Neuroprotection - Drugs, Markets and Companies

Table of Contents

0. Executive Summary 19

1. Introduction 23

• Definitions 23
• Historical development of neuroprotection 23
• Intrinsic neuroprotective factors 24
• Neuroprotective gene expression 25
• Neurotrophic factors 25
• Intrinsic non-enzymatic antioxidants 26
• Intrinsic neuroprotective proteins 26
• Excitatory amino acid transporters (EAATs) 26
• Extracellular serine protease thrombin 26
• Neuroglobin 27
• Galanin 27
• Prion protein 28
• Rai (Shc C) adaptor protein 28
• Stem cell factor 28
• Role of the immune system in neuroprotection 28
• Pathomechanisms of CNS injury as basis for neuroprotection 29
• Biomarkers of neurological disorders and neuroprotection 30
• CNS biomarker identification using proteomics 30
• Brain imaging for detection of biomarkers 30
• Role of neuroprotection in various neurological disorders 30
• Neuroprotection and neuroregeneration 32
• Acute versus chronic neuroprotection 32
• Discovery and evaluation of neuroprotective agents 32
• Neuroprotective drug discovery 32
• Discovery of CNS drugs that penetrate the blood-brain barrier 33
• In vitro assays for the evaluation of neuroprotective agents 33
• Oxidative injury model to test neuroprotective drugs 34
• Apoptosis model for designing neuroprotective drugs 34
• Transgenic mouse models of neurological disorders 35
• Brain-on-a-Chip"! technology 35
• Evaluating effects of neuroprotective drugs on living brain slices 35
• Role of brain imaging in neuroprotective drug discovery and development 36
• Role of single photon emission computed tomography 36
• Functional CT scanning to evaluate cerebrovascular protection 36
• Magnetic resonance imaging for the evaluation of neuroprotectives 36
• Application of nanotechnology to neuroprotection 37
• Evaluation criteria for potential neuroprotective agents 37
• Evaluation of neuroprotective effect of drugs approved for other indications 38

2. Neuroprotective Agents 39

• Classification of neuroprotective agents 39
• Activated protein C 43
• Activity-dependent neuroprotective protein 44
• Adenosine analogs 44
• Propentofylline 44
• Andepressants 45
• Antiepileptic drugs as neuroprotectives 45
• Phenytoin 46
• Valproic acid 46
• Levetiracetam 46
• Antiinflammatory agents 47
• Aspirin 47
• Interleukin-1 antagonists 47
• COX-2 inhibitors 47
• Nimesulide 48
• NS-398 48
• Minocycline 48
• VP015 49
• Anti-apoptosis agents 50
• Activated protein C 50
• Calpain inhibitors 51
• Caspase inhibitors 51
• Clusterin 51
• DNA binding drugs 52
• Lithium 52
• Omega-3 fatty acids 52
• Docosahexaenoic acid 52
• Poly (ADP-ribose) polymerase (PARP) inhibitors 53
• Prevention of apoptosis by binding of proNGF to Sortilin 54
• TRO19622 54
• Antioxidants/free radical scavengers 54
• Free radical generation 54
• Natural defenses against oxidative stress 55
• Effects of oxidative damage 55
• Oxidative damage and aging 55
• Neuronal damage by free radicals 56
• Oxidative damage and neurodegenerative disorders 56
• Measures to control oxidative stress 56
• Categories of therapeutic antioxidants 57
• Alpha-phenyl-tert-butylnitrone 57
• Coenzyme Q10 57
• Dihydroergocryptine 58
• Flavonoids 59
• Mitochondria-targeted antioxidants 59
• Nanoparticles as neuroprotective antioxidants 59
• Neuroleptics as antioxidants 60
• Nitrones 60
• Translation of antioxidant neuroprotection from preclinical to clinical 60
• Carbon monoxide and heme oxygenase 61
• Cell transplants 61
• Cells secreting neuroprotective substances 61
• Stem cells 62
• Cytokines 62
• Erythropoietin 62
• Non-erythropoietic EPO variants and mimics 64
• Granulocyte colony-stimulating factor 64
• Delta-opioid receptor agonists 65
• FK960 65
• GABA agonists 65
• Gene therapy 66
• Glucagon-like peptide 67
• Glatiramer acetate 67
• Glutamate antagonists 67
• Neuroprotection by scavenging blood glutamate 68
• N-acylethanolamines for protection against glutamatergic excitotoxicity 69
• Glutamate transporters 69
• Glutamate transporter-mediated neuroprotective effect of drugs 69
• Neuroprotection by targeting KAI subunit of kainate receptor 70
• Glycine-proline-glutamate analogs 70
• Herbal preparations 71
• Flavonoid wogonin 71
• Ginseng 71
• Hydrogen sulfide 72
• NMDA receptor ion channel complex 72
• NMDA receptor antagonists 73
• NPS 1506 73
• NMDA NR2B subunit receptor antagonists 73
• Ifenprodil 74
• Memantine 74
• Magnesium 74
• NAALADase inhibitors 75
• 3,3-bis (3-fluorophenyl) propylamine 75
• Gacyclidine (GK-11) 75
• N-alkylglycines 75
• Partial NMDA agonists at glycine site 75
• AMPA receptor modulators 76
• Metabotropic glutamate receptor modulators 76
• Cannabinoids 77
• Dexanabinol (HU-211) 77
• Glutathione 78
• Heat shock proteins 78
• Hormones 79
• Estrogen and neuroprotection 79
• Neuroprotective effect of estrogen receptor ligands 79
• Selective estrogen receptor modulators 80
• Receptor-independent neuroprotective effects of estrogens 80
• Mitochondrial mechanisms of estrogen neuroprotection 80
• Insulin 81
• Ion Channel modulators 81
• Calcium channel blockers 81
• Ziconotide 82
• Na+ channel blockers 82
• Neuroprotective potassium channel inhibitors 82
• Kynurenine inhibitors 83
• Leukocyte adhesion inhibitors 83
• Modafinil 84
• Neural regeneration protein 84
• Neurite outgrowth-promoting prostaglandin compounds 85
• Neuroimmunophilins 85
• Cyclosporin-A 85
• FK506 86
• GPI 1485 86
• Rapamycin 86
• Neuropeptides 87
• Corticotropin-releasing hormone 87
• Neuroprotective peptide NAP 87
• Thyrotropin-releasing hormone 88
• Vasoactive intestinal peptide (VIP) 88
• Neurotrophic factors 88
• Activity-dependent neurotrophic factor 89
• Bone morphogenetic proteins 89
• Brain-derived neurotrophic factor 89
• Ciliary neurotrophic factor 90
• Fibroblast growth factors 90
• Glial cell line-derived neurotrophic factor 91
• Insulin-like growth factor 91
• Nerve growth factor 92
• Neurotrophins 93
• Osteogenic protein-1 93
• Pigment epithelium-derived factor 93
• Transforming growth factor-β 93
• Vascular endothelial growth factor 93
• Neurotrophic factor-related neuroprotective agents 94
• Colivelin 94
• Gambogic amide 94
• Inosine 94
• Meteorin 95
• Oxygen-regulated protein 150 kD (ORP150) 95
• Prosaptide 95
• Siagoside (GM1 ganglioside) 95
• Nicotine and nicotinic receptor agonists 96
• Nitric oxide-based neuroprotection 98
• Nitric oxide synthase inhibitors 98
• Nitric oxide mimetics 98
• Nootropics 99
• Piracetam 99
• Nutraceuticals and food constituents 100
• Creatine 100
• Curcumrin/curry 101
• Glyceryltriacetate 101
• Green tea 101
• Nicotinamide 102
• Resveratrol/ red wine 102
• Osmotic diuretics 103
• Mannitol 103
• Osteopontin 103
• Oxygen therapeutics 104
• Oxygen carriers 104
• Hemoglobin-based oxygen carriers 104
• Perfluorocarbons as oxygen carriers 105
• Hyperbaric oxygen therapy 106
• PPARs as drug targets for neuroprotection 106
• Riluzole 107
• Role of RNA interference in neuroprotection 107
• Signaling pathway activator 107
• Fructose-1,6-bisphosphate 107
• Sir 2 group of proteins 107
• Statins 108
• Steroids 109
• Dehydroepiandrosterone 109
• HF0220 109
• Sulforaphane 110
• Tauroursodeoxycholic acid 110
• Tetanus toxin as a neuroprotective agent 110
• Uncoupling protein 2 111
• Vaccines as neuroprotectives 111
• Vitamins as neuroprotective agents 111
• Vitamin B12 112
• Non-pharmacological approaches to neuroprotection 112
• Environmental enrichment 112
• Hypothermia 112
• Limitations of hypothermia 113
• Hypothermic neuroprotection in hypoxia-ischemia 114
• Hibernation induced by hydrogen sulfide 114
• Ketogenic diet 114
• Preconditioning-induced neuroprotection 115
• Hypoxic preconditioning 115
• Moderate stimulation of reactive oxygen species 115
• Chemical preconditioning 116
• Transcranial magnetic stimulation 116
• Electrical fields for improvement of cerebral function in neurodegeneration 117
• Neuroprotective effect of exercise 117
• Hibernation and neuroprotection 118
• Suspended animation and neuroprotection 118

3. Neuroprotection in Cerebrovascular Disease 119

• Introduction 119
• Epidemiology of stroke 119
• Pathophysiology of cerebral ischemia 120
• Calcium overload 120
• Ion channel dysfunction in stroke 121
• Role of oxygen free radicals in cerebral ischemia 121
• Role of nitric oxide in cerebral ischemia 121
• Glutamate as a marker of stroke 121
• Cerebral edema in stroke 122
• Gene expression in response to cerebral ischemia 122
• Induction of heat shock proteins in stroke 122
• Role of cytokines and adhesion molecules in stroke 123
• Tumor necrosis factor (TNF)-α 123
• Interleukin (IL)-1 and IL-6 123
• Adhesion molecules 123
• DNA damage and repair in cerebral ischemia 124
• Role of neurotrophic factors 124
• Problems requiring investigation of the role of NTFs in stroke 125
• Role of Poly(ADP-ribose) polymerase (PARP) gene 125
• Role of protease-activated receptor 1 125
• Reperfusion injury after cerebral ischemia 125
• Neuroprotection according to zones in cerebral infarction 126
• Zone of ischemic infarction 126
• Penumbra 126
• Current management of stroke 127
• Neuroprotection in stenosis of intracranial arteries 128
• Neuroprotective therapies for stroke 128
• Agents in research/preclinical stage for neuroprotection in stroke 129
• Acid-sensing ion channel blockers 131
• AMPA receptor antagonists as neuroprotectives for stroke 131
• Zonampanel 131
• Anti-apoptotic neuroprotectives 131
• NIM811 131
• Creatine as neuroprotective in stroke 132
• Lithium as a neuroprotective in stroke 132
• TUDCA as a neuroprotective in stroke 132
• Anti-HMGB1 monoclonal antibody 133
• Antioxidant approaches 133
• Dehydroascorbic acid 133
• Tocotrienols 134
• Carnosine as a neuroprotective in stroke 135
• Antiglutamate compounds 135
• 202W92 135
• AR-R15896AR 135
• MRZ 2/576 136
• L-Phenylalanine 136
• Arimoclomol for stroke 136
• Cardiac glycosides as neuroprotectives in stroke 136
• Clenbuterol 137
• Cox-2 inhibitors for ischemic stroke 137
• Enoxaparin 137
• Estrogen for stroke 138
• Granulocyte-macrophage colony-stimulating factor for cerebral ischemia 139
• Histamine H2-receptor antagonists 139
• Inosine for stroke 140
• Intravenous immunoglobulin as neuroprotective in stroke 140
• Insulin-like growth factor-I 140
• Ischemic preconditioning for neuroprotection in stroke 140
• Ketone bodies 142
• Minalocorticoid receptor blockade for neuroprotection 142
• Multifunctional neuroprotective agents 142
• Nasal delivery of neuroprotective agents in stroke 143
• Neuroserpin as a neuroprotective in stroke 143
• N-2-mercaptopropionyl glycine 143
• NeuroAid 144
• Neurotrophic factors as neuroprotectives for stroke 144
• AX200 144
• Brain-derived neurotrophic factor 144
• Neuregulin-1 144
• NO-based strategies for neuroprotection in cerebral ischemia 145
• Peroxisome proliferator-activated receptor-γ agonists 145
• PGE2 EP2 receptor activation 145
• Pioglitazone for reduction of stroke risk in diabetes 146
• Progesterone 146
• Proteosome inhibitors 146
• Statins for stroke prevention 146
• Thrombosis inhibitors 147
• Aspirin 147
• Clopidogrel 147
• Dipyridamole 148
• CBL1309 148
• SB-239063 148
• Sildenafil 149
• Src receptor blockade 149
• Stroke vaccine 149
• SUN N4057 149
• Tiagabine 150
• Topiramate 150
• Zonisamide 150
• Neuroprotectives in reperfusion injury 150
• Prevention of hemorrhage following ischemic stroke 151
• Non-pharmacological neuroprotective therapies for stroke 151
• Preconditioning for neuroprotection against cerebral ischemia 152
• Hypothermia for neuroprotection in acute stroke 152
• Hyperbaric oxygen therapy for neuroprotection in acute stroke 152
• Infrared laser therapy for ischemic stroke 153
• Role of neurosurgical procedures for neuroprotection in stroke 154
• Neurorehabilitation in relation to neuroprotection in stroke 154
• Cell therapy for stroke 154
• Gene therapy for neuroprotection in cerebrovascular disease 155
• Neuroprotective genetic vaccine 157
• COX-1/PGIS and COX-1 gene transfer in cerebral ischemia 157
• Transfer of the bcl-2 gene for neuroprotection in cerebral ischemia 157
• Neuroglobin gene therapy 158
• Regulation of microRNAs 158
• Neuroprotective therapies for cerebral ischemia: clinical trials 158
• Albumin 159
• Free radical scavengers 159
• DP-b99 161
• Erythropoietin as a neuroprotective in stroke 162
• Minocycline for neuroprotection in stroke 162
• Perindopril 162
• Failed clinical trials of neuroprotection in stroke 162
• Ancrod 164
• Aptiganel 164
• Cerovive (NXY-059) 164
• Citicoline 165
• Desmoteplase 166
• SPD 502 167
• Tirilazad mesylate 167
• Selfotel (CGS 19755) 168
• Lubeluzole 168
• Nalmefene (Cervene) 169
• Gavestinel (GV150526) 169
• Nimodipine 169
• Repinotan 169
• Sipatrigine 170
• Causes of failure of stroke trials 170
• Measures for prevention of failures in stroke trials 172
• Design of acute stroke trial to facilitate drug approval 173
• The ideal neuroprotective agent for stroke 173
• Future prospects for neuroprotection in stroke 174

4. Neuroprotection in CNS Trauma 177

• Introduction 177
• Cerebral hypoxia/ischemia as a complication of trauma 177
• Traumatic brain injury (TBI) 177
• Pathophysiology of TBI 177
• Immediate damage following TBI 178
• Cerebral edema following TBI 178
• Delayed damage following TBI 179
• Mechanism of axonal damage after TBI 179
• Role of neuroinflammation in TBI 179
• Molecular events following TBI 179
• BBB damage after TBI 180
• Chronic traumatic encephalopathy 180
• Changes in neurotrophic factors following TBI 181
• Changes in neurotransmitters following TBI 181
• Aβ deposition following TBI 181
• Genetic influences on outcome following TBI 182
• Management of TBI 182
• Control of intracranial pressure and cerebral edema 183
• Corticosteroids 183
• Neuroprotection in TBI 183
• Antiepileptic drugs for prevention of seizures and neuroprotection 184
• Antioxidants 185
• Barbiturates 185
• β and β secretase inhibitors 185
• Beta blockers 186
• Bradykinin B2 antagonists 186
• Cell cycle inhibitors for TBI 186
• Creatine for neuroprotection in TBI 187
• COX-2 inhibitors for neuroprotection in TBI 187
• Cyclosporin for neuroprotection in TBI 187
• Dexanabinol for TBI 188
• Erythropoietin for neuroprotection in TBI 188
• Gold implants for neuroprotection in focal TBI 188
• KN 38-7271 189
• Magnesium sulfate 189
• Neurotrophic factors for TBI 189
• Neurosteroids as neuroprotective agents for TBI 190
• Nicotinamide for neuroprotection in TBI 191
• NMDA receptor antagonists 191
• Non-NMDA receptor antagonists 192
• Nogo-A inhibitor 192
• NP-1 192
• Omega 3 fatty acids as neuroprotectives in TBI 192
• Oxygen carriers for TBI 193
• Polyethylene glycol for neuroprotection in TBI 193
• Propofol for neuroprotection in TBI 194
• Rapamycin as neuroprotective in TBI 194
• Simvastatin as neuroprotective in TBI 194
• Thyrotropin-releasing hormone analogs 194
• Traxoprodil 195
• Biological approaches to neuroprotection in TBI 195
• Antisense approaches to TBI 195
• Cell therapy for TBI 196
• Gene therapy for TBI 196
• Vaccine for TBI 196
• Non-pharmaceutical approches to neuroprotection in TBI 197
• Hyperbaric oxygen therapy for TBI 197
• Hypothermia 197
• Reduction of microglial migration after TBI 197
• Deep brain stimulation for TBI 197
• Prophylactic neuroprotection against TBI 198
• Role of physical exercise in protection against TBI 198
• Clinical trials of neuroprotective agents in TBI 198
• Failed clinical trials in TBI 199
• Differences between clinical trials and studies in animal models of TBI 200
• Subgroup analysis 201
• Improving the clinical trial design 201
• Clinical trials combining multipotential treatment strategies 201
• Shortening the trial time 201
• Concluding remarks and future prospects of neuroprotection in TBI 202
• Acute spinal cord injury (SCI) 202
• Epidemiology of SCI 202
• Pathophysiology of SCI 203
• Secondary mechanisms of SCI 203
• Neurotrophic factor changes in SCI 204
• Management of SCI 205
• Pharmacological neuroprotective agents for SCI 206
• 4-aminopyridine(4-AP, famprodine) 206
• Antibodies as neurite growth inhibitors in SCI 206
• Bacterial enzyme chondroitinase ABC 207
• CRL-5861 207
• Docosahexaenoic acid as neuroprotective in SCI 208
• Erythropoietin as a neuroprotective in SCI 208
• Free radical scavengers for neuroprotection in SCI 208
• Gacyclidine 209
• GYKI 52466 209
• Immunosuppressants as neuroprotectants in SCI 209
• Matrix metalloproteinase inhibitors for SCI 209
• Methylprednisolone 209
• Minocyline as neuroprotective in SCI 210
• Neurotrotrophic factors for neuroprotection after SCI 211
• Rho pathway and Rho antagonists in SCI 211
• Selenium as a neuroprotective for SCI 212
• Targeting the inflammatory response for neuroprotection in SCI 212
• Uric acid as neuroprotective in SCI 212
• Non-pharmacological approaches to SCI 213
• Hyperbaric oxygen therapy 213
• Hypothermia for SCI 213
• Cell and gene therapy for SCI 213
• Cell transplants 213
• Gene therapy for SCI 215
• Combined approaches to spinal cord injury 215
• Discovery of new targets for neuroprotective therapies in SCI 216
• Clinical trials in SCI 216

5. Neuroprotection in Neurodegenerative Disorders 219

• Introduction 219
• Pathomechanism of neurodegeneration 219
• Dual role of αsynuclein in neuroprotection and neurodegeneration 219
• Lack of neurotrophic factors 220
• Neuroinflammation in neurodegenerative disorders 220
• Neurodegeneration associated with protein misfolding 220
• Modulation of neurodegeneration by molecular chaperones 220
• Intrabodies targeting protein misfolding in neurodegeneration 221
• Targeting in proteins aggregation to prevent amyloid formation 221
• Role of apoptosis in neurodegenerative disorders 221
• Role of glia in neurodegeneration 222
• Role of metals in neurodegeneration 222
• Viral infections and neurodegeneration 222
• AIDS and the nervous system 222
• Avian influenza as cause of neurodegeneration 223
• Glutamate-based therapies for neurodegenerative disorders 224
• Parkinson' s disease 224
• Epidemiology of Parkinson' s disease 225
• Pathophysiology of Parkinson' s disease 225
• Oxidative stress 226
• Excitotoxicity 226
• Asynchronous neuronal activity 227
• Apoptosis 227
• Role of neurotrophic factors 227
• Role of misfolding proteins 227
• Genetic factors in PD 228
• Alteration of dopamine homeostasis 229
• Neuroprotective strategies for PD based on pathomechanism 229
• RNAi screening to identify neuroprotective genes in a PD model 230
• Management of Parkinson' s disease 230
• Limitation of conventionally administered dopamine therapy 232
• Treatment of dementia associated with Parkinson' s disease 232
• Neuroprotective therapy in Parkinson' s disease 232
• Neuroprotective effect of currently used drugs for Parkinson' s disease 233
• Pramipexole 233
• Rasagiline mesylate 233
• Ropinirole 234
• Selegiline 234
• Free radical scavengers for neuroprotection in Parkinson' s disease 235
• Antioxidants 235
• Melatonin 235
• Tea extracts as neuroprotectives 236
• Nicotine as a neuroprotective in PD 236
• Non-pharmacological strategies for neuroprotection in Parkinson' s disease 237
• Preventive effect of exercise and environmental enrichment 237
• Low-calorie diet 237
• Research in neuroprotection for Parkinson' s disease 237
• Activation of the hedgehog signaling pathway 238
• Activation of endogenous stem cells and neural precursors 238
• Adenosine AA2 receptor antagonists 239
• Anti-apoptotic strategies for PD 239
• Conserved dopamine neurotrophic factor for PD 240
• Heat shock protein 70 (Hsp70) 240
• Neuroprotective effect of DJ-1 protein 240
• Nrf2-mediated neuroprotection in PD 241
• Omega-3 polyunsaturated fatty acids 241
• Sirtuin 2 inhibitors for neuroprotection in PD 241
• Statins and PD 242
• Targeting Bax 242
• Tobacco smoke constituents 242
• Synergistic effect of dopamine and cannabinoid agonists in PD 242
• Clinical trials of neuroprotection in Parkinson' s disease 243
• CEP-1347 244
• Creatine and minocycline 245
• Neurotrophic factors 245
• PYM50028 247
• Safinamide 248
• Cell therapies 248
• Gene therapy 249
• RNAi therapy for Parkinson' s disease 252
• Vaccine for PD 252
• Evaluation of neuroprotective therapies for PD 252
• Current status and future challenges for neuroprotection in PD 253
• Alzheimer' s disease 254
• Introduction 254
• Pathomechanism of Alzheimer' s disease 254
• Role of glutamate transport dysfunction in AD 255
• Role of neurotrophic factors in the pathomechanism of AD 256
• Management of Alzheimer' s disease 256
• Neuroprotection in Alzheimer' s disease 257
• Inhibition of amyloid β-protein aggregation 258
• Secretase inhibitors 258
• AN-1792 258
• Monoclonal antibody m266 259
• Inhibition of the transformation of spherons into amyloid plaques 259
• Clioquinol 259
• FKBP52 for neuroprotection from Cu toxicity in AD 260
• Phenserine 260
• Colostrinin 261
• Inhibition of neuroinflammation 261
• MW01-5-188WH 261
• Etanercept 262
• Neurotrophic factors/ gene therapy 262
• NGF gene therapy 262
• Neotrofin (leteprinim potassium, AIT-082) 264
• AL-108 264
• Targeting plasminogen activator inhibitor type-1 gene 264
• Estrogen 265
• ABS-205 265
• Nimodipine 265
• Antioxidants 266
• NSAIDS 266
• P-3012 266
• Vitamin E 266
• Memantine 266
• Dimebon 268
• Cerebrolysin 269
• Ginko biloba 269
• Tetrahydrocannabinol for neuroprotection in AD 270
• CPI-1189 270
• Ladostigil tartrate 271
• Phosphodiesterase inhibitors 271
• PPAR-γ gamma agonists 271
• Role of statins in reducing the risk of Alzheimer' s disease 272
• Combined therapeutic approaches to Alzheimer' s disease 272
• Clinical trials in Alzheimer' s disease 272
• Future prospects of neuroprotection in AD 279
• Huntington' s disease 279
• Epidemiology of HD 280
• Pathophysiology of HD 280
• Management of Huntington' s disease 281
• Neuroprotection in Huntington' s disease 281
• Free radical scavengers 282
• Inhibitors of polyglutamine aggregation HD 283
• Enhancing protease activity for clearance of mHtt 283
• Eicosapentaenoic acid 284
• Single chain Fv antibodies 284
• Creatine for stabilizing bioenergetic defects 284
• Caspase inhibitors 285
• Clioquinol for HD 285
• Cysteamine 285
• Drugs that block inappropriate calcium release from neurons 285
• Histone deacetylase inhibitors 286
• Antipsychotic D2 and 5-HT1A antagonists 286
• Tetrabenazine 286
• Combinatorial therapy and targeting multiple pathways in HD 286
• Cell transplants 287
• Neurotrophic factors and gene therapy 287
• RNAi therapy for Huntington' s disease 288
• Amyotrophic lateral sclerosis (ALS) 289
• Epidemiology of ALS 289
• Pathophysiology of ALS 289
• Neuroprotective therapies for ALS 291
• Activated protein C 292
• AEOL 10150 293
• Arimoclomol for ALS 293
• Antisense therapy 293
• Ceatine for ALS 293
• Ceftriaxone for ALS 294
• Coenzyme Q10 for ALS 294
• COX-2 inhibitors for ALS 294
• Diallyl trisulfide 295
• Gene therapy for ALS 295
• Glatiramer acetate 296
• Insulin-like growth factor 296
• Ketogenic diet for neuroprotection in ALS 296
• Lithium for neuroprotection in ALS 297
• Minocycline for ALS 297
• Other neurotrophic factors for ALS 297
• ONO-2506 for ALS 298
• Riluzole 298
• RNAi-based therapy for ALS 298
• Sodium phenylbutyrate 299
• Stem cell therapy 299
• Talampanel 299
• Tamoxifen 300
• TRO19622 as neuroprotective for ALS 300
• Vaccination for ALS caused by SOD1 mutations 300
• Status of development of neuroprotective therapies for ALS 300
• Concluding remarks and future prospects of neuroprotection in ALS 302

6. Neuroprotection in Miscellaneous Neurological Disorders 305

• Dementias due to miscellaneous causes 305
• Age-related dementia 305
• Enhancing endogenous neurotrophic support of the aging brain 305
• Pharmacological approaches for treatment of age-related dementia 306
• Physical exercise to prevent decline of mental function with aging 307
• Vascular dementia 307
• A test for prediction of dementia in persons with vascular risk factors 307
• Management of subcortical vascular dementia 308
• Dementia with Lewy bodies 308
• Creutzfeldt-Jakob disease 309
• TDP-43 proteinopathy and neurodegenerative diseases 310
• Genetic disorders with neurodegeneration 310
• Batten' s disease 310
• Friedrich' s ataxia 311
• Niemann-Pick type C disease 311
• Epilepsy 312
• Mechanisms of neuronal damage in epilepsy 312
• Strategies for neuroprotection in epilepsy 313
• Control of seizures and neuroprotection 314
• Responsive Neurostimulator System 315
• Neuroprotective effect of estrogens in epilepsy 315
• Cell therapy for neuroprotection in epilepsy 315
• Gene therapy for neuroprotection in epilepsy 316
• Multiple sclerosis 317
• Introduction 317
• Epidemiology of multiple sclerosis 317
• Pathophysiology 317
• Current management of multiple sclerosis 318
• Specific therapies for MS based on pathomechanism 319
• Neuroprotection in multiple sclerosis 319
• Neuroprotection by control of progressive forms of multiple sclerosis 321
• Neuroprotection by controlling autoimmune inflammation in the brain 321
• 4-aminopyridine(4-AP, fampridine) in MS 322
• Angiotensin-II inhibitors 322
• Antiglutamate agents 322
• Antioxidants for neuroprotection in MS 322
• Antisense and RNAi approaches to MS 323
• Cell therapy for multiple sclerosis 323
• Cladribine 324
• Dexanabinol for MS 325
• DNA vaccine for MS 325
• Erythropoietin as a neuroprotective in MS 325
• Fingolimod (FTY720) 325
• Fusokine composed of GM-CSF and IL-15 for immune suppression 326
• Gene therapy for MS 326
• IVIG for MS 327
• Laquinimod 327
• MBP8298 327
• Monoclonal antibodies for MS 327
• Natalizumab 328
• Natural human antibodies for repair of myelin 328
• Neurotrophic factors for multiple sclerosis 328
• Recombinant T-cell ligands 330
• Statins for MS 330
• Concluding remarks on neuroprotection in MS 330
• Chronic inflammatory demyelinating polyradiculoneuropathy 331
• Neuroprotection in CIDP 331
• Neuroprotection in transverse myelitis 331
• Neuroprotection in decompression sickness 332
• Neuroprotection in hydrocephalus 332
• Neuroprotection in normal pressure hydrocephalus 333
• Neuroprotection in infections of the CNS 333
• Neuroprotection in bacterial meningitis 333
• Mechanism of neural injury in bacterial meningitis 333
• Strategies for neuroprotection 334
• Neuroprotection in AIDS dementia 334
• Neuroprotective approach to rabies 335
• Neuroprotection in cerebral malaria 336
• Neuroprotection in toxic encephalopathies 336
• Hepatic encephalopathy 336
• Encephalopathy due to organophosphorus poisoning 337
• Neuroprotection against chemotherapy-induced brain damage 337
• Neuroprotection against alcohol 338
• Alcoholic neurologic disorders 338
• Fetal alcohol syndrome 338
• Pathogenesis of alcohol-induced damage to the nervous system 338
• Neuroprotection against neurotoxicity of alcohol 339
• Neuroprotection in sleep apnea 339
• Neuroprotection in hypoglycemic coma 340
• Neuroprotection in neonatal hypoxic-ischemic brain injury 341
• Neuroprotection in mitochondrial dysfunction 343
• Mitochondrial permeability transition 343
• Mitochondrial approaches for neuroprotection 344
• Methylene blue 344
• Role of nanolasers in evaluation of mitochondrial neuroprotectants 345
• Neuroprotection in mitochondrial encephalopathies 345
• Neuroprotection in schizophrenia 345
• Neuroprotection of the optic nerve and the retina 346
• Neuroprotection in optic nerve trauma 346
• Potential regeneration of the optic nerve 346
• Neuroprotection of optic nerve in glaucoma 347
• Aminoguanidine as a neuroprotective in glaucoma 348
• Antiglutamate agents for neuroprotection of optic nerve 348
• Betaxolol 348
• NGF eye drops 349
• Targeting Aβ in glaucoma treatment 349
• TNF-α blockers for neuroprotection in glaucoma 349
• Concluding remarks about neuroprotection in glaucoma 349
• Neuroprotection in retinal ischemia 350
• Endogenous neuroprotection in the retina 350
• β-adrenoceptor antagonists 350
• Brimonidine as a neuroprotective is ischemic retinopathy 351
• Thioredoxin as a neuroprotective agent in retinal ischemia 351
• Erythropoietin for neuroprotection of retinal ischemia 351
• Gene therapy for retinal neuroprotection 352
• Hyperbaric oxygen for central retinal artery occlusion 352
• Protection against oxygen-induced retinopathy 352
• Neuroprotection in macular degeneration 353
• Antiangiogenic agents 353
• Protection of retinal cells from oxidative-stress-induced apoptosis 354
• Nutritional protection against AMD 354
• Cell therapy for macular degeneration 355
• Gene therapy for retinal degeneration 355
• RNAi-based treatments for AMD 356
• Neuroprotection in proliferative diabetic retinopathy 356
• Companies developing products for retinal neuroprotection 357
• Neuroprotection in hearing loss 358
• Neuroprotection of peripheral nerves 358
• Neuroprotection in diabetic neuropathy 359
• Neuroprotection in chemotherapy-induced neuropathy 359

7. Neuroprotection during Anesthesia and Surgery 361

• Introduction 361
• Anesthetic agents as neuroprotectives 361
• Barbiturates 361
• Thiopental 362
• Etomidate 363
• Propofol 363
• Ketamine 363
• Gaseous anesthetics 364
• Isoflurane 364
• Xenon 364
• Local anesthetics 365
• Monitoring of CNS function during anesthesia and surgery 365
• Monitoring of cerebral function 365
• Monitoring of spinal cord function during surgery on the spine 365
• Neuroprotection during cardiovascular procedures 365
• CNS complications of cardiac surgery 365
• Neuroprotective strategies during cardiac surgery 366
• Neuroprotection during coronary artery bypass grafting 367
• Neuroprotection before anticipated or induced cardiac arrest 368
• Surgery on the aorta 369
• Spinal protection during cardiovascular surgery 369
• Cerebral protection during organ transplantation surgery 369
• Cerebral protection during neurosurgery 369
• Cerebral angiography and endovascular surgery 370
• Cerebral protection during surgery for arteriovenous malformations 370
• Cerebral protection during surgery of intracranial aneurysms 370
• Management of subarachnoid hemorrhage 371
• Vasospasm associated with subarachnoid hemorrhage 371
• Cerebral protection during carotid endarterectomy 372
• Neuroprotection during spinal surgery 373
• Neuroprotective measures prior to surgery 373

8. Commercial aspects of Neuroprotective Therapy 375

• Introduction 375
• The financial burden of CNS damage 375
• Markets for neuroprotective therapies 375
• Markets according to therapeutic areas 375
• Values of neuroprotective therapies in major world markets 377
• Unmet needs in neuroprotectives 377
• Future prospects of neuroprotective therapies 378
• Challenges in neuroprotective drug development 379
• Promising areas of research in neuroprotection 379
• Autoreactive antibodies 379
• Protective genes 380

9. References 381

Tables

• Table 1 1: Historical landmarks in the development of neuroprotection 23
• Table 1 2: Intrinsic neuroprotective factors 24
• Table 1 3: Common features of pathophysiology of brain damage in diseases 29
• Table 1 4: Place of neuroprotection in management of CNS disorders 31
• Table 1 5: Indications for the use of neuroprotection 31
• Table 2 1: A classification of neuroprotective agents 39
• Table 2 2: The neuroprotective effect of antiepileptic drugs 45
• Table 2 3: Neuroprotective affect of minocycline in animal models 49
• Table 2 4: Classification of antiodixants or free radical scavengers with neuroprotective potential 57
• Table 2 5: Role of erythropoietin in the nervous system 63
• Table 2 6: Ionotropic glutamate receptors 68
• Table 2 7: Classification of metabotropic glutamate receptors (mGluRs) 68
• Table 2 8: Methods for preconditioning-induced neuroprotection 115
• Table 3 1: Cerebrovascular diseases that are relevant to neuroprotection 119
• Table 3 2: Neuroprotective strategies for stroke 128
• Table 3 3: Pharmacological products in research/preclinical stage for stroke 129
• Table 3 4: Neuroprotective gene therapy in animal stroke models 156
• Table 3 5: Neuroprotective agents in clinical development for acute cerebrovascular disease 158
• Table 3 6: Some failed trials for neuroprotective therapy for stroke 162
• Table 3 7: Preclinical assessment of neuroprotective agents in acute stroke models 172
• Table 4 1: Current conventional management of traumatic brain injury 182
• Table 4 2: Neuroprotective strategies for traumatic brain injury 183
• Table 4 3: Ongoing or completed clinical trials for neuroprotection in TBI 199
• Table 4 4: Discontinued or failed clinical trials for neuroprotection in TBI 200
• Table 4 5: Secondary mechanisms in spinal cord injury 204
• Table 4 6: Neuroprotective and regenerative approaches for SCI 205
• Table 4 7: Clinical trials for neuroprotection in SCI 216
• Table 5 1: Glutamate-based therapies in clinical development for neurodegenerative disorders 224
• Table 5 2: Prevalence of Parkinson' s Disease in major markets 2005-2015 225
• Table 5 3: Factors in the etiology of Parkinson' s disease 225
• Table 5 4: Strategies for the treatment of Parkinson' s disease 230
• Table 5 5: Neuroprotective therapies in preclinical development for Parkinson' s disease 238
• Table 5 6: Current clinical trials of neuroprotective therapies for Parkinson' s disease 243
• Table 5 7: Failed clinical trials of neuroprotective therapies for Parkinson' s disease 244
• Table 5 8: Evaluation of neuroprotective agents for PD 253
• Table 5 9: Cholinergic approaches to the treatment of Alzheimer' s disease 256
• Table 5 10: Neuroprotective agents for Alzheimer' s disease 257
• Table 5 11: Clinical trials in Alzheimer disease 273
• Table 5 12: Discontinued, failed or inconclusive clinical trials of Alzheimer disease 277
• Table 5 13: Strategies for discovery of neuroprotective therapies for AD 279
• Table 5 14: Neuroprotective approaches in HD 282
• Table 5 15: Classification of neuroprotective agents for amyotrophic lateral sclerosis 292
• Table 5 16: Clinical trials of neuroprotective therapies for ALS 301
• Table 5 17: Failed or discontinued trials of neuroprotective therapies for ALS 301
• Table 6 1: Therapeutic approaches to subcortical vascular dementia 308
• Table 6 2: Pharmacological neuroprotection against the sequelae of seizures 314
• Table 6 3: Neuroprotective effect of AEDs in animal models of status epilepticus (SE) 314
• Table 6 4: Specific therapies for multiple sclerosis based on postulated pathomechanisms 319
• Table 6 5: Neuroprotective therapies for multiple sclerosis 320
• Table 6 6: Approaches to neuroprotection in neonatal hypoxia-ischemia 341
• Table 6 7: Drugs with neuroprotective effect at mitochondrial level 344
• Table 6 8: Neuroprotection of the optic nerve in glaucoma 347
• Table 6 9: Strategies for neuroprotection in retinal ischemia 350
• Table 6 10: Novel neuroprotective strategies against retinal degeneration 353
• Table 6 11: Companies developing products for retinal neuroprotection 357
• Table 7 1: CNS complications associated with cardiac procedures 366
• Table 7 2: Neuroprotective strategies for cardiac surgery 367
• Table 7 3: Medical and surgical methods of cerebral vasospasm management 372
• Table 7 4: Neuroprotection by prevention of vasospasm 372
• Table 8 1: Neuroprotective market values 2008-2018 376
• Table 8 2: Values of neuroprotective therapies in major world markets from 2008-2018 377

Figures

• Figure 2 1: NMDA receptor ion channel complex 72
• Figure 2 2: Neuroprotective effect of galantamine 97
• Figure 3 1: Some steps in the ischemic cascade and site of action of neuroprotectives 120
• Figure 3 2: A roadmap for neuroprotection 173
• Figure 4 1: Cascade of events following traumatic brain injury 178
• Figure 4 2: Pathomechanism of acute spinal cord injury 203
• Figure 5 1: Neuroprotective strategies against death of dopamine-containing neurons in PD 229
• Figure 6 1: Common mechanisms of neural damage in cerebral ischemia and seizures 313
• Figure 6 2: Role of neuroprotection in epilepsy and its treatment 313
• Figure 8 1: Unmet therapeutic needs in neuroprotective therapies 378