神經保護：藥品・市場・企業

Abstract

Summary

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 a profile of 134 companies that have a neuroprotective product or products along with 98 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 850 references are included, a considerable amount of information has not been published anywhere else. Clinical trials of various neuroprotective agents are described and failures of trials in stroke and head injury are analyzed with suggestions for improving the selection of drugs and design of trials.The report is supplemented with 63 tables and 10 figures.

Market analysis of currently used productsthat have a neuroprotective effect are analyzed for the year 2008. 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 2013 when it will constitute a major and important component of the CNS market. Forecasts are made until 2018. 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

0. Executive Summary 17

1. Introduction 21

• Definitions 21
• Historical development of neuroprotection 21
• Intrinsic neuroprotective factors 22
• Neuroprotective gene expression 23
• Neurotrophic factors 23
• Intrinsic non-enzymatic antioxidants 24
• Intrinsic neuroprotective proteins 24
• Excitatory amino acid transporters (EAATs) 24
• Extracellular serine protease thrombin 24
• Neuroglobin 25
• Galanin 25
• Prion protein 26
• Rai (Shc C) adaptor protein 26
• Stem cell factor 26
• Role of the immune system in neuroprotection 26
• Pathomechanisms of CNS injury as basis for neuroprotection 27
• Biomarkers of neurological disorders and neuroprotection 28
• CNS biomarker identification using proteomics 28
• Brain imaging for detection of biomarkers 28
• Role of neuroprotection in various neurological disorders 28
• Neuroprotection and neuroregeneration 30
• Acute versus chronic neuroprotection 30
• Discovery and evaluation of neuroprotective agents 30
• Neuroprotective drug discovery 30
• Discovery of CNS drugs that penetrate the blood-brain barrier 31
• In vitro assays for the evaluation of neuroprotective agents 31
• Oxidative injury model to test neuroprotective drugs 32
• Apoptosis model for designing neuroprotective drugs 32
• Transgenic mouse models of neurological disorders 33
• Brain-on-a-Chip"! technology 33
• Evaluating effects of neuroprotective drugs on living brain slices 33
• Role of brain imaging in neuroprotective drug discovery and development 34
• Role of single photon emission computed tomography 34
• Functional CT scanning to evaluate cerebrovascular protection 34
• Magnetic resonance imaging for the evaluation of neuroprotectives 34
• Application of nanotechnology to neuroprotection 35
• Evaluation criteria for potential neuroprotective agents 35
• Evaluation of neuroprotective effect of drugs approved for other indications 36

2. Neuroprotective Agents 37

• Classification of neuroprotective agents 37
• Activated protein C 41
• Activity-dependent neuroprotective protein 42
• Adenosine analogs 42
• Propentofylline 42
• Andepressants 43
• Antiepileptic drugs as neuroprotectives 43
• Phenytoin 44
• Valproic acid 44
• Levetiracetam 44
• Antiinflammatory agents 45
• Aspirin 45
• Interleukin-1 antagonists 45
• COX-2 inhibitors 45
• Nimesulide 46
• NS-398 46
• Minocycline 46
• VP015 47
• Anti-apoptosis agents 48
• Activated protein C 48
• Calpain inhibitors 49
• Caspase inhibitors 49
• Clusterin 49
• DNA binding drugs 50
• Lithium 50
• Omega-3 fatty acids 50
• Docosahexaenoic acid 50
• Poly (ADP-ribose) polymerase (PARP) inhibitors 51
• Prevention of apoptosis by binding of proNGF to Sortilin 52
• TRO19622 52
• Antioxidants/free radical scavengers 52
• Free radical generation 52
• Natural defenses against oxidative stress 53
• Effects of oxidative damage 53
• Oxidative damage and aging 53
• Neuronal damage by free radicals 54
• Oxidative damage and neurodegenerative disorders 54
• Measures to control oxidative stress 54
• Categories of therapeutic antioxidants 55
• Alpha-phenyl-tert-butylnitrone 55
• Coenzyme Q10 55
• Dihydroergocryptine 56
• Flavonoids 57
• Mitochondria-targeted antioxidants 57
• Nanoparticles as neuroprotective antioxidants 57
• Neuroleptics as antioxidants 58
• Nitrones 58
• Carbon monoxide and heme oxygenase 58
• Cell transplants 59
• Cells secreting neuroprotective substances 59
• Stem cells 59
• Cytokines 60
• Erythropoietin 60
• Non-erythropoietic EPO variants and mimics 61
• Granulocyte colony-stimulating factor 62
• Delta-opioid receptor agonists 62
• FK960 62
• GABA agonists 63
• Gene therapy 63
• Glucagon-like peptide 64
• Glatiramer acetate 64
• Glutamate antagonists 65
• Neuroprotection by scavenging blood glutamate 66
• N-acylethanolamines for protection against glutamatergic excitotoxicity 66
• Glutamate transporters 66
• Glutamate transporter-mediated neuroprotective effect of drugs 67
• Neuroprotection by targeting KAI subunit of kainate receptor 67
• Glycine-proline-glutamate analogs 68
• Herbal preparations 68
• Flavonoid wogonin 68
• Ginseng 69
• NMDA receptor ion channel complex 69
• NMDA receptor antagonists 71
• NPS 1506 71
• NMDA NR2B subunit receptor antagonists 71
• Ifenprodil 71
• Memantine 71
• Magnesium 72
• NAALADase inhibitors 72
• 3,3-bis (3-fluorophenyl) propylamine 72
• Gacyclidine (GK-11) 72
• N-alkylglycines 73
• Partial NMDA agonists at glycine site 73
• AMPA receptor modulators 73
• Metabotropic glutamate receptor modulators 74
• Cannabinoids 74
• Dexanabinol (HU-211) 75
• Glutathione 75
• Heat shock proteins 76
• Hormones 76
• Estrogen and neuroprotection 76
• Neuroprotective effect of estrogen receptor ligands 77
• Selective estrogen receptor modulators 77
• Receptor-independent neuroprotective effects of estrogens 78
• Mitochondrial mechanisms of estrogen neuroprotection 78
• Insulin 78
• Ion Channel modulators 79
• Calcium channel blockers. 79
• Ziconotide 79
• Na+ channel blockers. 79
• Neuroprotective potassium channel inhibitors 80
• Kynurenine inhibitors 80
• Leukocyte adhesion inhibitors 81
• Modafinil 81
• Neural regeneration protein 82
• Neurite outgrowth-promoting prostaglandin compounds 82
• Neuroimmunophilins 82
• Cyclosporin-A 83
• FK506 83
• GPI 1485 83
• Rapamycin 84
• Neuropeptides 84
• Corticotropin-releasing hormone 84
• Neuroprotective peptide NAP 85
• Thyrotropin-releasing hormone 85
• Vasoactive intestinal peptide (VIP). 85
• Neurotrophic factors 86
• Activity-dependent neurotrophic factor 86
• Bone morphogenetic proteins 87
• Brain-derived neurotrophic factor 87
• Ciliary neurotrophic factor 87
• Fibroblast growth factors 88
• Glial cell line-derived neurotrophic factor 88
• Insulin-like growth factor 89
• Nerve growth factor 89
• Neurotrophins 90
• Osteogenic protein-1 90
• Pigment epithelium-derived factor 91
• Transforming growth factor-β 91
• Vascular endothelial growth factor 91
• Neurotrophic factor-related neuroprotective agents 91
• Colivelin 91
• Gambogic amide 92
• Inosine 92
• Meteorin 92
• Oxygen-regulated protein 150 kD (ORP150) 92
• Prosaptide 93
• Siagoside (GM1 ganglioside) 93
• Nicotine and nicotinic receptor agonists 94
• Nitric oxide-based neuroprotection 95
• Nitric oxide synthase inhibitors 95
• Nitric oxide mimetics 96
• Nootropics 96
• Piracetam 97
• Nutraceuticals and food constituents 97
• Creatine 97
• Curcumrin/ curry 98
• Glyceryltriacetate 99
• Green tea 99
• Nicotinamide 99
• Resveratrol/ red wine 100
• Osmotic diuretics 100
• Mannitol 100
• Osteopontin 101
• Oxygen therapeutics 101
• Oxygen carriers 102
• Hemoglobin-based oxygen carriers 102
• Perfluorocarbons as oxygen carriers 103
• Hyperbaric oxygen therapy 104
• PPARs as drug targets for neuroprotection 104
• Riluzole 104
• Role of RNA interference in neuroprotection 104
• Signaling pathway activator 105
• Fructose-1,6-bisphosphate 105
• Sir 2 group of proteins 105
• Statins 106
• Steroids 106
• Dehydroepiandrosterone 107
• HF0220 107
• Sulforaphane 107
• Tauroursodeoxycholic acid 108
• Tetanus toxin as a neuroprotective agent 108
• Uncoupling protein 2 108
• Vaccines as neuroprotectives 108
• Vitamins as neuroprotective agents 109
• Vitamin B12 109
• Non-pharmacological approaches to neuroprotection 110
• Environmental enrichment 110
• Hypothermia 110
• Limitations of hypothermia 111
• Hypothermic neuroprotection in hypoxia-ischemia 111
• Hibernation induced by hydrogen sulfide 111
• Ketogenic diet 112
• Preconditioning-induced neuroprotection 112
• Hypoxic preconditioning 112
• Moderate stimulation of reactive oxygen species 113
• Chemical preconditioning 113
• Transcranial magnetic stimulation 114
• Electrical fields for improvement of cerebral function in neurodegeneration 114
• Neuroprotective effect of exercise 115
• Hibernation and neuroprotection 115
• Suspended animation and neuroprotection 116

3. Neuroprotection in Cerebrovascular Disease 117

• Introduction 117
• Epidemiology of stroke 117
• Pathophysiology of cerebral ischemia 118
• Calcium overload 118
• Ion channel dysfunction in stroke 119
• Role of oxygen free radicals in cerebral ischemia 119
• Role of nitric oxide in cerebral ischemia 119
• Glutamate as a marker of stroke 119
• Cerebral edema in stroke 120
• Gene expression in response to cerebral ischemia 120
• Induction of heat shock proteins in stroke 120
• Role of cytokines and adhesion molecules in stroke 121
• Tumor necrosis factor (TNF)-α 121
• Interleukin (IL)-1 and IL-6 121
• Adhesion molecules 121
• DNA damage and repair in cerebral ischemia 122
• Role of neurotrophic factors 122
• Problems requiring investigation of the role of NTFs in stroke 123
• Role of Poly(ADP-ribose) polymerase (PARP) gene 123
• Role of protease-activated receptor 1 123
• Reperfusion injury after cerebral ischemia 123
• Neuroprotection according to zones in cerebral infarction 124
• Zone of ischemic infarction 124
• Penumbra 124
• Current management of stroke 125
• Neuroprotection in stenosis of intracranial arteries 126
• Neuroprotective therapies for stroke 126
• Agents in research/preclinical stage for neuroprotection in stroke 127
• Acid-sensing ion channel blockers 129
• AMPA receptor antagonists as neuroprotectives for stroke 129
• Zonampanel 129
• Anti-apoptotic neuroprotectives 129
• NIM811 129
• Creatine as neuroprotective in stroke 130
• Lithium as a neuroprotective in stroke 130
• TUDCA as a neuroprotective in stroke 130
• Anti-HMGB1 monoclonal antibody 131
• Antioxidant approaches 131
• Dehydroascorbic acid 131
• Tocotrienols 132
• Carnosine as a neuroprotective in stroke 133
• Antiglutamate compounds 133
• 202W92 133
• AR-R15896AR 133
• MRZ 2/576 134
• L-Phenylalanine 134
• Arimoclomol for stroke 134
• Cardiac glycosides as neuroprotectives in stroke 134
• Clenbuterol 135
• Cox-2 inhibitors for ischemic stroke 135
• Enoxaparin 135
• Estrogen for stroke 136
• Granulocyte-macrophage colony-stimulating factor for cerebral ischemia 137
• Histamine H2-receptor antagonists 137
• Inosine for stroke 138
• Intravenous immunoglobulin as neuroprotective in stroke 138
• Insulin-like growth factor-I 138
• Ischemic preconditioning for neuroprotection in stroke 138
• Ketone bodies 140
• Minalocorticoid receptor blockade for neuroprotection 140
• Multifunctional neuroprotective agents 140
• Nasal delivery of neuroprotective agents in stroke 141
• Neuroserpin as a neuroprotective in stroke 141
• N-2-mercaptopropionyl glycine 141
• NeuroAid 142
• Neurotrophic factors as neuroprotectives for stroke 142
• AX200 142
• Brain-derived neurotrophic factor 142
• Neuregulin-1 142
• NO-based strategies for neuroprotection in cerebral ischemia 143
• Peroxisome proliferator-activated receptor-γ agonists 143
• PGE2 EP2 receptor activation 143
• Pioglitazone for reduction of stroke risk in diabetes 144
• Progesterone 144
• Proteosome inhibitors 144
• Statins for stroke prevention 144
• Thrombosis inhibitors 145
• Aspirin 145
• Clopidogrel 145
• Dipyridamole 146
• CBL1309 146
• SB-239063 146
• Sildenafil 147
• Src receptor blockade 147
• Stroke vaccine 147
• SUN N4057 147
• Tiagabine 148
• Topiramate 148
• Zonisamide 148
• Neuroprotectives in reperfusion injury 148
• Prevention of hemorrhage following ischemic stroke 149
• Non-pharmacological neuroprotective therapies for stroke 149
• Preconditioning for neuroprotection against cerebral ischemia 150
• Hypothermia for neuroprotection in acute stroke 150
• Hyperbaric oxygen therapy for neuroprotection in acute stroke 150
• Infrared laser therapy for ischemic stroke 151
• Role of neurosurgical procedures for neuroprotection in stroke 152
• Neurorehabilitation in relation to neuroprotection in stroke 152
• Cell therapy for stroke 152
• Gene therapy for neuroprotection in cerebrovascular disease 153
• Neuroprotective genetic vaccine 155
• COX-1/PGIS and COX-1 gene transfer in cerebral ischemia 155
• Transfer of the bcl-2 gene for neuroprotection in cerebral ischemia 155
• Neuroglobin gene therapy 156
• Regulation of microRNAs 156
• Neuroprotective therapies for cerebral ischemia: clinical trials 156
• Albumin 157
• Free radical scavengers 158
• DP-b99 159
• Erythropoietin as a neuroprotective in stroke 160
• MaxiPost (BMS-204352) 160
• Minocycline for neuroprotection in stroke 160
• Perindopril 160
• Failed clinical trials of neuroprotection in stroke 161
• Ancrod 162
• Aptiganel 162
• Cerovive (NXY-059) 163
• Citicoline 163
• Desmoteplase 165
• SPD 502 165
• Tirilazad mesylate 166
• Selfotel (CGS 19755) 166
• Lubeluzole 166
• Nalmefene (Cervene) 167
• Gavestinel (GV150526) 167
• Nimodipine 167
• Repinotan 168
• Sipatrigine 168
• Causes of failure of stroke trials 168
• Measures for prevention of failures in stroke trials 170
• Design of acute stroke trial to facilitate drug approval 171
• The ideal neuroprotective agent for stroke 172
• Future prospects for neuroprotection in stroke 172

4. Neuroprotection in CNS Trauma 175

• Introduction 175
• Cerebral hypoxia/ischemia as a complication of trauma 175
• Traumatic brain injury (TBI) 175
• Pathophysiology of TBI 175
• Immediate damage following TBI 176
• Cerebral edema following TBI 176
• Delayed damage following TBI 177
• Mechanism of axonal damage after TBI 177
• Role of neuroinflammation in TBI 177
• Molecular events following TBI 177
• BBB damage after TBI 178
• Chronic traumatic encephalopathy 178
• Changes in neurotrophic factors following TBI 178
• Changes in neurotransmitters following TBI 179
• Genetic influences on outcome following TBI 179
• Management of TBI 180
• Control of intracranial pressure and cerebral edema 180
• Corticosteroids 180
• Neuroprotection in TBI 181
• Antiepileptic drugs for prevention of seizures and neuroprotection 182
• Antioxidants 182
• Barbiturates 183
• Beta blockers 183
• Bradykinin B2 antagonists 183
• Cell cycle inhibitors for TBI 183
• Creatine for neuroprotection in TBI 184
• COX-2 inhibitors for neuroprotection in TBI 184
• Cyclosporin for neuroprotection in TBI 184
• Dexanabinol for TBI 185
• Erythropoietin for neuroprotection in TBI 185
• Gold implants for neuroprotection in focal TBI 186
• KN 38-7271 186
• Magnesium sulfate 186
• Neurotrophic factors for TBI 186
• Neurosteroids as neuroprotective agents for TBI 187
• Nicotinamide for neuroprotection in TBI 188
• NMDA receptor antagonists 189
• Non-NMDA receptor antagonists 189
• Nogo-A inhibitor 189
• NP-1 189
• Omega 3 fatty acids as neuroprotectives in TBI 190
• Oxygen carriers for TBI 190
• Polyethylene glycol for neuroprotection in TBI 191
• Propofol for neuroprotection in TBI 191
• Rapamycin as neuroprotective in TBI 191
• Simvastatin as neuroprotective in TBI 191
• Thyrotropin-releasing hormone analogs 192
• Traxoprodil 192
• Antisense approaches to TBI 192
• Cell therapy for TBI 193
• Gene therapy for TBI 193
• Vaccine for TBI 194
• Hyperbaric oxygen therapy for TBI 194
• Hypothermia 194
• Reduction of microglial migration after TBI 194
• Deep brain stimulation for TBI 195
• Clinical trials of neuroprotective agents in TBI 195
• Failed clinical trials in TBI 196
• Differences between clinical trials and studies in animal models of TBI 197
• Subgroup analysis 197
• Improving the clinical trial design 198
• Clinical trials combining multipotential treatment strategies 198
• Shortening the trial time 198
• Concluding remarks and future prospects of neuroprotection in TBI 198
• Acute spinal cord injury (SCI) 199
• Epidemiology of SCI 199
• Pathophysiology of SCI 199
• Secondary mechanisms of SCI 200
• Neurotrophic factor changes in SCI 201
• Management of SCI 202
• Pharmacological neuroprotective agents for SCI 202
• 4-aminopyridine(4-AP, famprodine) 203
• Antibodies as neurite growth inhibitors in SCI 203
• Bacterial enzyme chondroitinase ABC 204
• CRL-5861 204
• Docosahexaenoic acid as neuroprotective in SCI 204
• Erythropoietin as a neuroprotective in SCI 205
• Free radical scavengers for neuroprotection in SCI 205
• Gacyclidine 205
• GYKI 52466 205
• Immunosuppressants as neuroprotectants in SCI 206
• Matrix metalloproteinase inhibitors for SCI 206
• Methylprednisolone 206
• Minocyline as neuroprotective in SCI 207
• Neurotrotrophic factors for neuroprotection after SCI 207
• Rho pathway and Rho antagonists in SCI 208
• Selenium as a neuroprotective for SCI 208
• Targeting the inflammatory response for neuroprotection in SCI 209
• Uric acid as neuroprotective in SCI 209
• Non-pharmacological approaches to SCI 209
• Hyperbaric oxygen therapy 209
• Hypothermia for SCI 210
• Cell and gene therapy for SCI 210
• Cell transplants 210
• Gene therapy for SCI 212
• Combined approaches to spinal cord injury 212
• Discovery of new targets for neuroprotective therapies in SCI 213
• Clinical trials in SCI 213

5. Neuroprotection in Neurodegenerative Disorders 215

• Introduction 215
• Pathomechanism of neurodegeneration 215
• Lack of neurotrophic factors 215
• Dual role of α-synuclein in neuroprotection and neurodegeneration 216
• Role of apoptosis in neurodegenerative disorders 216
• Role of glia in neurodegeneration 216
• Role of metals in neurodegeneration 217
• Role of neuroinflammation in neurodegenerative disorders 217
• Modulation of neurodegeneration by molecular chaperones 217
• Targeting aggregation-prone regions in proteins to prevent amyloid formation 218
• Glutamate-based therapies for neurodegenerative disorders 218
• Parkinson' s disease 218
• Epidemiology of Parkinson' s disease 219
• Pathophysiology of Parkinson' s disease 219
• Oxidative stress 219
• Excitotoxicity 220
• Asynchronous neuronal activity 221
• Apoptosis 221
• Role of neurotrophic factors 221
• Role of misfolding proteins 221
• Genetic factors in PD 221
• Alteration of dopamine homeostasis 223
• Neuroprotective strategies for PD based on pathomechanism 223
• RNAi screening to identify neuroprotective genes in a PD model 224
• Management of Parkinson' s disease 224
• Limitation of conventionally administered dopamine therapy 225
• Treatment of dementia associated with Parkinson' s disease 226
• Neuroprotective therapy in Parkinson' s disease 226
• Neuroprotective effect of currently used drugs for Parkinson' s disease 227
• Pramipexole 227
• Rasagiline mesylate 227
• Ropinirole 228
• Selegiline 228
• Free radical scavengers for neuroprotection in Parkinson' s disease 229
• Antioxidants 229
• Melatonin 229
• Tea extracts as neuroprotectives 230
• Nicotine as a neuroprotective in PD 230
• Non-pharmacological strategies for neuroprotection in Parkinson' s disease 231
• Preventive effect of exercise and environmental enrichment 231
• Low-calorie diet 231
• Research in neuroprotection for Parkinson' s disease 231
• Activation of the hedgehog signaling pathway 232
• Activation of endogenous stem cells by D3 receptor agonists 232
• Adenosine AA2 receptor antagonists 233
• Anti-apoptotic strategies for PD 233
• Conserved dopamine neurotrophic factor for PD 233
• Heat shock protein 70 (Hsp70) 234
• Neuroprotective effect of DJ-1 protein 234
• Nrf2-mediated neuroprotection in PD 234
• Omega-3 polyunsaturated fatty acids 235
• Sirtuin 2 inhibitors for neuroprotection in PD 235
• Statins and PD 235
• Targeting Bax 236
• Tobacco smoke constituents 236
• Synergistic effect of dopamine and cannabinoid agonists in PD 236
• Clinical trials of neuroprotection in Parkinson' s disease 236
• CEP-1347 238
• Creatine and minocycline 238
• Neurotrophic factors 239
• PYM50028 241
• Safinamide 241
• Cell therapies 242
• Gene therapy 243
• RNAi therapy for Parkinson' s disease 245
• Vaccine for PD 246
• Evaluation of neuroprotective therapies for PD 246
• Current status and future challenges for neuroprotection in PD 247
• Alzheimer' s disease 248
• Introduction 248
• Pathomechanism of Alzheimer' s disease 248
• Role of glutamate transport dysfunction in AD 249
• Role of neurotrophic factors in the pathomechanism of AD 249
• Management of Alzheimer' s disease 250
• Neuroprotection in Alzheimer' s disease 250
• Inhibition of amyloid βprotein aggregation 252
• Secretase inhibitors 252
• AN-1792 252
• Monoclonal antibody m266 253
• Inhibition of the transformation of spherons into amyloid plaques 253
• Clioquinol 253
• FKBP52 for neuroprotection from Cu toxicity in AD 254
• Phenserine 254
• Colostrinin 255
• Inhibition of neuroinflammation 255
• MW01-5-188WH 255
• Etanercept 256
• Neurotrophic factors/ gene therapy 256
• NGF gene therapy 256
• Neotrofin (leteprinim potassium, AIT-082) 258
• AL-108 258
• Targeting plasminogen activator inhibitor type-1 gene 258
• Estrogen 258
• ABS-205 259
• Nimodipine 259
• Antioxidants 259
• NSAIDS 259
• P-3012 260
• Vitamin E 260
• Memantine 260
• Dimebon 262
• Cerebrolysin 262
• Ginko biloba 263
• Tetrahydrocannabinol for neuroprotection in AD 264
• CPI-1189 264
• Ladostigil tartrate 265
• Phosphodiesterase inhibitors 265
• PPAR-γ gamma agonists 265
• Role of statins in reducing the risk of Alzheimer' s disease 265
• Combined therapeutic approaches to Alzheimer' s disease 266
• Clinical trials in Alzheimer' s disease 266
• Future prospects of neuroprotection in AD 273
• Huntington' s disease 273
• Epidemiology of HD 273
• Pathophysiology of HD 273
• Management of Huntington' s disease 275
• Neuroprotection in Huntington' s disease 275
• Free radical scavengers 276
• Inhibitors of polyglutamine aggregation HD 277
• Enhancing protease activity for clearance of mHtt 277
• Eicosapentaenoic acid 277
• Single chain Fv antibodies 278
• Creatine for stabilizing bioenergetic defects 278
• Caspase inhibitors 278
• Clioquinol for HD 279
• Drugs that block inappropriate calcium release from neurons 279
• Histone deacetylase inhibitors 279
• Antipsychotic D2 and 5-HT1A antagonists 279
• Tetrabenazine 280
• Combinatorial therapy and targeting multiple pathways in HD 280
• Cell transplants 280
• Neurotrophic factors and gene therapy 281
• RNAi therapy for Huntington' s disease 282
• Amyotrophic lateral sclerosis (ALS) 282
• Epidemiology of ALS 282
• Pathophysiology of ALS 282
• Neuroprotective therapies for ALS 285
• AEOL 10150 286
• Arimoclomol for ALS 286
• Antisense therapy 286
• Ceatine for ALS 287
• Ceftriaxone for ALS 287
• Coenzyme Q10 for ALS 287
• COX-2 inhibitors for ALS 288
• Gene therapy for ALS 288
• Glatiramer acetate 289
• Insulin-like growth factor 289
• Ketogenic diet for neuroprotection in ALS 289
• Lithium for neuroprotection in ALS 290
• Minocycline for ALS 290
• Other neurotrophic factors for ALS 290
• ONO-2506 for ALS 291
• Riluzole 291
• RNAi-based therapy for ALS 291
• Sodium phenylbutyrate 292
• Stem cell therapy 292
• Talampanel 292
• Tamoxifen 293
• TRO19622 as neuroprotective for ALS 293
• Vaccination for ALS caused by SOD1 mutations 293
• Status of development of neuroprotective therapies for ALS 293
• Concluding remarks and future prospects of neuroprotection in ALS 295

6. Neuroprotection in Miscellaneous Neurological Disorders 297

• Dementias due to miscellaneous causes 297
• Age-related dementia 297
• Enhancing endogenous neurotrophic support of the aging brain 297
• Pharmacological approaches for treatment of age-related dementia 298
• Physical exercise to prevent decline of mental function with aging 299
• Vascular dementia 299
• A test for prediction of dementia in persons with vascular risk factors 299
• Management of subcortical vascular dementia 300
• Dementia with Lewy bodies 300
• Creutzfeldt-Jakob disease 301
• TDP-43 proteinopathy and neurodegenerative diseases 302
• Genetic disorders with neurodegeneration 302
• Niemann-Pick type C disease 302
• Friedrich' s ataxia 303
• Epilepsy 303
• Mechanisms of neuronal damage in epilepsy 303
• Strategies for neuroprotection in epilepsy 304
• Control of seizures and neuroprotection 305
• Responsive Neurostimulator System 306
• Neuroprotective effect of estrogens in epilepsy 306
• Cell therapy for neuroprotection in epilepsy 306
• Gene therapy for neuroprotection in epilepsy 307
• Multiple sclerosis 308
• Introduction 308
• Epidemiology of multiple sclerosis 308
• Pathophysiology 308
• Current management of multiple sclerosis 309
• Specific therapies for MS based on pathomechanism 310
• Neuroprotection in multiple sclerosis 310
• Neuroprotection by control of progressive forms of multiple sclerosis 312
• Neuroprotection by controlling autoimmune inflammation in the brain 312
• 4-aminopyridine(4-AP, fampridine) in MS 313
• Antiglutamate agents 313
• Antioxidants for neuroprotection in MS 313
• Antisense and RNAi approaches to MS 313
• Cell therapy for multiple sclerosis 314
• Cladribine 315
• Dexanabinol for MS 315
• DNA vaccine for MS 316
• Erythropoietin as a neuroprotective in MS 316
• Fingolimod (FTY720) 316
• Gene therapy for MS 317
• IVIG for MS 317
• Laquinimod 317
• MBP8298 317
• Monoclonal antibodies for MS 318
• Natalizumab 318
• Natural human antibodies for repair of myelin 318
• Neurotrophic factors for multiple sclerosis 319
• Recombinant T-cell ligands 320
• Statins for MS 320
• Concluding remarks on neuroprotection in MS 320
• Chronic inflammatory demyelinating polyradiculoneuropathy 321
• Neuroprotection in CIDP 321
• Neuroprotection in transverse myelitis 321
• Neuroprotection in decompression sickness 322
• Neuroprotection in hydrocephalus 323
• Neuroprotection in normal pressure hydrocephalus 323
• Neuroprotection in infections of the CNS 323
• Neuroprotection in bacterial meningitis 323
• Mechanism of neural injury in bacterial meningitis 324
• Strategies for neuroprotection 324
• Neuroprotection in AIDS 325
• AIDS dementia 325
• Role of neurotrophic factors in AIDS dementia 326
• Neuroprotection in AIDS dementia 326
• Neuroprotective approach to rabies 327
• Neuroprotection in cerebral malaria 327
• Neuroprotection in toxic encephalopathies 328
• Hepatic encephalopathy 328
• Encephalopathy due to organophosphorus poisoning 328
• Neuroprotection against chemotherapy-induced brain damage 329
• Neuroprotection against alcohol 329
• Alcoholic neurologic disorders 329
• Fetal alcohol syndrome 330
• Pathogenesis of alcohol-induced damage to the nervous system 330
• Neuroprotection against neurotoxicity of alcohol 330
• Neuroprotection in sleep apnea 331
• Neuroprotection in hypoglycemic coma 332
• Neuroprotection in neonatal hypoxic-ischemic brain injury 333
• Neuroprotection in mitochondrial dysfunction 333
• Mitochondrial permeability transition 334
• Mitochondrial approaches for neuroprotection 334
• Methylene blue 335
• Role of nanolasers in evaluation of mitochondrial neuroprotectants 335
• Neuroprotection in mitochondrial encephalopathies 335
• Neuroprotection in schizophrenia 336
• Neuroprotection of the optic nerve and the retina 336
• Neuroprotection in optic nerve trauma 336
• Potential regeneration of the optic nerve 337
• Neuroprotection of optic nerve in glaucoma 337
• Aminoguanidine as a neuroprotective in glaucoma 338
• Antiglutamate agents for neuroprotection of optic nerve 338
• Axonal growth factors for neuroprotection of the optic nerve 339
• Betaxolol 339
• Targeting Aβ in glaucoma treatment 339
• Concluding remarks about neuroprotection in glaucoma 339
• Neuroprotection in retinal ischemia 339
• Endogenous neuroprotection in the retina 340
• β adrenoceptor antagonists 340
• Brimonidine as a neuroprotective is ischemic retinopathy 341
• Thioredoxin as a neuroprotective agent in retinal ischemia 341
• Erythropoietin for neuroprotection of retinal ischemia 341
• Gene therapy for retinal neuroprotection 342
• Hyperbaric oxygen for central retinal artery occlusion 342
• Protection against oxygen-induced retinopathy 342
• Neuroprotection in macular degeneration 342
• Antiangiogenic agents 343
• Protection of retinal cells from oxidative-stress-induced apoptosis 344
• Nutritional protection against AMD 344
• Cell therapy for macular degeneration 345
• Gene therapy for retinal degeneration 345
• RNAi-based treatments for AMD 346
• Neuroprotection in proliferative diabetic retinopathy 346
• Companies developing products for retinal neuroprotection 347
• Neuroprotection in hearing loss 347
• Neuroprotection of peripheral nerves 348
• Neuroprotection in diabetic neuropathy 349
• Neuroprotection in chemotherapy-induced neuropathy 349

7. Neuroprotection during Anesthesia and Surgery 351

• Introduction 351
• Anesthetic agents as neuroprotectives 351
• Barbiturates 351
• Thiopental 352
• Etomidate 353
• Propofol 353
• Ketamine 353
• Gaseous anesthetics 354
• Isoflurane 354
• Xenon 354
• Local anesthetics 355
• Monitoring of CNS function during anesthesia and surgery 355
• Monitoring of cerebral function 355
• Monitoring of spinal cord function during surgery on the spine 355
• Neuroprotection during cardiovascular procedures 355
• CNS complications of cardiac surgery 355
• Neuroprotective strategies during cardiac surgery 356
• Neuroprotection during coronary artery bypass grafting 357
• Neuroprotection before anticipated or induced cardiac arrest 358
• Surgery on the aorta 359
• Spinal protection during cardiovascular surgery 359
• Cerebral protection during organ transplantation surgery 359
• Cerebral protection during neurosurgery 359
• Cerebral angiography and endovascular surgery 360
• Cerebral protection during surgery for arteriovenous malformations 360
• Cerebral protection during surgery of intracranial aneurysms 360
• Management of subarachnoid hemorrhage 361
• Vasospasm associated with subarachnoid hemorrhage 361
• Cerebral protection during carotid endarterectomy 362
• Neuroprotection during spinal surgery 363
• Neuroprotective measures prior to surgery 363

8. Commercial aspects of Neuroprotective Therapy 365

• Introduction 365
• The financial burden of CNS damage 365
• Markets for neuroprotective therapies 365
• Markets according to therapeutic areas 365
• Values of neuroprotective therapies in major world markets 367
• Unmet needs in neuroprotectives 367
• Future prospects of neuroprotective therapies 368
• Challenges in neuroprotective drug development 369
• Promising areas of research in neuroprotection 369
• Autoreactive antibodies 369
• Protective genes 370

9. References 371

Tables

• Table 1 1: Historical landmarks in the development of neuroprotection 21
• Table 1 2: Intrinsic neuroprotective factors 22
• Table 1 3: Common features of pathophysiology of brain damage in diseases 27
• Table 1 4: Place of neuroprotection in management of CNS disorders 29
• Table 1 5: Indications for the use of neuroprotection 29
• Table 2 1: A classification of neuroprotective agents 37
• Table 2 2: The neuroprotective effect of antiepileptic drugs 43
• Table 2 3: Neuroprotective affect of minocycline in animal models 47
• Table 2 4: Classification of antiodixants or free radical scavengers with neuroprotective potential 55
• Table 2 5: Role of erythropoietin in the nervous system 60
• Table 2 6: Ionotropic glutamate receptors 65
• Table 2 7: Classification of metabotropic glutamate receptors (mGluRs) 65
• Table 2 8: Methods for preconditioning-induced neuroprotection 112
• Table 3 1: Cerebrovascular diseases that are relevant to neuroprotection 117
• Table 3 2: Neuroprotective strategies for stroke 126
• Table 3 3: Pharmacological products in research/preclinical stage for stroke 127
• Table 3 4: Neuroprotective gene therapy in animal stroke models 154
• Table 3 5: Neuroprotective agents in clinical development for acute cerebrovascular disease 156
• Table 3 6: Some failed trials for neuroprotective therapy for stroke 161
• Table 3 7: Preclinical assessment of neuroprotective agents in acute stroke models 170
• Table 4 1: Current conventional management of traumatic brain injury 180
• Table 4 2: Neuroprotective strategies for traumatic brain injury 181
• Table 4 3: Ongoing or completed clinical trials for neuroprotection in TBI 195
• Table 4 4: Discontinued or failed clinical trials for neuroprotection in TBI 196
• Table 4 5: Secondary mechanisms in spinal cord injury 201
• Table 4 6: Neuroprotective and regenerative approaches for SCI 202
• Table 4 7: Clinical trials for neuroprotection in SCI 213
• Table 5 1: Glutamate-based therapies in clinical development for neurodegenerative disorders 218
• Table 5 2: Prevalence of Parkinson' s Disease in major markets 2005-2015 219
• Table 5 3: Factors in the etiology of Parkinson' s disease 219
• Table 5 4: Strategies for the treatment of Parkinson' s disease 224
• Table 5 5: Neuroprotective therapies in preclinical development for Parkinson' s disease 232
• Table 5 6: Current clinical trials of neuroprotective therapies for Parkinson' s disease 237
• Table 5 7: Failed clinical trials of neuroprotective therapies for Parkinson' s disease 237
• Table 5 8: Evaluation of neuroprotective agents for PD 246
• Table 5 9: Cholinergic approaches to the treatment of Alzheimer' s disease 250
• Table 5 10: Neuroprotective agents for Alzheimer' s disease 251
• Table 5 11: Clinical trials in Alzheimer disease 266
• Table 5 12: Discontinued, failed or inconclusive clinical trials of Alzheimer disease 271
• Table 5 13: Strategies for discovery of neuroprotective therapies for AD 273
• Table 5 14: Neuroprotective approaches in HD 275
• Table 5 15: Classification of neuroprotective agents for amyotrophic lateral sclerosis 285
• Table 5 16: Clinical trials of neuroprotective therapies for ALS 294
• Table 5 17: Failed or discontinued trials of neuroprotective therapies for ALS 294
• Table 6 1: Therapeutic approaches to subcortical vascular dementia 300
• Table 6 2: Pharmacological neuroprotection against the sequelae of seizures 305
• Table 6 3: Neuroprotective effect of AEDs in animal models of status epilepticus (SE) 305
• Table 6 4: Specific therapies for multiple sclerosis based on postulated pathomechanisms 310
• Table 6 5: Neuroprotective therapies for multiple sclerosis 311
• Table 6 6: Drugs with neuroprotective effect at mitochondrial level 334
• Table 6 7: Neuroprotection of the optic nerve in glaucoma 338
• Table 6 8: Strategies for neuroprotection in retinal ischemia 340
• Table 6 9: Novel neuroprotective strategies against retinal degeneration 343
• Table 6 10: Companies developing products for retinal neuroprotection 347
• Table 7 1: CNS complications associated with cardiac procedures 356
• Table 7 2: Neuroprotective strategies for cardiac surgery 357
• Table 7 3: Medical and surgical methods of cerebral vasospasm management 362
• Table 7 4: Neuroprotection by prevention of vasospasm 362
• Table 8 1: Neuroprotective market values 2008-2018 366
• Table 8 2: Values of neuroprotective therapies in major world markets from 2008-2018 367

Figures

• Figure 2 1: NMDA receptor ion channel complex 70
• Figure 2 2: Neuroprotective effect of galantamine 94
• Figure 3 1: Some steps in the ischemic cascade and site of action of neuroprotectives 118
• Figure 3 2: A roadmap for neuroprotection 171
• Figure 4 1: Cascade of events following traumatic brain injury 176
• Figure 4 2: Pathomechanism of acute spinal cord injury 200
• Figure 5 1: Neuroprotective strategies against death of dopamine-containing neurons in PD 223
• Figure 6 1: Common mechanisms of neural damage in cerebral ischemia and seizures 304
• Figure 6 2: Role of neuroprotection in epilepsy and its treatment 304
• Figure 8 1: Unmet therapeutic needs in neuroprotective therapies 368