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Neuroprotection - Drugs, Markets and Companies

This report describes the role of neuroprotection in acute disorders such as stroke and injuries of the nervous system as well as in chronic diseases such as neurodegenerative disorders because many of the underlying mechanisms of damage to neural tissues are similar in all these conditions and several products are used in more than one disorder. Over 500 products have been investigated for neuroprotective effects including those from the categories of free radical scavengers, anti-excitotoxic agents, apoptosis (programmed cell death) inhibitors, anti-inflammatory agents, neurotrophic factors, metal ion chelators, ion channel modulators and gene therapy. Some of the agents are old established pharmaceuticals whereas others are new biotechnology products.

Pathomechanisms of diseases are described with steps at which neuroprotective therapies are directed. Diseases covered include cerebrovascular disorders, traumatic brain injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy and ischemic optic neuropathy as well as retinal degeneration. Although anesthetics such as propofol are neuroprotective as well, neuroprotection during surgery and anesthesia is discussed with the aim of preventing and treating complications that result in CNS damage.

The report contains profiles of 139 companies that have a neuroprotective product or products along with 120 collaborations. Some of the products in development at academic institutions that do not have a commercial sponsor are also included. Although an up-to-date search of the literature was performed and selected 1,040 references are included. Clinical trials of various neuroprotective agents are described and failures of trials are analyzed with suggestions for improving the selection of drugs and design of trials.The report is supplemented with 71 tables and 15 figures.

Market analysis of currently used products that have a neuroprotective effect are analyzed for the year 2013. Some of these products are approved for other indications but are known to have a neuroprotective effect. With the approval of new products and takeover of markets for obsolete symptomatic therapies, the neuroprotection market value will rise by the year 2018 when it will constitute a major and important component of the CNS market. Forecasts are made until 2023. By that time neuroprotection will be an established part of the neurological practice and measures will be available to achieve this effectively.

Table of Contents

Part I

0. Executive Summary 26

1. Introduction 30

  • Definitions 30
  • Historical development of neuroprotection 30
  • Intrinsic neuroprotective factors 31
  • Neuroprotective gene expression 32
  • Upregulation of GADD34 32
  • Induction of NR4A proteins by CREB in neurons 33
  • Elevation PGC-1α for neuroprotection in PD 33
  • Neurotrophic factors 33
  • Intrinsic nonenzymatic antioxidants 34
  • Activation of transcription factor Nrf2 34
  • Intrinsic neuroprotective proteins 34
  • αB-crystallin 34
  • Excitatory amino acid transporters 35
  • Extracellular serine protease thrombin 35
  • Galanin 35
  • Neuroglobin 35
  • Nuclear factor I-A 36
  • Prion protein 36
  • Rai adaptor protein 37
  • Stem cell factor 37
  • Role of the immune system in neuroprotection 37
  • Role of cerebral metabolism in neuroprotection 38
  • Role of circadian genes in neuroprotection 38
  • Role of blood-brain barrier in neuroprotection 39
  • Role of the gut microbiota in development of integrity of the BBB 39
  • Induction of DNA repair enzymes for neuroprotection 39
  • Microtubule-based neuroprotective response to axonal injury 40
  • Pathomechanisms of CNS injury as basis for neuroprotection 40
  • Biomarkers of neurological disorders and neuroprotection 40
  • CNS biomarker identification using proteomics 41
  • Brain imaging for detection of biomarkers 41
  • Role of neuroprotection in various neurological disorders 41
  • Neuroprotection and neuroregeneration 42
  • Acute versus chronic neuroprotection 43
  • Discovery and evaluation of neuroprotective agents 43
  • Neuroprotective drug discovery 43
  • Discovery of CNS drugs that penetrate the blood-brain barrier 44
  • In vitro assays for the evaluation of neuroprotective agents 44
  • Oxidative injury model to test neuroprotective drugs 45
  • Apoptosis model for designing neuroprotective drugs 45
  • Transgenic mouse models of neurological disorders 45
  • Evaluating effects of neuroprotective drugs on living brain slices 45
  • Role of brain imaging in neuroprotective drug discovery and development 46
  • Positron emission tomography 46
  • Role of single photon emission computed tomography 47
  • Functional CT scanning to evaluate cerebrovascular protection 47
  • Magnetic resonance imaging for the evaluation of neuroprotectives 47
  • Application of nanotechnology to neuroprotection 48
  • Evaluation criteria for potential neuroprotective agents 48

2. Neuroprotective Agents 50

  • Classification of neuroprotective agents 50
  • α2 adrenoreceptor agonists 54
  • Dexmedetomidine 54
  • Activated protein C 55
  • Activity-dependent neuroprotective protein 55
  • Davunetide 55
  • Adenosine analogs 55
  • Propentofylline 56
  • Antidepressants 56
  • Antidepressant-induced neurogenesis 56
  • Neurogenesis induced by electroconvulsive therapy 57
  • Neuroprotective effect of selective serotonin reuptake inhibitors 57
  • Antiepileptic drugs as neuroprotectives 59
  • Phenytoin 60
  • Valproic acid 60
  • Levetiracetam 60
  • Antiinflammatory agents 61
  • Aspirin 61
  • Interleukin-1 antagonists 61
  • COX-2 inhibitors 62
  • Nimesulide 62
  • Gold microparticles as anti-neuroinflammatory agents 62
  • Minocycline 62
  • Prostaglandin receptor antagonists 63
  • Anti-apoptosis agents 64
  • Activated protein C 65
  • Calpain inhibitors 65
  • Caspase inhibitors 65
  • DNA binding drugs 65
  • Lithium 66
  • Melatonin 66
  • Olesoxime 66
  • Omega-3 fatty acids 67
  • Docosahexaenoic acid 67
  • Poly(ADP-ribose) polymerase inhibitors 67
  • Prevention of apoptosis by binding of proNGF to sortilin 68
  • Antioxidants/free radical scavengers 69
  • Free radical generation 69
  • Natural defenses against oxidative stress 69
  • Effects of oxidative damage 69
  • Oxidative damage and aging 69
  • Neuronal damage by free radicals 70
  • Oxidative damage and neurodegenerative disorders 70
  • Measures to control oxidative stress 70
  • Categories of therapeutic antioxidants 71
  • Alpha-phenyl-tert-butylnitrone 71
  • Coenzyme Q10 72
  • Dihydroergocryptine 72
  • Flavonoids 73
  • Mitochondria-targeted antioxidants 73
  • Nanoparticles as neuroprotective antioxidants 73
  • Neuroleptics as antioxidants 74
  • Nitrones 74
  • Translation of antioxidant neuroprotection from preclinical to clinical 75
  • Carbon monoxide and heme oxygenase 75
  • Cell transplants 75
  • Cells secreting neuroprotective substances 75
  • Stem cells 76
  • Stem cell activation for neuroprotection/regeneration by glucocorticoids 76
  • Use of neural stem cells to construct the blood brain barrier 76
  • Cytokines 77
  • Erythropoietin 77
  • Non-erythropoietic EPO variants and mimics 78
  • Granulocyte colony-stimulating factor 79
  • Delta-opioid receptor agonists 79
  • Delta opioid peptide-induced hibernation for neuroprotection 80
  • FK960 80
  • Gene therapy 80
  • Glucagon-like peptide 81
  • Glatiramer acetate 81
  • Glutamate antagonists 82
  • Neuroprotection by scavenging blood glutamate 83
  • N-acylethanolamines for protection against glutamatergic excitotoxicity 83
  • Glutamate transporters 83
  • Glutamate transporter-mediated neuroprotective effect of drugs 84
  • Neuroprotection by targeting KAI subunit of kainate receptor 85
  • Glycine-proline-glutamate analogs 85
  • Hydrogen sulfide 85
  • Hibernation induced by hydrogen sulfide 86
  • NMDA receptor ion channel complex 86
  • NMDA receptor antagonists 87
  • NMDA NR2B subunit receptor antagonists 87
  • Ifenprodil 87
  • Memantine as a neuroprotective agent 88
  • Magnesium 88
  • NAALADase inhibitors 88
  • Gacyclidine 88
  • N-alkylglycines 89
  • AMPA receptor modulators 89
  • Metabotropic glutamate receptor modulators 89
  • Cannabinoids 90
  • Dexanabinol 91
  • Glutathione 91
  • Heat shock proteins 91
  • Histone deacetylase inhibitors for neuroprotection 92
  • Hormones 92
  • Estrogen and neuroprotection 92
  • Neuroprotective effect of estrogen receptor ligands 93
  • Selective estrogen receptor modulators 93
  • Mitochondrial mechanisms of estrogen neuroprotection 94
  • Insulin 94
  • Ion Channel modulators 95
  • Calcium channel blockers. 95
  • Ziconotide 95
  • Na+ channel blockers. 96
  • Neuroprotective potassium channel inhibitors 96
  • Kynurenine inhibitors 96
  • Leukocyte adhesion inhibitors 97
  • Modafinil 98
  • Neural regeneration protein 98
  • Neurite outgrowth-promoting prostaglandin compounds 98
  • Neuroimmunophilins 99
  • Cyclosporin-A 99
  • FK506 99
  • Rapamycin 100
  • Neurotrophic factors 100
  • Activity-dependent neurotrophic factor 100
  • Bone morphogenetic proteins 101
  • Brain-derived neurotrophic factor 101
  • Ciliary neurotrophic factor 101
  • Fibroblast growth factors 102
  • Glial cell line-derived neurotrophic factor 103
  • Insulin-like growth factor 103
  • Nerve growth factor 103
  • Neurotrophins 104
  • Osteogenic protein-1 105
  • Pigment epithelium-derived factor 105
  • Transforming growth factor-β1 105
  • Vascular endothelial growth factor 105
  • Neurotrophic factor-related neuroprotective agents 106
  • Amitriptyline as a TrkA and TrkB receptor agonist 106
  • Colivelin 106
  • Gambogic amide 106
  • Inosine 107
  • Meteorin 107
  • Oxygen-regulated protein 150 kD 107
  • Prosaptide 107
  • Siagoside 108
  • Small molecule activators of the Trk receptors 108
  • Nicotine and nicotinic receptor agonists 108
  • Neuroprotective effect of galantamine mediated via α7nAChRs 109
  • Galantamine-induced Aβ clearance via α7nAChRs 109
  • Nitric oxide-based neuroprotection 110
  • Nitric oxide synthase inhibitors 110
  • Nitric oxide mimetics 110
  • Nitric oxide donating derivatives 111
  • Nootropics 111
  • Piracetam 112
  • Nutraceuticals and naturally-derived compounds 112
  • Cinnamon 112
  • Coffee 113
  • Creatine 113
  • Curcumin/curry 113
  • Mechanism of neuroprotective effect of curcumin 114
  • Flavonoids 114
  • Glyceryltriacetate 114
  • Green tea 114
  • Herbal preparations 115
  • Flavonoid wogonin 115
  • Ginseng 115
  • Nicotinamide 115
  • Punicalagin from pomegranate 116
  • Resveratrol 116
  • Osmotic diuretics 117
  • Mannitol 117
  • Osteopontin 117
  • Oxygen therapeutics 118
  • Oxygen carriers 118
  • Hemoglobin-based oxygen carriers 118
  • Perfluorocarbons as oxygen carriers 119
  • Hyperbaric oxygen therapy 120
  • P7C3 compounds 120
  • Peptides 120
  • C3-derived peptide for neuroprotection and neuroregeneration 120
  • Corticotropin-releasing hormone 121
  • Thyrotropin-releasing hormone 121
  • Vasoactive intestinal peptide 121
  • Pharmacological preconditioning 122
  • PPARs as drug targets for neuroprotection 122
  • Riluzole 123
  • Role of RNA interference in neuroprotection 123
  • Role of miRNA in neuroprotection 123
  • Sigma receptor agonists as neuroprotective agents 124
  • SIRT group of proteins 124
  • Statins 125
  • Steroids 126
  • Dehydroepiandrosterone 126
  • HF0220 126
  • Sulforaphane 127
  • Tauroursodeoxycholic acid 127
  • Tetanus toxin as a neuroprotective agent 127
  • Thrombolytic agents as neuroprotective agents 128
  • Uncoupling protein 2 128
  • Vaccines as neuroprotectives 128
  • Vitamins as neuroprotective agents 129
  • Vitamin B12 129
  • Vitamin D 129
  • Non-pharmacological approaches to neuroprotection 130
  • Caloric restriction 130
  • Electrical fields for improvement of cerebral function in neurodegeneration 130
  • Environmental enrichment 131
  • Hypothermia 131
  • Limitations of hypothermia 131
  • Hypothermic neuroprotection in hypoxia-ischemia 132
  • Ketogenic diet 132
  • Mental training 133
  • Mediterranean diet 133
  • Nonpharmacological preconditioning for neuroprotection 133
  • Physical exercise 134
  • Suspended animation and neuroprotection 135
  • Transcranial magnetic stimulation 135

3. Neuroprotection in Cerebrovascular Disease 136

  • Introduction 136
  • Pathophysiology of cerebral ischemia 136
  • Calcium overload 137
  • Ion channel dysfunction in stroke 137
  • Role of oxygen free radicals in cerebral ischemia 138
  • Role of nitric oxide in cerebral ischemia 138
  • Glutamate as a biomarker of stroke 138
  • Cerebral edema in stroke 138
  • Gene expression in response to cerebral ischemia 139
  • Induction of heat shock proteins in stroke 139
  • Role of cytokines and adhesion molecules in stroke 139
  • Tumor necrosis factor-α 140
  • Interleukin-1 and IL-6 140
  • Adhesion molecules 140
  • DNA damage and repair in cerebral ischemia 140
  • Role of neurotrophic factors in stroke 141
  • Problems requiring investigation of the role of NTFs in stroke 141
  • Role of Poly(ADP-ribose) polymerase (PARP) gene 141
  • Role of protease-activated receptor 1 142
  • Reperfusion injury after cerebral ischemia 142
  • Neuroprotection according to zones in cerebral infarction 142
  • Zone of ischemic infarction 142
  • Penumbra 143
  • Current management of stroke 143
  • Neuroprotection in stenosis of intracranial arteries 144
  • Neuroprotection in transient ischemic attacks 144
  • Secondary prevention of stroke 144
  • Neuroprotective therapies for stroke 145
  • αB-crystallin as a neuroprotectant in stroke 146
  • Acid-sensing ion channel blockers 146
  • AMPA receptor antagonists as neuroprotectives for stroke 146
  • Zonampanel 146
  • Antiapoptotic neuroprotectives 146
  • NIM811 147
  • Creatine as neuroprotective in stroke 147
  • Lithium as a neuroprotective in stroke 147
  • TUDCA as a neuroprotective in stroke 147
  • Antiepileptic drugs as neuroprotectives in stroke 148
  • Tiagabine 148
  • Topiramate 148
  • Zonisamide 148
  • Anti-HMGB1 monoclonal antibody 149
  • Antioxidant approaches 149
  • Carnosine as a neuroprotective in stroke 149
  • Dehydroascorbic acid 150
  • Tocotrienols 150
  • Uric acid 151
  • Antiglutamate compounds 151
  • MRZ 2/576 151
  • L-Phenylalanine 151
  • Arimoclomol for stroke 152
  • Cardiac glycosides as neuroprotectives in stroke 152
  • Clenbuterol 152
  • Coagulation inhibitors as neuroprotectives 152
  • Heparin and enoxaparin 153
  • Warfarin vs dabigatran 153
  • Apixaban 153
  • Cox-2 inhibitors for ischemic stroke 153
  • Curcumin as a neuroprotectant in stroke 154
  • Docosahexaenoic acid for ischemic stroke 154
  • Ephrin-A5 blockers 154
  • Estrogen for stroke 155
  • Extendin-4 156
  • Flavones for neuroprotection in stroke 156
  • Granulocyte-macrophage colony-stimulating factor for cerebral ischemia 157
  • Hamartin induction by cerebral ischemia as a basis for neuroprotection 157
  • Histone deacetylase inhibitors for neuroprotection in stroke 157
  • Modulation of histamine H2-receptors 158
  • Inosine for stroke 158
  • Insulin-like growth factor-I 158
  • Intravenous immunoglobulin as neuroprotective in stroke 158
  • Ischemic preconditioning for neuroprotection in stroke 159
  • Ketone bodies for neuroprotection in stroke 159
  • Mineralocorticoid receptor blockade for neuroprotection 160
  • miR-223 and neuroprotection in stroke 160
  • Multifunctional neuroprotective agents 160
  • NA-1 as neuroprotective against ischemic stroke 161
  • Nasal delivery of neuroprotective agents in stroke 161
  • Neuroserpin as a neuroprotective in stroke 161
  • N-2-mercaptopropionyl glycine 161
  • NeuroAid 162
  • Neurotrophic factors as neuroprotectives for stroke 162
  • Brain-derived neurotrophic factor 162
  • Fibroblast growth factor 163
  • G-CSF 163
  • Glial cell line-derived neurotrophic factor 163
  • Insulin-like growth factor-1 163
  • Neuregulin-1 164
  • NO-based strategies for neuroprotection in cerebral ischemia 164
  • Pannexin channel blockers for neuroprotection in stroke 165
  • Perlecan domain V 165
  • Peroxisome proliferator-activated receptor-γ agonists 165
  • PGE2 EP2 receptor activation 165
  • Pioglitazone for reduction of stroke risk in diabetes 166
  • Progesterone 166
  • Propofol as neuroprotective in stroke 166
  • Proteoglycan-degrading enzymes 166
  • Proteosome inhibitors 167
  • Statins for prevention and neuroprotection in stroke 167
  • Sildenafil 168
  • Src receptor blockade 168
  • Stroke vaccine 168
  • SUN N4057 169
  • Thrombosis inhibitors 169
  • Aspirin 169
  • Clopidogrel 169
  • Dipyridamole 170
  • Vitamin E for neuroprotection in stroke 170
  • Neuroprotection in reperfusion injury 170
  • Prevention of hemorrhage following ischemic stroke 171
  • Non-pharmacological neuroprotective therapies for stroke 171
  • Preconditioning for neuroprotection against cerebral ischemia 171
  • Hypothermia for neuroprotection in acute stroke 172
  • Hyperbaric oxygen therapy for neuroprotection in acute stroke 172
  • Infrared laser therapy for ischemic stroke 173
  • Neurostimulation of sphenopalatine ganglion 174
  • Neurosurgical procedures for neuroprotection in stroke 174
  • Neurorehabilitation in relation to neuroprotection in stroke 175
  • Protective effect of physical activity on stroke in the elderly 175
  • Cell therapy for stroke 175
  • Stem cell transplant for stroke 176
  • Immortalized cell grafts for stroke 176
  • Stimulation of instrinsic stem cells for repair of brain in stroke 177
  • Neuroprotective vaccines for stroke 177
  • Gene therapy for neuroprotection in cerebrovascular disease 177
  • Regulation of microRNAs for neuroprotection in cerebral ischemia 179
  • RNAi-based therapy for neuroprotection in stroke 179
  • Neuroprotective therapies for cerebral ischemia: clinical trials 180
  • Albumin 181
  • Free radical scavengers 181
  • DP-b99 182
  • Mildronate 183
  • Minocycline for neuroprotection in stroke 183
  • Perindopril 183
  • Failed clinical trials of neuroprotection in stroke 183
  • Ancrod 185
  • Aptiganel 185
  • Cerovive 185
  • Citicoline 186
  • Desmoteplase 187
  • Erythropoietin as a neuroprotective in stroke 188
  • SPD 502 189
  • Tirilazad mesylate 189
  • Selfotel 189
  • Lubeluzole 189
  • Nalmefene 190
  • Gavestinel 190
  • Nimodipine 190
  • Sipatrigine 190
  • Causes of failure of stroke trials 191
  • Measures for prevention of failures in stroke trials 192
  • Design of acute stroke trial to facilitate drug approval 194
  • The ideal neuroprotective agent for stroke 194
  • Future prospects for neuroprotection in stroke 195

4. Neuroprotection in Traumatic Brain Injury 198

  • Introduction 198
  • Cerebral hypoxia/ischemia as a complication of trauma 198
  • Epidemiology of TBI 198
  • TBI in the military 199
  • Pathophysiology of TBI 199
  • Immediate damage following TBI 200
  • Cerebral edema following TBI 200
  • Neurometabolic cascade after TBI 201
  • Delayed damage following TBI 201
  • Mechanism of axonal damage after TBI 202
  • Role of neuroinflammation in TBI 202
  • BBB damage after TBI 202
  • Molecular events following TBI 203
  • Chronic traumatic encephalopathy 203
  • Neurocognitive sequelae of TBI 204
  • Changes in neurotrophic factors following TBI 205
  • Changes in neurotransmitters following TBI 205
  • Proteomics of TBI 205
  • Genetic influences on outcome following TBI 206
  • Management of TBI 206
  • Control of intracranial pressure and cerebral edema 207
  • Corticosteroids 207
  • Neuroprotection in TBI 208
  • Amantadine 209
  • Antiepileptic drugs for prevention of seizures and neuroprotection 209
  • Antioxidants 210
  • Barbiturates 210
  • β- and γ-secretase inhibitors 210
  • Beta blockers 210
  • Bradykinin B2 antagonists 211
  • Cell cycle inhibitors for TBI 211
  • COX-2 inhibitors for neuroprotection in TBI 211
  • Cyclosporin for neuroprotection in TBI 212
  • Dexanabinol for TBI 212
  • Erythropoietin for neuroprotection in TBI 212
  • Gold implants for neuroprotection in focal TBI 213
  • Histone deacetylase inhibitors for neuroprotection in TBI 213
  • KN 38-7271 213
  • Levosimendan 213
  • Magnesium sulfate 214
  • Minocycline for TBI 214
  • Multipotential neuroprotective agents for TBI 214
  • Nutritional approaches to neuroprotection in TBI 214
  • Branched chain amino acids to ameliorate cognitive impairment in TBI 215
  • Creatine for neuroprotection in TBI 215
  • Nicotinamide for neuroprotection in TBI 216
  • Omega 3 fatty acids as neuroprotectives in TBI 216
  • Neurotrophic factors for TBI 216
  • Neurosteroids as neuroprotective agents for TBI 217
  • NMDA receptor antagonists 218
  • NP-1 218
  • Nogo-A inhibitor 219
  • Oxygen carriers for TBI 219
  • Polyethylene glycol for neuroprotection in TBI 220
  • Propofol for neuroprotection in TBI 220
  • Rapamycin as neuroprotective in TBI 220
  • Simvastatin as neuroprotective in TBI 220
  • Thyrotropin-releasing hormone analogs 221
  • Traxoprodil 221
  • Biological approaches to neuroprotection in TBI 221
  • Antisense approaches to TBI 221
  • Cell therapy for TBI 222
  • Gene therapy for TBI 222
  • Vaccines for TBI 222
  • Non-pharmaceutical approaches to neuroprotection in TBI 223
  • Deep brain stimulation for TBI 223
  • Hyperbaric oxygen therapy for TBI 223
  • Hypothermia 223
  • Reduction of microglial migration after TBI 224
  • Vacuum for mechanical tissue resuscitation in TBI 224
  • Prophylactic neuroprotection against TBI 224
  • Role of helmets in protection against TBI 224
  • Role of physical exercise in protection against TBI 225
  • Clinical trials of neuroprotective agents in TBI 225
  • Ongoing clinical trials in TBI 225
  • Failed clinical trials in TBI 226
  • Differences between clinical trials and studies in animal models of TBI 227
  • Subgroup analysis 227
  • Improving the clinical trial design 227
  • Clinical trials combining multiple treatment strategies 228
  • Shortening the trial time 228
  • Conclusions and future prospects of neuroprotection in TBI 228

5. Neuroprotection in Spinal Cord Injury 230

  • Introduction 230
  • Pathophysiology of SCI 230
  • Secondary mechanisms of SCI 231
  • Neurotrophic factor changes in SCI 232
  • Management of SCI 233
  • Pharmacological neuroprotective agents for SCI 234
  • 4-aminopyridine 234
  • Antibodies as neurite growth inhibitors in SCI 234
  • Bacterial enzyme chondroitinase ABC 234
  • Docosahexaenoic acid as neuroprotective in SCI 235
  • Erythropoietin as a neuroprotective in SCI 235
  • Free radical scavengers for neuroprotection in SCI 235
  • Gacyclidine 236
  • GYKI 52466 236
  • Immunosuppressants as neuroprotectants in SCI 236
  • Interleukin-10 for neuroprotection in SCI 236
  • Matrix metalloproteinase inhibitors for SCI 237
  • Methylprednisolone 237
  • Minocycline as neuroprotective in SCI 237
  • Neurotrophic factors for neuroprotection after SCI 238
  • Promotion of regeneration of neurons in SCI 239
  • Rho pathway and Rho antagonists in SCI 239
  • Selenium as a neuroprotective for SCI 239
  • Sialidase for enhancing recovery after SCI 240
  • Targeting the inflammatory response for neuroprotection in SCI 240
  • Uric acid as neuroprotective in SCI 240
  • Non-pharmacological approaches to SCI 240
  • Hyperbaric oxygen therapy 240
  • Hypothermia for SCI 241
  • Cell therapy for SCI 241
  • Autoimmune T cells against CNS myelin-associated peptide 241
  • Fetal neural grafts for SCI 241
  • Olfactory-ensheathing cells for SCI 241
  • Oligodendrocyte precursor cells for treatment of SCI 242
  • Schwann cell transplants for SCI 242
  • Transplantation of glial cells for SCI 242
  • Stem cells for SCI 243
  • Bone marrow stem cells for SCI 243
  • Embryonic stem cells for SCI 243
  • Transplantation of induced pluripotent stem cells in SCI 244
  • Transplantation of MSCs for SCI 244
  • Transplantation of NSCs for SCI 244
  • Transdifferentiation of stem cells into cholinergic neurons for SCI 245
  • Gene therapy for SCI 245
  • Combined approaches to spinal cord injury 246
  • Discovery of new targets for neuroprotective therapies in SCI 247
  • Clinical trials in SCI 247

6. Neuroprotection in Neurodegenerative Disorders 250

  • Introduction 250
  • Pathomechanism of neurodegeneration 250
  • Dual role of γ-synuclein in neuroprotection and neurodegeneration 250
  • Lack of neurotrophic factors 251
  • Neuroinflammation in neurodegenerative disorders 251
  • Neurodegeneration associated with protein misfolding 251
  • Modulation of neurodegeneration by molecular chaperones 251
  • Intrabodies targeting protein misfolding in neurodegeneration 252
  • Targeting proteins aggregation to prevent amyloid formation 252
  • Tau and neurodegeneration 252
  • Role of apoptosis in neurodegenerative disorders 253
  • Role of glia in neurodegeneration 253
  • Role of metals in neurodegeneration 253
  • Spread of neurodegeneration 254
  • TDP-43 proteinopathy and neurodegenerative diseases 254
  • Viral infections and neurodegeneration 254
  • AIDS and the nervous system 254
  • Avian influenza as cause of neurodegeneration 256
  • Neurodegenerative disorders with dementia 256
  • Dementia with Lewy bodies 257
  • Pick disease 257
  • Progressive supranuclear palsy 258
  • Genetic disorders with neurodegeneration 258
  • Batten disease 258
  • Friedrich ataxia 259
  • Pathomechanism of FA 259
  • Neuroprotection in FA 259
  • Niemann-Pick type C disease 260
  • Creutzfeldt-Jakob disease 260
  • Potential neuroprotectants for CJD 260
  • Approaches to neuroprotection in neurodegenerative disorders 261
  • Glutamate-based therapies for neurodegenerative disorders 262
  • Histone deacetylase inhibitors for neurodegenerative disorders 262
  • Iron chelation for neuroprotection 263
  • Mitochondria permeability transition pore complex and neuroprotection 263
  • Genomics-based research in neurodegenerative diseases 263

7. Neuroprotection in Parkinson Disease 264

  • Introduction 264
  • Epidemiology of Parkinson's disease 264
  • Pathophysiology of Parkinson's disease 264
  • Oxidative stress 265
  • Excitotoxicity 266
  • Asynchronous neuronal activity 266
  • Apoptosis 266
  • Role of neurotrophic factors 266
  • Role of misfolding proteins 266
  • Genetic factors in PD 267
  • Alteration of dopamine homeostasis 268
  • Neuroprotective strategies for PD based on pathomechanism 269
  • A genetic animal model of PD for testing neuroprotective strategies 269
  • Aldehyde dehydrogenase 1 protects nigrostriatal dopaminergic neurons 270
  • RNAi screening to identify neuroprotective genes in a PD model 270
  • Management of Parkinson's disease 270
  • Limitation of conventionally administered dopamine therapy 272
  • Treatment of dementia associated with PD 272
  • Neuroprotective therapy in PD 273
  • Neuroprotective effect of currently used drugs for PD 273
  • Pramipexole 273
  • Rasagiline mesylate 274
  • Ropinirole 275
  • Selegiline 275
  • Non-pharmacological strategies for neuroprotection in PD 276
  • Effect of exercise and environmental enrichment on PD 276
  • Low-calorie diet in PD 276
  • Development of neuroprotective therapies for PD 277
  • 2B3-201 for targeted delivery of methylprednisolone 277
  • 9-methyl-β-carboline 277
  • Adenosine AA2 receptor antagonists 277
  • Antiapoptotic strategies for PD 278
  • Augmenting CNS glucocerebrosidase activity 278
  • Calcium channel blockers for PD 278
  • Cell therapies for PD 279
  • Stem cells for PD 279
  • Activation of endogenous stem cells and neural precursors 279
  • Cogane 280
  • Creatine and minocycline 281
  • Conserved dopamine neurotrophic factor for PD 281
  • Free radical scavengers for neuroprotection in Parkinsonγs disease 281
  • Antioxidants 281
  • Diapocynin 282
  • Tea extracts as neuroprotectives 282
  • Gene therapy for PD 282
  • Implantation of genetically engineered cells 282
  • Gene therapy using GDNF and neurturin 283
  • Glutamic acid decarboxylase gene therapy 283
  • Parkin gene therapy 284
  • Concluding remarks about gene therapy for PD 284
  • Heat shock protein 70 285
  • Liver X receptor β agonists 285
  • Melatonin as a neuroprotectant in PD 285
  • Nicotine as a neuroprotective in PD 285
  • Neuroprotective effect of leucine-rich repeat kinase-2 inhibitors 286
  • Neuroprotective effect of DJ-1 protein 286
  • Neurotrophic factors 286
  • Basic fibroblast growth factor for PD 286
  • BDNF for PD 287
  • GDNF for PD 287
  • MANF for PD 288
  • Neurturin for PD 288
  • Platelet derived growth factor 288
  • Clinical trials with NTFs 288
  • Nrf2-mediated neuroprotection in PD 289
  • Omega-3 polyunsaturated fatty acids 289
  • RAB3B overexpression 289
  • RNAi therapy for PD 290
  • Safinamide 290
  • Sirtuin 2 inhibitors for neuroprotection in PD 290
  • Statins and PD 291
  • Targeting Bax 291
  • Vitamin D for neuroprotection in PD 291
  • Vaccine for PD 292
  • Clinical trials of neuroprotection in Parkinson's disease 292
  • Evaluation of neuroprotective therapies for PD 294
  • Current status and future challenges for neuroprotection in PD 295

8. Neuroprotection in Alzheimer Disease 298

  • Introduction 298
  • Pathomechanism of Alzheimer's disease 298
  • Role of glutamate transport dysfunction in AD 299
  • Role of neurotrophic factors in the pathomechanism of AD 299
  • Management of Alzheimer's disease 299
  • Neuroprotection in Alzheimer's disease 300
  • Inhibition of Aβ formation and aggregation 301
  • AN-1792 301
  • Cadmium telluride nanoparticles prevent Aβ fibril formation 302
  • Clioquinol 302
  • Colostrinin 303
  • FKBP52 for neuroprotection from Cu toxicity in AD 303
  • Monoclonal antibody m266 303
  • Phenserine 303
  • Secretase inhibitors 304
  • Inhibition of neuroinflammation 304
  • Etanercept 304
  • Neurotrophic factors/ gene therapy 305
  • NGF gene therapy 305
  • AL-108 306
  • Targeting plasminogen activator inhibitor type-1 gene 306
  • Estrogen and AD 307
  • Antioxidants 307
  • NSAIDS 307
  • Melatonin for AD 307
  • Memantine 308
  • Dimebon 308
  • Cerebrolysin 309
  • Curcumin as a neuroprotectant in Alzheimer disease 310
  • Ginko biloba 310
  • Tetrahydrocannabinol for neuroprotection in AD 311
  • Ladostigil tartrate 311
  • Phosphodiesterase inhibitors as neuroprotectives 311
  • PPAR-γ agonists 312
  • Role of statins in reducing the risk of AD 312
  • Combined therapeutic approaches to AD 313
  • Clinical trials in AD 313
  • Future prospects of neuroprotection in AD 320
  • Mild cognitive impairment 321
  • Relation of MCI to AD 321
  • Neuroprotection in MCI 322

9. Neuroprotection in Huntington Disease 324

  • Introduction 324
  • Pathophysiology of HD 324
  • Management of Huntington's disease 326
  • Neuroprotection in Huntington's disease 326
  • Antipsychotic D2 and 5-HT1A antagonists 327
  • Caspase inhibitors 327
  • Clioquinol for HD 327
  • Creatine for stabilizing bioenergetic defects 328
  • Cysteamine 328
  • Drugs that block inappropriate calcium release from neurons 328
  • Enhancing protease activity for clearance of mHtt 328
  • Eicosapentaenoic acid 329
  • Free radical scavengers 329
  • Histone deacetylase inhibitors 329
  • Inhibitors of polyglutamine aggregation HD 330
  • Metal-protein attenuating compounds 330
  • Pridopidine 331
  • RRAS signaling pathway inhibition 331
  • Simvastatin as a neuroprotective in HD 331
  • Single chain Fv antibodies 331
  • SIRT1 activators for neuroprotection in HD 332
  • SIRT2 inhibitors for neuroprotection in HD 332
  • Synaptic activation of NMDA receptors 333
  • Targeting mutant huntingtin protein 333
  • Tetrabenazine 333
  • Combinatorial therapy and targeting multiple pathways in HD 334
  • Cell transplants 334
  • Neurotrophic factors and gene therapy 335
  • RNAi and antisense therapies for Huntington's disease 335

10. Neuroprotection in Amyotrophic Lateral Sclerosis 338

  • Introduction 338
  • Pathophysiology of ALS 338
  • Neuroprotective therapies for ALS 341
  • Activated protein C 342
  • AEOL 10150 343
  • AIMSPRO 343
  • Anakinra 343
  • Antisense therapy 344
  • Arimoclomol for ALS 344
  • Ceftriaxone for ALS 344
  • Coenzyme Q10 for ALS 345
  • COX-2 inhibitors for ALS 345
  • Creatine for ALS 345
  • Dexpramipexole 346
  • Diallyl trisulfide 346
  • Erythropoietin for ALS 346
  • Gene therapy for ALS 346
  • Glatiramer acetate 347
  • GM602 347
  • Insulin-like growth factor 348
  • Ketogenic diet for neuroprotection in ALS 348
  • Lenalidomide 349
  • Lithium for neuroprotection in ALS 349
  • Melatonin for ALS 349
  • Methylcobalamin 350
  • Minocycline for ALS 350
  • Olesoxime as neuroprotective for ALS 350
  • ONO-2506 for ALS 350
  • Riluzole 351
  • RNAi-based therapy for ALS 351
  • Sodium phenylbutyrate 351
  • Stem cell therapy 352
  • Clinical applications 352
  • Stem cell-based drug discovery for ALS 352
  • Suppressors of mTDP-43 toxicity 353
  • Talampanel 353
  • Tamoxifen 354
  • Vaccination for ALS caused by SOD1 mutations 354
  • Vascular endothelial growth factor for ALS 354
  • Vitamin E for ALS 355
  • Clinical trials of neuroprotective therapies for ALS 355
  • Concluding remarks and future prospects 358

11. Neuroprotection in Miscellaneous Neurological Disorders 360

  • Introduction 360
  • Age-related dementia 360
  • Aging brain and oxidative stress 360
  • Enhancing endogenous neurotrophic support of the aging brain 361
  • Pharmacological approaches for treatment of age-related dementia 361
  • Physical exercise to prevent decline of mental function with aging 362
  • Vascular dementia 362
  • Prediction of dementia in persons with vascular risk factors 363
  • Management of subcortical vascular dementia 363
  • Dementia with Lewy bodies 364
  • Neuroprotection in AIDS dementia 364
  • Multiple system atrophy 365
  • Epilepsy 366
  • Mechanisms of neuronal damage in epilepsy 366
  • Strategies for neuroprotection in epilepsy 367
  • Control of seizures by AEDs and neuroprotection 367
  • Prevention of seizures by ketogenic diet 368
  • Hyalurona-based preservation of brain ECS volume for seizure control 369
  • Cell therapy for neuroprotection in epilepsy 369
  • Cell therapy of posttraumatic epilepsy 369
  • Cell therapy for temporal lobe epilepsy 370
  • Cell therapy for pharmacoresistant epilepsies 370
  • Gene therapy for neuroprotection in epilepsy 370
  • Neurogenetic disorders 371
  • Leigh syndrome 371
  • Spinal and bulbar muscular atrophy 372
  • Spinal muscular atrophy 372
  • Multiple sclerosis 373
  • Introduction 373
  • Epidemiology of multiple sclerosis 373
  • Pathophysiology 373
  • Current management of multiple sclerosis 374
  • Specific therapies for MS based on pathomechanism 375
  • Neuroprotection in multiple sclerosis 375
  • Clinical trials of neuroprotective therapies for MS 376
  • Neuroprotection by control of progressive forms of multiple sclerosis 379
  • Neuroprotection by controlling autoimmune inflammation in the brain 379
  • Neuroprotection by sealing the BBB with imatinib 380
  • TRPM4 cation channel blockers 380
  • Remyelination for neuroprotection in multiple sclerosis 380
  • Agents for neuroprotection in multiple sclerosis 380
  • Angiotensin-II inhibitors 380
  • Antiglutamate agents 381
  • Antioxidants for neuroprotection in MS 381
  • Antisense and RNAi approaches to MS 381
  • Cell therapy for multiple sclerosis 382
  • Cladribine 385
  • Curcumin as a neuroprotectant in multiple sclerosis 385
  • Dalfampridine in MS 385
  • Dimethyl fumarate 386
  • DNA vaccine for MS 386
  • Erythropoietin as a neuroprotective in MS 386
  • Fingolimod 386
  • Fusokine composed of GM-CSF and IL-15 for immune suppression 387
  • Gene therapy for MS 388
  • Ibudilast for MS 388
  • Iron chelators 388
  • IVIG for MS 389
  • Kinase inhibitors 389
  • Laquinimod 389
  • Monoclonal antibodies for MS 389
  • Natalizumab 390
  • Natural human antibodies for repair of myelin 390
  • Neurotrophic factors for multiple sclerosis 391
  • Oral immunomodulatory agents for MS 392
  • Protein kinase Cβ as a therapeutic target for stabilizing BBB in MS 392
  • Recombinant T-cell ligands 392
  • Statins for MS 392
  • Teriflunomide 393
  • Tolerance-directed immunotherapy for MS 393
  • Concluding remarks and future prospects for neuroprotection in MS 394
  • Neuroprotection in transverse myelitis 394
  • Neuroprotection in decompression sickness 395
  • Neuroprotection in victims of drowning 396
  • Neuroprotection in CSF circulatory disorders 396
  • Neuroprotection in hydrocephalus 396
  • Neuroprotection in normal pressure hydrocephalus 397
  • Neuroprotection in infections of the CNS 397
  • Neuroprotection in bacterial meningitis 398
  • Mechanism of neural injury in bacterial meningitis 398
  • Strategies for neuroprotection 398
  • Neuroprotection in cryptococcal meningitis 399
  • Neuroprotective approach to rabies 399
  • Neuroprotection in cerebral malaria 399
  • Neuroprotection in hypertensive encephalopathy 400
  • Neuroprotection in toxic encephalopathies 400
  • Hepatic encephalopathy 400
  • Management of hepatic encephalopathy 401
  • Bilirubin encephalopathy 401
  • Encephalopathy due to organophosphorus poisoning 402
  • Neuroprotection against chemotherapy-induced brain damage 403
  • Neuroprotection against alcohol 403
  • Alcoholic neurologic disorders 403
  • Fetal alcohol syndrome 404
  • Pathogenesis of alcohol-induced damage to the nervous system 404
  • Neuroprotection against neurotoxicity of alcohol 404
  • Neuroprotection against exposure to therapeutic radiation 405
  • Neuroprotection against radiation encephalopathy 405
  • Role of SOD in protection again radiation-induced hippocampal dysfunction 405
  • Catalase reduces mitochondrial ROS for neuroprotection from proton irradiation 406
  • Neuroprotection in hypoxia-ischemia 406
  • Neuroprotection in neonatal hypoxic-ischemic brain injury 406
  • Hyperbaric oxygen for neonatal hypoxia-ischemia 407
  • Hypothermia for neonatal hypoxia-ischemia 407
  • Minocycline for neonatal hypoxia-ischemia 408
  • Nicotinamide mononucleotide adenylyl transferase 1 408
  • Nitric oxide inhalation for neonatal hypoxia-ischemia 408
  • Plasminogen activator inhibitor-1 for neonatal hypoxia-ischemia 408
  • Recombinant erythropoietin for neonatal hypoxia-ischemia 409
  • Neuroprotection in carbon monoxide poisoning 409
  • Pathomechanism of CO poisoning as a basis for neuroprotection 409
  • Management of CO poisoning 410
  • Syndrome of delayed post-hypoxic leukoencephalopathy 410
  • Neuroprotection of the fetus 411
  • Neuroprotection in sleep apnea 411
  • Neuroprotection in complications of diabetes 412
  • Neuroprotection in hypoglycemic coma 412
  • Neuroprotection in diabetic retinopathy 413
  • Neuroprotection in mitochondrial dysfunction 414
  • Mitochondrial permeability transition 414
  • Mitochondrial approaches for neuroprotection 415
  • Methylene blue 415
  • Role of nanolasers in evaluation of mitochondrial neuroprotectants 416
  • Neuroprotection in mitochondrial encephalopathies 416
  • Neuroprotection in psychiatric disorders 416
  • Cognitive impairment in schizophrenia 416
  • Neuroprotection in schizophrenia 417
  • Electroconvulsive therapy and neuroprotection 417
  • Neuroprotection in hearing loss 418
  • Causes of hearing loss 418
  • Pathomechanism of hearing loss 419
  • Prevention and treatment of hearing loss 419
  • Hyperbaric oxygen for hearing loss 420
  • Stem cell therapy for hearing loss 420
  • Auditory hair cell replacement by gene therapy 420
  • Pharmaceutical approaches to hearing loss 421
  • Neuroprotection of peripheral nerves 422
  • Neuroprotective agents for peripheral nerves 422
  • Acetyl-L-carnitine for peripheral nerve injuries 423
  • Atorvastatin for peripheral nerve injuries 423
  • Erythropoietin for neuroprotection in peripheral nerve injuries 423
  • Neuroprotection in peripheral nerve injuries 424
  • Role of hyperbaric oxygen in peripheral nerve injuries 424
  • Role of neurotrophic factors in peripheral nerve injuries 424
  • Pharmacological approaches to Schwann cells 424
  • Role of gene therapy in neuroprotection of injured peripheral nerves 425
  • Schwann cell transplantation for peripheral nerve injury 425
  • Peripheral neuropathy 425
  • Neuroprotection in diabetic neuropathy 425
  • Cell therapy for neuroprotection in diabetic neuropathy 426
  • Gene therapy with zinc finger DNA-binding proteins 426
  • Neuroprotection in chemotherapy-induced neuropathy 426
  • Chronic inflammatory demyelinating polyradiculoneuropathy 427
  • Neuroprotection in CIDP 427

12. Neuroprotection of the Optic nerve and the Retina 428

  • Introduction 428
  • Neuroprotection in optic neuropathy 428
  • Neuroprotection in optic neuritis 429
  • Neuroprotection in optic nerve trauma 429
  • Potential regeneration of the optic nerve 430
  • Subthreshold transpupillary thermotherapy for protection of RGCs 430
  • Neuroprotection of optic nerve in glaucoma 430
  • Aminoguanidine as a neuroprotective in glaucoma 432
  • Antiglutamate agents for neuroprotection of optic nerve 432
  • Betaxolol 432
  • NGF eye drops 432
  • Targeting Aβ in glaucoma treatment 433
  • TNF-α blockers for neuroprotection in glaucoma 433
  • Concluding remarks about neuroprotection in glaucoma 433
  • Neuroprotection in retinal ischemia 433
  • Endogenous neuroprotection in the retina 434
  • β-adrenoceptor antagonists 434
  • Brimonidine as a neuroprotective is ischemic retinopathy 435
  • Thioredoxin as a neuroprotective agent in retinal ischemia 435
  • Erythropoietin for neuroprotection of retinal ischemia 435
  • Gene therapy for retinal neuroprotection 436
  • Hyperbaric oxygen for central retinal artery occlusion 436
  • Protection against oxygen-induced retinopathy 436
  • Neuroprotection in macular degeneration 437
  • Epidemiology 437
  • Pathomechanism of AMD 437
  • Current treatment of AMD 437
  • Novel neuroprotective strategies against retinal degeneration 438
  • Antiangiogenic agents 439
  • Humanized MAb against Aβ 440
  • LXR agonists 440
  • Neurotrophic factors for neuroprotection in AMD 440
  • CNTF for neuroprotection in AMD 440
  • N-acetylserotonin derivatives 441
  • Nutritional protection against AMD 441
  • Progestogenic hormones 441
  • Protection of retinal cells from oxidative-stress-induced apoptosis 441
  • Sulindac 442
  • Tandospirone 442
  • Cell therapy for macular degeneration 442
  • Retinal pigment epithelial cells 442
  • Stem cells 443
  • Neural progenitor cells 443
  • Gene therapy for retinal degeneration 443
  • RNAi-based treatments for AMD 443
  • Neuroprotection in proliferative diabetic retinopathy 444
  • RNAi-based approaches to diabetic retinopathy 445
  • Clinical trials for optic nerve and retinal neuroprotection 445

13. Neuroprotection during Anesthesia and Surgery 448

  • Introduction 448
  • Anesthetic agents as neuroprotectives 448
  • Barbiturates 448
  • Thiopental 449
  • Etomidate 450
  • Propofol 450
  • Ketamine 450
  • Gaseous anesthetics 451
  • Isoflurane 451
  • Xenon 451
  • Local anesthetics 452
  • Monitoring of CNS function during anesthesia and surgery 452
  • Monitoring of cerebral function 452
  • Monitoring of spinal cord function during spinal surgery 452
  • Perioperative neuroprotection 453
  • Neuroprotection during cardiovascular procedures 454
  • CNS complications of cardiac surgery 454
  • Neuroprotective strategies during cardiac surgery 455
  • Neuroprotection during coronary artery bypass grafting 456
  • Neuroprotection before anticipated or induced cardiac arrest 457
  • Spinal cord protection during cardiovascular surgery 457
  • Cerebral protection during organ transplantation surgery 458
  • Cerebral protection during neurosurgery 458
  • Cerebral angiography and endovascular surgery 458
  • Cerebral protection during surgery for arteriovenous malformations 458
  • Cerebral protection during surgery of intracranial aneurysms 459
  • Management of subarachnoid hemorrhage 459
  • Vasospasm associated with subarachnoid hemorrhage 460
  • Cerebral protection during carotid endarterectomy 461
  • Cerebral protection during surgery of brain tumors 462
  • Neuroprotective measures prior to surgery 462
  • Neuroprotection following surgery 462

14. Markets for Neuroprotective Therapies 464

  • Introduction 464
  • The financial burden of CNS damage 464
  • Markets for neuroprotective therapies 464
  • Markets according to therapeutic areas 464
  • Stroke 465
  • CNS injury 465
  • Alzheimer disease 465
  • Parkinson disease 466
  • Multiple sclerosis 466
  • Epilepsy 466
  • Values of neuroprotective therapies in major world markets 466
  • Unmet needs in neuroprotectives 467
  • Future prospects of neuroprotective therapies 468
  • Challenges in neuroprotective drug development 468
  • Promising areas of research in neuroprotection 469
  • Autoreactive antibodies 469
  • Biological therapies for neuroprotection 469
  • Multidisciplinary approaches to neuroprotection 470

15. References 472

Tables

  • Table 1-1: Historical landmarks in the development of neuroprotection 30
  • Table 1-2: Intrinsic neuroprotective factors 31
  • Table 1-3: Common features of pathophysiology of brain damage in diseases 40
  • Table 1-4: Place of neuroprotection in management of CNS disorders 41
  • Table 1-5: Indications for the use of neuroprotection 42
  • Table 2-1: A classification of neuroprotective agents 50
  • Table 2-2: The neuroprotective effect of antiepileptic drugs 59
  • Table 2-3: Neuroprotective affect of minocycline in animal models 63
  • Table 2-4: Classification of antioxidants or free radical scavengers with neuroprotective potential 71
  • Table 2-5: Role of erythropoietin in the nervous system 77
  • Table 2-6: Ionotropic glutamate receptors 82
  • Table 2-7: Classification of metabotropic glutamate receptors (mGluRs) 82
  • Table 2-8: Methods for neuroprotection based on nonpharmacological preconditioning 133
  • Table 3-1: Cerebrovascular diseases that are relevant to neuroprotection 136
  • Table 3-2: Neuroprotective strategies for stroke 145
  • Table 3-3: Neuroprotective gene transfer in models of cerebral ischemia 177
  • Table 3-4: Neuroprotective gene therapy in animal stroke models 178
  • Table 3-5: Neuroprotective agents in clinical development for acute cerebrovascular disease 180
  • Table 3-6: Some failed trials for neuroprotective therapy for stroke 183
  • Table 3-7: Preclinical assessment of neuroprotective agents in acute stroke models 192
  • Table 4-1: Classification of closed TBI 198
  • Table 4-2: Current conventional management of traumatic brain injury 206
  • Table 4-3: Neuroprotective strategies for traumatic brain injury 208
  • Table 4-4: Ongoing or completed clinical trials for neuroprotection in TBI 225
  • Table 4-5: Discontinued or failed clinical trials for neuroprotection in TBI 226
  • Table 5-1: Secondary mechanisms in spinal cord injury 232
  • Table 5-2: Neuroprotective and regenerative approaches for SCI 233
  • Table 5-3: Clinical trials for neuroprotection in SCI 247
  • Table 6-1: Neurodegenerative disorders with dementia 256
  • Table 6-2: Glutamate-based therapies in clinical development for neurodegenerative disorders 262
  • Table 7-1: Prevalence of Parkinson's disease in major markets 2013-2023 264
  • Table 7-2: Factors in the etiology of Parkinson's disease 264
  • Table 7-3: Strategies for the treatment of Parkinson's disease 271
  • Table 7-4: Current clinical trials of neuroprotective therapies for Parkinson disease 293
  • Table 7-5: Failed clinical trials of neuroprotective therapies for Parkinson disease 293
  • Table 7-6: Evaluation of neuroprotective agents for PD 294
  • Table 8-1: Cholinergic approaches to the treatment of Alzheimer's disease 300
  • Table 8-2: Neuroprotective agents for Alzheimer's disease 300
  • Table 8-3: Clinical trials for neuroprotection in Alzheimer disease 313
  • Table 8-4: Discontinued, failed or inconclusive clinical trials of Alzheimer disease 318
  • Table 8-5: Strategies for discovery of neuroprotective therapies for AD 320
  • Table 9-1: Neuroprotective approaches in HD 326
  • Table 10-1: Hypotheses for the pathogenesis of amyotrophic lateral sclerosis 338
  • Table 10-2: Classification of neuroprotective agents for amyotrophic lateral sclerosis 341
  • Table 10-3: Clinical trials of neuroprotective therapies for ALS 355
  • Table 10-4: Failed or discontinued trials of neuroprotective therapies for ALS 356
  • Table 11-1: Therapeutic approaches to subcortical vascular dementia 363
  • Table 11-2: Pharmacological neuroprotection against the sequelae of seizures 367
  • Table 11-3: Neuroprotective effect of AEDs in animal models of status epilepticus (SE) 368
  • Table 11-4: Specific therapies for MS based on postulated pathomechanisms 375
  • Table 11-5: Approved neuroprotective therapies for multiple sclerosis 376
  • Table 11-6: Neuroprotective therapies for multiple sclerosis in clinical trials 377
  • Table 11-7: Failed or discontinued trials of neuroprotective therapies for ALS 377
  • Table 11-8: Measures to prevent acute bilirubin encephalopathy 402
  • Table 11-9: Approaches to neuroprotection in neonatal hypoxia-ischemia 407
  • Table 11-10: Drugs with neuroprotective effect at mitochondrial level 415
  • Table 11-11: Causes of sensorineural hearing impairment 418
  • Table 11-12: Strategies for prevention and treatment of sensorineural hearing loss 419
  • Table 11-13: Agents for neuroprotection of the peripheral nervous system 422
  • Table 12-1: Causes of optic neuropathy 428
  • Table 12-2: Neuroprotection of the optic nerve in glaucoma 431
  • Table 12-3: Strategies for neuroprotection in retinal ischemia 434
  • Table 12-4: Novel neuroprotective strategies against retinal degeneration 438
  • Table 12-5: Clinical trials for optic nerve and retinal neuroprotection 445
  • Table 13-1: CNS complications associated with cardiac procedures 454
  • Table 13-2: Strategies for protection of the brain during cardiac surgery 455
  • Table 13-3: Medical and surgical methods of cerebral vasospasm management 460
  • Table 13-4: Neuroprotection by prevention of vasospasm 460
  • Table 14-1: Neuroprotective market values 2013-2023 465
  • Table 14-2: Values of neuroprotective therapies in major world markets from 2013-23 466

Figures

  • Figure 2-1: Mechanism of neuroprotective effect of sigma-1 receptor agonists 58
  • Figure 2-2: NMDA receptor ion channel complex 86
  • Figure 2-3: Neuroprotective effect of galantamine 109
  • Figure 3-1: Some steps in the ischemic cascade and site of action of neuroprotectives 137
  • Figure 3-2: A roadmap for neuroprotection 193
  • Figure 4-1: Cascade of events following traumatic brain injury 200
  • Figure 4-2: Neurometabolic cascade of mild TBI 201
  • Figure 4-3: Secondary injury mechanisms after TBI 202
  • Figure 5-1: Pathomechanism of acute spinal cord injury 231
  • Figure 7-1: Neuroprotective strategies against death of dopamine-containing neurons in PD 269
  • Figure 9-1: Role of HTT protein in pathogenesis of HD and points of intervention 333
  • Figure 9-2: Antisense therapeutic approaches to HD for lowering huntingtin 336
  • Figure 11-1: Common mechanisms of neural damage in cerebral ischemia and seizures 366
  • Figure 11-2: Role of neuroprotection in epilepsy and its treatment 367
  • Figure 14-1: Unmet therapeutic needs in neuroprotective therapies 468

Part II

16. Companies Developing Neuroprotective Therapies 5

  • Introduction 5
  • Profiles of companies 5
  • Collaborations 152

Tables

  • Table 16-1: Neuroprotectives in development by AstraZeneca 22
  • Table 16-2: Collaborations of companies in the area of neuroprotection 152
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