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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 138 companies that have a neuroprotective product or products along with 119 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 14 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 25

1. Introduction 29

  • Definitions 29
  • Historical development of neuroprotection 29
  • Intrinsic neuroprotective factors 30
  • Neuroprotective gene expression 31
  • Upregulation of GADD34 31
  • Induction of NR4A proteins by CREB in neurons 32
  • Elevation PGC-1α for neuroprotection in PD 32
  • Neurotrophic factors 32
  • Intrinsic nonenzymatic antioxidants 33
  • Activation of transcription factor Nrf2 33
  • Intrinsic neuroprotective proteins 33
  • αB-crystallin 33
  • Excitatory amino acid transporters 34
  • Extracellular serine protease thrombin 34
  • Galanin 34
  • Neuroglobin 34
  • Nuclear factor I-A 35
  • Prion protein 35
  • Rai adaptor protein 36
  • Stem cell factor 36
  • Role of the immune system in neuroprotection 36
  • Role of cerebral metabolism in neuroprotection 37
  • Role of circadian genes in neuroprotection 37
  • Role of blood-brain barrier in neuroprotection 38
  • Induction of DNA repair enzymes for neuroprotection 38
  • Microtubule-based neuroprotective response to axonal injury 38
  • Pathomechanisms of CNS injury as basis for neuroprotection 39
  • Biomarkers of neurological disorders and neuroprotection 39
  • CNS biomarker identification using proteomics 39
  • Brain imaging for detection of biomarkers 40
  • Role of neuroprotection in various neurological disorders 40
  • Neuroprotection and neuroregeneration 41
  • Acute versus chronic neuroprotection 41
  • Discovery and evaluation of neuroprotective agents 42
  • Neuroprotective drug discovery 42
  • Discovery of CNS drugs that penetrate the blood-brain barrier 42
  • In vitro assays for the evaluation of neuroprotective agents 43
  • Oxidative injury model to test neuroprotective drugs 43
  • Apoptosis model for designing neuroprotective drugs 44
  • Transgenic mouse models of neurological disorders 44
  • Evaluating effects of neuroprotective drugs on living brain slices 44
  • Role of brain imaging in neuroprotective drug discovery and development 45
  • Positron emission tomography 45
  • Role of single photon emission computed tomography 45
  • Functional CT scanning to evaluate cerebrovascular protection 46
  • Magnetic resonance imaging for the evaluation of neuroprotectives 46
  • Application of nanotechnology to neuroprotection 46
  • Evaluation criteria for potential neuroprotective agents 47

2. Neuroprotective Agents 49

  • Classification of neuroprotective agents 49
  • α2 adrenoreceptor agonists 53
  • Dexmedetomidine 53
  • Activated protein C 54
  • Activity-dependent neuroprotective protein 54
  • Davunetide 54
  • Adenosine analogs 54
  • Propentofylline 55
  • Antidepressants 55
  • Antidepressant-induced neurogenesis 55
  • Neurogenesis induced by electroconvulsive therapy 56
  • Neuroprotective effect of selective serotonin reuptake inhibitors 56
  • Antiepileptic drugs as neuroprotectives 58
  • Phenytoin 59
  • Valproic acid 59
  • Levetiracetam 59
  • Antiinflammatory agents 60
  • Aspirin 60
  • Interleukin-1 antagonists 60
  • COX-2 inhibitors 61
  • Nimesulide 61
  • Gold microparticles as anti-neuroinflammatory agents 61
  • Minocycline 61
  • Prostaglandin receptor antagonists 62
  • Anti-apoptosis agents 63
  • Activated protein C 64
  • Calpain inhibitors 64
  • Caspase inhibitors 64
  • DNA binding drugs 64
  • Lithium 65
  • Melatonin 65
  • Olesoxime 65
  • Omega-3 fatty acids 66
  • Docosahexaenoic acid 66
  • Poly(ADP-ribose) polymerase inhibitors 66
  • Prevention of apoptosis by binding of proNGF to sortilin 67
  • Antioxidants/free radical scavengers 68
  • Free radical generation 68
  • Natural defenses against oxidative stress 68
  • Effects of oxidative damage 68
  • Oxidative damage and aging 68
  • Neuronal damage by free radicals 69
  • Oxidative damage and neurodegenerative disorders 69
  • Measures to control oxidative stress 69
  • Categories of therapeutic antioxidants 70
  • Alpha-phenyl-tert-butylnitrone 70
  • Coenzyme Q10 71
  • Dihydroergocryptine 71
  • Flavonoids 72
  • Mitochondria-targeted antioxidants 72
  • Nanoparticles as neuroprotective antioxidants 72
  • Neuroleptics as antioxidants 73
  • Nitrones 73
  • Translation of antioxidant neuroprotection from preclinical to clinical 74
  • Carbon monoxide and heme oxygenase 74
  • Cell transplants 74
  • Cells secreting neuroprotective substances 74
  • Stem cells 75
  • Stem cell activation for neuroprotection/regeneration by glucocorticoids 75
  • Use of neural stem cells to construct the blood brain barrier 75
  • Cytokines 76
  • Erythropoietin 76
  • Non-erythropoietic EPO variants and mimics 77
  • Granulocyte colony-stimulating factor 78
  • Delta-opioid receptor agonists 78
  • Delta opioid peptide-induced hibernation for neuroprotection 79
  • FK960 79
  • Gene therapy 79
  • Glucagon-like peptide 80
  • Glatiramer acetate 80
  • Glutamate antagonists 81
  • Neuroprotection by scavenging blood glutamate 82
  • N-acylethanolamines for protection against glutamatergic excitotoxicity 82
  • Glutamate transporters 82
  • Glutamate transporter-mediated neuroprotective effect of drugs 83
  • Neuroprotection by targeting KAI subunit of kainate receptor 84
  • Glycine-proline-glutamate analogs 84
  • Hydrogen sulfide 84
  • Hibernation induced by hydrogen sulfide 85
  • NMDA receptor ion channel complex 85
  • NMDA receptor antagonists 86
  • NMDA NR2B subunit receptor antagonists 86
  • Ifenprodil 86
  • Memantine as a neuroprotective agent 87
  • Magnesium 87
  • NAALADase inhibitors 87
  • Gacyclidine 87
  • N-alkylglycines 88
  • AMPA receptor modulators 88
  • Metabotropic glutamate receptor modulators 88
  • Cannabinoids 89
  • Dexanabinol 90
  • Glutathione 90
  • Heat shock proteins 90
  • Histone deacetylase inhibitors for neuroprotection 91
  • Hormones 91
  • Estrogen and neuroprotection 91
  • Neuroprotective effect of estrogen receptor ligands 92
  • Selective estrogen receptor modulators 92
  • Mitochondrial mechanisms of estrogen neuroprotection 93
  • Insulin 93
  • Ion Channel modulators 94
  • Calcium channel blockers. 94
  • Ziconotide 94
  • Na+ channel blockers. 95
  • Neuroprotective potassium channel inhibitors 95
  • Kynurenine inhibitors 95
  • Leukocyte adhesion inhibitors 96
  • Modafinil 97
  • Neural regeneration protein 97
  • Neurite outgrowth-promoting prostaglandin compounds 97
  • Neuroimmunophilins 98
  • Cyclosporin-A 98
  • FK506 98
  • Rapamycin 99
  • Neurotrophic factors 99
  • Activity-dependent neurotrophic factor 99
  • Bone morphogenetic proteins 100
  • Brain-derived neurotrophic factor 100
  • Ciliary neurotrophic factor 100
  • Fibroblast growth factors 101
  • Glial cell line-derived neurotrophic factor 102
  • Insulin-like growth factor 102
  • Nerve growth factor 102
  • Neurotrophins 103
  • Osteogenic protein-1 104
  • Pigment epithelium-derived factor 104
  • Transforming growth factor-β1 104
  • Vascular endothelial growth factor 104
  • Neurotrophic factor-related neuroprotective agents 105
  • Amitriptyline as a TrkA and TrkB receptor agonist 105
  • Colivelin 105
  • Gambogic amide 105
  • Inosine 106
  • Meteorin 106
  • Oxygen-regulated protein 150 kD 106
  • Prosaptide 106
  • Siagoside 107
  • Small molecule activators of the Trk receptors 107
  • Nicotine and nicotinic receptor agonists 107
  • Neuroprotective effect of galantamine mediated via α7nAChRs 108
  • Galantamine-induced Aβ clearance via α7nAChRs 108
  • Nitric oxide-based neuroprotection 109
  • Nitric oxide synthase inhibitors 109
  • Nitric oxide mimetics 109
  • Nitric oxide donating derivatives 110
  • Nootropics 110
  • Piracetam 111
  • Nutraceuticals and naturally-derived compounds 111
  • Cinnamon 111
  • Coffee 112
  • Creatine 112
  • Curcumin/curry 112
  • Mechanism of neuroprotective effect of curcumin 113
  • Flavonoids 113
  • Glyceryltriacetate 113
  • Green tea 113
  • Herbal preparations 114
  • Flavonoid wogonin 114
  • Ginseng 114
  • Nicotinamide 114
  • Punicalagin from pomegranate 115
  • Resveratrol 115
  • Osmotic diuretics 116
  • Mannitol 116
  • Osteopontin 116
  • Oxygen therapeutics 117
  • Oxygen carriers 117
  • Hemoglobin-based oxygen carriers 117
  • Perfluorocarbons as oxygen carriers 118
  • Hyperbaric oxygen therapy 119
  • Peptides 119
  • C3-derived peptide for neuroprotection and neuroregeneration 119
  • Corticotropin-releasing hormone 119
  • Thyrotropin-releasing hormone 120
  • Vasoactive intestinal peptide 120
  • Pharmacological preconditioning 120
  • PPARs as drug targets for neuroprotection 121
  • Riluzole 121
  • Role of RNA interference in neuroprotection 122
  • Sigma receptor agonists as neuroprotective agents 122
  • SIRT group of proteins 122
  • Statins 123
  • Steroids 124
  • Dehydroepiandrosterone 124
  • HF0220 124
  • Sulforaphane 125
  • Tauroursodeoxycholic acid 125
  • Tetanus toxin as a neuroprotective agent 125
  • Thrombolytic agents as neuroprotective agents 126
  • Uncoupling protein 2 126
  • Vaccines as neuroprotectives 126
  • Vitamins as neuroprotective agents 127
  • Vitamin B12 127
  • Vitamin D 128
  • Non-pharmacological approaches to neuroprotection 128
  • Caloric restriction 128
  • Electrical fields for improvement of cerebral function in neurodegeneration 128
  • Environmental enrichment 129
  • Hypothermia 129
  • Limitations of hypothermia 130
  • Hypothermic neuroprotection in hypoxia-ischemia 130
  • Ketogenic diet 130
  • Mental training 131
  • Mediterranean diet 131
  • Nonpharmacological preconditioning for neuroprotection 131
  • Physical exercise 132
  • Suspended animation and neuroprotection 133
  • Transcranial magnetic stimulation 133

3. Neuroprotection in Cerebrovascular Disease 135

  • Introduction 135
  • Pathophysiology of cerebral ischemia 135
  • Calcium overload 136
  • Ion channel dysfunction in stroke 136
  • Role of oxygen free radicals in cerebral ischemia 137
  • Role of nitric oxide in cerebral ischemia 137
  • Glutamate as a biomarker of stroke 137
  • Cerebral edema in stroke 137
  • Gene expression in response to cerebral ischemia 138
  • Induction of heat shock proteins in stroke 138
  • Role of cytokines and adhesion molecules in stroke 138
  • Tumor necrosis factor-α 139
  • Interleukin-1 and IL-6 139
  • Adhesion molecules 139
  • DNA damage and repair in cerebral ischemia 139
  • Role of neurotrophic factors in stroke 140
  • Problems requiring investigation of the role of NTFs in stroke 140
  • Role of Poly(ADP-ribose) polymerase (PARP) gene 140
  • Role of protease-activated receptor 1 141
  • Reperfusion injury after cerebral ischemia 141
  • Neuroprotection according to zones in cerebral infarction 141
  • Zone of ischemic infarction 141
  • Penumbra 142
  • Current management of stroke 142
  • Neuroprotection in stenosis of intracranial arteries 143
  • Neuroprotection in transient ischemic attacks 143
  • Secondary prevention of stroke 143
  • Neuroprotective therapies for stroke 144
  • αB-crystallin as a neuroprotectant in stroke 145
  • Acid-sensing ion channel blockers 145
  • AMPA receptor antagonists as neuroprotectives for stroke 145
  • Zonampanel 145
  • Antiapoptotic neuroprotectives 146
  • NIM811 146
  • Creatine as neuroprotective in stroke 146
  • Lithium as a neuroprotective in stroke 146
  • TUDCA as a neuroprotective in stroke 147
  • Antiepileptic drugs as neuroprotectives in stroke 147
  • Tiagabine 147
  • Topiramate 147
  • Zonisamide 148
  • Anti-HMGB1 monoclonal antibody 148
  • Antioxidant approaches 148
  • Carnosine as a neuroprotective in stroke 148
  • Dehydroascorbic acid 149
  • Tocotrienols 149
  • Uric acid 150
  • Antiglutamate compounds 150
  • MRZ 2/576 150
  • L-Phenylalanine 151
  • Arimoclomol for stroke 151
  • Cardiac glycosides as neuroprotectives in stroke 151
  • Clenbuterol 151
  • Coagulation inhibitors as neuroprotectives 152
  • Heparin and enoxaparin 152
  • Warfarin vs dabigatran 152
  • Apixaban 152
  • Cox-2 inhibitors for ischemic stroke 153
  • Curcumin as a neuroprotectant in stroke 153
  • Docosahexaenoic acid for ischemic stroke 153
  • Ephrin-A5 blockers 153
  • Estrogen for stroke 154
  • Extendin-4 155
  • Flavones for neuroprotection in stroke 155
  • Granulocyte-macrophage colony-stimulating factor for cerebral ischemia 156
  • Hamartin induction by cerebral ischemia as a basis for neuroprotection 156
  • Histone deacetylase inhibitors for neuroprotection in stroke 156
  • Modulation of histamine H2-receptors 157
  • Inosine for stroke 157
  • Insulin-like growth factor-I 157
  • Intravenous immunoglobulin as neuroprotective in stroke 157
  • Ischemic preconditioning for neuroprotection in stroke 158
  • Ketone bodies for neuroprotection in stroke 159
  • Mineralocorticoid receptor blockade for neuroprotection 159
  • miR-223 and neuroprotection in stroke 159
  • Multifunctional neuroprotective agents 159
  • NA-1 as neuroprotective against ischemic stroke 160
  • Nasal delivery of neuroprotective agents in stroke 160
  • Neuroserpin as a neuroprotective in stroke 160
  • N-2-mercaptopropionyl glycine 161
  • NeuroAid 161
  • Neurotrophic factors as neuroprotectives for stroke 161
  • Brain-derived neurotrophic factor 161
  • Fibroblast growth factor 162
  • G-CSF 162
  • Glial cell line-derived neurotrophic factor 162
  • Insulin-like growth factor-1 163
  • Neuregulin-1 163
  • NO-based strategies for neuroprotection in cerebral ischemia 163
  • Pannexin channel blockers for neuroprotection in stroke 164
  • Perlecan domain V 164
  • Peroxisome proliferator-activated receptor-γ agonists 164
  • PGE2 EP2 receptor activation 165
  • Pioglitazone for reduction of stroke risk in diabetes 165
  • Progesterone 165
  • Propofol as neuroprotective in stroke 165
  • Proteoglycan-degrading enzymes 166
  • Proteosome inhibitors 166
  • Statins for prevention and neuroprotection in stroke 166
  • Sildenafil 167
  • Src receptor blockade 167
  • Stroke vaccine 168
  • SUN N4057 168
  • Thrombosis inhibitors 168
  • Aspirin 168
  • Clopidogrel 169
  • Dipyridamole 169
  • Vitamin E for neuroprotection in stroke 169
  • Neuroprotection in reperfusion injury 170
  • Prevention of hemorrhage following ischemic stroke 170
  • Non-pharmacological neuroprotective therapies for stroke 170
  • Preconditioning for neuroprotection against cerebral ischemia 171
  • Hypothermia for neuroprotection in acute stroke 171
  • Hyperbaric oxygen therapy for neuroprotection in acute stroke 172
  • Infrared laser therapy for ischemic stroke 173
  • Neurostimulation of sphenopalatine ganglion 173
  • Neurosurgical procedures for neuroprotection in stroke 173
  • Neurorehabilitation in relation to neuroprotection in stroke 174
  • Protective effect of physical activity on stroke in the elderly 174
  • Cell therapy for stroke 175
  • Stem cell transplant for stroke 175
  • Immortalized cell grafts for stroke 175
  • Stimulation of instrinsic stem cells for repair of brain in stroke 176
  • Neuroprotective vaccines for stroke 176
  • Gene therapy for neuroprotection in cerebrovascular disease 176
  • Regulation of microRNAs for neuroprotection in cerebral ischemia 178
  • RNAi-based therapy for neuroprotection in stroke 179
  • Neuroprotective therapies for cerebral ischemia: clinical trials 179
  • Albumin 180
  • Free radical scavengers 180
  • DP-b99 181
  • Mildronate 182
  • Minocycline for neuroprotection in stroke 182
  • Perindopril 182
  • Failed clinical trials of neuroprotection in stroke 182
  • Ancrod 184
  • Aptiganel 184
  • Cerovive 185
  • Citicoline 186
  • Desmoteplase 187
  • Erythropoietin as a neuroprotective in stroke 187
  • SPD 502 188
  • Tirilazad mesylate 188
  • Selfotel 188
  • Lubeluzole 188
  • Nalmefene 189
  • Gavestinel 189
  • Nimodipine 189
  • Sipatrigine 190
  • Causes of failure of stroke trials 190
  • Measures for prevention of failures in stroke trials 191
  • Design of acute stroke trial to facilitate drug approval 193
  • The ideal neuroprotective agent for stroke 193
  • Future prospects for neuroprotection in stroke 194

4. Neuroprotection in Traumatic Brain Injury 197

  • Introduction 197
  • Cerebral hypoxia/ischemia as a complication of trauma 197
  • Epidemiology of TBI 197
  • TBI in the military 198
  • Pathophysiology of TBI 198
  • Immediate damage following TBI 199
  • Cerebral edema following TBI 199
  • Delayed damage following TBI 200
  • Mechanism of axonal damage after TBI 200
  • Role of neuroinflammation in TBI 200
  • BBB damage after TBI 201
  • Molecular events following TBI 201
  • Chronic traumatic encephalopathy 202
  • Neurocognitive sequelae of TBI 202
  • Changes in neurotrophic factors following TBI 203
  • Changes in neurotransmitters following TBI 203
  • Proteomics of TBI 203
  • Genetic influences on outcome following TBI 204
  • Management of TBI 204
  • Control of intracranial pressure and cerebral edema 205
  • Corticosteroids 205
  • Neuroprotection in TBI 206
  • Amantadine 207
  • Antiepileptic drugs for prevention of seizures and neuroprotection 207
  • Antioxidants 208
  • Barbiturates 208
  • β- and γ-secretase inhibitors 208
  • Beta blockers 209
  • Bradykinin B2 antagonists 209
  • Cell cycle inhibitors for TBI 209
  • COX-2 inhibitors for neuroprotection in TBI 209
  • Cyclosporin for neuroprotection in TBI 210
  • Dexanabinol for TBI 210
  • Erythropoietin for neuroprotection in TBI 210
  • Gold implants for neuroprotection in focal TBI 211
  • Histone deacetylase inhibitors for neuroprotection in TBI 211
  • KN 38-7271 211
  • Levosimendan 211
  • Magnesium sulfate 212
  • Minocycline for TBI 212
  • Multipotential neuroprotective agents for TBI 212
  • Nutritional approaches to neuroprotection in TBI 213
  • Branched chain amino acids to ameliorate cognitive impairment in TBI 213
  • Creatine for neuroprotection in TBI 213
  • Nicotinamide for neuroprotection in TBI 214
  • Omega 3 fatty acids as neuroprotectives in TBI 214
  • Neurotrophic factors for TBI 215
  • Neurosteroids as neuroprotective agents for TBI 215
  • NMDA receptor antagonists 216
  • NP-1 216
  • Nogo-A inhibitor 217
  • Oxygen carriers for TBI 217
  • Polyethylene glycol for neuroprotection in TBI 218
  • Propofol for neuroprotection in TBI 218
  • Rapamycin as neuroprotective in TBI 218
  • Simvastatin as neuroprotective in TBI 219
  • Thyrotropin-releasing hormone analogs 219
  • Traxoprodil 219
  • Biological approaches to neuroprotection in TBI 219
  • Antisense approaches to TBI 219
  • Cell therapy for TBI 220
  • Gene therapy for TBI 220
  • Vaccines for TBI 220
  • Non-pharmaceutical approaches to neuroprotection in TBI 221
  • Deep brain stimulation for TBI 221
  • Hyperbaric oxygen therapy for TBI 221
  • Hypothermia 221
  • Reduction of microglial migration after TBI 222
  • Vacuum for mechanical tissue resuscitation in TBI 222
  • Prophylactic neuroprotection against TBI 222
  • Role of helmets in protection against TBI 222
  • Role of physical exercise in protection against TBI 223
  • Clinical trials of neuroprotective agents in TBI 223
  • Ongoing clinical trials in TBI 223
  • Failed clinical trials in TBI 224
  • Differences between clinical trials and studies in animal models of TBI 225
  • Subgroup analysis 225
  • Improving the clinical trial design 226
  • Clinical trials combining multiple treatment strategies 226
  • Shortening the trial time 226
  • Conclusions and future prospects of neuroprotection in TBI 226

5. Neuroprotection in Spinal Cord Injury 229

  • Introduction 229
  • Pathophysiology of SCI 229
  • Secondary mechanisms of SCI 230
  • Neurotrophic factor changes in SCI 231
  • Management of SCI 232
  • Pharmacological neuroprotective agents for SCI 233
  • 4-aminopyridine 233
  • Antibodies as neurite growth inhibitors in SCI 233
  • Bacterial enzyme chondroitinase ABC 233
  • Docosahexaenoic acid as neuroprotective in SCI 234
  • Erythropoietin as a neuroprotective in SCI 234
  • Free radical scavengers for neuroprotection in SCI 234
  • Gacyclidine 235
  • GYKI 52466 235
  • Immunosuppressants as neuroprotectants in SCI 235
  • Interleukin-10 for neuroprotection in SCI 235
  • Matrix metalloproteinase inhibitors for SCI 236
  • Methylprednisolone 236
  • Minocycline as neuroprotective in SCI 236
  • Neurotrophic factors for neuroprotection after SCI 237
  • Promotion of regeneration of neurons in SCI 238
  • Rho pathway and Rho antagonists in SCI 238
  • Selenium as a neuroprotective for SCI 238
  • Sialidase for enhancing recovery after SCI 239
  • Targeting the inflammatory response for neuroprotection in SCI 239
  • Uric acid as neuroprotective in SCI 239
  • Non-pharmacological approaches to SCI 239
  • Hyperbaric oxygen therapy 239
  • Hypothermia for SCI 240
  • Cell therapy for SCI 240
  • Autoimmune T cells against CNS myelin-associated peptide 240
  • Fetal neural grafts for SCI 240
  • Olfactory-ensheathing cells for SCI 240
  • Oligodendrocyte precursor cells for treatment of SCI 241
  • Schwann cell transplants for SCI 241
  • Transplantation of glial cells for SCI 241
  • Stem cells for SCI 242
  • Bone marrow stem cells for SCI 242
  • Embryonic stem cells for SCI 242
  • Transplantation of induced pluripotent stem cells in SCI 243
  • Transplantation of MSCs for SCI 243
  • Transplantation of NSCs for SCI 243
  • Transdifferentiation of stem cells into cholinergic neurons for SCI 244
  • Gene therapy for SCI 244
  • Combined approaches to spinal cord injury 245
  • Discovery of new targets for neuroprotective therapies in SCI 246
  • Clinical trials in SCI 246

6. Neuroprotection in Neurodegenerative Disorders 249

  • Introduction 249
  • Pathomechanism of neurodegeneration 249
  • Dual role of α-synuclein in neuroprotection and neurodegeneration 249
  • Lack of neurotrophic factors 250
  • Neuroinflammation in neurodegenerative disorders 250
  • Neurodegeneration associated with protein misfolding 250
  • Modulation of neurodegeneration by molecular chaperones 250
  • Intrabodies targeting protein misfolding in neurodegeneration 251
  • Targeting proteins aggregation to prevent amyloid formation 251
  • Tau and neurodegeneration 251
  • Role of apoptosis in neurodegenerative disorders 252
  • Role of glia in neurodegeneration 252
  • Role of metals in neurodegeneration 252
  • Spread of neurodegeneration 253
  • TDP-43 proteinopathy and neurodegenerative diseases 253
  • Viral infections and neurodegeneration 253
  • AIDS and the nervous system 253
  • Avian influenza as cause of neurodegeneration 255
  • Neurodegenerative disorders with dementia 255
  • Dementia with Lewy bodies 256
  • Pick disease 256
  • Progressive supranuclear palsy 257
  • Genetic disorders with neurodegeneration 257
  • Batten disease 257
  • Friedrich ataxia 258
  • Pathomechanism of FA 258
  • Neuroprotection in FA 258
  • Niemann-Pick type C disease 259
  • Creutzfeldt-Jakob disease 259
  • Potential neuroprotectants for CJD 259
  • Approaches to neuroprotection in neurodegenerative disorders 260
  • Glutamate-based therapies for neurodegenerative disorders 261
  • Histone deacetylase inhibitors for neurodegenerative disorders 261
  • Iron chelation for neuroprotection 262
  • Mitochondria permeability transition pore complex and neuroprotection 262
  • Genomics-based research in neurodegenerative diseases 262

7. Neuroprotection in Parkinson Disease 263

  • Introduction 263
  • Epidemiology of Parkinson's disease 263
  • Pathophysiology of Parkinson's disease 263
  • Oxidative stress 264
  • Excitotoxicity 265
  • Asynchronous neuronal activity 265
  • Apoptosis 265
  • Role of neurotrophic factors 265
  • Role of misfolding proteins 265
  • Genetic factors in PD 266
  • Alteration of dopamine homeostasis 267
  • Neuroprotective strategies for PD based on pathomechanism 268
  • A genetic animal model of PD for testing neuroprotective strategies 268
  • Aldehyde dehydrogenase 1 protects nigrostriatal dopaminergic neurons 269
  • RNAi screening to identify neuroprotective genes in a PD model 269
  • Management of Parkinson's disease 269
  • Limitation of conventionally administered dopamine therapy 271
  • Treatment of dementia associated with PD 271
  • Neuroprotective therapy in PD 272
  • Neuroprotective effect of currently used drugs for PD 272
  • Pramipexole 272
  • Rasagiline mesylate 273
  • Ropinirole 274
  • Selegiline 274
  • Non-pharmacological strategies for neuroprotection in PD 275
  • Effect of exercise and environmental enrichment on PD 275
  • Low-calorie diet in PD 275
  • Development of neuroprotective therapies for PD 276
  • 2B3-201 for targeted delivery of methylprednisolone 276
  • 9-methyl-β-carboline 276
  • Adenosine AA2 receptor antagonists 276
  • Antiapoptotic strategies for PD 277
  • Augmenting CNS glucocerebrosidase activity 277
  • Calcium channel blockers for PD 277
  • Cell therapies for PD 278
  • Stem cells for PD 278
  • Activation of endogenous stem cells and neural precursors 278
  • Cogane 279
  • Creatine and minocycline 280
  • Conserved dopamine neurotrophic factor for PD 280
  • Free radical scavengers for neuroprotection in Parkinson's disease 280
  • Antioxidants 280
  • Diapocynin 281
  • Tea extracts as neuroprotectives 281
  • Gene therapy for PD 281
  • Implantation of genetically engineered cells 281
  • Gene therapy using GDNF and neurturin 282
  • Glutamic acid decarboxylase gene therapy 282
  • Parkin gene therapy 283
  • Concluding remarks about gene therapy for PD 283
  • Heat shock protein 70 284
  • Liver X receptor β agonists 284
  • Melatonin as a neuroprotectant in PD 284
  • Nicotine as a neuroprotective in PD 284
  • Neuroprotective effect of leucine-rich repeat kinase-2 inhibitors 285
  • Neuroprotective effect of DJ-1 protein 285
  • Neurotrophic factors 285
  • Basic fibroblast growth factor for PD 285
  • BDNF for PD 286
  • GDNF for PD 286
  • MANF for PD 287
  • Neurturin for PD 287
  • Platelet derived growth factor 287
  • Clinical trials with NTFs 287
  • Nrf2-mediated neuroprotection in PD 288
  • Omega-3 polyunsaturated fatty acids 288
  • RAB3B overexpression 288
  • RNAi therapy for PD 289
  • Safinamide 289
  • Sirtuin 2 inhibitors for neuroprotection in PD 289
  • Statins and PD 290
  • Targeting Bax 290
  • Vitamin D for neuroprotection in PD 290
  • Vaccine for PD 291
  • Clinical trials of neuroprotection in Parkinson's disease 291
  • Evaluation of neuroprotective therapies for PD 293
  • Current status and future challenges for neuroprotection in PD 294

8. Neuroprotection in Alzheimer Disease 297

  • Introduction 297
  • Pathomechanism of Alzheimer's disease 297
  • Role of glutamate transport dysfunction in AD 298
  • Role of neurotrophic factors in the pathomechanism of AD 298
  • Management of Alzheimer's disease 298
  • Neuroprotection in Alzheimer's disease 299
  • Inhibition of Aβ formation and aggregation 300
  • AN-1792 300
  • Cadmium telluride nanoparticles prevent Aβ fibril formation 301
  • Clioquinol 301
  • Colostrinin 302
  • FKBP52 for neuroprotection from Cu toxicity in AD 302
  • Monoclonal antibody m266 302
  • Phenserine 302
  • Secretase inhibitors 303
  • Inhibition of neuroinflammation 303
  • Etanercept 303
  • Neurotrophic factors/ gene therapy 304
  • NGF gene therapy 304
  • AL-108 305
  • Targeting plasminogen activator inhibitor type-1 gene 305
  • Estrogen and AD 306
  • Antioxidants 306
  • NSAIDS 306
  • Melatonin for AD 306
  • Memantine 307
  • Dimebon 307
  • Cerebrolysin 308
  • Curcumin as a neuroprotectant in Alzheimer disease 309
  • Ginko biloba 309
  • Tetrahydrocannabinol for neuroprotection in AD 310
  • Ladostigil tartrate 310
  • Phosphodiesterase inhibitors as neuroprotectives 310
  • PPAR-γ agonists 311
  • Role of statins in reducing the risk of AD 311
  • Combined therapeutic approaches to AD 312
  • Clinical trials in AD 312
  • Future prospects of neuroprotection in AD 319
  • Mild cognitive impairment 320
  • Relation of MCI to AD 320
  • Neuroprotection in MCI 321

9. Neuroprotection in Huntington Disease 323

  • Introduction 323
  • Pathophysiology of HD 323
  • Management of Huntington's disease 325
  • Neuroprotection in Huntington's disease 325
  • Antipsychotic D2 and 5-HT1A antagonists 326
  • Caspase inhibitors 326
  • Clioquinol for HD 326
  • Creatine for stabilizing bioenergetic defects 327
  • Cysteamine 327
  • Drugs that block inappropriate calcium release from neurons 327
  • Enhancing protease activity for clearance of mHtt 327
  • Eicosapentaenoic acid 328
  • Free radical scavengers 328
  • Histone deacetylase inhibitors 328
  • Inhibitors of polyglutamine aggregation HD 329
  • Metal-protein attenuating compounds 329
  • Pridopidine 330
  • RRAS signaling pathway inhibition 330
  • Simvastatin as a neuroprotective in HD 330
  • Single chain Fv antibodies 330
  • SIRT1 activators for neuroprotection in HD 331
  • SIRT2 inhibitors for neuroprotection in HD 331
  • Synaptic activation of NMDA receptors 332
  • Targeting mutant huntingtin protein 332
  • Tetrabenazine 332
  • Combinatorial therapy and targeting multiple pathways in HD 333
  • Cell transplants 333
  • Neurotrophic factors and gene therapy 334
  • RNAi and antisense therapies for Huntington's disease 334

10. Neuroprotection in Amyotrophic Lateral Sclerosis 337

  • Introduction 337
  • Pathophysiology of ALS 337
  • Neuroprotective therapies for ALS 340
  • Activated protein C 341
  • AEOL 10150 342
  • AIMSPRO 342
  • Anakinra 342
  • Antisense therapy 343
  • Arimoclomol for ALS 343
  • Ceftriaxone for ALS 343
  • Coenzyme Q10 for ALS 344
  • COX-2 inhibitors for ALS 344
  • Creatine for ALS 344
  • Dexpramipexole 345
  • Diallyl trisulfide 345
  • Erythropoietin for ALS 345
  • Gene therapy for ALS 346
  • Glatiramer acetate 346
  • GM602 347
  • Insulin-like growth factor 347
  • Ketogenic diet for neuroprotection in ALS 347
  • Lenalidomide 348
  • Lithium for neuroprotection in ALS 348
  • Melatonin for ALS 348
  • Methylcobalamin 349
  • Minocycline for ALS 349
  • Olesoxime as neuroprotective for ALS 349
  • ONO-2506 for ALS 350
  • Riluzole 350
  • RNAi-based therapy for ALS 350
  • Sodium phenylbutyrate 350
  • Stem cell therapy 351
  • Clinical applications 351
  • Stem cell-based drug discovery for ALS 352
  • Suppressors of mTDP-43 toxicity 352
  • Talampanel 353
  • Tamoxifen 353
  • Vaccination for ALS caused by SOD1 mutations 353
  • Vascular endothelial growth factor for ALS 353
  • Vitamin E for ALS 354
  • Clinical trials of neuroprotective therapies for ALS 354
  • Concluding remarks and future prospects 357

11. Neuroprotection in Miscellaneous Neurological Disorders 359

  • Introduction 359
  • Age-related dementia 359
  • Aging brain and oxidative stress 359
  • Enhancing endogenous neurotrophic support of the aging brain 360
  • Pharmacological approaches for treatment of age-related dementia 360
  • Physical exercise to prevent decline of mental function with aging 361
  • Vascular dementia 361
  • Prediction of dementia in persons with vascular risk factors 362
  • Management of subcortical vascular dementia 362
  • Dementia with Lewy bodies 363
  • Neuroprotection in AIDS dementia 363
  • Multiple system atrophy 364
  • Epilepsy 365
  • Mechanisms of neuronal damage in epilepsy 365
  • Strategies for neuroprotection in epilepsy 366
  • Control of seizures by AEDs and neuroprotection 366
  • Prevention of seizures by ketogenic diet 367
  • Hyalurona-based preservation of brain ECS volume for seizure control 368
  • Cell therapy for neuroprotection in epilepsy 368
  • Cell therapy of posttraumatic epilepsy 368
  • Cell therapy for temporal lobe epilepsy 369
  • Cell therapy for pharmacoresistant epilepsies 369
  • Gene therapy for neuroprotection in epilepsy 369
  • Neurogenetic disorders 370
  • Leigh syndrome 370
  • Spinal and bulbar muscular atrophy 371
  • Spinal muscular atrophy 371
  • Multiple sclerosis 372
  • Introduction 372
  • Epidemiology of multiple sclerosis 372
  • Pathophysiology 372
  • Current management of multiple sclerosis 373
  • Specific therapies for MS based on pathomechanism 374
  • Neuroprotection in multiple sclerosis 374
  • Clinical trials of neuroprotective therapies for MS 375
  • Neuroprotection by control of progressive forms of multiple sclerosis 378
  • Neuroprotection by controlling autoimmune inflammation in the brain 378
  • Neuroprotection by sealing the BBB with imatinib 379
  • TRPM4 cation channel blockers 379
  • Remyelination for neuroprotection in multiple sclerosis 379
  • Agents for neuroprotection in multiple sclerosis 379
  • Angiotensin-II inhibitors 379
  • Antiglutamate agents 380
  • Antioxidants for neuroprotection in MS 380
  • Antisense and RNAi approaches to MS 380
  • Cell therapy for multiple sclerosis 381
  • Cladribine 384
  • Curcumin as a neuroprotectant in multiple sclerosis 384
  • Dalfampridine in MS 384
  • Dimethyl fumarate 385
  • DNA vaccine for MS 385
  • Erythropoietin as a neuroprotective in MS 385
  • Fingolimod 385
  • Fusokine composed of GM-CSF and IL-15 for immune suppression 386
  • Gene therapy for MS 387
  • Ibudilast for MS 387
  • Iron chelators 387
  • IVIG for MS 388
  • Kinase inhibitors 388
  • Laquinimod 388
  • Monoclonal antibodies for MS 388
  • Natalizumab 389
  • Natural human antibodies for repair of myelin 389
  • Neurotrophic factors for multiple sclerosis 390
  • Oral immunomodulatory agents for MS 391
  • Protein kinase Cβ as a therapeutic target for stabilizing BBB in MS 391
  • Recombinant T-cell ligands 391
  • Statins for MS 391
  • Teriflunomide 392
  • Tolerance-directed immunotherapy for MS 392
  • Concluding remarks and future prospects for neuroprotection in MS 393
  • Neuroprotection in transverse myelitis 393
  • Neuroprotection in decompression sickness 394
  • Neuroprotection in victims of drowning 395
  • Neuroprotection in CSF circulatory disorders 395
  • Neuroprotection in hydrocephalus 395
  • Neuroprotection in normal pressure hydrocephalus 396
  • Neuroprotection in infections of the CNS 396
  • Neuroprotection in bacterial meningitis 397
  • Mechanism of neural injury in bacterial meningitis 397
  • Strategies for neuroprotection 397
  • Neuroprotection in cryptococcal meningitis 398
  • Neuroprotective approach to rabies 398
  • Neuroprotection in cerebral malaria 398
  • Neuroprotection in hypertensive encephalopathy 399
  • Neuroprotection in toxic encephalopathies 399
  • Hepatic encephalopathy 399
  • Management of hepatic encephalopathy 400
  • Bilirubin encephalopathy 400
  • Encephalopathy due to organophosphorus poisoning 401
  • Neuroprotection against chemotherapy-induced brain damage 402
  • Neuroprotection against alcohol 402
  • Alcoholic neurologic disorders 402
  • Fetal alcohol syndrome 403
  • Pathogenesis of alcohol-induced damage to the nervous system 403
  • Neuroprotection against neurotoxicity of alcohol 403
  • Neuroprotection against exposure to therapeutic radiation 404
  • Neuroprotection against radiation encephalopathy 404
  • Role of SOD in protection again radiation-induced hippocampal dysfunction 404
  • Catalase reduces mitochondrial ROS for neuroprotection from proton irradiation 405
  • Neuroprotection in hypoxia-ischemia 405
  • Neuroprotection in neonatal hypoxic-ischemic brain injury 405
  • Hyperbaric oxygen for neonatal hypoxia-ischemia 406
  • Hypothermia for neonatal hypoxia-ischemia 406
  • Minocycline for neonatal hypoxia-ischemia 407
  • Nicotinamide mononucleotide adenylyl transferase 1 407
  • Nitric oxide inhalation for neonatal hypoxia-ischemia 407
  • Plasminogen activator inhibitor-1 for neonatal hypoxia-ischemia 407
  • Recombinant erythropoietin for neonatal hypoxia-ischemia 408
  • Neuroprotection in carbon monoxide poisoning 408
  • Pathomechanism of CO poisoning as a basis for neuroprotection 408
  • Management of CO poisoning 409
  • Syndrome of delayed post-hypoxic leukoencephalopathy 409
  • Neuroprotection of the fetus 410
  • Neuroprotection in sleep apnea 410
  • Neuroprotection in complications of diabetes 411
  • Neuroprotection in hypoglycemic coma 411
  • Neuroprotection in diabetic retinopathy 412
  • Neuroprotection in mitochondrial dysfunction 413
  • Mitochondrial permeability transition 413
  • Mitochondrial approaches for neuroprotection 414
  • Methylene blue 414
  • Role of nanolasers in evaluation of mitochondrial neuroprotectants 415
  • Neuroprotection in mitochondrial encephalopathies 415
  • Neuroprotection in psychiatric disorders 415
  • Cognitive impairment in schizophrenia 415
  • Neuroprotection in schizophrenia 416
  • Electroconvulsive therapy and neuroprotection 416
  • Neuroprotection in hearing loss 417
  • Causes of hearing loss 417
  • Pathomechanism of hearing loss 418
  • Prevention and treatment of hearing loss 418
  • Hyperbaric oxygen for hearing loss 419
  • Stem cell therapy for hearing loss 419
  • Auditory hair cell replacement by gene therapy 419
  • Pharmaceutical approaches to hearing loss 420
  • Neuroprotection of peripheral nerves 421
  • Neuroprotective agents for peripheral nerves 421
  • Acetyl-L-carnitine for peripheral nerve injuries 422
  • Atorvastatin for peripheral nerve injuries 422
  • Erythropoietin for neuroprotection in peripheral nerve injuries 422
  • Neuroprotection in peripheral nerve injuries 423
  • Role of hyperbaric oxygen in peripheral nerve injuries 423
  • Role of neurotrophic factors in peripheral nerve injuries 423
  • Pharmacological approaches to Schwann cells 423
  • Role of gene therapy in neuroprotection of injured peripheral nerves 424
  • Schwann cell transplantation for peripheral nerve injury 424
  • Peripheral neuropathy 424
  • Neuroprotection in diabetic neuropathy 424
  • Cell therapy for neuroprotection in diabetic neuropathy 425
  • Gene therapy with zinc finger DNA-binding proteins 425
  • Neuroprotection in chemotherapy-induced neuropathy 425
  • Chronic inflammatory demyelinating polyradiculoneuropathy 426
  • Neuroprotection in CIDP 426

12. Neuroprotection of the Optic nerve and the Retina 427

  • Introduction 427
  • Neuroprotection in optic neuropathy 427
  • Neuroprotection in optic neuritis 428
  • Neuroprotection in optic nerve trauma 428
  • Potential regeneration of the optic nerve 429
  • Subthreshold transpupillary thermotherapy for protection of RGCs 429
  • Neuroprotection of optic nerve in glaucoma 429
  • Aminoguanidine as a neuroprotective in glaucoma 431
  • Antiglutamate agents for neuroprotection of optic nerve 431
  • Betaxolol 431
  • NGF eye drops 431
  • Targeting Aβ in glaucoma treatment 432
  • TNF-α blockers for neuroprotection in glaucoma 432
  • Concluding remarks about neuroprotection in glaucoma 432
  • Neuroprotection in retinal ischemia 432
  • Endogenous neuroprotection in the retina 433
  • β-adrenoceptor antagonists 433
  • Brimonidine as a neuroprotective is ischemic retinopathy 434
  • Thioredoxin as a neuroprotective agent in retinal ischemia 434
  • Erythropoietin for neuroprotection of retinal ischemia 434
  • Gene therapy for retinal neuroprotection 435
  • Hyperbaric oxygen for central retinal artery occlusion 435
  • Protection against oxygen-induced retinopathy 435
  • Neuroprotection in macular degeneration 436
  • Epidemiology 436
  • Pathomechanism of AMD 436
  • Current treatment of AMD 436
  • Novel neuroprotective strategies against retinal degeneration 437
  • Antiangiogenic agents 438
  • Humanized MAb against Aβ 439
  • LXR agonists 439
  • Protection of retinal cells from oxidative-stress-induced apoptosis 439
  • Neurotrophic factors for neuroprotection in AMD 440
  • CNTF for neuroprotection in AMD 440
  • N-acetylserotonin derivatives 440
  • Nutritional protection against AMD 440
  • Progestogenic hormones 441
  • Tandospirone 441
  • Cell therapy for macular degeneration 441
  • Retinal pigment epithelial cells 441
  • Stem cells 441
  • Neural progenitor cells 442
  • Gene therapy for retinal degeneration 442
  • RNAi-based treatments for AMD 442
  • Neuroprotection in proliferative diabetic retinopathy 443
  • RNAi-based approaches to diabetic retinopathy 443
  • Clinical trials for optic nerve and retinal neuroprotection 444

13. Neuroprotection during Anesthesia and Surgery 447

  • Introduction 447
  • Anesthetic agents as neuroprotectives 447
  • Barbiturates 447
  • Thiopental 448
  • Etomidate 449
  • Propofol 449
  • Ketamine 449
  • Gaseous anesthetics 450
  • Isoflurane 450
  • Xenon 450
  • Local anesthetics 451
  • Monitoring of CNS function during anesthesia and surgery 451
  • Monitoring of cerebral function 451
  • Monitoring of spinal cord function during spinal surgery 451
  • Perioperative neuroprotection 452
  • Neuroprotection during cardiovascular procedures 453
  • CNS complications of cardiac surgery 453
  • Neuroprotective strategies during cardiac surgery 454
  • Neuroprotection during coronary artery bypass grafting 455
  • Neuroprotection before anticipated or induced cardiac arrest 456
  • Spinal cord protection during cardiovascular surgery 456
  • Cerebral protection during organ transplantation surgery 457
  • Cerebral protection during neurosurgery 457
  • Cerebral angiography and endovascular surgery 457
  • Cerebral protection during surgery for arteriovenous malformations 457
  • Cerebral protection during surgery of intracranial aneurysms 458
  • Management of subarachnoid hemorrhage 458
  • Vasospasm associated with subarachnoid hemorrhage 459
  • Cerebral protection during carotid endarterectomy 460
  • Cerebral protection during surgery of brain tumors 461
  • Neuroprotective measures prior to surgery 461
  • Neuroprotection following surgery 461

14. Markets for Neuroprotective Therapies 463

  • Introduction 463
  • The financial burden of CNS damage 463
  • Markets for neuroprotective therapies 463
  • Markets according to therapeutic areas 463
  • Stroke 464
  • CNS injury 464
  • Alzheimer disease 464
  • Parkinson disease 465
  • Multiple sclerosis 465
  • Epilepsy 465
  • Values of neuroprotective therapies in major world markets 465
  • Unmet needs in neuroprotectives 466
  • Future prospects of neuroprotective therapies 467
  • Challenges in neuroprotective drug development 467
  • Promising areas of research in neuroprotection 468
  • Autoreactive antibodies 468
  • Biological therapies for neuroprotection 468
  • Multidisciplinary approaches to neuroprotection 469

15. References 471

Tables

  • Table 1-1: Historical landmarks in the development of neuroprotection 29
  • Table 1-2: Intrinsic neuroprotective factors 30
  • Table 1-3: Common features of pathophysiology of brain damage in diseases 39
  • Table 1-4: Place of neuroprotection in management of CNS disorders 40
  • Table 1-5: Indications for the use of neuroprotection 41
  • Table 2-1: A classification of neuroprotective agents 49
  • Table 2-2: The neuroprotective effect of antiepileptic drugs 58
  • Table 2-3: Neuroprotective affect of minocycline in animal models 62
  • Table 2-4: Classification of antioxidants or free radical scavengers with neuroprotective potential 70
  • Table 2-5: Role of erythropoietin in the nervous system 76
  • Table 2-6: Ionotropic glutamate receptors 81
  • Table 2-7: Classification of metabotropic glutamate receptors (mGluRs) 81
  • Table 2-8: Methods for neuroprotection based on nonpharmacological preconditioning 131
  • Table 3-1: Cerebrovascular diseases that are relevant to neuroprotection 135
  • Table 3-2: Neuroprotective strategies for stroke 144
  • Table 3-3: Neuroprotective gene transfer in models of cerebral ischemia 177
  • Table 3-4: Neuroprotective gene therapy in animal stroke models 177
  • Table 3-5: Neuroprotective agents in clinical development for acute cerebrovascular disease 179
  • 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 197
  • Table 4-2: Current conventional management of traumatic brain injury 205
  • Table 4-3: Neuroprotective strategies for traumatic brain injury 206
  • Table 4-4: Ongoing or completed clinical trials for neuroprotection in TBI 223
  • Table 4-5: Discontinued or failed clinical trials for neuroprotection in TBI 224
  • Table 5-1: Secondary mechanisms in spinal cord injury 231
  • Table 5-2: Neuroprotective and regenerative approaches for SCI 232
  • Table 5-3: Clinical trials for neuroprotection in SCI 246
  • Table 6-1: Neurodegenerative disorders with dementia 255
  • Table 6-2: Glutamate-based therapies in clinical development for neurodegenerative disorders 261
  • Table 7-1: Prevalence of Parkinson's disease in major markets 2013-2023 263
  • Table 7-2: Factors in the etiology of Parkinson's disease 263
  • Table 7-3: Strategies for the treatment of Parkinson's disease 270
  • Table 7-4: Current clinical trials of neuroprotective therapies for Parkinson disease 292
  • Table 7-5: Failed clinical trials of neuroprotective therapies for Parkinson disease 292
  • Table 7-6: Evaluation of neuroprotective agents for PD 293
  • Table 8-1: Cholinergic approaches to the treatment of Alzheimer's disease 299
  • Table 8-2: Neuroprotective agents for Alzheimer's disease 299
  • Table 8-3: Clinical trials for neuroprotection in Alzheimer disease 312
  • Table 8-4: Discontinued, failed or inconclusive clinical trials of Alzheimer disease 317
  • Table 8-5: Strategies for discovery of neuroprotective therapies for AD 319
  • Table 9-1: Neuroprotective approaches in HD 325
  • Table 10-1: Hypotheses for the pathogenesis of amyotrophic lateral sclerosis 337
  • Table 10-2: Classification of neuroprotective agents for amyotrophic lateral sclerosis 340
  • Table 10-3: Clinical trials of neuroprotective therapies for ALS 354
  • Table 10-4: Failed or discontinued trials of neuroprotective therapies for ALS 355
  • Table 11-1: Therapeutic approaches to subcortical vascular dementia 362
  • Table 11-2: Pharmacological neuroprotection against the sequelae of seizures 366
  • Table 11-3: Neuroprotective effect of AEDs in animal models of status epilepticus (SE) 367
  • Table 11-4: Specific therapies for MS based on postulated pathomechanisms 374
  • Table 11-5: Approved neuroprotective therapies for multiple sclerosis 375
  • Table 11-6: Neuroprotective therapies for multiple sclerosis in clinical trials 376
  • Table 11-7: Failed or discontinued trials of neuroprotective therapies for ALS 376
  • Table 11-8: Measures to prevent acute bilirubin encephalopathy 401
  • Table 11-9: Approaches to neuroprotection in neonatal hypoxia-ischemia 406
  • Table 11-10: Drugs with neuroprotective effect at mitochondrial level 414
  • Table 11-11: Causes of sensorineural hearing impairment 417
  • Table 11-12: Strategies for prevention and treatment of sensorineural hearing loss 418
  • Table 11-13: Agents for neuroprotection of the peripheral nervous system 421
  • Table 12-1: Causes of optic neuropathy 427
  • Table 12-2: Neuroprotection of the optic nerve in glaucoma 430
  • Table 12-3: Strategies for neuroprotection in retinal ischemia 433
  • Table 12-4: Novel neuroprotective strategies against retinal degeneration 437
  • Table 12-5: Clinical trials for optic nerve and retinal neuroprotection 444
  • Table 13-1: CNS complications associated with cardiac procedures 453
  • Table 13-2: Strategies for protection of the brain during cardiac surgery 454
  • Table 13-3: Medical and surgical methods of cerebral vasospasm management 459
  • Table 13-4: Neuroprotection by prevention of vasospasm 459
  • Table 14-1: Neuroprotective market values 2013-2023 464
  • Table 14-2: Values of neuroprotective therapies in major world markets from 2013-23 465

Figures

  • Figure 2-1: Mechanism of neuroprotective effect of sigma-1 receptor agonists 57
  • Figure 2-2: NMDA receptor ion channel complex 85
  • Figure 2-3: Neuroprotective effect of galantamine 108
  • Figure 3-1: Some steps in the ischemic cascade and site of action of neuroprotectives 136
  • Figure 3-2: A roadmap for neuroprotection 193
  • Figure 4-1: Cascade of events following traumatic brain injury 199
  • Figure 4-2: Secondary injury mechanisms after TBI 200
  • Figure 5-1: Pathomechanism of acute spinal cord injury 230

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
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