (Springer 2010; Chinese ed, Chemical Industry Press 2016, 2nd ed 2017), "Handbook of Neuroprotection” (Springer 2011, 2nd ed 2019), “Drug-induced Neurological Disorders” (4th ed, Springer 2020) “Applications of Biotechnology in Cardiovascular Therapeutics” (Springer 2011), “Applications of Biotechnology in Neurology” (Springer 2013), and “Applications of Biotechnology in Oncology” (Springer 2014). He has also edited “Drug Delivery to the Central Nervous System” (Humana/Springer, 2010) and “Applied Neurogenomics” (Springer 2015). Essentials of Personalized Medicine (in Russian, with Prof. K. Sharipov as co-author), 2019) was published by LITERRA Publishing House, Moscow.

Prof. Jain has been involved in various neuroprotective strategies during his active neurosurgical career including use of hypothermia, hyperbaric oxygen and induced coma. He has a personal experience of methods of neuroprotection used in the care of patients with stroke and CNS trauma as well as during neurosurgical operations.

March 2020 (first edition published in April 2000) Copyright © 2020 by:

Jain PharmaBiotech Bläsiring 7 CH-4057 Basel Switzerland

Tel & Fax: +4161-6924461 Email: info@pharmabiotech.ch Web site: http://pharmabiotech.ch/

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, or otherwise without the prior written permission of the Publisher. This report may not be lent, resold or otherwise traded in any manner without the consent of the Publisher. While all reasonable steps have been taken to ensure the accuracy of the information presented, the Publisher cannot accept responsibility for inadvertent errors or omissions.

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T A B L E O F C O N T E N T S

0. Executive Summary .............................................................................. 30

1. Introduction ......................................................................................... 34 Definitions ......................................................................................................................... 34 Historical development of neuroprotection ........................................................................ 34 Neurophysiological basis of neuroprotection ..................................................................... 35

Astrocytic glycogen-derived lactate as fuel for the brain........................................................ 35 Gene expression in the human brain .................................................................................. 35 Role of astrocytes in neuroprotection .................................................................................. 36 Role of glymphatic system in neuroprotection ...................................................................... 36 Role of sleep in neuroprotection ......................................................................................... 37 Role of cerebral metabolism in neuroprotection ................................................................... 37 Role of circadian genes in neuroprotection .......................................................................... 37 Role of blood-brain barrier in neuroprotection ...................................................................... 38 Role of the gut microbiota in development of integrity of the BBB .......................................... 38

Intrinsic neuroprotective factors ....................................................................................... 38 Neuroprotective gene expression ....................................................................................... 40

Upregulation of GADD34 .............................................................................................. 40 Induction of NR4A proteins by CREB in neurons .............................................................. 40 Elevation PGC-1α for neuroprotection in PD .................................................................... 40

Neurotrophic factors ......................................................................................................... 41 Intrinsic nonenzymatic antioxidants ................................................................................... 41 Activation of transcription factor Nrf2 ................................................................................. 41 Intrinsic neuroprotective factors ........................................................................................ 42

αB-crystallin ............................................................................................................... 42 Docosahexaenoic acid .................................................................................................. 42 Excitatory amino acid transporters ................................................................................ 42 Extracellular serine protease thrombin ........................................................................... 42 Galanin ...................................................................................................................... 43 Heat-shock proteins .................................................................................................... 43 Neuroglobin ............................................................................................................... 43 Nuclear factor I-A ....................................................................................................... 44 Prion protein .............................................................................................................. 44 Rai adaptor protein ..................................................................................................... 45

Stem cell factor ............................................................................................................... 45 Role of the immune system in neuroprotection .................................................................... 45 Induction of DNA repair enzymes for neuroprotection ........................................................... 46 Microtubule-based neuroprotective response to axonal injury ................................................ 46

Pathomechanisms of CNS injury as basis for neuroprotection ........................................... 47 Biomarkers of neurological disorders and neuroprotection ................................................ 47

CNS biomarker identification using proteomics .................................................................... 48 Brain imaging for detection of biomarkers ........................................................................... 48

Neuroprotection in cerebral hypoxia .................................................................................. 48 Effects of hypoxia on the brain .......................................................................................... 49

Cerebral Metabolism During Hypoxia ............................................................................. 49 Adaptive mechanisms in hypoxia ....................................................................................... 50 Neuroprotection in hypoxia-ischemia .................................................................................. 50

Neuroprotection in neuroinflammation .............................................................................. 51 Biomarkers of neuroinflammation ...................................................................................... 51

Neuroprotection in mental stress....................................................................................... 52 Neuroprotection in disruption of circadian rhythms ........................................................... 52 Role of neuroprotection in various neurological disorders ................................................. 53 Neuroprotection and neuroregeneration ............................................................................ 54 Acute versus chronic neuroprotection ............................................................................... 54 Discovery and evaluation of neuroprotective agents ......................................................... 55

Neuroprotective drug discovery ......................................................................................... 55 Discovery of CNS drugs that penetrate the blood-brain barrier .............................................. 55 In vitro assays for the evaluation of neuroprotective agents .................................................. 56 Oxidative injury model to test neuroprotective drugs ............................................................ 56 Apoptosis model for designing neuroprotective drugs ........................................................... 56 Transgenic mouse models of neurological disorders .............................................................. 57 Evaluating effects of neuroprotective drugs on living brain slices ............................................ 57 Role of brain imaging in neuroprotective drug discovery and development .............................. 58

Positron emission tomography ...................................................................................... 58 Role of single photon emission computed tomography ..................................................... 58 Functional CT scanning to evaluate cerebrovascular protection ......................................... 59 Magnetic resonance imaging for the evaluation of neuroprotectives ................................... 59

Application of nanotechnology to neuroprotection ................................................................ 59

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Anthocyanin-loaded PEG-gold nanoparticles ................................................................... 60 Buckminsterfullerene C60 derivatives ............................................................................ 60 Cadmium telluride nanoparticles prevent Aβ fibril formation ............................................. 61 Ceria nanoparticles as antioxidants ............................................................................... 61 Chitosan nanoparticles against oxidative stress ............................................................... 62 Nanoparticles as carriers of neuroprotective agents into the brain ..................................... 62 Polymer nanoparticles ................................................................................................. 62 Squalenoyl adenosine nanoparticles .............................................................................. 62

Evaluation criteria for potential neuroprotective agents ......................................................... 63

2. Neuroprotective Agents ........................................................................ 64 Classification of neuroprotective agents ............................................................................ 64 α2 adrenoreceptor agonists ............................................................................................... 68

Dexmedetomidine ............................................................................................................ 68 Activated protein C ............................................................................................................ 69 Activity-dependent neuroprotective protein ...................................................................... 69

Davunetide ..................................................................................................................... 69 Adenosine analogs ............................................................................................................. 70

Propentofylline ................................................................................................................ 70 Antidepressants ................................................................................................................. 70

Antidepressant-induced neurogenesis ................................................................................. 70 Neurogenesis induced by electroconvulsive therapy ............................................................. 71 Neuroprotective effect of selective serotonin reuptake inhibitors ............................................ 71

Fluoxetine as a neuroprotective agent ........................................................................... 73 Antiepileptic drugs as neuroprotectives ............................................................................. 73

BIS-001 .......................................................................................................................... 74 Levetiracetam ................................................................................................................. 74 Phenytoin ....................................................................................................................... 75 Valproic acid.................................................................................................................... 75

Anti-neuroinflammatory agents ......................................................................................... 75 Aspirin ............................................................................................................................ 75 Interleukin-1 antagonists .................................................................................................. 76 COX-2 inhibitors .............................................................................................................. 76

Nimesulide ................................................................................................................. 77 Gold microparticles as anti-neuroinflammatory agents .......................................................... 77 Matrix metalloproteinase inhibitors as anti-neuroinflammatory agents .................................... 77 Minocycline ..................................................................................................................... 77 Prostaglandin receptor antagonists ..................................................................................... 78

Anti-apoptosis agents ........................................................................................................ 79 Activated protein C .......................................................................................................... 80 Calpain inhibitors ............................................................................................................. 80 Caspase inhibitors ............................................................................................................ 80 DNA binding drugs ........................................................................................................... 80 Lithium ........................................................................................................................... 81 Melatonin ........................................................................................................................ 81 Olesoxime ....................................................................................................................... 81 Omega-3 fatty acids ......................................................................................................... 82

Docosahexaenoic acid .................................................................................................. 82 Poly(ADP-ribose) polymerase inhibitors .............................................................................. 82 Prevention of apoptosis by binding of proNGF to sortilin ........................................................ 83

Antioxidants/free radical scavengers ................................................................................ 84 Free radical generation ..................................................................................................... 84 Natural defenses against oxidative stress ............................................................................ 84 Effects of oxidative damage .............................................................................................. 84

Oxidative damage and aging ........................................................................................ 84 Neuronal damage by free radicals ................................................................................. 85 Oxidative damage and neurodegenerative disorders ........................................................ 85

Measures to control oxidative stress ................................................................................... 86 Categories of therapeutic antioxidants ........................................................................... 86 Alpha-phenyl-tert-butylnitrone ..................................................................................... 87 Coenzyme Q10 ........................................................................................................... 87 Dihydroergocryptine .................................................................................................... 87 Flavonoids.................................................................................................................. 88 Mitochondria-targeted antioxidants ............................................................................... 88 Neuroleptics as antioxidants ......................................................................................... 88 Nitrones ..................................................................................................................... 89 NRF2 for augmenting neuroprotection againt oxidative stress ........................................... 89 Nrf2/ARE-mediated antioxidant actions of pro-electrophilic drugs ...................................... 89 Quercetin ................................................................................................................... 90

Translation of antioxidant neuroprotection from preclinical to clinical ...................................... 90 Arimoclomol ...................................................................................................................... 90

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Carbon monoxide and heme oxygenase ............................................................................. 90 Cell transplants .................................................................................................................. 91

Cells secreting neuroprotective substances .......................................................................... 91 Stem cells ....................................................................................................................... 91 Stem cell activation for neuroprotection/regeneration by glucocorticoids ................................. 92 Use of neural stem cells to construct the blood brain barrier .................................................. 92

Cytokines ........................................................................................................................... 92 Erythropoietin ................................................................................................................. 92

Non-erythropoietic EPO variants and mimics .................................................................. 94 Granulocyte colony-stimulating factor ................................................................................. 94

Delta-opioid receptor agonists ........................................................................................... 95 Delta opioid peptide-induced hibernation for neuroprotection ................................................ 95

FK960 ................................................................................................................................ 95 Gene therapy ..................................................................................................................... 96 Glucagon-like peptide ........................................................................................................ 96 Glatiramer acetate ............................................................................................................. 97 Glutamate antagonists ....................................................................................................... 97

Neuroprotection by scavenging blood glutamate .................................................................. 98 Glutamate transporters ..................................................................................................... 98 Glutamate transporter-mediated neuroprotective effect of drugs............................................ 99 Neuroprotection by targeting KAI subunit of kainate receptor ................................................ 99

Glycine-proline-glutamate analogs .................................................................................. 100 Hydrogen sulfide.............................................................................................................. 100

Hibernation induced by hydrogen sulfide ........................................................................... 100 NMDA receptor ion channel complex................................................................................ 101

NMDA receptor antagonists ............................................................................................. 103 NMDA NR2B subunit receptor antagonists .................................................................... 103 Ifenprodil ................................................................................................................. 103 Memantine as a neuroprotective agent ........................................................................ 103 NAALADase inhibitors ................................................................................................ 103 Gacyclidine .............................................................................................................. 104 N-alkylglycines ......................................................................................................... 104

AMPA receptor modulators .............................................................................................. 104 Metabotropic glutamate receptor modulators ..................................................................... 105 Cannabinoids ................................................................................................................. 105 Dexanabinol .................................................................................................................. 106

Glutathione ...................................................................................................................... 106 Heat shock proteins ......................................................................................................... 106 Histone deacetylase inhibitors for neuroprotection ......................................................... 107 Hormones ........................................................................................................................ 107

Estrogen and neuroprotection .......................................................................................... 107 Neuroprotective effect of estrogen receptor ligands ....................................................... 108 Selective estrogen receptor modulators ....................................................................... 108 Mitochondrial mechanisms of estrogen neuroprotection ................................................. 109

Insulin .......................................................................................................................... 109 Ion Channel modulators .................................................................................................. 110

Calcium channel blockers. ............................................................................................... 110 Ziconotide ................................................................................................................ 110

Na+ channel blockers. ..................................................................................................... 111 Neuroprotective potassium channel inhibitors .................................................................... 111

Kynurenine inhibitors ...................................................................................................... 111 Leukocyte adhesion inhibitors ......................................................................................... 112 Modafinil .......................................................................................................................... 113 Neurite outgrowth-promoting agents .............................................................................. 113

Monoclonal antibodies .................................................................................................... 113 Neuroimmunophilins ........................................................................................................ 113

Cyclosporin-A ................................................................................................................ 114 FK506 .......................................................................................................................... 114 Rapamycin .................................................................................................................... 114

Neurotrophic factors ........................................................................................................ 115 Activity-dependent neurotrophic factor ............................................................................. 115 Bone morphogenetic proteins .......................................................................................... 115 Brain-derived neurotrophic factor ..................................................................................... 116 Ciliary neurotrophic factor ............................................................................................... 116 Fibroblast growth factors ................................................................................................ 116 Glial cell line-derived neurotrophic factor .......................................................................... 117 Insulin-like growth factor ................................................................................................ 117 Nerve growth factor ....................................................................................................... 118 Neurotrophins ............................................................................................................... 119 Osteogenic protein-1 ...................................................................................................... 119 Pigment epithelium-derived factor .................................................................................... 119

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Transforming growth factor-1 ........................................................................................ 119 Vascular endothelial growth factor ................................................................................... 120 Neurotrophic factor-related neuroprotective agents ............................................................ 120

Amitriptyline as a TrkA and TrkB receptor agonist ......................................................... 120 Colivelin ................................................................................................................... 120 Gambogic amide ....................................................................................................... 121 Inosine .................................................................................................................... 121 Meteorin .................................................................................................................. 121 Oxygen-regulated protein 150 kD ............................................................................... 121 Prosaptide ................................................................................................................ 122 Siagoside ................................................................................................................. 122 Small molecule activators of the Trk receptors .............................................................. 122

Nicotine and nicotinic receptor agonists .......................................................................... 123 Neuroprotective effect of galantamine mediated via α7nAChRs ....................................... 123 Galantamine-induced Aβ clearance via α7nAChRs ......................................................... 123

Nitric oxide-based neuroprotection ................................................................................. 124 Nitric oxide synthase inhibitors ........................................................................................ 124 Nitric oxide mimetics ...................................................................................................... 125 Nitric oxide donating derivatives ...................................................................................... 125

Nootropics ....................................................................................................................... 125 Piracetam ................................................................................................................ 126

Nutraceuticals and naturally-derived compounds ............................................................ 126 Cinnamon ..................................................................................................................... 126 Coffee .......................................................................................................................... 127 Creatine........................................................................................................................ 127 Curcumin/curry ............................................................................................................. 127

Mechanism of neuroprotective effect of curcumin .......................................................... 128 Flavonoids .................................................................................................................... 128 Glyceryltriacetate ........................................................................................................... 128 Green tea ..................................................................................................................... 128 Herbal preparations ........................................................................................................ 129

Flavonoid wogonin .................................................................................................... 129 Ginseng ................................................................................................................... 129

Nicotinamide ................................................................................................................. 129 Punicalagin from pomegranate ........................................................................................ 130 Resveratrol ................................................................................................................... 130

Osmotic diuretics ............................................................................................................. 131 Mannitol ....................................................................................................................... 131 Osteopontin .................................................................................................................. 131

Oxygen therapeutics ........................................................................................................ 132 Oxygen carriers ............................................................................................................. 132 Hemoglobin-based oxygen carriers ................................................................................... 132 Perfluorocarbons as oxygen carriers ................................................................................. 133 Hyperbaric oxygen therapy ............................................................................................. 134

P7C3 compounds ............................................................................................................. 134 Peptides ........................................................................................................................... 134

C3-derived peptide for neuroprotection and neuroregeneration ............................................ 134 Corticotropin-releasing hormone ...................................................................................... 135 Thyrotropin-releasing hormone ........................................................................................ 135 Vasoactive intestinal peptide ........................................................................................... 135

Pharmacological preconditioning ..................................................................................... 136 PPARs as drug targets for neuroprotection ...................................................................... 136 Proteins ........................................................................................................................... 137

Amyloid precursor protein ............................................................................................... 137 Protein kinase C activators .............................................................................................. 137 PSD-5 antagonists ......................................................................................................... 138

Riluzole ............................................................................................................................ 138 Role of RNA interference in neuroprotection ................................................................... 138

Role of miRNA in neuroprotection ..................................................................................... 138 Sigma receptor agonists as neuroprotective agents ........................................................ 139 SIRT group of proteins ..................................................................................................... 139 Statins ............................................................................................................................. 140 Steroids ........................................................................................................................... 141

Dehydroepiandrosterone ................................................................................................. 141 Sulforaphane ................................................................................................................... 141 Tauroursodeoxycholic acid .............................................................................................. 142 Tetanus toxin as a neuroprotective agent ........................................................................ 142 Thrombolytic agents as neuroprotective agents .............................................................. 142 Uncoupling protein 2 ....................................................................................................... 143 Vaccines as neuroprotectives .......................................................................................... 143 Vitamins as neuroprotective agents ................................................................................. 143

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Vitamin B12 .................................................................................................................. 143 Vitamin D ..................................................................................................................... 144

Unconventional biologicals .............................................................................................. 144 Non-pharmacological approaches to neuroprotection ...................................................... 144

Caloric restriction ........................................................................................................... 145 Cerebral exercise ........................................................................................................... 145

Bilingualism for prevention of decline of mental function ................................................ 145 Electrical fields for improvement of cerebral function in neurodegeneration ........................... 145 Environmental enrichment .............................................................................................. 146 Hypothermia ................................................................................................................. 146

Limitations of hypothermia ......................................................................................... 147 Hypothermic neuroprotection in hypoxia-ischemia ......................................................... 147

Ketogenic diet ............................................................................................................... 148 Mediterranean diet ......................................................................................................... 148 Nonpharmacological preconditioning for neuroprotection ..................................................... 148 Physical exercise ............................................................................................................ 149 Suspended animation and neuroprotection ........................................................................ 150 Transcranial magnetic stimulation .................................................................................... 150

3. Neuroprotection in Cerebrovascular Disease ...................................... 152 Introduction .................................................................................................................... 152 Pathophysiology of cerebral ischemia .............................................................................. 153

Calcium overload ........................................................................................................... 153 Cerebral edema in stroke ................................................................................................ 153 Cytokines and adhesion molecules in stroke ...................................................................... 154

Adhesion molecules ................................................................................................... 154 Interleukin-1 and IL-6 ............................................................................................... 154 Tumor necrosis factor-α ............................................................................................. 155

DNA damage and repair in cerebral ischemia ..................................................................... 155 Gene expression in response to cerebral ischemia .............................................................. 155 Glutamate as a biomarker of stroke ................................................................................. 156 Heat shock proteins in stroke .......................................................................................... 156 Ion channel dysfunction in stroke ..................................................................................... 156 Neuroinflammation in cerebral infarction ........................................................................... 156 Neurotrophic factors in stroke.......................................................................................... 157

Problems requiring investigation of the role of NTFs in stroke ......................................... 157 Nitric oxide in cerebral ischemia....................................................................................... 157 Oxygen free radicals in cerebral ischemia .......................................................................... 158 Poly(ADP-ribose) polymerase (PARP) gene ........................................................................ 158 Protease-activated receptor 1 .......................................................................................... 158

Effect on the brain of cessation of cerebral circulation .................................................... 158 Reperfusion injury after cerebral ischemia ...................................................................... 159 Neuroprotection according to zones in cerebral infarction ............................................... 159

Zone of ischemic infarction .............................................................................................. 159 Penumbra ..................................................................................................................... 159

Current management of stroke ........................................................................................ 160 Neuroprotection in stenosis of intracranial arteries ............................................................. 161 Neuroprotection in stroke with intracerebral hemorrhage .................................................... 161 Neuroprotection in cerebrovascular malformations ............................................................. 161

Arteriovenous malformations ...................................................................................... 161 Cavernous cerebrovascular malformations ................................................................... 162

Neuroprotective strategies for ischemic stroke in patients with dementia .............................. 162 Neuroprotection in transient ischemic attacks .................................................................... 163 Secondary prevention of stroke ....................................................................................... 163

Neuroprotective therapies for stroke ............................................................................... 164 Neuroprotective strategies according to pathomechanism of stroke ...................................... 165

Pharmacologic neuroprotective agents for stroke............................................................ 166 αB-crystallin as a neuroprotectant in stroke ...................................................................... 166 Acid-sensing ion channel blockers .................................................................................... 166 Adrenergic receptor antagonists....................................................................................... 166 AMPA receptor antagonists as neuroprotectives for stroke ................................................... 166 Anesthetic agents as neuroprotectives in stroke ................................................................. 167

Propofol as neuroprotective in stroke ........................................................................... 167 Antiapoptotic neuroprotectives ........................................................................................ 167

NIM811 ................................................................................................................... 167 Creatine as neuroprotective in stroke .......................................................................... 168 Lithium as a neuroprotective in stroke ......................................................................... 168 TUDCA as a neuroprotective in stroke .......................................................................... 168

Antidepressants as neuroprotectives agents in stroke ......................................................... 169 Fluoxetine as neuroprotectectant in stroke ................................................................... 169

Antiepileptic drugs as neuroprotectives in stroke ................................................................ 169

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Tiagabine ................................................................................................................. 169 Topiramate .............................................................................................................. 169

Anti-HMGB1 monoclonal antibody .................................................................................... 170 Antiinflammatory agents ................................................................................................. 170

Cox-2 inhibitors for ischemic stroke ............................................................................. 170 Minocycline for neuroprotection in stroke ..................................................................... 170

Antioxidant approaches .................................................................................................. 171 Carnosine as a neuroprotective in stroke...................................................................... 171 Dehydroascorbic acid................................................................................................. 171 Tocotrienols ............................................................................................................. 172 Uric acid .................................................................................................................. 172

Arimoclomol for stroke ................................................................................................... 173 Cardiac glycosides as neuroprotectives in stroke ................................................................ 173 Clenbuterol ................................................................................................................... 173 Coagulation inhibitors as neuroprotectives ........................................................................ 173

Heparin and enoxaparin ............................................................................................. 173 Warfarin vs dabigatran .............................................................................................. 174 Apixaban ................................................................................................................. 174

Curcumin as a neuroprotectant in stroke ........................................................................... 174 Docosahexaenoic acid for ischemic stroke ......................................................................... 175 Ephrin-A5 blockers ......................................................................................................... 175 Estrogen for stroke ........................................................................................................ 175 Extendin-4 .................................................................................................................... 176 Flavones for neuroprotection in stroke .............................................................................. 177

Epicatechin .............................................................................................................. 177 Isorhamnetin ............................................................................................................ 177

Glutamate clearance from blood ...................................................................................... 177 Hamartin induction by cerebral ischemia as a basis for neuroprotection ................................ 178 Histone deacetylase inhibitors for neuroprotection in stroke ................................................ 178 Histamine H2-receptor modulation .................................................................................... 178 Inosine for stroke .......................................................................................................... 179 Insulin-like growth factor-I .............................................................................................. 179 Intravenous immunoglobulin as neuroprotective in stroke ................................................... 179 Ischemic preconditioning for neuroprotection in stroke ....................................................... 179 Ketone bodies for neuroprotection in stroke ...................................................................... 180 Magnesium ................................................................................................................... 181 Mineralocorticoid receptor blockade for neuroprotection ...................................................... 181 miR-223 and neuroprotection in stroke ............................................................................. 181 NA-1 as neuroprotective against ischemic stroke ............................................................... 181 Nasal delivery of neuroprotective agents in stroke ............................................................. 182 Nerinetide ..................................................................................................................... 182 Neuroserpin as a neuroprotective in stroke ....................................................................... 182 N-2-mercaptopropionyl glycine ........................................................................................ 183 NeuroAiD ...................................................................................................................... 183 Neurotrophic factors as neuroprotectives for stroke ............................................................ 183

Brain-derived neurotrophic factor ................................................................................ 183 Cerebral dopamine neurotrophic factor ........................................................................ 184 Fibroblast growth factor ............................................................................................. 184 Granulocyte colony stimulating factor .......................................................................... 184 Granulocyte-macrophage colony-stimulating factor ....................................................... 185 Glial cell line-derived neurotrophic factor ..................................................................... 185 Insulin-like growth factor-1 ........................................................................................ 185 Neuregulin-1 ............................................................................................................ 186

NO-based strategies for neuroprotection in cerebral ischemia .............................................. 186 NOX-4 inhibitors for neuroprotection in stroke ................................................................... 186 Omega-3 fatty acids for neuroprotection after cerebral ischemia-hypoxia .............................. 186 Pannexin channel blockers for neuroprotection in stroke ..................................................... 187 Perlecan domain V ......................................................................................................... 187 Peroxisome proliferator-activated receptor- agonists ......................................................... 187

Pioglitazone for reduction of stroke risk ....................................................................... 187 PGE2 EP2 receptor activation ........................................................................................... 188 Progesterone ................................................................................................................. 188 Proteoglycan-degrading enzymes ..................................................................................... 188 Proteosome inhibitors ..................................................................................................... 189 Statins for prevention and neuroprotection in stroke .......................................................... 189 Sildenafil ...................................................................................................................... 190 Stroke vaccine ............................................................................................................... 190 Thrombosis inhibitors ..................................................................................................... 190

Aspirin ..................................................................................................................... 191 Clopidogrel ............................................................................................................... 191 Dipyridamole ............................................................................................................ 191

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Ticagrelor ................................................................................................................ 191 Tissue plasminogen activator as neurorestorative in cstroke ................................................ 192 Vitamin E for neuroprotection in stroke ............................................................................. 192

Neuroprotection in ischemia-reperfusion injury .............................................................. 192 Aminoguanidine ............................................................................................................. 193 Dexmedetomidine .......................................................................................................... 193 Methylene blue for neuroprotection in ischemia-reperfusion injury ....................................... 193 Miscellaneous agents for neuroprotection in reperfusion injury............................................. 193

Neuroprotection by treatment of cerebrovascular malformations .................................... 194 Arteriovenous malformations ...................................................................................... 194 Cerebral cavernous malformations .............................................................................. 194

Prevention of hemorrhage following ischemic stroke ...................................................... 195 Non-pharmacological neuroprotective therapies for stroke ............................................. 195

Hypothermia for neuroprotection in acute stroke................................................................ 195 Hyperbaric oxygen therapy for neuroprotection in acute stroke ............................................ 196 Hypothermia combination with other neuroprotective strategies .......................................... 197 Infrared laser therapy for ischemic stroke ......................................................................... 198 Preconditioning for neuroprotection against cerebral ischemia ............................................. 198

Neuroprotection in ischemia/reperfusion injury ............................................................. 198 Neurosurgical procedures for stroke ................................................................................ 199

Neurosurgical procedures for neuroprotection in acute stroke .............................................. 199 Decompressive hemicraniectomy ................................................................................ 199 Thrombectomy ......................................................................................................... 200 Stenting................................................................................................................... 201 Multiple endovascular modalities ................................................................................. 201

Neurosurgical procedures for chronic cerebral ischemia ...................................................... 202 Neurostimulation of sphenopalatine ganglion ..................................................................... 202 Stent versus surgery for asymptomatic carotid stenosis ...................................................... 203

Neurorehabilitation in relation to neuroprotection in stroke ............................................ 203 Protective effect of physical activity on stroke in the elderly ................................................ 203

Biological therapies for stroke ......................................................................................... 203 Cell therapy for stroke .................................................................................................... 203

Stem cell transplant for stroke .................................................................................... 204 Preconditioning with hyperbaric oxygen for stem cell therapy ......................................... 204 Immortalized cell grafts for stroke............................................................................... 204 Stimulation of instrinsic stem cells for repair of brain in stroke ....................................... 205

Gene therapy for neuroprotection in cerebrovascular disease .............................................. 205 Regulation of microRNAs for neuroprotection in cerebral ischemia ........................................ 207 RNAi-based therapy for neuroprotection in stroke .............................................................. 207 Vaccines for neuroprotection in stroke .............................................................................. 207

Neuroprotective therapies for cerebral ischemia: clinical trials ....................................... 208 Albumin ........................................................................................................................ 209 Free radical scavengers .................................................................................................. 209 DP-b99 ......................................................................................................................... 210 Mildronate ..................................................................................................................... 211 Perindopril .................................................................................................................... 211 Failed clinical trials of neuroprotection in stroke ................................................................. 211

Ancrod ..................................................................................................................... 213 Aptiganel ................................................................................................................. 213 Cerovive .................................................................................................................. 213 Citicoline .................................................................................................................. 214 Desmoteplase ........................................................................................................... 215 Erythropoietin as a neuroprotective in stroke ................................................................ 216 Selfotel .................................................................................................................... 216 Lubeluzole ............................................................................................................... 216 Nalmefene ............................................................................................................... 217 Gavestinel ................................................................................................................ 217 Nimodipine ............................................................................................................... 217 Sipatrigine ............................................................................................................... 218 Causes of failure of stroke trials .................................................................................. 218

Measures for prevention of failures in stroke trials ............................................................. 219 Design of acute stroke trial to facilitate drug approval ........................................................ 221

The ideal neuroprotective agent for stroke ...................................................................... 221 Prevention of stroke ........................................................................................................ 222 Concluding remarks and future of neuroprotection in stroke ........................................... 222

4. Neuroprotection in Traumatic Brain Injury ......................................... 226 Introduction .................................................................................................................... 226 Cerebral hypoxia/ischemia as a complication of trauma.................................................. 226 Epidemiology of TBI ......................................................................................................... 226

TBI in the military .......................................................................................................... 227

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Pathophysiology of TBI .................................................................................................... 227 Immediate damage following TBI ..................................................................................... 229 Blast injury sequelae ...................................................................................................... 229 Cerebral edema following TBI .......................................................................................... 229 Neurometabolic cascade after TBI .................................................................................... 229 Delayed damage following TBI ......................................................................................... 230 Mechanism of axonal damage after TBI ............................................................................ 231 Role of neuroinflammation in TBI ..................................................................................... 231 BBB damage after TBI .................................................................................................... 231 Molecular events following TBI ......................................................................................... 232 Chronic traumatic encephalopathy ................................................................................... 232 Neurocognitive sequelae of TBI ........................................................................................ 233 Changes in neurotrophic factors following TBI ................................................................... 234 Changes in neurotransmitters following TBI....................................................................... 234 Proteomics of TBI .......................................................................................................... 234 Genetic influences on outcome following TBI ..................................................................... 235

Management of TBI ......................................................................................................... 235 Mana7gement during acute phase of head injury ............................................................... 236

Control of intracranial pressure and cerebral edema ...................................................... 236 Corticosteroids ......................................................................................................... 238 Decompressive craniectomy ....................................................................................... 238

Neuroprotection in TBI .................................................................................................... 238 Amantadine................................................................................................................... 239 Antioxidants .................................................................................................................. 240 Barbiturates .................................................................................................................. 240 β- and γ-secretase inhibitors ........................................................................................... 240 Beta blockers ................................................................................................................ 240 Bradykinin B2 antagonists ............................................................................................... 241 Cell cycle inhibitors for TBI .............................................................................................. 241 COX-2 inhibitors for neuroprotection in TBI ....................................................................... 241 Cyclosporin for neuroprotection in TBI .............................................................................. 242 Dexanabinol for TBI ....................................................................................................... 242 Erythropoietin for neuroprotection in TBI .......................................................................... 242 Gold implants for neuroprotection in focal TBI ................................................................... 243 Histone deacetylase inhibitors for neuroprotection in TBI .................................................... 243 Inhibitors of integrated stress response ............................................................................ 243 Levosimendan ............................................................................................................... 243 Magnesium sulfate ......................................................................................................... 244 Minocycline for TBI ......................................................................................................... 244 Multipotential neuroprotective agents for TBI .................................................................... 244 Neurotrophic factors for TBI ............................................................................................ 244 Neurosteroids as neuroprotective agents for TBI ................................................................ 245 NMDA receptor antagonists ............................................................................................. 246

Neuroprotection in TBI against glutamate-induced excitotoxicity ..................................... 246 NP-1 ....................................................................................................................... 247

Nogo-A inhibitor ............................................................................................................ 247 Nutritional approaches to neuroprotection in TBI................................................................ 247

Branched chain amino acids to ameliorate cognitive impairment in TBI ............................ 248 Creatine for neuroprotection in TBI ............................................................................. 248 Nicotinamide for neuroprotection in TBI ....................................................................... 249 Omega 3 fatty acids as neuroprotectives in TBI ............................................................ 249

Oxygen carriers for TBI................................................................................................... 249 Polyethylene glycol for neuroprotection in TBI ................................................................... 250 Propofol for neuroprotection in TBI ................................................................................... 250 Rapamycin as neuroprotective in TBI ................................................................................ 250 Simvastatin as neuroprotective in TBI .............................................................................. 251 Statins as neuroprotective agents in concussion ................................................................ 251 Targeting mitochondrial pathology in TBI .......................................................................... 251 Thyrotropin-releasing hormone analogs ............................................................................ 251 Tissue plasminogen activator ........................................................................................... 252

Biological approaches to neuroprotection in TBI ............................................................. 252 Antisense approaches to TBI ........................................................................................... 252 Cell therapy for TBI ........................................................................................................ 252

Limitations of stem cell therapy for acute TBI ............................................................... 253 Stem cell-derived exosomes for treatment of TBI .......................................................... 254

Gene therapy for TBI ...................................................................................................... 254 Vaccines for TBI ............................................................................................................. 255

Non-pharmaceutical approaches to neuroprotection in TBI ............................................. 255 Deep brain stimulation for TBI ......................................................................................... 255 Hyperbaric oxygen therapy for TBI ................................................................................... 256 Hypothermia ................................................................................................................. 256

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Reduction of microglial migration after TBI ........................................................................ 256 Vacuum for mechanical tissue resuscitation in TBI ............................................................. 256

Prophylactic neuroprotection against TBI ........................................................................ 257 Role of helmets in protection against TBI .......................................................................... 257 Role of physical exercise in protection against TBI ............................................................. 257

Neuroprotection against late sequelae of TBI .................................................................. 258 Antiepileptic drugs for prevention of seizures and neuroprotection ....................................... 258

Neuroprotection during rehabilitation phase of TBI ......................................................... 258 Neuroregeneration following TBI ...................................................................................... 259

Intrinsic factors that influence regeneration following TBI .............................................. 259 Causes of lack of regeneration following TBI ................................................................. 259 Approaches to regeneration of the brain following TBI ................................................... 259

Clinical trials of neuroprotective agents in TBI ................................................................ 261 Ongoing clinical trials in TBI ............................................................................................ 261 Failed clinical trials in TBI ................................................................................................ 261

Differences between clinical trials and studies in animal models of TBI ............................ 262 Subgroup analysis ..................................................................................................... 263 Improving the clinical trial design ................................................................................ 263 Clinical trials combining multiple treatment strategies ................................................... 263 Shortening the trial time ............................................................................................ 264

Conclusions and future of neuroprotection in TBI ............................................................ 264

5. Neuroprotection in Spinal Cord Injury ................................................ 266 Introduction .................................................................................................................... 266 Pathophysiology of SCI .................................................................................................... 266

Secondary mechanisms of SCI .................................................................................... 267 Neurotrophic factor changes in SCI ............................................................................. 268

Management of SCI ......................................................................................................... 268 Pharmacological neuroprotective agents for SCI ............................................................. 269

4-aminopyridine ............................................................................................................ 270 Antibodies as neurite growth inhibitors in SCI .................................................................... 270 Antiexcitotoxic agents .................................................................................................... 270

Gacyclidine .............................................................................................................. 270 GM-1 ganglioside ...................................................................................................... 271

Bacterial enzyme chondroitinase ABC ............................................................................... 271 Docosahexaenoic acid as neuroprotective in SCI ................................................................ 271 Erythropoietin as a neuroprotective in SCI ........................................................................ 271 Free radical scavengers for neuroprotection in SCI ............................................................. 271 Immunosuppressants as neuroprotectants in SCI ............................................................... 272 Interleukin-10 for neuroprotection in SCI .......................................................................... 272 Matrix metalloproteinase inhibitors for SCI ........................................................................ 272 Methylprednisolone ........................................................................................................ 273 Minocycline as neuroprotective in SCI ............................................................................... 273 Modulation of macrophage responses for neuroprotection after SCI ...................................... 274 Neurotrophic factors for neuroprotection after SCI ............................................................. 274

Fibroblast growth factors in the management of SCI ..................................................... 275 Promotion of regeneration of neurons in SCI ................................................................ 275

Rho pathway and Rho antagonists in SCI .......................................................................... 275 Riluzole and methylprednisone as neuroprotectants in SCI .................................................. 276 Selenium as a neuroprotective for SCI .............................................................................. 276 Sialidase for enhancing recovery after SCI ........................................................................ 276 Targeting the inflammatory response for neuroprotection in SCI .......................................... 277 Uric acid as neuroprotective in SCI ................................................................................... 277

Non-pharmacological approaches to SCI ......................................................................... 277 Hyperbaric oxygen therapy ............................................................................................. 277 Hypothermia for SCI ...................................................................................................... 277

Cell therapy for SCI ......................................................................................................... 278 Fetal neural grafts for SCI ............................................................................................... 278 Olfactory-ensheathing cells for SCI .................................................................................. 278 Oligodendrocyte precursor cells for treatment of SCI .......................................................... 279 Schwann cell transplants for SCI ...................................................................................... 280 Transplantation of glial cells for SCI ................................................................................. 280 Stem cells for SCI .......................................................................................................... 280

Bone marrow stem cells for SCI .................................................................................. 280 Transplantation of ESCs for SCI .................................................................................. 280 Transplantation of induced pluripotent stem cells in SCI ................................................ 280 Transplantation of MSCs for SCI ................................................................................. 281 Transplantation of NSCs for SCI .................................................................................. 281 Transdifferentiation of stem cells into cholinergic neurons for SCI ................................... 282

Gene therapy for SCI ....................................................................................................... 282 Combined approaches to spinal cord injury ..................................................................... 283

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Discovery of new targets for neuroprotective therapies in SCI ........................................ 284 Clinical trials in SCI.......................................................................................................... 284 Concluding remarks ......................................................................................................... 285

6. Neuroprotection in Neurodegenerative Disorders ............................... 286 Introduction .................................................................................................................... 286 Pathomechanism of neurodegeneration .......................................................................... 286

Aging and neurodegeneration .......................................................................................... 286 α-synuclein in neurodegeneration and neuroprotection ....................................................... 287 Dysregulation of cyclin-dependent kinase 5 ....................................................................... 287 Dysregulation of translation ............................................................................................ 288 Exosomes in CNS neurodegeneration and neuroregeneration............................................... 288 Genomics of neurodegenerative diseases .......................................................................... 288 Impairment of neural transport in neurodegenerative disorders ........................................... 289 Lack of neurotrophic factors ............................................................................................ 289 Mitochondrial damage leading to apoptosis ....................................................................... 289 Neuroinflammation in neurodegenerative disorders ............................................................ 289 Neurodegeneration associated with chronic repeated cerebral injuries .................................. 290 Neurodegeneration associated with protein misfolding ........................................................ 290

Modulation of neurodegeneration by molecular chaperones ............................................ 290 Intrabodies targeting protein misfolding in neurodegeneration ........................................ 290 Targeting proteins aggregation to prevent amyloid formation ......................................... 291 Tau and neurodegeneration ........................................................................................ 291

Role of apoptosis in neurodegenerative disorders ............................................................... 291 Role of glia in neurodegeneration ..................................................................................... 292 Role of metals in neurodegeneration ................................................................................ 292 Spread of neurodegeneration .......................................................................................... 292 TDP-43 proteinopathy and neurodegenerative diseases ...................................................... 292 Viral infections and neurodegeneration ............................................................................. 293

AIDS and the nervous system .................................................................................... 293 Avian influenza as cause of neurodegeneration ............................................................. 294

Neurodegenerative disorders with dementia ................................................................... 294 Dementia with Lewy bodies ............................................................................................. 295 Frontotemporal dementia ................................................................................................ 295 Progressive supranuclear palsy ........................................................................................ 296

Genetic disorders with neurodegeneration ...................................................................... 296 Batten disease ............................................................................................................... 297

Cell and gene therapies ............................................................................................. 297 Cerliponase alfa ........................................................................................................ 298

Familial dysautonomia .................................................................................................... 298 Friedrich ataxia .............................................................................................................. 299

Pathomechanism of FA .............................................................................................. 299 Neuroprotection in FA ................................................................................................ 299

Leigh syndrome ............................................................................................................. 299 Niemann-Pick type C disease ........................................................................................... 300 Spinal and bulbar muscular atrophy ................................................................................. 300

Spinal muscular atrophy ............................................................................................ 301 Creutzfeldt-Jakob disease ................................................................................................ 303

Neuroprotection in Creutzfeldt-Jakob disease .................................................................... 303 Pharmacological neuroprotectants against CJD ............................................................. 304 Innovative approaches to neuroprotection in CJD and future prospects ............................ 305

Approaches to neuroprotection in neurodegenerative disorders ...................................... 305 Glutamate-based therapies for neurodegenerative disorders ............................................... 306 Histone deacetylase inhibitors for neurodegenerative disorders ............................................ 306 Intermittent fasting for neuroprotection ............................................................................ 306 Iron chelation for neuroprotection .................................................................................... 307 Mitochondria permeability transition pore complex and neuroprotection ................................ 307 Modulation of proteostasis in neurodegenerative disorders .................................................. 308 Targets to limit protein aggregation in neurodegenerative diseases ...................................... 308

7. Neuroprotection in Parkinson Disease ................................................ 310 Introduction .................................................................................................................... 310 Epidemiology of Parkinson's disease ............................................................................... 310 Pathophysiology of Parkinson's disease .......................................................................... 310

Alteration of dopamine homeostasis ................................................................................. 311 Apoptosis ...................................................................................................................... 311 Calcium interaction with α-synuclein................................................................................. 311 Disruption of iron homeostasis ......................................................................................... 312 Excitotoxicity ................................................................................................................. 312 Genes and PD ................................................................................................................ 312 Histone deacetylase 4 as a regulator of progression of PD ................................................... 314

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Oxidative stress ............................................................................................................. 314 Propagation of pathologic α-synuclein from the gut to the brain in PD .................................. 315 Role of neurotrophic factors ............................................................................................ 315 Role of misfolding proteins .............................................................................................. 315 Role of -synuclein in dementia of PD ............................................................................... 316 Synaptic vesicle glycoprotein 2C disruption in PD ............................................................... 316

Neuroprotective strategies for PD based on pathomechanism ......................................... 316 A genetic animal model of PD for testing neuroprotective strategies ..................................... 317 Aldehyde dehydrogenase 1 protects nigrostriatal dopaminergic neurons ............................... 317 RNAi screening to identify neuroprotective genes in a PD model .......................................... 318 Strategies to stop aggregation of -synuclein .................................................................... 318 Targeting mitochondrial dysfunction in PD ......................................................................... 318

Management of Parkinson's disease ................................................................................ 319 Limitation of conventionally administered dopamine therapy ............................................... 320

Neuroprotective therapy in PD ......................................................................................... 321 Neuroprotective effect of currently used drugs for PD ..................................................... 321

Pramipexole .................................................................................................................. 321 Rasagiline mesylate ....................................................................................................... 322 Ropinirole ..................................................................................................................... 323 Rivastigmine for treatment of dementia and falls associated with PD .................................... 323 Selegiline ...................................................................................................................... 324

Non-pharmacological strategies for neuroprotection in PD .............................................. 324 Deep brain stimulation for PD .......................................................................................... 324 Effect of exercise and environmental enrichment on PD ...................................................... 325 Calorie restriction in PD .................................................................................................. 325

Development of neuroprotective therapies for PD ........................................................... 326 2B3-201 for targeted delivery of methylprednisolone.......................................................... 326 9-methyl-β-carboline ...................................................................................................... 326 Adenosine AA2 receptor antagonists ................................................................................. 326 Antiapoptotic strategies for PD ........................................................................................ 327 ATP13A2 activation ........................................................................................................ 327 Atremorine .................................................................................................................... 327 Augmenting CNS glucocerebrosidase activity ..................................................................... 328 β2-Adrenoreceptor agonists ............................................................................................ 328 BT13 as GDNF receptor agonist ....................................................................................... 328 Calcium channel blockers for PD ...................................................................................... 329 Cell therapies for PD ....................................................................................................... 329

Stem cells for PD ...................................................................................................... 329 Activation of endogenous stem cells and neural precursors ............................................ 329 Pluripotent stem cell-derived neurons .......................................................................... 330 Transplantation of iPSC-derived neural progenitors ....................................................... 331

Cogane ......................................................................................................................... 331 Conserved dopamine neurotrophic factor for PD................................................................. 331 Doxycyline as a neuroprotectant in PD .............................................................................. 332 Free radical scavengers for neuroprotection in Parkinson’s disease ....................................... 332

Antioxidants ............................................................................................................. 332 Diapocynin ............................................................................................................... 332 Tea extracts as neuroprotectives................................................................................. 333

Gene therapy for PD ....................................................................................................... 333 Implantation of genetically engineered cells ................................................................. 334 Gene therapy using GDNF .......................................................................................... 334 Parkin gene therapy .................................................................................................. 336 Viral vector-based ubiquitination to prevent spread of α-synuclein .................................. 336 Concluding remarks about gene therapy for PD............................................................. 336

Heat shock protein 70 .................................................................................................... 337 Liver X receptor β agonists .............................................................................................. 337 Melatonin as a neuroprotectant in PD ............................................................................... 338 Nicotine as a neuroprotective in PD .................................................................................. 338 Nilotinib for PD .............................................................................................................. 338 Neuroprotective effect of leucine-rich repeat kinase-2 inhibitors .......................................... 339 Neuroprotective effect of DJ-1 protein .............................................................................. 339 Neurotrophic factors ....................................................................................................... 339

Basic fibroblast growth factor for PD ............................................................................ 339 BDNF for PD ............................................................................................................. 340 GDNF for PD ............................................................................................................. 340 MANF for PD ............................................................................................................. 340 Neurturin for PD ....................................................................................................... 341 Platelet derived growth factor ..................................................................................... 341

Nrf2-mediated neuroprotection in PD ................................................................................ 341 Nuclear receptor-related 1:Retinoid X receptor α activation ................................................. 342 Omega-3 polyunsaturated fatty acids ............................................................................... 342

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RAB3B overexpression .................................................................................................... 342 Reservatrol for PD .......................................................................................................... 343 RNAi therapy for PD ....................................................................................................... 343 Safinamide .................................................................................................................... 344 Sirtuin 2 inhibitors for neuroprotection in PD ..................................................................... 344 Squalamine and PD ........................................................................................................ 345 Statins and PD ............................................................................................................... 345 Targeting Bax ................................................................................................................ 345 Vitamin D for neuroprotection in PD ................................................................................. 345 Vaccine for PD ............................................................................................................... 346

Clinical trials of neuroprotection in Parkinson's disease .................................................. 346 Evaluation of neuroprotective therapies for PD ............................................................... 348 Current status and future challenges for neuroprotection in PD ...................................... 349

8. Neuroprotection in Alzheimer Disease ................................................ 351 Introduction .................................................................................................................... 351 Pathomechanism of Alzheimer's disease ......................................................................... 351

Pathology of AD ............................................................................................................. 351 Cerebral atrophy and neuronal loss ............................................................................. 351

Neuritic plaques and neurofibrillary tangles ....................................................................... 351 Role of tau in the pathogenesis of AD ............................................................................... 352 RNA-binding proteins and AD .......................................................................................... 352 Amyloid precursor protein ............................................................................................... 352

APP intracellular domain ............................................................................................ 353 Relation of APP mutations to CNS disorders .................................................................. 353 Relation of APP to Aβ deposits and pathogenesis of AD .................................................. 354 Role of neprilysin in Aβ degradation ............................................................................ 354 Role of secretases in amyloid cascade ......................................................................... 355 Role of nicastrin ........................................................................................................ 356

Neurotoxicity of Aβ deposits ............................................................................................ 356 Aβ production and clearance ...................................................................................... 356 Aβ-mediated synaptic and cognitive deficits ................................................................. 357 Interaction of Aβ with neuron-specific Na+/K+-ATPase α3 subunit .................................. 357 Relation of Aβ deposits to synaptic activity ................................................................... 358 Role of dsDNA breaks in neurodegeneration due to Aß ................................................... 358 Sequence of events in neurotoxicity of Aβ .................................................................... 358

Impairment of mitochondrial energy metabolism ............................................................... 359 Disturbances in brain metabolism in early AD .................................................................... 359 Disturbance of lipid metabolism in the brain ...................................................................... 360 Dopamine and AD .......................................................................................................... 360 Functioning role of genes in pathomechanism of AD ........................................................... 360 Insulin, diabetes and AD ................................................................................................. 361

Mechanisms underlying cognitive deficits in AD ............................................................. 362 Microglia and AD ............................................................................................................ 362 Neuroinflammation and AD ............................................................................................. 362

Nitric oxide and AD ................................................................................................... 363 Oxidative stress and AD ............................................................................................. 365

Spread of neurodegeneration .......................................................................................... 366 Risk factors in the etiology of AD ..................................................................................... 367

Epigenetic link between aging and AD ......................................................................... 367 Level of education/type of job and risk of AD ................................................................ 368 Metals and AD .......................................................................................................... 368 Psychosocial stress and risk of AD ............................................................................... 369 Sleep deprivation ...................................................................................................... 370 Traumatic brain injury and AD .................................................................................... 370

AD and cognitive impairment with aging ........................................................................... 371 Concluding remarks on pathophysiology of AD ................................................................... 371

Management of Alzheimer's disease ................................................................................ 373 Neuroprotective approaches to Alzheimer's disease ........................................................ 374 Antiapoptotic agents ........................................................................................................ 376

Phenserine .................................................................................................................... 376 Antiinflammatory drugs for neuroinflammation ............................................................... 376

Etanercept .................................................................................................................... 376 NSAIDS for AD .............................................................................................................. 377

Nitric oxide-donating NSAIDs ..................................................................................... 378 PPARgamma agonists ..................................................................................................... 378

Antioxidant and free radical scavengers .......................................................................... 378 Colostrinin .................................................................................................................... 378 Curcumin ...................................................................................................................... 379 Dehydroascorbic acid ..................................................................................................... 379 Melatonin ...................................................................................................................... 379

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Reservatrol for AD ......................................................................................................... 380 Antisense approaches to AD ............................................................................................ 380

Antisense PNA in AD ....................................................................................................... 381 Antisense tau in AD ........................................................................................................ 381

Cell therapy for AD........................................................................................................... 381 Choroid plexus epithelial cells for AD ................................................................................ 381 Stem cell transplantation for AD ...................................................................................... 382

Autologous adipose tissue derived mesenchymal stem cells............................................ 382 Neural stem cells transplantation ................................................................................ 382 Neuronal differentiation of implanted NSCs enhanced by drugs ....................................... 382 NSCs improve cognition in AD via BDNF ....................................................................... 383 Potential benefits of grafting NSCs in AD ...................................................................... 383 Use of autologous stem cells for dementia ................................................................... 383

Clearance of Aβ deposits and plaques .............................................................................. 384 Galantamine-induced Aβ clearance ................................................................................... 384 Monoclonal antibodies for removal of Aβ ........................................................................... 384

Crenezumab ............................................................................................................. 384 Gantenerumab ......................................................................................................... 384 Solanezumab............................................................................................................ 385

Nanotechnology for removal of Aβ deposits ....................................................................... 385 Nilotinib ........................................................................................................................ 386

Cholesterol lowering agents for AD ................................................................................. 386 Statins for reducing the risk of AD.................................................................................... 386

Gene therapy for Alzheimer disease ................................................................................ 386 Rationale ...................................................................................................................... 386 NGF gene therapy for AD ................................................................................................ 387

FGF2 gene transfer in AD ........................................................................................... 388 Neprilysin gene therapy ............................................................................................. 388 Viral gene transfer of APPsα for rescuing synaptic failure in AD ....................................... 389 Gene vaccination ...................................................................................................... 389 Combination of gene therapy with other treatments for AD ............................................ 389

Glutamate antagonists ..................................................................................................... 390 Memantine .................................................................................................................... 390

Inhibition of Aβ formation ............................................................................................... 391 Chelation of metals ........................................................................................................ 391

Clioquinol ................................................................................................................. 391 Copper chelation ....................................................................................................... 391 Next generation multifunctional chelating agents for AD ................................................ 392

Secretase modulators ..................................................................................................... 392 Neuroprotection by α-secretase cleaved APP ................................................................ 392 Inhibitors of β-secretase ............................................................................................ 393 Inhibitors of γ-secretase ............................................................................................ 394

Miscellaneous neuroprotective agents ............................................................................. 395 Cerebrolysin .................................................................................................................. 395 Ginko biloba .................................................................................................................. 395 Tetrahydrocannabinol for neuroprotection in AD ................................................................ 396

Nanobiotechnology-based therapeutics for AD ................................................................ 397 Nanobody-based drugs for AD ......................................................................................... 397 Nanoencapsulation for delivery of vitamin E for Alzheimer disease ....................................... 397 Selegiline-PEG nanoparticles targeting Aβ fibrils in Alzheimer disease ................................... 397

Neurotrophic factors for neuroprotection in AD ............................................................... 398 AL-108 ......................................................................................................................... 398 Brain derived neurotrophic factor ..................................................................................... 398 Neotrofin (AIT-082)........................................................................................................ 398 Small molecule compounds binding to neurotrophin receptor p75NTR ................................... 399 Limitations of the use of NTFs for AD ................................................................................ 399

Neuroprotective effect drugs not primarily developed for AD .......................................... 400 Antiepiletic drugs ........................................................................................................... 400

Lamotrigine .............................................................................................................. 400 Levetiracetam .......................................................................................................... 400

Antimicrobial drugs ........................................................................................................ 400 Dapsone .................................................................................................................. 400 Antimicrobial drugs against Chlamydia pneumoniae ...................................................... 401 Antiviral therapy in AD............................................................................................... 401

Antidiabetic drugs .......................................................................................................... 402 Insulin ..................................................................................................................... 402 Metformin ................................................................................................................ 402 Rosiglitazone ............................................................................................................ 403

Antihypertensive drugs ................................................................................................... 403 Angiotensin-converting enzyme inhibitors .................................................................... 403 Angiotensin receptor blockers ..................................................................................... 403

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Bexarotene ................................................................................................................... 404 Dimebon ....................................................................................................................... 404 Drugs acting on estrogen receptors .................................................................................. 405

Estrogen .................................................................................................................. 405 Raloxifene ................................................................................................................ 406 Granulocyte-macrophage colony-stimulating factor ....................................................... 406

Inhibitors of neuroinflammation ....................................................................................... 406 Ceramide ................................................................................................................. 406 CSP-1103 ................................................................................................................ 406 Fingolimod ............................................................................................................... 407 Interferon beta-1a .................................................................................................... 407

Lithium ......................................................................................................................... 407 MAO-B inhibitors ............................................................................................................ 408

Ladostigil tartrate ..................................................................................................... 408 Methylene blue .............................................................................................................. 408 Phosphodiesterase inhibitors as neuroprotectives ............................................................... 408 Rapamycin .................................................................................................................... 409 Saracatinib .................................................................................................................... 409 Testosterone ................................................................................................................. 409 Valproic acid.................................................................................................................. 410

Restoration of factors deficient in the aging brain ........................................................... 410 Reversal of cognitive impairment in aging by activation of creb protein ................................. 410 Reversal of cognitive impairment in aging by GDF11 protein ............................................... 411 Restoration of repressor element 1-silencing transcription factor.......................................... 411

Vaccines for AD ................................................................................................................ 411 Active immunization with Aβ ........................................................................................... 412 Passive immunization with MAbs ...................................................................................... 412 Other vaccines for AD ..................................................................................................... 413 Mechanism of reduction of A plaque pathology by immunization ......................................... 413 Perspectives on vaccines for AD ....................................................................................... 414

Vitamins .......................................................................................................................... 414 Vitamin E as antioxidant ................................................................................................. 414 Vitamin B for lowering homocysteine ................................................................................ 414 Folic acid ...................................................................................................................... 415

Combined therapeutic approaches to AD ......................................................................... 415 Clinical trials in AD........................................................................................................... 415

Concluding remarks on clinical trials of AD ........................................................................ 424 Future prospects of neuroprotection in AD ...................................................................... 425 Mild cognitive impairment ............................................................................................... 425

Relation of MCI to AD ..................................................................................................... 426 Neuroprotection in MCI ................................................................................................... 426

Pharmacological approaches for MCI ........................................................................... 426 Non-pharmacological approaches to MCI and AD ........................................................... 428

9. Neuroprotection in Huntington Disease .............................................. 429 Introduction .................................................................................................................... 429 Pathophysiology of HD ..................................................................................................... 429 Management of Huntington's disease .............................................................................. 431 Neuroprotection in Huntington's disease ......................................................................... 431

Antipsychotic D2 and 5-HT1A antagonists ........................................................................... 432 Caspase inhibitors .......................................................................................................... 432 Cysteine and neuroprotection in HD ................................................................................. 433

Cysteine metabolism reprogramming for neuroprotection in HD ...................................... 433 Cysteamine .............................................................................................................. 433

Drugs that block inappropriate calcium release from neurons .............................................. 433 Enhancing protease activity for clearance of mHtt .............................................................. 433 Eicosapentaenoic acid ..................................................................................................... 434 Fingolimod .................................................................................................................... 434 Free radical scavengers .................................................................................................. 434 Histone deacetylase inhibitors ......................................................................................... 435 Phosphodiesterase inhibitors ........................................................................................... 435 Polyglutamine aggregation inhibitors ................................................................................ 435 Pramipexole .................................................................................................................. 436 Pridopidine .................................................................................................................... 436 RRAS signaling pathway inhibition .................................................................................... 436 Simvastatin as a neuroprotective in HD ............................................................................ 436 Single chain Fv antibodies ............................................................................................... 437 SIRT1 activators for neuroprotection in HD ....................................................................... 437 SIRT2 inhibitors for neuroprotection in HD ........................................................................ 437 Synaptic activation of NMDA receptors.............................................................................. 438 Targeting mutant huntingtin protein ................................................................................. 438

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Tetrabenazine ............................................................................................................... 439 Combinatorial therapy and targeting multiple pathways in HD ............................................. 439 Cell therapy for HD ........................................................................................................ 439

Cell transplants for HD ............................................................................................... 440 Stem cell-based therapy for HD .................................................................................. 440

Neurotrophic factors and gene therapy ............................................................................. 441 Antisense therapeutics for Huntington's disease ................................................................. 441

HTTRx/RG6042 for HD ................................................................................................ 441 RNAi-based therapies for Huntington's disease .................................................................. 442

10. Neuroprotection in Amyotrophic Lateral Sclerosis ............................ 443 Introduction .................................................................................................................... 443 Pathophysiology of ALS ................................................................................................... 443 Neuroprotective therapies for ALS ................................................................................... 448

Activated protein C ........................................................................................................ 449 AIMSPRO ...................................................................................................................... 449 Anakinra ....................................................................................................................... 450 Antisense therapy .......................................................................................................... 450 Arimoclomol for ALS ....................................................................................................... 450 Ceftriaxone for ALS ........................................................................................................ 451 Coenzyme Q10 for ALS ................................................................................................... 451 COX-2 inhibitors for ALS ................................................................................................. 451 Dexpramipexole ............................................................................................................. 451 Diallyl trisulfide .............................................................................................................. 452 Edaravone for ALS ......................................................................................................... 452 Erythropoietin for ALS .................................................................................................... 452 Gene therapy for ALS ..................................................................................................... 453

Gene editing for ALS ................................................................................................. 453 Glatiramer acetate ......................................................................................................... 454 GM604 ......................................................................................................................... 454 Insulin-like growth factor ................................................................................................ 454 Ketogenic diet for neuroprotection in ALS.......................................................................... 455 Lenalidomide ................................................................................................................. 455 Lithium for neuroprotection in ALS ................................................................................... 455 Masitinib ....................................................................................................................... 456 Melatonin for ALS ........................................................................................................... 456 Methylcobalamin ............................................................................................................ 456 Olesoxime as neuroprotective for ALS............................................................................... 457 ONO-2506 .................................................................................................................... 457 Riluzole ........................................................................................................................ 457 RNAi-based therapy for ALS ............................................................................................ 458 Sodium phenylbutyrate ................................................................................................... 458 Stem cell therapy ........................................................................................................... 458

Clinical applications ................................................................................................... 458 Stem cell-based drug discovery for ALS ....................................................................... 459 Suppressors of mTDP-43 toxicity ................................................................................ 460

Talampanel ................................................................................................................... 460 Tamoxifen ..................................................................................................................... 460 Vaccination for ALS caused by SOD1 mutations ................................................................. 461 Vascular endothelial growth factor for ALS ........................................................................ 461 Vitamin E for ALS ........................................................................................................... 461

Clinical trials of neuroprotective therapies for ALS ......................................................... 461 Concluding remarks and future prospects........................................................................ 462

Multi-omics approach to ALS ........................................................................................... 462 Use of CRISPR/Cas9 technology to find new targets in ALS ................................................. 463 Concluding remarks on neuroprotection in ALS .................................................................. 463

11. Neuroprotection in Miscellaneous Neurological Disorders ................ 465 Introduction .................................................................................................................... 465 Neuroprotection in synaptopathies .................................................................................. 465

Neuroprotection in ASD .................................................................................................. 466 Neuroprotection in fragile X syndrome .............................................................................. 466

Neuroprotection in dementia ........................................................................................... 466 Age-related dementia ..................................................................................................... 466

Aging brain and oxidative stress ................................................................................. 467 Hsp70 and age-related neurodegeneration ................................................................... 467 Pharmacological approaches for treatment of age-related dementia ................................ 468 Mental training to prevent decline of mental function with aging ..................................... 468 Physical exercise to prevent decline of mental function with aging................................... 469 Concluding remarks on neuroprotection of the aging brain ............................................. 469

Vascular dementia ......................................................................................................... 470

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Prediction of dementia in persons with vascular risk factors ............................................ 470 Management of subcortical vascular dementia .............................................................. 470

Neuroprotection in Lewy body dementia ........................................................................... 471 Neuroprotection in AIDS dementia ................................................................................... 472

Multiple system atrophy .................................................................................................. 473 Epilepsy ........................................................................................................................... 473

Mechanisms of neuronal damage in epilepsy ..................................................................... 473 Strategies for neuroprotection in epilepsy ......................................................................... 474 AEDs and neuroprotection ............................................................................................... 475 Cell therapy for neuroprotection in epilepsy ....................................................................... 476

Cell therapy of posttraumatic epilepsy ......................................................................... 476 Cell therapy for temporal lobe epilepsy ........................................................................ 477 Cell therapy for pharmacoresistant epilepsies ............................................................... 477

Drugs targeting mossy cells in drug-resistant epilepsy ........................................................ 477 Gene therapy for neuroprotection in epilepsy .................................................................... 478 Hyaluronan-based preservation of brain ECS volume .......................................................... 478 Hypothermia for neuroprotection in status epilepticus ......................................................... 479 Ketogenic diet for prevention of seizures ........................................................................... 479 miR-211 as an attenuator of cholinergic-mediated seizures ................................................. 479

Multiple sclerosis ............................................................................................................. 480 Introduction .................................................................................................................. 480 Epidemiology of multiple sclerosis .................................................................................... 480 Pathophysiology ............................................................................................................ 480 Current management of multiple sclerosis ......................................................................... 481 Specific therapies for MS based on pathomechanism .......................................................... 481 Neuroprotection in multiple sclerosis ................................................................................ 482 Clinical trials of neuroprotective therapies for MS ............................................................... 483 Neuroprotection by control of progressive forms of multiple sclerosis ................................... 485 Neuroprotection by controlling autoimmune inflammation in the brain .................................. 485 Neuroprotection by sealing the BBB with imatinib .............................................................. 486 TRPM4 cation channel blockers ........................................................................................ 486 Remyelination for neuroprotection in multiple sclerosis ....................................................... 486 Agents for neuroprotection in multiple sclerosis ................................................................. 487

Angiotensin-II inhibitors ............................................................................................ 487 Antiglutamate agents ................................................................................................ 487 Antioxidants for neuroprotection in MS ........................................................................ 487 Antisense and RNAi approaches to MS ......................................................................... 488 B cell depletion therapy ............................................................................................. 488 Cell therapy for multiple sclerosis ................................................................................ 488 Cannabinoids for neuroprotection in MS ....................................................................... 491 Cladribine ................................................................................................................ 491 Curcumin as a neuroprotectant in multiple sclerosis ...................................................... 492 Cytokine-directed therapies in MS ............................................................................... 492 Dalfampridine in MS .................................................................................................. 492 Dimethyl fumarate .................................................................................................... 493 DNA vaccine for MS ................................................................................................... 493 Erythropoietin as a neuroprotective in MS .................................................................... 493 Evobrutinib .............................................................................................................. 493 Fingolimod ............................................................................................................... 494 Fusokine composed of GM-CSF and IL-15 for immune suppression .................................. 495 Gene therapy for MS ................................................................................................. 495 Ibudilast for MS ........................................................................................................ 496 Iron chelators ........................................................................................................... 496 IVIG for MS .............................................................................................................. 496 Kinase inhibitors ....................................................................................................... 497 Laquinimod .............................................................................................................. 497 Melatonin for MS ....................................................................................................... 497 Minocycline for MS .................................................................................................... 497 Monoclonal antibodies for MS ..................................................................................... 498 Natalizumab ............................................................................................................. 499 Natural human antibodies for repair of myelin .............................................................. 499 Neurotrophic factors for multiple sclerosis .................................................................... 500 Nimodipine ............................................................................................................... 500 Oral immunomodulatory agents for MS ........................................................................ 501 Protein kinase Cβ as a therapeutic target for stabilizing BBB in MS .................................. 501 Recombinant T-cell ligands ......................................................................................... 501 Statins for MS........................................................................................................... 502 Teriflunomide ........................................................................................................... 502 Tolerance-directed immunotherapy for MS ................................................................... 502

Concluding remarks and future prospects for neuroprotection in MS ..................................... 503 Neuroprotection in anti-NMDA receptor encephalitis ....................................................... 504

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Neuroprotection in transverse myelitis ............................................................................ 504 Neuroprotection in decompression sickness .................................................................... 505 Neuroprotection in victims of drowning ........................................................................... 505 Neuroprotection in CSF circulatory disorders ................................................................... 506

Neuroprotection in hydrocephalus .................................................................................... 506 Neuroprotection in normal pressure hydrocephalus ............................................................ 506

Neuroprotection in infections of the CNS ......................................................................... 507 Neuroprotection in bacterial meningitis ............................................................................. 507

Mechanism of neural injury in bacterial meningitis ........................................................ 507 Strategies for neuroprotection .................................................................................... 508

Neuroprotection in progressive multifocal leukoencephalopathy ........................................... 508 Neuroprotection in cryptococcal meningitis ........................................................................ 509 Neuroprotective approach to rabies .................................................................................. 509 Neuroprotection in cerebral malaria .................................................................................. 510

Neuroprotection in complications of systemic disorders .................................................. 511 Neurological complications of cardiovascular disorders ........................................................ 511

Neuroprotection after myocardial infarction .................................................................. 511 Neuroprotection in hypertensive encephalopathy .......................................................... 511 Management of hypertension to prevent dementia ........................................................ 512

Neuroprotection in complications of diabetes ..................................................................... 512 Neuroprotection in hypoglycemic coma ........................................................................ 512 Neuroprotection in diabetic ketoacidosis ...................................................................... 513 Neuroprotection in diabetic retinopathy ....................................................................... 513

Neurological complications of liver disorders ...................................................................... 514 Hepatic encephalopathy ............................................................................................. 514 Bilirubin encephalopathy ............................................................................................ 515

Neuroprotection in neurological complications of renal disease. ........................................... 516 Neuroprotection in fever ................................................................................................. 516

Pharmacologic approaches for fever ............................................................................ 518 Cooling the brain for neuroprotection .......................................................................... 519

Neuroprotection in toxic encephalopathies ...................................................................... 519 Encephalopathy due to organophosphorus poisoning .......................................................... 519

Sarin gas ................................................................................................................. 520 Neuroprotection against chemotherapy-induced brain damage ............................................ 520 Neuroprotection against alcohol ....................................................................................... 521

Alcoholic neurologic disorders ..................................................................................... 521 Fetal alcohol syndrome .............................................................................................. 521 Pathogenesis of alcohol-induced damage to the nervous system ..................................... 522 Neuroprotection against neurotoxicity of alcohol ........................................................... 522

Neuroprotection against exposure to therapeutic radiation ............................................. 522 Neuroprotection against radiation encephalopathy ............................................................. 522 Role of SOD in protection again radiation-induced hippocampal dysfunction .......................... 523 Catalase reduces mitochondrial ROS for neuroprotection from proton irradiation .................... 523

Neuroprotection of the fetus and the neonate ................................................................. 524 Neuroprotection in preterm babies ................................................................................... 524 Neuroprotection in neonatal hypoxic-ischemic brain injury .................................................. 524

Pathomechanism of neonatal hypoxic-ischemic brain injury ............................................ 524 Management of neonatal hypoxia-ischemia .................................................................. 525 Approaches to neuroprotection in neonatal hypoxia-ischemia ......................................... 525 Hyperbaric oxygen for neonatal hypoxia-ischemia ......................................................... 526 Hypothermia for neonatal hypoxia-ischemia ................................................................. 526 Melatonin for neonatal hypoxia-ischemia ...................................................................... 526 Minocycline for neonatal hypoxia-ischemia ................................................................... 527 Nicotinamide mononucleotide adenylyl transferase 1 ..................................................... 527 Nitric oxide inhalation for neonatal hypoxia-ischemia ..................................................... 527 Plasminogen activator inhibitor-1 for neonatal hypoxia-ischemia ..................................... 527 Recombinant erythropoietin for neonatal hypoxia-ischemia ............................................ 528

Neuroprotection in carbon monoxide poisoning ............................................................... 528 Pathomechanism of CO poisoning as a basis for neuroprotection .......................................... 528 Management of CO poisoning .......................................................................................... 529

Neuroprotection after cardiac arrest ................................................................................ 529 Neuroprotection in delayed post-hypoxic leukoencephalopathy ...................................... 530 Neuroprotection in sleep apnea ....................................................................................... 531 Neuroprotection in mitochondrial dysfunction ................................................................. 531

Mitochondrial permeability transition ................................................................................ 532 Mitochondrial approaches for neuroprotection .................................................................... 532 Methylene blue .............................................................................................................. 533 Mitochondrial encephalopathies ....................................................................................... 533

Neuroprotection in mitochondrial encephalopathies ....................................................... 534 Neuroprotection in psychiatric disorders ......................................................................... 534

Electroconvulsive therapy and neuroprotection .................................................................. 534

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Neuroprotection in schizophrenia ..................................................................................... 535 Cognitive impairment in schizophrenia ......................................................................... 535

Neuroprotection in stress-induced neuropsychiatric disorders .............................................. 536 Adenosine A2A receptor antagonists for neuroprotection in stress .................................... 536 Role of neurotrophic factors in stress-induced psychiatric disorders ................................. 536 Stress and dementia ................................................................................................. 536

Neuroprotection in hearing loss ....................................................................................... 537 Causes of hearing loss .................................................................................................... 537 Pathomechanism of hearing loss ...................................................................................... 538 Prevention and treatment of hearing loss .......................................................................... 538

Hyperbaric oxygen for hearing loss ............................................................................. 538 Stem cell therapy for sensory hearing loss ................................................................... 539 Gene therapy for sensorineural hearing loss ................................................................. 539 Pharmaceutical approaches to hearing loss................................................................... 540 Prevention of drug-induced hearing loss ...................................................................... 541

Neuroprotection of peripheral nerves .............................................................................. 541 Neuroprotective agents for peripheral nerves .................................................................... 542

Acetyl-L-carnitine for peripheral nerve injuries .............................................................. 542 Atorvastatin for peripheral nerve injuries ..................................................................... 542 Erythropoietin for neuroprotection in peripheral nerve injuries ........................................ 543

Neuroprotection in peripheral nerve injuries ...................................................................... 543 Role of hyperbaric oxygen in peripheral nerve injuries ................................................... 543 Role of neurotrophic factors in peripheral nerve injuries ................................................. 544 Pharmacological approaches to Schwann cells .............................................................. 544 Role of gene therapy in neuroprotection of injured peripheral nerves ............................... 544 Schwann cell transplantation for peripheral nerve injury ................................................ 544 Targeting Wallerian degeneration slow protein for neuroprotection .................................. 544

Peripheral neuropathy .................................................................................................... 545 Neuroprotection in diabetic neuropathy ........................................................................ 545 Cell therapy for neuroprotection in diabetic neuropathy ................................................. 545 Gene therapy in diabetic neuropathy ........................................................................... 546 Neuroprotection in chemotherapy-induced neuropathy .................................................. 546

Neuroprotection in chronic inflammatory demyelinating polyradiculoneuropathy .................... 547 Neuroprotection in Charcot-Marie-Tooth disease 1A ........................................................... 547

12. Neuroprotection of the Optic nerve and the Retina ........................... 548 Introduction .................................................................................................................... 548 Optic neuropathy ............................................................................................................. 548

Pathophysiology ............................................................................................................ 548 Neuroprotection in optic neuritis ...................................................................................... 549

Azathioprine ............................................................................................................. 550 Flupirtine ................................................................................................................. 551 Eculizumab for neuromyelitis optica ............................................................................ 551 Sodium channel blockers ........................................................................................... 551 Resveratrol .............................................................................................................. 552 Satralizumab ............................................................................................................ 552

Neuroprotection in optic nerve trauma ............................................................................ 552 Potential regeneration of the optic nerve ........................................................................... 552

Neuroprotection of optic nerve in glaucoma .................................................................... 553 Aminoguanidine as a neuroprotective in glaucoma ............................................................. 554 Antiglutamate agents for neuroprotection of optic nerve ..................................................... 554 Betaxolol ...................................................................................................................... 554 NGF eye drops ............................................................................................................... 555 Targeting Aβ in glaucoma treatment ................................................................................. 555 TNF-α blockers for neuroprotection in glaucoma ................................................................ 555 Concluding remarks about neuroprotection in glaucoma...................................................... 556

Neuroprotection in retinal ischemia ................................................................................. 556 β-adrenoceptor antagonists ............................................................................................. 556 Brimonidine as a neuroprotective is ischemic retinopathy .................................................... 557 Endogenous neuroprotection in the retina ......................................................................... 557 Erythropoietin for neuroprotection of retinal ischemia ......................................................... 557 Gene therapy for retinal neuroprotection........................................................................... 558 Hyperbaric oxygen for central retinal artery occlusion ......................................................... 558 Levodopa for treating non-arteritic anterior ischemic optic neuropathy ................................. 558 Thioredoxin as a neuroprotective agent in retinal ischemia .................................................. 558

Protection against oxygen-induced retinopathy .............................................................. 559 Neuroprotection in macular degeneration ....................................................................... 559

Epidemiology ................................................................................................................. 559 Pathomechanism of AMD ................................................................................................ 559 Current treatment of AMD ............................................................................................... 560 Novel neuroprotective strategies against retinal degeneration ............................................. 561

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Antiangiogenic agents .................................................................................................... 562 Humanized MAb against Aβ ............................................................................................. 562 LXR agonists ................................................................................................................. 563 Neurotrophic factors for neuroprotection in AMD ................................................................ 563

CNTF for neuroprotection in AMD ................................................................................ 563 N-acetylserotonin derivatives ..................................................................................... 563

Nutritional protection against AMD ................................................................................... 563 Progestogenic hormones ................................................................................................. 564 Protection of retinal cells from oxidative-stress-induced apoptosis ........................................ 564 Sulindac ....................................................................................................................... 564 Tandospirone ................................................................................................................ 565 Cell therapy for macular degeneration .............................................................................. 565

Retinal pigment epithelial cells .................................................................................... 565 Stem cell transplantation in the retina ......................................................................... 565 Neural progenitor cells ............................................................................................... 566 hESC-derived RPE cells for AMD .................................................................................. 566

Gene therapy for retinal degeneration .............................................................................. 567 Combining stem cell and gene therapies for retinal disorders .......................................... 568

RNAi-based treatments for AMD ....................................................................................... 568 Neuroprotection in proliferative diabetic retinopathy ...................................................... 569

RNAi-based approaches to diabetic retinopathy.................................................................. 569 Clinical trials for optic nerve and retinal neuroprotection ................................................ 569

13. Neuroprotection during Anesthesia and Surgery .............................. 572 Introduction .................................................................................................................... 572 Anesthetic agents as neuroprotectives ............................................................................ 572

Barbiturates .................................................................................................................. 572 Thiopental ................................................................................................................ 573

Etomidate ..................................................................................................................... 574 Propofol ........................................................................................................................ 574 Ketamine ...................................................................................................................... 574 Gaseous anesthetics ....................................................................................................... 575

Isoflurane ................................................................................................................ 575 Xenon...................................................................................................................... 575

Local anesthetics ........................................................................................................... 576 Monitoring of CNS function during anesthesia and surgery ............................................. 576

Monitoring of cerebral function ........................................................................................ 576 Monitoring of spinal cord function during spinal surgery ...................................................... 576

Perioperative neuroprotection ......................................................................................... 577 Neuroprotection during cardiovascular procedures ......................................................... 578

CNS complications of cardiac surgery ............................................................................... 578 Neuroprotective strategies during cardiac surgery .............................................................. 579

Neuroprotection before anticipated or induced cardiac arrest .......................................... 580 Neuroprotection during coronary artery bypass grafting ................................................. 580 Preconditioing with hyperbaric oxygen ......................................................................... 581 Neuroprotection in aortic surgery ................................................................................ 582 Pharmacologic strategies for neuroprotection in aortic surgery ........................................ 582

Cerebral protection during organ transplantation surgery ............................................... 583 Cerebral protection in neurosurgery ................................................................................ 583

Cerebral angiography and endovascular surgery ................................................................ 583 Cerebral protection during surgery for arteriovenous malformations ..................................... 583 Cerebral protection during surgery of intracranial aneurysms .............................................. 583 Management of subarachnoid hemorrhage ........................................................................ 584

Vasospasm associated with subarachnoid hemorrhage ................................................... 584 Cerebral protection during carotid endarterectomy ............................................................. 587 Cerebral protection during surgery of brain tumors ............................................................ 587 Neuroprotective measures prior to surgery ........................................................................ 588

HBO preconditioning for neuroprotection during surgery ................................................ 588 Neuroprotection following surgery .................................................................................... 588

Neuroprotection by cranioplasty after decompressive craniectomy .................................. 589

Tables

Table 1-1: Historical landmarks in the development of neuroprotection ............................................ 34 Table 1-2: Intrinsic neuroprotective factors ................................................................................... 39 Table 1-3: Common features of pathophysiology of brain damage in diseases ................................... 47 Table 1-4: Place of neuroprotection in management of CNS disorders .............................................. 53 Table 1-5: Indications for the use of neuroprotection ..................................................................... 53 Table 1-6: Neuroprotective nanoparticles ...................................................................................... 60

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Table 2-1: A classification of neuroprotective agents ...................................................................... 64 Table 2-2: The neuroprotective effect of antiepileptic drugs ............................................................ 74 Table 2-3: Neuroprotective affect of minocycline in animal models ................................................... 78 Table 2-4: Classification of antioxidants or free radical scavengers with neuroprotective potential........ 86 Table 2-5: Role of erythropoietin in the nervous system ................................................................. 92 Table 2-6: Ionotropic glutamate receptors .................................................................................... 98 Table 2-7: Classification of metabotropic glutamate receptors (mGluRs) ........................................... 98 Table 2-8: Methods for neuroprotection based on nonpharmacological preconditioning ..................... 149 Table 3-1: Cerebrovascular diseases that are relevant to neuroprotection ....................................... 152 Table 3-2: Neuroprotective strategies for stroke .......................................................................... 164 Table 3-3: Selected effective combinations of hypothermia with other neuroprotective strategies

for the treatment of ischemic stroke in experimental models ................................................ 197 Table 3-4: Neuroprotective gene transfer in models of cerebral ischemia ........................................ 205 Table 3-5: Neuroprotective gene therapy in animal stroke models ................................................. 206 Table 3-6: Neuroprotective agents in clinical development for acute cerebrovascular disease ............ 208 Table 3-7: Some failed trials for neuroprotective therapy for stroke ............................................... 211 Table 3-8: Preclinical assessment of neuroprotective agents in acute stroke models ......................... 220 Table 3-9: Stroke prevention based on control of risk factors ........................................................ 222 Table 4-1: Classification of closed TBI ........................................................................................ 226 Table 4-2: Pathophysiologic responses to TBI and for neuroprotective strategies ............................. 228 Table 4-3: Current conventional management of traumatic brain injury .......................................... 236 Table 4-4: Neuroprotective strategies for traumatic brain injury .................................................... 238 Table 4-5: Intrinsic factors that influence regeneration in the central nervous system ...................... 259 Table 4-6: A classification of approaches to regeneration of the brain following injury ...................... 259 Table 4-7: Ongoing or completed clinical trials for neuroprotection in TBI ....................................... 261 Table 4-8: Discontinued or failed clinical trials for neuroprotection in TBI ........................................ 262 Table 5-1: Secondary mechanisms in spinal cord injury ................................................................ 267 Table 5-2: Neuroprotective and regenerative approaches for SCI ................................................... 269 Table 5-3: Clinical trials for neuroprotection in SCI ...................................................................... 284 Table 6-1: Neurodegenerative disorders with dementia ................................................................ 295 Table 6-2: Drugs in clinical trials for spinal muscular atrophy ........................................................ 302 Table 6-3: Pharmacological approaches to neuroprotection in CJD ................................................. 304 Table 6-4: Glutamate-based therapies in clinical development for neurodegenerative disorders ......... 306 Table 7-1: Prevalence of Parkinson's disease in major markets 2018-2028 ..................................... 310 Table 7-2: Factors in the etiology of Parkinson's disease ............................................................... 310 Table 7-3: Strategies for the treatment of Parkinson's disease ...................................................... 319 Table 7-4: Gene therapy techniques applicable to Parkinson disease .............................................. 333 Table 7-5: Current clinical trials of neuroprotective therapies for Parkinson disease ......................... 347 Table 7-6: Failed clinical trials of neuroprotective therapies for Parkinson disease ............................ 347 Table 7-7: Evaluation of neuroprotective agents for PD ................................................................ 348 Table 8-1: Relation of mutations in amyloid precursor protein to CNS disorders ............................... 353 Table 8-2: Risk factors for Alzheimer's disease ............................................................................ 367 Table 8-3: Cholinergic approaches to the treatment of Alzheimer's disease ..................................... 373 Table 8-4: Neuroprotective approaches to Alzheimer's disease ...................................................... 374 Table 8-5: Clinical trials in Alzheimer disease .............................................................................. 415 Table 8-6: Discontinued, failed or inconclusive clinical trials of Alzheimer disease ............................ 421 Table 8-7: Strategies for discovery of neuroprotective therapies for AD .......................................... 425 Table 9-1: Neuroprotective approaches in HD.............................................................................. 431 Table 10-1: Hypotheses for the pathogenesis of amyotrophic lateral sclerosis ................................. 443 Table 10-2: Genetic diagnostic biomarkers of ALS ........................................................................ 446 Table 10-3: Classification of neuroprotective agents for amyotrophic lateral sclerosis ....................... 448 Table 11-1: Therapeutic approaches to subcortical vascular dementia ............................................ 470 Table 11-2: Measures for neuroprotection against the sequelae of seizures ..................................... 475 Table 11-3: Neuroprotective effect of AEDs in animal models of status epilepticus (SE) .................... 475 Table 11-4: Specific therapies for MS based on postulated pathomechanisms .................................. 482 Table 11-5: Approved neuroprotective therapies for multiple sclerosis ............................................ 483 Table 11-6: Neuroprotective therapies for multiple sclerosis in clinical trials .................................... 484 Table 11-7: Measures to prevent acute bilirubin encephalopathy ................................................... 515 Table 11-8: Fever associated with neurologic disorders ................................................................ 517 Table 11-9: Approaches to neuroprotection in neonatal hypoxia-ischemia ....................................... 525 Table 11-10: Drugs with neuroprotective effect at mitochondrial level ............................................ 532 Table 11-11: Causes of sensorineural hearing impairment ............................................................ 537 Table 11-12: Strategies for prevention and treatment of sensorineural hearing loss ......................... 538 Table 11-13: Agents for neuroprotection of the peripheral nervous system ..................................... 542 Table 11-14: Neuroprotective agents for chemotherapy-induced peripheral neuropathy ................... 546 Table 12-1: Causes of optic neuropathy ...................................................................................... 548 Table 12-2: Clinical trials of neuroprotective therapies in optic neuritis ........................................... 550 Table 12-3: Neuroprotection of the optic nerve in glaucoma .......................................................... 553 Table 12-4: Strategies for neuroprotection in retinal ischemia ....................................................... 556 Table 12-5: Novel neuroprotective strategies against retinal degeneration ...................................... 561 Table 12-6: Clinical trials for retinal neuroprotection .................................................................... 570

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Table 13-1: CNS complications associated with cardiac procedures ................................................ 578 Table 13-2: Strategies for protection of the brain during cardiac surgery ........................................ 579 Table 13-3: Medical and surgical methods of cerebral vasospasm management ............................... 585 Table 13-4: Neuroprotection by prevention of vasospasm ............................................................. 585

Figures

Figure 1-1: A three-stage model of ischemic hypoxic disturbances of the brain .................................. 51 Figure 2-1: Mechanism of neuroprotective effect of sigma-1 receptor agonists .................................. 72 Figure 2-2: NMDA receptor ion channel complex .......................................................................... 102 Figure 2-3: Neuroprotective effect of galantamine ....................................................................... 123 Figure 3-1: Some steps in the ischemic cascade and site of action of neuroprotectives ..................... 153 Figure 3-2: Relationship between dementia and acute ischemic stroke ........................................... 163 Figure 3-3: Pathomechanism of ischemic stroke and neuroprotective strategies .............................. 165 Figure 3-4: Molecules involved in preconditioning for neuroprotection in ischemia ............................ 199 Figure 3-5: A roadmap for neuroprotection ................................................................................. 221 Figure 4-1: Cascade of events following traumatic brain injury ...................................................... 228 Figure 4-2: Neurometabolic cascade of mild TBI .......................................................................... 230 Figure 4-3: Secondary injury mechanisms after TBI ..................................................................... 231 Figure 4-4: Management of raised ICP after TBI .......................................................................... 237 Figure 5-1: Pathomechanism of acute spinal cord injury ............................................................... 267 Figure 6-1: Identification of protein targets in neurodegenerative disorders .................................... 309 Figure 7-1: Neuroprotective strategies against death of dopamine-containing neurons in PD ............. 316 Figure 8-1: Mechanisms of Aβ clearance ..................................................................................... 357 Figure 8-2: Nitric oxide neurotoxicity and neuroprotection in relation to Alzheimer disease ............... 364 Figure 8-3: Oxidative stress and Alzheimer disease ...................................................................... 366 Figure 8-4: Pathomechanism of AD ............................................................................................ 373 Figure 9-1: Role of HTT protein in pathogenesis of HD and points of intervention ............................. 439 Figure 11-1: A schematic overview of synaptopathies................................................................... 465 Figure 11-2: Common mechanisms of neural damage in cerebral ischemia and seizures ................... 474 Figure 11-3: Role of neuroprotection in epilepsy and its treatment ................................................. 474 Figure 11-4: Mechanisms of neonatal hypoxia-ischemia and targets for neuroprotection ................... 525