Reportlinker Adds Neuroprotection - Drugs, Markets and Companies

Jun 03, 2010, 12:39 ET from Reportlinker

NEW YORK, June 3 /PRNewswire/ -- announces that a new market research report is available in its catalogue:

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 a profile of 138 companies that have a neuroprotective product or products along with 99 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 products that have a neuroprotective effect are analyzed for the year 2009. 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 2014 when it will constitute a major and important component of the CNS market. Forecasts are made until 2019. By that time neuroprotection will be an established part of the neurological practice and measures will be available to achieve this effectively.


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

Induction of DNA repair enzymes for neuroprotection 29

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 31

Role of neuroprotection in various neurological disorders 31

Neuroprotection and neuroregeneration 32

Acute versus chronic neuroprotection 32

Discovery and evaluation of neuroprotective agents 33

Neuroprotective drug discovery 33

Discovery of CNS drugs that penetrate the blood-brain barrier 33

In vitro assays for the evaluation of neuroprotective agents 34

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 37

Application of nanotechnology to neuroprotection 37

Evaluation criteria for potential neuroprotective agents 38

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

Antidepressants 45

Preclinical studies of neuroprotective action of antidepressants 45

Antidepressant-induced neurogenesis 45

Neurogenesis induced by electroconvulsive therapy 45

Antiepileptic drugs as neuroprotectives 46

Phenytoin 46

Valproic acid 46

Levetiracetam 47

Antiinflammatory agents 47

Aspirin 47

Interleukin-1 antagonists 48

COX-2 inhibitors 48

Nimesulide 48

NS-398 49

Minocycline 49

VP015 50

Anti-apoptosis agents 50

Activated protein C 51

Calpain inhibitors 51

Caspase inhibitors 52

Clusterin 52

DNA binding drugs 52

Lithium 52

Omega-3 fatty acids 53

Docosahexaenoic acid 53

Poly (ADP-ribose) polymerase (PARP) inhibitors 54

Prevention of apoptosis by binding of proNGF to Sortilin 54

TRO19622 55

Antioxidants/free radical scavengers 55

Free radical generation 55

Natural defenses against oxidative stress 55

Effects of oxidative damage 56

Oxidative damage and aging 56

Neuronal damage by free radicals 56

Oxidative damage and neurodegenerative disorders 57

Measures to control oxidative stress 57

Categories of therapeutic antioxidants 57

Alpha-phenyl-tert-butylnitrone 58

Coenzyme Q10 58

Dihydroergocryptine 59

Flavonoids 59

Mitochondria-targeted antioxidants 59

Nanoparticles as neuroprotective antioxidants 60

Neuroleptics as antioxidants 60

Nitrones 61

Translation of antioxidant neuroprotection from preclinical to clinical 61

Carbon monoxide and heme oxygenase 61

Cell transplants 62

Cells secreting neuroprotective substances 62

Stem cells 62

Stem cell activation for neuroprotection/regeneration by using glucocortoids 63

Cytokines 63

Erythropoietin 63

Non-erythropoietic EPO variants and mimics 64

Granulocyte colony-stimulating factor 65

Delta-opioid receptor agonists 65

FK960 66

GABA agonists 66

Gene therapy 66

Glucagon-like peptide 67

Glatiramer acetate 68

Glutamate antagonists 68

Neuroprotection by scavenging blood glutamate 69

N-acylethanolamines for protection against glutamatergic excitotoxicity 69

Glutamate transporters 70

Glutamate transporter-mediated neuroprotective effect of drugs 70

Neuroprotection by targeting KAI subunit of kainate receptor 70

Glycine-proline-glutamate analogs 71

Herbal preparations 71

Flavonoid wogonin 72

Ginseng 72

Hydrogen sulfide 72

NMDA receptor ion channel complex 73

NMDA receptor antagonists 74

NPS 1506 74

NMDA NR2B subunit receptor antagonists 74

Ifenprodil 74

Memantine 74

Magnesium 75

NAALADase inhibitors 75

3,3-bis (3-fluorophenyl) propylamine 75

Gacyclidine (GK-11) 76

N-alkylglycines 76

Partial NMDA agonists at glycine site 76

AMPA receptor modulators 76

Metabotropic glutamate receptor modulators 77

Cannabinoids 78

Dexanabinol 78

Glutathione 79

Heat shock proteins 79

Hormones 79

Estrogen and neuroprotection 79

Neuroprotective effect of estrogen receptor ligands 80

Selective estrogen receptor modulators 80

Receptor-independent neuroprotective effects of estrogens 81

Mitochondrial mechanisms of estrogen neuroprotection 81

Insulin 81

Ion Channel modulators 82

Calcium channel blockers 82

Ziconotide 82

Na+ channel blockers. 83

Neuroprotective potassium channel inhibitors 83

Kynurenine inhibitors 84

Leukocyte adhesion inhibitors 84

Modafinil 85

Neural regeneration protein 85

Neurite outgrowth-promoting prostaglandin compounds 86

Neuroimmunophilins 86

Cyclosporin-A 86

FK506 87

GPI 1485 87

Rapamycin 87

Neurotrophic factors 88

Activity-dependent neurotrophic factor 88

Bone morphogenetic proteins 88

Brain-derived neurotrophic factor 89

Ciliary neurotrophic factor 89

Fibroblast growth factors 90

Glial cell line-derived neurotrophic factor 90

Insulin-like growth factor 91

Nerve growth factor 91

Neurotrophins 92

Osteogenic protein-1 92

Pigment epithelium-derived factor 92

Transforming growth factor- 1 93

Vascular endothelial growth factor 93

Neurotrophic factor-related neuroprotective agents 93

Amitriptyline as a TrkA and TrkB receptor agonist 93

Colivelin 94

Gambogic amide 94

Inosine 94

Meteorin 94

Oxygen-regulated protein 150 kD (ORP150) 95

Prosaptide 95

Siagoside (GM1 ganglioside) 95

Small molecule activators of the Trk receptors 96

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

Reservatrol 102

Osmotic diuretics 103

Mannitol 103

Osteopontin 104

Oxygen therapeutics 104

Oxygen carriers 104

Hemoglobin-based oxygen carriers 105

Perfluorocarbons as oxygen carriers 105

Hyperbaric oxygen therapy 106

Peptides 106

C3-derived peptide for neuroprotection and neuroregeneration 106

Corticotropin-releasing hormone 107

Neuroprotective peptide NAP 107

Thyrotropin-releasing hormone 108

Vasoactive intestinal peptide (VIP). 108

PPARs as drug targets for neuroprotection 109

Riluzole 109

Role of RNA interference in neuroprotection 109

Signaling pathway activator 109

Fructose-1,6-bisphosphate 109

Sir 2 group of proteins 110

Statins 110

Steroids 111

Dehydroepiandrosterone 111

HF0220 112

Sulforaphane 112

Tauroursodeoxycholic acid 112

Tetanus toxin as a neuroprotective agent 113

Thrombolytic agents as neuroprotective agents 113

Uncoupling protein 2 113

Vaccines as neuroprotectives 114

Vitamins as neuroprotective agents 114

Vitamin B12 114

Non-pharmacological approaches to neuroprotection 115

Environmental enrichment 115

Hypothermia 115

Limitations of hypothermia 116

Hypothermic neuroprotection in hypoxia-ischemia 116

Hibernation induced by hydrogen sulfide 117

Ketogenic diet 117

Preconditioning-induced neuroprotection 117

Hypoxic preconditioning 118

Moderate stimulation of reactive oxygen species 118

Chemical preconditioning 118

Transcranial magnetic stimulation 119

Electrical fields for improvement of cerebral function in neurodegeneration 119

Neuroprotective effect of exercise 120

Hibernation and neuroprotection 120

Suspended animation and neuroprotection 121

3. Neuroprotection in Cerebrovascular Disease 123

Introduction 123

Epidemiology of stroke 123

Pathophysiology of cerebral ischemia 124

Calcium overload 124

Ion channel dysfunction in stroke 125

Role of oxygen free radicals in cerebral ischemia 125

Role of nitric oxide in cerebral ischemia 125

Glutamate as a marker of stroke 125

Cerebral edema in stroke 126

Gene expression in response to cerebral ischemia 126

Induction of heat shock proteins in stroke 126

Role of cytokines and adhesion molecules in stroke 127

Tumor necrosis factor (TNF) - 127

Interleukin (IL)-1 and IL-6 127

Adhesion molecules 127

DNA damage and repair in cerebral ischemia 128

Role of neurotrophic factors 128

Problems requiring investigation of the role of NTFs in stroke 129

Role of Poly(ADP-ribose) polymerase (PARP) gene 129

Role of protease-activated receptor 1 129

Reperfusion injury after cerebral ischemia 129

Neuroprotection according to zones in cerebral infarction 130

Zone of ischemic infarction 130

Penumbra 130

Current management of stroke 131

Neuroprotection in stenosis of intracranial arteries 132

Neuroprotective therapies for stroke 132

Agents in research/preclinical stage for neuroprotection in stroke 133

Acid-sensing ion channel blockers 135

AMPA receptor antagonists as neuroprotectives for stroke 135

Zonampanel 135

Anti-apoptotic neuroprotectives 135

NIM811 136

Creatine as neuroprotective in stroke 136

Lithium as a neuroprotective in stroke 136

TUDCA as a neuroprotective in stroke 136

Anti-HMGB1 monoclonal antibody 137

Antioxidant approaches 137

Dehydroascorbic acid 138

Tocotrienols 138

Carnosine as a neuroprotective in stroke 139

Antiglutamate compounds 139

202W92 139

AR-R15896AR 139

MRZ 2/576 140

L-Phenylalanine 140

Arimoclomol for stroke 140

Cardiac glycosides as neuroprotectives in stroke 140

Clenbuterol 141

Cox-2 inhibitors for ischemic stroke 141

Enoxaparin 141

Estrogen for stroke 142

Flavones for neuroprotection in stroke 143

Granulocyte-macrophage colony-stimulating factor for cerebral ischemia 143

Histamine H2-receptor antagonists 144

Inosine for stroke 144

Intravenous immunoglobulin as neuroprotective in stroke 144

Insulin-like growth factor-I 144

Ischemic preconditioning for neuroprotection in stroke 145

Ketone bodies 146

Minalocorticoid receptor blockade for neuroprotection 146

Multifunctional neuroprotective agents 147

Nasal delivery of neuroprotective agents in stroke 147

Neuroserpin as a neuroprotective in stroke 147

N-2-mercaptopropionyl glycine 148

NeuroAid 148

Neurotrophic factors as neuroprotectives for stroke 148

AX200 148

Brain-derived neurotrophic factor 148

Neuregulin-1 149

NO-based strategies for neuroprotection in cerebral ischemia 149

Peroxisome proliferator-activated receptor- agonists 149

PGE2 EP2 receptor activation 150

Pioglitazone for reduction of stroke risk in diabetes 150

Progesterone 150

Proteosome inhibitors 150

Statins for prevention and neuroprotection in stroke 151

Thrombosis inhibitors 151

Aspirin 151

Clopidogrel 152

Dipyridamole 152

CBL1309 152

SB-239063 152

Sildenafil 153

Src receptor blockade 153

Stroke vaccine 153

SUN N4057 154

Tiagabine 154

Topiramate 154

Zonisamide 155

Neuroprotectives in reperfusion injury 155

Prevention of hemorrhage following ischemic stroke 156

Non-pharmacological neuroprotective therapies for stroke 156

Preconditioning for neuroprotection against cerebral ischemia 156

Hypothermia for neuroprotection in acute stroke 156

Hyperbaric oxygen therapy for neuroprotection in acute stroke 157

Infrared laser therapy for ischemic stroke 158

Neurostimulation of sphenopalatine ganglion 158

Role of neurosurgical procedures for neuroprotection in stroke 158

Neurorehabilitation in relation to neuroprotection in stroke 159

Cell therapy for stroke 159

Gene therapy for neuroprotection in cerebrovascular disease 160

Neuroprotective genetic vaccine 161

COX-1/PGIS and COX-1 gene transfer in cerebral ischemia 162

Transfer of the bcl-2 gene for neuroprotection in cerebral ischemia 162

Neuroglobin gene therapy 162

Regulation of microRNAs 162

Neuroprotective therapies for cerebral ischemia: clinical trials 163

Albumin 164

Free radical scavengers 164

DP-b99 166

Erythropoietin as a neuroprotective in stroke 166

Minocycline for neuroprotection in stroke 167

Perindopril 167

Failed clinical trials of neuroprotection in stroke 167

Ancrod 169

Aptiganel 169

Cerovive (NXY-059) 169

Citicoline 170

Desmoteplase 171

SPD 502 172

Tirilazad mesylate 172

Selfotel (CGS 19755) 173

Lubeluzole 173

Nalmefene (Cervene) 173

Gavestinel (GV150526) 174

Nimodipine 174

Repinotan 174

Sipatrigine 174

Causes of failure of stroke trials 175

Measures for prevention of failures in stroke trials 176

Design of acute stroke trial to facilitate drug approval 178

The ideal neuroprotective agent for stroke 178

Future prospects for neuroprotection in stroke 179

4. Neuroprotection in CNS Trauma 181

Introduction 181

Cerebral hypoxia/ischemia as a complication of trauma 181

Traumatic brain injury (TBI) 181

Pathophysiology of TBI 181

Immediate damage following TBI 182

Cerebral edema following TBI 182

Delayed damage following TBI 183

Mechanism of axonal damage after TBI 183

Role of neuroinflammation in TBI 183

Molecular events following TBI 183

BBB damage after TBI 184

Chronic traumatic encephalopathy 184

Changes in neurotrophic factors following TBI 185

Changes in neurotransmitters following TBI 185

A deposition following TBI 185

Genetic influences on outcome following TBI 186

Management of TBI 186

Control of intracranial pressure and cerebral edema 187

Corticosteroids 187

Neuroprotection in TBI 187

Antiepileptic drugs for prevention of seizures and neuroprotection 188

Antioxidants 189

Barbiturates 189

- and secretase inhibitors 189

Beta blockers 190

Bradykinin B2 antagonists 190

Branched chain amino acids to ameliorate cognitive impairment in TBI 190

Cell cycle inhibitors for TBI 191

Creatine for neuroprotection in TBI 191

COX-2 inhibitors for neuroprotection in TBI 191

Cyclosporin for neuroprotection in TBI 192

Dexanabinol for TBI 192

Erythropoietin for neuroprotection in TBI 193

Gold implants for neuroprotection in focal TBI 193

KN 38-7271 193

Magnesium sulfate 193

Neurotrophic factors for TBI 194

Neurosteroids as neuroprotective agents for TBI 195

Nicotinamide for neuroprotection in TBI 195

NMDA receptor antagonists 196

Non-NMDA receptor antagonists 196

Nogo-A inhibitor 196

NP-1 196

Omega 3 fatty acids as neuroprotectives in TBI 197

Oxygen carriers for TBI 197

Polyethylene glycol for neuroprotection in TBI 198

Propofol for neuroprotection in TBI 198

Rapamycin as neuroprotective in TBI 198

Simvastatin as neuroprotective in TBI 199

Thyrotropin-releasing hormone analogs 199

Traxoprodil 199

Biological approaches to neuroprotection in TBI 200

Antisense approaches to TBI 200

Cell therapy for TBI 200

Gene therapy for TBI 201

Vaccine for TBI 201

Non-pharmaceutical approaches to neuroprotection in TBI 201

Hyperbaric oxygen therapy for TBI 201

Hypothermia 201

Reduction of microglial migration after TBI 202

Deep brain stimulation for TBI 202

Prophylactic neuroprotection against TBI 202

Role of physical exercise in protection against TBI 203

Clinical trials of neuroprotective agents in TBI 203

Failed clinical trials in TBI 204

Differences between clinical trials and studies in animal models of TBI 205

Subgroup analysis 205

Improving the clinical trial design 205

Clinical trials combining multipotential treatment strategies 206

Shortening the trial time 206

Concluding remarks and future prospects of neuroprotection in TBI 206

Acute spinal cord injury (SCI) 207

Epidemiology of SCI 207

Pathophysiology of SCI 207

Secondary mechanisms of SCI 208

Neurotrophic factor changes in SCI 209

Management of SCI 210

Pharmacological neuroprotective agents for SCI 211

4-aminopyridine(4-AP, famprodine) 211

Antibodies as neurite growth inhibitors in SCI 211

Bacterial enzyme chondroitinase ABC 212

CRL-5861 212

Docosahexaenoic acid as neuroprotective in SCI 212

Erythropoietin as a neuroprotective in SCI 213

Free radical scavengers for neuroprotection in SCI 213

Gacyclidine 213

GYKI 52466 214

Immunosuppressants as neuroprotectants in SCI 214

Matrix metalloproteinase inhibitors for SCI 214

Methylprednisolone 214

Minocyline as neuroprotective in SCI 215

Neurotrotrophic factors for neuroprotection after SCI 215

Nicotinamide adenine dinucleotide 216

Rho pathway and Rho antagonists in SCI 216

Selenium as a neuroprotective for SCI 217

Targeting the inflammatory response for neuroprotection in SCI 217

Uric acid as neuroprotective in SCI 217

Non-pharmacological approaches to SCI 218

Hyperbaric oxygen therapy 218

Hypothermia for SCI 218

Cell and gene therapy for SCI 218

Cell transplants 218

Gene therapy for SCI 220

Combined approaches to spinal cord injury 220

Discovery of new targets for neuroprotective therapies in SCI 221

Clinical trials in SCI 222

5. Neuroprotection in Neurodegenerative Disorders 223

Introduction 223

Pathomechanism of neurodegeneration 223

Dual role of synuclein in neuroprotection and neurodegeneration 223

Lack of neurotrophic factors 224

Neuroinflammation in neurodegenerative disorders 224

Neurodegeneration associated with protein misfolding 224

Modulation of neurodegeneration by molecular chaperones 224

Intrabodies targeting protein misfolding in neurodegeneration 225

Targeting in proteins aggregation to prevent amyloid formation 225

Tau and neurodegeneration 225

Role of apoptosis in neurodegenerative disorders 226

Role of glia in neurodegeneration 226

Role of metals in neurodegeneration 226

Viral infections and neurodegeneration 227

AIDS and the nervous system 227

Avian influenza as cause of neurodegeneration 228

Glutamate-based therapies for neurodegenerative disorders 228

Parkinson's disease 229

Epidemiology of Parkinson's disease 229

Pathophysiology of Parkinson's disease 230

Oxidative stress 230

Excitotoxicity 231

Asynchronous neuronal activity 231

Apoptosis 231

Role of neurotrophic factors 232

Role of misfolding proteins 232

Genetic factors in PD 232

Alteration of dopamine homeostasis 233

Neuroprotective strategies for PD based on pathomechanism 234

RNAi screening to identify neuroprotective genes in a PD model 235

Management of Parkinson's disease 235

Limitation of conventionally administered dopamine therapy 236

Treatment of dementia associated with Parkinson's disease 237

Neuroprotective therapy in Parkinson's disease 237

Neuroprotective effect of currently used drugs for Parkinson's disease 237

Pramipexole 237

Rasagiline mesylate 238

Ropinirole 238

Selegiline 239

Free radical scavengers for neuroprotection in Parkinson's disease 240

Antioxidants 240

Melatonin 240

Tea extracts as neuroprotectives 241

Nicotine as a neuroprotective in PD 241

Non-pharmacological strategies for neuroprotection in Parkinson's disease 242

Preventive effect of exercise and environmental enrichment 242

Low-calorie diet 242

Research in neuroprotection for Parkinson's disease 242

Activation of the hedgehog signaling pathway 243

Activation of endogenous stem cells and neural precursors 243

Adenosine AA2 receptor antagonists 244

Anti-apoptotic strategies for PD 244

Conserved dopamine neurotrophic factor for PD 244

Heat shock protein 70 (Hsp70) 245

Neuroprotective effect of DJ-1 protein 245

Nrf2-mediated neuroprotection in PD 245

Omega-3 polyunsaturated fatty acids 246

RAB3B overexpression 246

Sirtuin 2 inhibitors for neuroprotection in PD 246

Statins and PD 247

Targeting Bax 247

Tobacco smoke constituents 247

Synergistic effect of dopamine and cannabinoid agonists in PD 247

Clinical trials of neuroprotection in Parkinson's disease 248

CEP-1347 249

Creatine and minocycline 250

Neurotrophic factors 250

PYM50028 252

Safinamide 253

Cell therapies 253

Gene therapy 254

RNAi therapy for Parkinson's disease 256

Vaccine for PD 256

Evaluation of neuroprotective therapies for PD 257

Current status and future challenges for neuroprotection in PD 258

Alzheimer's disease 259

Introduction 259

Pathomechanism of Alzheimer's disease 259

Role of glutamate transport dysfunction in AD 260

Role of neurotrophic factors in the pathomechanism of AD 260

Management of Alzheimer's disease 261

Neuroprotection in Alzheimer's disease 261

Inhibition of amyloid protein aggregation 263

Secretase inhibitors 263

AN-1792 263

Monoclonal antibody m266 264

Inhibition of the transformation of spherons into amyloid plaques 264

Clioquinol 264

FKBP52 for neuroprotection from Cu toxicity in AD 265

Phenserine 265

Colostrinin 266

Inhibition of neuroinflammation 266

MW01-5-188WH 266

Etanercept 266

Neurotrophic factors/ gene therapy 267

NGF gene therapy 267

Neotrofin (leteprinim potassium, AIT-082) 268

AL-108 269

Targeting plasminogen activator inhibitor type-1 gene 269

Estrogen 269

ABS-205 270

Nimodipine 270

Antioxidants 270


P-3012 270

Vitamin E 271

Memantine 271

Dimebon 273

Cerebrolysin 273

Ginko biloba 274

Tetrahydrocannabinol for neuroprotection in AD 275

CPI-1189 275

Ladostigil tartrate 275

Phosphodiesterase inhibitors 276

PPAR - gamma agonists 276

Role of statins in reducing the risk of Alzheimer's disease 276

Combined therapeutic approaches to Alzheimer's disease 277

Clinical trials in Alzheimer's disease 277

Future prospects of neuroprotection in AD 284

Huntington's disease 284

Epidemiology of HD 284

Pathophysiology of HD 284

Management of Huntington's disease 286

Neuroprotection in Huntington's disease 286

Antipsychotic D2 and 5-HT1A antagonists 287

Caspase inhibitors 287

Clioquinol for HD 288

Creatine for stabilizing bioenergetic defects 288

Cysteamine 288

Drugs that block inappropriate calcium release from neurons 288

Enhancing protease activity for clearance of mHtt 289

Eicosapentaenoic acid 289

Free radical scavengers 289

Histone deacetylase inhibitors 290

Inhibitors of polyglutamine aggregation HD 290

Pridopidine 291

Simvastatin as a neuroprotective in HD 291

Single chain Fv antibodies 291

SIRT2 inhibitors for neuroprotection in HD 291

Synaptic activation of NMDA receptors 292

Tetrabenazine 292

Combinatorial therapy and targeting multiple pathways in HD 292

Cell transplants 293

Neurotrophic factors and gene therapy 293

RNAi therapy for Huntington's disease 294

Amyotrophic lateral sclerosis (ALS) 294

Epidemiology of ALS 294

Pathophysiology of ALS 295

Neuroprotective therapies for ALS 297

Activated protein C 298

AEOL 10150 298


Arimoclomol for ALS 299

Antisense therapy 299

Ceatine for ALS 299

Ceftriaxone for ALS 300

Coenzyme Q10 for ALS 300

COX-2 inhibitors for ALS 301

Diallyl trisulfide 301

Gene therapy for ALS 301

Glatiramer acetate 302

Insulin-like growth factor 302

Ketogenic diet for neuroprotection in ALS 302

Lithium for neuroprotection in ALS 303

Minocycline for ALS 303

Other neurotrophic factors for ALS 303

ONO-2506 for ALS 304

Riluzole 304

RNAi-based therapy for ALS 304

Sodium phenylbutyrate 305

Stem cell therapy 305

Talampanel 306

Tamoxifen 306

TRO19622 as neuroprotective for ALS 306

Vaccination for ALS caused by SOD1 mutations 306

Status of development of neuroprotective therapies for ALS 307

Concluding remarks and future prospects of neuroprotection in ALS 308

Spinal and bulbar muscular atrophy 309

6. Neuroprotection in Miscellaneous Neurological Disorders 310

Dementias due to miscellaneous causes 310

Age-related dementia 310

Enhancing endogenous neurotrophic support of the aging brain 310

Pharmacological approaches for treatment of age-related dementia 311

Physical exercise to prevent decline of mental function with aging 312

Vascular dementia 312

A test for prediction of dementia in persons with vascular risk factors 312

Management of subcortical vascular dementia 313

Dementia with Lewy bodies 314

Creutzfeldt-Jakob disease 314

TDP-43 proteinopathy and neurodegenerative diseases 315

Genetic disorders with neurodegeneration 315

Batten's disease 315

Friedrich's ataxia 316

Niemann-Pick type C disease 317

Epilepsy 317

Mechanisms of neuronal damage in epilepsy 317

Strategies for neuroprotection in epilepsy 318

Control of seizures and neuroprotection 319

Responsive Neurostimulator System 320

Neuroprotective effect of estrogens in epilepsy 320

Cell therapy for neuroprotection in epilepsy 320

Gene therapy for neuroprotection in epilepsy 321

Multiple sclerosis 322

Introduction 322

Epidemiology of multiple sclerosis 322

Pathophysiology 322

Current management of multiple sclerosis 323

Specific therapies for MS based on pathomechanism 324

Neuroprotection in multiple sclerosis 324

Neuroprotection by control of progressive forms of multiple sclerosis 326

Neuroprotection by controlling autoimmune inflammation in the brain 326

Angiotensin-II inhibitors 327

Antiglutamate agents 327

Antioxidants for neuroprotection in MS 327

Antisense and RNAi approaches to MS 327

Cell therapy for multiple sclerosis 328

Cladribine 329

Dalfampridine in MS 330

DNA vaccine for MS 330

Erythropoietin as a neuroprotective in MS 330

Fingolimod (FTY720) 330

Fusokine composed of GM-CSF and IL-15 for immune suppression 331

Gene therapy for MS 332

IVIG for MS 332

Laquinimod 332

MBP8298 332

Monoclonal antibodies for MS 333

Natalizumab 333

Natural human antibodies for repair of myelin 334

Neurotrophic factors for multiple sclerosis 334

Recombinant T-cell ligands 335

Statins for MS 335

Concluding remarks on neuroprotection in MS 335

Chronic inflammatory demyelinating polyradiculoneuropathy 336

Neuroprotection in CIDP 336

Neuroprotection in transverse myelitis 336

Neuroprotection in decompression sickness 337

Neuroprotection in hydrocephalus 338

Neuroprotection in normal pressure hydrocephalus 338

Neuroprotection in infections of the CNS 338

Neuroprotection in bacterial meningitis 338

Mechanism of neural injury in bacterial meningitis 339

Strategies for neuroprotection 339

Neuroprotection in AIDS dementia 340

Neuroprotective approach to rabies 341

Neuroprotection in cerebral malaria 341

Neuroprotection in hypertensive encephalopathy 341

Neuroprotection in toxic encephalopathies 342

Hepatic encephalopathy 342

Encephalopathy due to organophosphorus poisoning 342

Neuroprotection against chemotherapy-induced brain damage 343

Neuroprotection against alcohol 344

Alcoholic neurologic disorders 344

Fetal alcohol syndrome 344

Pathogenesis of alcohol-induced damage to the nervous system 344

Neuroprotection against neurotoxicity of alcohol 345

Neuroprotection in sleep apnea 345

Neuroprotection in hypoglycemic coma 346

Neuroprotection in neonatal hypoxic-ischemic brain injury 347

Neuroprotection in mitochondrial dysfunction 349

Mitochondrial permeability transition 349

Mitochondrial approaches for neuroprotection 349

Methylene blue 350

Role of nanolasers in evaluation of mitochondrial neuroprotectants 350

Neuroprotection in mitochondrial encephalopathies 351

Neuroprotection in schizophrenia 351

Neuroprotection of the optic nerve and the retina 352

Neuroprotection in optic nerve trauma 352

Potential regeneration of the optic nerve 352

Neuroprotection of optic nerve in glaucoma 352

Aminoguanidine as a neuroprotective in glaucoma 354

Antiglutamate agents for neuroprotection of optic nerve 354

Betaxolol 354

NGF eye drops 354

Targeting A in glaucoma treatment 355

TNF blockers for neuroprotection in glaucoma 355

Concluding remarks about neuroprotection in glaucoma 355

Neuroprotection in retinal ischemia 355

Endogenous neuroprotection in the retina 356

-adrenoceptor antagonists 356

Brimonidine as a neuroprotective is ischemic retinopathy 357

Thioredoxin as a neuroprotective agent in retinal ischemia 357

Erythropoietin for neuroprotection of retinal ischemia 357

Gene therapy for retinal neuroprotection 357

Hyperbaric oxygen for central retinal artery occlusion 358

Protection against oxygen-induced retinopathy 358

Neuroprotection in macular degeneration 358

Antiangiogenic agents 359

Protection of retinal cells from oxidative-stress-induced apoptosis 360

Nutritional protection against AMD 360

Cell therapy for macular degeneration 360

Gene therapy for retinal degeneration 361

RNAi-based treatments for AMD 361

Neuroprotection in proliferative diabetic retinopathy 362

Companies developing products for retinal neuroprotection 362

Neuroprotection in hearing loss 363

Neuroprotection of peripheral nerves 364

Neuroprotection in diabetic neuropathy 364

Neuroprotection in chemotherapy-induced neuropathy 365

7. Neuroprotection during Anesthesia and Surgery 366

Introduction 366

Anesthetic agents as neuroprotectives 366

Barbiturates 366

Thiopental 367

Etomidate 368

Propofol 368

Ketamine 368

Gaseous anesthetics 369

Isoflurane 369

Xenon 369

Local anesthetics 370

Monitoring of CNS function during anesthesia and surgery 370

Monitoring of cerebral function 370

Monitoring of spinal cord function during surgery on the spine 370

Neuroprotection during cardiovascular procedures 370

CNS complications of cardiac surgery 370

Neuroprotective strategies during cardiac surgery 371

Neuroprotection during coronary artery bypass grafting 372

Neuroprotection before anticipated or induced cardiac arrest 373

Surgery on the aorta 374

Spinal protection during cardiovascular surgery 374

Cerebral protection during organ transplantation surgery 374

Cerebral protection during neurosurgery 374

Cerebral angiography and endovascular surgery 375

Cerebral protection during surgery for arteriovenous malformations 375

Cerebral protection during surgery of intracranial aneurysms 375

Management of subarachnoid hemorrhage 376

Vasospasm associated with subarachnoid hemorrhage 376

Cerebral protection during carotid endarterectomy 377

Neuroprotection during spinal surgery 378

Neuroprotective measures prior to surgery 378

8. Commercial aspects of Neuroprotective Therapy 380

Introduction 380

The financial burden of CNS damage 380

Markets for neuroprotective therapies 380

Markets according to therapeutic areas 380

Values of neuroprotective therapies in major world markets 382

Unmet needs in neuroprotectives 382

Future prospects of neuroprotective therapies 383

Challenges in neuroprotective drug development 384

Promising areas of research in neuroprotection 384

Autoreactive antibodies 384

Protective genes 385

9. References 386


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 disease

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Nicolas Bombourg



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