Reportlinker Adds Neuroprotection - Drugs, Markets and Companies

Dec 21, 2010, 18:29 ET from Reportlinker

NEW YORK, Dec. 21, 2010 /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.

Table of Contents

0. Executive Summary 23

1. Introduction 27

Definitions 27

Historical development of neuroprotection 27

Intrinsic neuroprotective factors 28

Neuroprotective gene expression 29

Upregulation of GADD34 29

Induction of NR4A proteins by CREB in neurons 30

Neurotrophic factors 30

Intrinsic nonenzymatic antioxidants 30

Intrinsic neuroprotective proteins 31

Excitatory amino acid transporters 31

Extracellular serine protease thrombin 31

Galanin 31

Neuroglobin 31

Nuclear factor I-A 32

Prion protein 32

Rai adaptor protein 32

Stem cell factor 33

Role of the immune system in neuroprotection 33

Induction of DNA repair enzymes for neuroprotection 34

Pathomechanisms of CNS injury as basis for neuroprotection 34

Biomarkers of neurological disorders and neuroprotection 35

CNS biomarker identification using proteomics 35

Brain imaging for detection of biomarkers 35

Role of neuroprotection in various neurological disorders 35

Neuroprotection and neuroregeneration 37

Acute versus chronic neuroprotection 37

Discovery and evaluation of neuroprotective agents 37

Neuroprotective drug discovery 37

Discovery of CNS drugs that penetrate the blood-brain barrier 38

In vitro assays for the evaluation of neuroprotective agents 38

Oxidative injury model to test neuroprotective drugs 39

Apoptosis model for designing neuroprotective drugs 39

Transgenic mouse models of neurological disorders 39

Evaluating effects of neuroprotective drugs on living brain slices 40

Role of brain imaging in neuroprotective drug discovery and development 40

Positron emission tomography 41

Role of single photon emission computed tomography 41

Functional CT scanning to evaluate cerebrovascular protection 41

Magnetic resonance imaging for the evaluation of neuroprotectives 42

Application of nanotechnology to neuroprotection 42

Evaluation criteria for potential neuroprotective agents 42

2. Neuroprotective Agents 43

Classification of neuroprotective agents 43

Activated protein C 47

Activity-dependent neuroprotective protein 47

Adenosine analogs 48

Propentofylline 48

Antidepressants 49

Antidepressant-induced neurogenesis 49

Neurogenesis induced by electroconvulsive therapy 49

Neuroprotective effect of selective serotonin reuptake inhibitors 49

Antiepileptic drugs as neuroprotectives 51

Phenytoin 52

Valproic acid 52

Levetiracetam 52

Antiinflammatory agents 53

Aspirin 53

Interleukin-1 antagonists 53

COX-2 inhibitors 54

Nimesulide 54

Gold microparticles as anti-neuroinflammatory agents 54

Minocycline 55

Anti-apoptosis agents 56

Activated protein C 56

Calpain inhibitors 57

Caspase inhibitors 57

DNA binding drugs 57

Lithium 57

Olesoxime 58

Omega-3 fatty acids 58

Docosahexaenoic acid 58

Poly(ADP-ribose) polymerase inhibitors 59

Prevention of apoptosis by binding of proNGF to sortilin 59

Antioxidants/free radical scavengers 60

Free radical generation 60

Natural defenses against oxidative stress 60

Effects of oxidative damage 60

Oxidative damage and aging 60

Neuronal damage by free radicals 61

Oxidative damage and neurodegenerative disorders 61

Measures to control oxidative stress 62

Categories of therapeutic antioxidants 62

Alpha-phenyl-tert-butylnitrone 62

Coenzyme Q10 63

Dihydroergocryptine 63

Flavonoids 64

Mitochondria-targeted antioxidants 64

Nanoparticles as neuroprotective antioxidants 64

Neuroleptics as antioxidants 65

Nitrones 65

Translation of antioxidant neuroprotection from preclinical to clinical 66

Carbon monoxide and heme oxygenase 66

Cell transplants 66

Cells secreting neuroprotective substances 66

Stem cells 67

Stem cell activation for neuroprotection/regeneration by glucocorticoids 67

Cytokines 67

Erythropoietin 67

Non-erythropoietic EPO variants and mimics 69

Granulocyte colony-stimulating factor 70

Delta-opioid receptor agonists 70

FK960 70

Gene therapy 71

Glucagon-like peptide 72

Glatiramer acetate 72

Glutamate antagonists 72

Neuroprotection by scavenging blood glutamate 73

N-acylethanolamines for protection against glutamatergic excitotoxicity 74

Glutamate transporters 74

Glutamate transporter-mediated neuroprotective effect of drugs 74

Neuroprotection by targeting KAI subunit of kainate receptor 75

Glycine-proline-glutamate analogs 75

Herbal preparations 75

Flavonoid wogonin 76

Ginseng 76

Hydrogen sulfide 76

NMDA receptor ion channel complex 77

NMDA receptor antagonists 78

NMDA NR2B subunit receptor antagonists 78

Ifenprodil 78

Memantine as a neuroprotective agent 78

Magnesium 79

NAALADase inhibitors 79

Gacyclidine 79

N-alkylglycines 79

AMPA receptor modulators 80

Metabotropic glutamate receptor modulators 80

Cannabinoids 81

Dexanabinol 81

Glutathione 82

Heat shock proteins 82

Hormones 83

Estrogen and neuroprotection 83

Neuroprotective effect of estrogen receptor ligands 83

Selective estrogen receptor modulators 83

Mitochondrial mechanisms of estrogen neuroprotection 84

Insulin 84

Ion Channel modulators 85

Calcium channel blockers. 85

Ziconotide 85

Na+ channel blockers. 86

Neuroprotective potassium channel inhibitors 86

Kynurenine inhibitors 87

Leukocyte adhesion inhibitors 87

Modafinil 88

Neural regeneration protein 88

Neurite outgrowth-promoting prostaglandin compounds 88

Neuroimmunophilins 89

Cyclosporin-A 89

FK506 90

Rapamycin 90

Neurotrophic factors 90

Activity-dependent neurotrophic factor 91

Bone morphogenetic proteins 91

Brain-derived neurotrophic factor 91

Ciliary neurotrophic factor 92

Fibroblast growth factors 92

Glial cell line-derived neurotrophic factor 93

Insulin-like growth factor 93

Nerve growth factor 93

Neurotrophins 94

Osteogenic protein-1 95

Pigment epithelium-derived factor 95

Transforming growth factor-b1 95

Vascular endothelial growth factor 95

Neurotrophic factor-related neuroprotective agents 96

Amitriptyline as a TrkA and TrkB receptor agonist 96

Colivelin 96

Gambogic amide 96

Inosine 97

Meteorin 97

Oxygen-regulated protein 150 kD 97

Prosaptide 97

Siagoside 98

Small molecule activators of the Trk receptors 98

Nicotine and nicotinic receptor agonists 98

Neuroprotective effect of galantamine mediated via a7nAChRs 99

Galantamine-induced AB clearance via a7nAChRs 99

Nitric oxide-based neuroprotection 100

Nitric oxide synthase inhibitors 100

Nitric oxide mimetics 100

Nootropics 101

Piracetam 101

Nutraceuticals and food constituents 102

Creatine 102

Curcumin/curry 102

Curcumin as a neuroprotectant in Alzheimer disease 103

Curcumin as a neuroprotectant in stroke 103

Curcumin as a neuroprotectant in multiple sclerosis 103

Mechanism of neuroprotective effect of curcumin 103

Glyceryltriacetate 104

Green tea 104

Nicotinamide 104

Resveratrol 104

Osmotic diuretics 105

Mannitol 105

Osteopontin 106

Oxygen therapeutics 106

Oxygen carriers 106

Hemoglobin-based oxygen carriers 107

Perfluorocarbons as oxygen carriers 107

Hyperbaric oxygen therapy 108

Peptides 108

C3-derived peptide for neuroprotection and neuroregeneration 108

Corticotropin-releasing hormone 109

Thyrotropin-releasing hormone 109

Vasoactive intestinal peptide 109

Pharmacological preconditioning 110

PPARs as drug targets for neuroprotection 110

Riluzole 111

Role of RNA interference in neuroprotection 111

Sigma receptor agonists as neuroprotective agents 111

SIRT group of proteins 112

Statins 112

Steroids 113

Dehydroepiandrosterone 113

HF0220 113

Sulforaphane 114

Tauroursodeoxycholic acid 114

Tetanus toxin as a neuroprotective agent 114

Thrombolytic agents as neuroprotective agents 115

Uncoupling protein 2 115

Vaccines as neuroprotectives 115

Vitamins as neuroprotective agents 116

Vitamin B12 116

Non-pharmacological approaches to neuroprotection 116

Environmental enrichment 117

Mental training 117

Physical exercise 117

Hypothermia 117

Limitations of hypothermia 118

Hypothermic neuroprotection in hypoxia-ischemia 118

Hibernation induced by hydrogen sulfide 119

Ketogenic diet 119

Nonpharmacological preconditioning for neuroprotection 120

Transcranial magnetic stimulation 120

Electrical fields for improvement of cerebral function in neurodegeneration 121

Neuroprotective effect of exercise 122

Hibernation and neuroprotection 122

Suspended animation and neuroprotection 122

3. Neuroprotection in Cerebrovascular Disease 123

Introduction 123

Pathophysiology of cerebral ischemia 123

Calcium overload 124

Ion channel dysfunction in stroke 124

Role of oxygen free radicals in cerebral ischemia 125

Role of nitric oxide in cerebral ischemia 125

Glutamate as a biomarker of stroke 125

Cerebral edema in stroke 125

Gene expression in response to cerebral ischemia 126

Induction of heat shock proteins in stroke 126

Role of cytokines and adhesion molecules in stroke 126

Tumor necrosis factor-a 126

Interleukin-1 and IL-6 127

Adhesion molecules 127

DNA damage and repair in cerebral ischemia 127

Role of neurotrophic factors in stroke 128

Problems requiring investigation of the role of NTFs in stroke 128

Role of Poly(ADP-ribose) polymerase (PARP) gene 128

Role of protease-activated receptor 1 129

Reperfusion injury after cerebral ischemia 129

Neuroprotection according to zones in cerebral infarction 129

Zone of ischemic infarction 129

Penumbra 130

Current management of stroke 130

Neuroprotection in stenosis of intracranial arteries 131

Neuroprotection in transient ischemic attacks 131

Neuroprotective therapies for stroke 131

Acid-sensing ion channel blockers 132

AMPA receptor antagonists as neuroprotectives for stroke 132

Zonampanel 132

Antiapoptotic neuroprotectives 133

NIM811 133

Creatine as neuroprotective in stroke 133

Lithium as a neuroprotective in stroke 134

TUDCA as a neuroprotective in stroke 134

Anticoagulant neuroprotectives 134

Heparin and enoxaparin 134

Warfarin vs dabigatran 135

Antiepileptic drugs as neuroprotectives in stroke 135

Tiagabine 135

Topiramate 135

Zonisamide 136

Anti-HMGB1 monoclonal antibody 136

Antioxidant approaches 136

Carnosine as a neuroprotective in stroke 136

Dehydroascorbic acid 137

Tocotrienols 137

Uric acid 138

Antiglutamate compounds 138

MRZ 2/576 138

L-Phenylalanine 139

Arimoclomol for stroke 139

Cardiac glycosides as neuroprotectives in stroke 139

Clenbuterol 139

Cox-2 inhibitors for ischemic stroke 140

Docosahexaenoic acid for ischemic stroke 140

Estrogen for stroke 140

Flavones for neuroprotection in stroke 141

Granulocyte-macrophage colony-stimulating factor for cerebral ischemia 142

Modulation of histamine H2-receptors 142

Inosine for stroke 142

Insulin-like growth factor-I 143

Intravenous immunoglobulin as neuroprotective in stroke 143

Ischemic preconditioning for neuroprotection in stroke 143

Ketone bodies for neuroprotection in stroke 144

Minalocorticoid receptor blockade for neuroprotection 144

Multifunctional neuroprotective agents 145

Nasal delivery of neuroprotective agents in stroke 145

Neuroserpin as a neuroprotective in stroke 145

N-2-mercaptopropionyl glycine 145

NeuroAid 146

Neurotrophic factors as neuroprotectives for stroke 146

AX200 146

Brain-derived neurotrophic factor 146

Fibroblast growth factor 147

Glial cell line-derived neurotrophic factor 147

Insulin-like growth factor-1 147

Neuregulin-1 148

NO-based strategies for neuroprotection in cerebral ischemia 148

Peroxisome proliferator-activated receptor-g agonists 149

PGE2 EP2 receptor activation 149

Pioglitazone for reduction of stroke risk in diabetes 149

Progesterone 149

Proteosome inhibitors 149

Statins for prevention and neuroprotection in stroke 150

Sildenafil 151

Src receptor blockade 151

Stroke vaccine 151

SUN N4057 151

Thrombosis inhibitors 152

Aspirin 152

Clopidogrel 152

Dipyridamole 152

Neuroprotectives in reperfusion injury 153

Prevention of hemorrhage following ischemic stroke 153

Non-pharmacological neuroprotective therapies for stroke 153

Preconditioning for neuroprotection against cerebral ischemia 154

Hypothermia for neuroprotection in acute stroke 154

Hyperbaric oxygen therapy for neuroprotection in acute stroke 155

Infrared laser therapy for ischemic stroke 156

Neurostimulation of sphenopalatine ganglion 156

Role of neurosurgical procedures for neuroprotection in stroke 156

Neurorehabilitation in relation to neuroprotection in stroke 157

Cell therapy for stroke 157

Stem cell transplant for stroke 157

Immortalized cell grafts for stroke 158

Stimulation of instrinsic stem cells for repair of brain in stroke 158

Neuroprotective vaccines for stroke 158

Gene therapy for neuroprotection in cerebrovascular disease 159

Regulation of microRNAs for neuroprotection in cerebral ischemia 161

Neuroprotective therapies for cerebral ischemia: clinical trials 161

Albumin 162

Free radical scavengers 162

DP-b99 164

Minocycline for neuroprotection in stroke 164

Perindopril 164

Failed clinical trials of neuroprotection in stroke 164

Ancrod 166

Aptiganel 166

Cerovive 167

Citicoline 167

Desmoteplase 169

Erythropoietin as a neuroprotective in stroke 169

SPD 502 170

Tirilazad mesylate 170

Selfotel 170

Lubeluzole 170

Nalmefene 171

Gavestinel 171

Nimodipine 171

Sipatrigine 172

Causes of failure of stroke trials 172

Measures for prevention of failures in stroke trials 173

Design of acute stroke trial to facilitate drug approval 175

The ideal neuroprotective agent for stroke 175

Future prospects for neuroprotection in stroke 176

4. Neuroprotection in Traumatic Brain Injury 179

Introduction 179

Cerebral hypoxia/ischemia as a complication of trauma 179

Traumatic brain injury 179

Pathophysiology of TBI 179

Immediate damage following TBI 180

Cerebral edema following TBI 180

Delayed damage following TBI 181

Mechanism of axonal damage after TBI 181

Role of neuroinflammation in TBI 181

Molecular events following TBI 181

BBB damage after TBI 182

Chronic traumatic encephalopathy 182

Neurocognitive sequelae of TBI 183

Changes in neurotrophic factors following TBI 183

Changes in neurotransmitters following TBI 184

Proteomics of TBI 184

Genetic influences on outcome following TBI 184

Management of TBI 185

Control of intracranial pressure and cerebral edema 185

Corticosteroids 186

Neuroprotection in TBI 186

Antiepileptic drugs for prevention of seizures and neuroprotection 187

Antioxidants 188

Barbiturates 188

B- and -secretase inhibitors 188

Beta blockers 188

Bradykinin B2 antagonists 189

Branched chain amino acids to ameliorate cognitive impairment in TBI 189

Cell cycle inhibitors for TBI 189

Creatine for neuroprotection in TBI 190

COX-2 inhibitors for neuroprotection in TBI 190

Cyclosporin for neuroprotection in TBI 190

Dexanabinol for TBI 191

Erythropoietin for neuroprotection in TBI 191

Gold implants for neuroprotection in focal TBI 191

KN 38-7271 192

Magnesium sulfate 192

Minocycline for TBI 192

Neurotrophic factors for TBI 192

Neurosteroids as neuroprotective agents for TBI 193

Nicotinamide for neuroprotection in TBI 194

NMDA receptor antagonists 194

Nogo-A inhibitor 195

NP-1 195

Omega 3 fatty acids as neuroprotectives in TBI 195

Oxygen carriers for TBI 195

Polyethylene glycol for neuroprotection in TBI 196

Propofol for neuroprotection in TBI 196

Rapamycin as neuroprotective in TBI 197

Simvastatin as neuroprotective in TBI 197

Thyrotropin-releasing hormone analogs 197

Traxoprodil 197

Biological approaches to neuroprotection in TBI 198

Antisense approaches to TBI 198

Cell therapy for TBI 198

Gene therapy for TBI 198

Vaccine for TBI 199

Non-pharmaceutical approaches to neuroprotection in TBI 199

Hyperbaric oxygen therapy for TBI 199

Hypothermia 199

Reduction of microglial migration after TBI 200

Deep brain stimulation for TBI 200

Prophylactic neuroprotection against TBI 200

Role of helmets in protection against TBI 200

Role of physical exercise in protection against TBI 201

Clinical trials of neuroprotective agents in TBI 201

Failed clinical trials in TBI 202

Differences between clinical trials and studies in animal models of TBI 203

Subgroup analysis 203

Improving the clinical trial design 204

Clinical trials combining multiple treatment strategies 204

Shortening the trial time 204

Concluding remarks and future prospects of neuroprotection in TBI 204

5. Neuroprotection in Spinal Cord Injury 207

Introduction 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 211

Antibodies as neurite growth inhibitors in SCI 211

Bacterial enzyme chondroitinase ABC 211

Docosahexaenoic acid as neuroprotective in SCI 212

Erythropoietin as a neuroprotective in SCI 212

Free radical scavengers for neuroprotection in SCI 212

Gacyclidine 213

GYKI 52466 213

Immunosuppressants as neuroprotectants in SCI 213

Interleukin-10 for neuroprotection in SCI 213

Matrix metalloproteinase inhibitors for SCI 214

Methylprednisolone 214

Minocycline as neuroprotective in SCI 214

Neurotrophic factors for neuroprotection after SCI 215

Promotion of regeneration of neurons in SCI 215

Rho pathway and Rho antagonists in SCI 216

Selenium as a neuroprotective for SCI 216

Sialidase for enhancing recovery after SCI 216

Targeting the inflammatory response for neuroprotection in SCI 217

Uric acid as neuroprotective in SCI 217

Non-pharmacological approaches to SCI 217

Hyperbaric oxygen therapy 217

Hypothermia for SCI 217

Cell therapy for SCI 218

Autoimmune T cells against CNS myelin-associated peptide 218

Fetal neural grafts for SCI 218

Olfactory-ensheathing cells for SCI 218

Oligodendrocyte precursor cells for treatment of SCI 219

Schwann cell transplants for SCI 219

Transplantation of glial cells for SCI 219

Stem cells for SCI 219

Bone marrow stem cells for SCI 219

Embryonic stem cells for SCI 220

Transplantation of induced pluripotent stem cells in SCI 220

Transplantation of MSCs for SCI 221

Transplantation of NSCs for SCI 221

Transdifferentiation of stem cells into cholinergic neurons for SCI 222

Gene therapy for SCI 222

Combined approaches to spinal cord injury 223

Discovery of new targets for neuroprotective therapies in SCI 223

Clinical trials in SCI 224

6. Neuroprotection in Neurodegenerative Disorders 225

Introduction 225

Pathomechanism of neurodegeneration 225

Dual role of a-synuclein in neuroprotection and neurodegeneration 225

Lack of neurotrophic factors 226

Neuroinflammation in neurodegenerative disorders 226

Neurodegeneration associated with protein misfolding 226

Modulation of neurodegeneration by molecular chaperones 226

Intrabodies targeting protein misfolding in neurodegeneration 227

Targeting in proteins aggregation to prevent amyloid formation 227

Tau and neurodegeneration 227

TDP-43 proteinopathy and neurodegenerative diseases 228

Role of apoptosis in neurodegenerative disorders 228

Role of glia in neurodegeneration 228

Role of metals in neurodegeneration 229

Viral infections and neurodegeneration 229

AIDS and the nervous system 229

Avian influenza as cause of neurodegeneration 230

Genetic disorders with neurodegeneration 231

Batten disease 231

Friedrich ataxia 232

Pathomechanism of FA 232

Neuroprotection in FA 232

Niemann-Pick type C disease 232

Creutzfeldt-Jakob disease 233

Approaches to neuroprotection in neurodegenerative disorders 234

Glutamate-based therapies for neurodegenerative disorders 234

Mitochondria permeability transition pore complex and neuroprotection 235

7. Neuroprotection in Parkinson Disease 237

Introduction 237

Epidemiology of Parkinson's disease 237

Pathophysiology of Parkinson's disease 237

Oxidative stress 238

Excitotoxicity 239

Asynchronous neuronal activity 239

Apoptosis 239

Role of neurotrophic factors 239

Role of misfolding proteins 239

Genetic factors in PD 240

Alteration of dopamine homeostasis 241

Neuroprotective strategies for PD based on pathomechanism 241

RNAi screening to identify neuroprotective genes in a PD model 242

Management of Parkinson's disease 242

Limitation of conventionally administered dopamine therapy 244

Treatment of dementia associated with PD 244

Neuroprotective therapy in PD 245

Neuroprotective effect of currently used drugs for PD 245

Pramipexole 245

Rasagiline mesylate 246

Ropinirole 247

Selegiline 247

Non-pharmacological strategies for neuroprotection in PD 248

Preventive effect of exercise and environmental enrichment 248

Low-calorie diet 248

Development of neuroprotective therapies for PD 248

Adenosine AA2 receptor antagonists 248

Antiapoptotic strategies for PD 249

Calcium channel blockers for PD 249

Cell therapies for PD 249

Stem cells for PD 250

Activation of endogenous stem cells and neural precursors 250

Cogane 251

Creatine and minocycline 251

Conserved dopamine neurotrophic factor for PD 252

Free radical scavengers for neuroprotection in Parkinson's disease 252

Antioxidants 252

Melatonin 252

Tea extracts as neuroprotectives 253

Nicotine as a neuroprotective in PD 253

Gene therapy for PD 253

Implantation of genetically engineered cells 254

Gene therapy using GDNF and neurturin 254

Glutamic acid decarboxylase gene therapy 255

Parkin gene therapy 255

Concluding remarks about gene therapy for PD 255

Heat shock protein 70 256

Neuroprotective effect of DJ-1 protein 256

Neurotrophic factors 256

GDNF for PD 257

Neurturin for PD 257

BDNF for PD 257

Basic fibroblast growth factor for PD 258

Platelet derived growth factor 258

Clinical trials with NTFs 258

Nrf2-mediated neuroprotection in PD 258

Omega-3 polyunsaturated fatty acids 259

RAB3B overexpression 259

RNAi therapy for PD 259

Safinamide 260

Sirtuin 2 inhibitors for neuroprotection in PD 260

Statins and PD 261

Targeting Bax 261

Vitamin D for neuroprotection in PD 261

Vaccine for PD 261

Clinical trials of neuroprotection in Parkinson's disease 262

Evaluation of neuroprotective therapies for PD 264

Current status and future challenges for neuroprotection in PD 265

8. Neuroprotection in Alzheimer Disease 267

Introduction 267

Pathomechanism of Alzheimer's disease 267

Role of glutamate transport dysfunction in AD 268

Role of neurotrophic factors in the pathomechanism of AD 268

Management of Alzheimer's disease 268

Neuroprotection in Alzheimer's disease 269

Inhibition of Aß aggregation 270

Secretase inhibitors 270

AN-1792 271

Monoclonal antibody m266 271

Clioquinol 271

FKBP52 for neuroprotection from Cu toxicity in AD 272

Phenserine 272

Colostrinin 273

Inhibition of neuroinflammation 273

Etanercept 273

Neurotrophic factors/ gene therapy 274

NGF gene therapy 274

AL-108 275

Targeting plasminogen activator inhibitor type-1 gene 275

Estrogen and AD 275

Antioxidants 276


Memantine 276

Dimebon 277

Cerebrolysin 278

Ginko biloba 278

Tetrahydrocannabinol for neuroprotection in AD 279

Ladostigil tartrate 279

Phosphodiesterase inhibitors as neuroprotectives 280

PPAR-agonists 280

Role of statins in reducing the risk of AD 280

Combined therapeutic approaches to AD 281

Clinical trials in AD 281

Future prospects of neuroprotection in AD 288

Mild cognitive impairment 288

Relation of MCI to AD 288

Neuroprotection in MCI 289

9. Neuroprotection in Huntington Disease 291

Introduction 291

Pathophysiology of HD 291

Management of Huntington's disease 292

Neuroprotection in Huntington's disease 293

Antipsychotic D2 and 5-HT1A antagonists 294

Caspase inhibitors 294

Clioquinol for HD 294

Creatine for stabilizing bioenergetic defects 294

Cysteamine 295

Drugs that block inappropriate calcium release from neurons 295

Enhancing protease activity for clearance of mHtt 295

Eicosapentaenoic acid 295

Free radical scavengers 296

Histone deacetylase inhibitors 296

Inhibitors of polyglutamine aggregation HD 296

Pridopidine 297

Simvastatin as a neuroprotective in HD 297

Single chain Fv antibodies 298

SIRT2 inhibitors for neuroprotection in HD 298

Synaptic activation of NMDA receptors 298

Tetrabenazine 298

Combinatorial therapy and targeting multiple pathways in HD 299

Cell transplants 299

Neurotrophic factors and gene therapy 300

RNAi therapy for Huntington's disease 300

10. Neuroprotection in Amyotrophic Lateral Sclerosis 303

Introduction 303

Pathophysiology of ALS 303

Neuroprotective therapies for ALS 305

Activated protein C 306

AEOL 10150 307


Arimoclomol for ALS 307

Antisense therapy 307

Creatine for ALS 308

Ceftriaxone for ALS 308

Coenzyme Q10 for ALS 309

COX-2 inhibitors for ALS 309

Dexpramipexole 309

Diallyl trisulfide 309

Erythropoietin for ALS 310

Gene therapy for ALS 310

Glatiramer acetate 311

Insulin-like growth factor 311

Ketogenic diet for neuroprotection in ALS 311

Lenalidomide 312

Lithium for neuroprotection in ALS 312

Methylcobalamin 313

Minocycline for ALS 313

Olesoxime as neuroprotective for ALS 313

ONO-2506 for ALS 313

Riluzole 314

RNAi-based therapy for ALS 314

Sodium phenylbutyrate 314

Stem cell therapy 315

Talampanel 315

Tamoxifen 315

Vaccination for ALS caused by SOD1 mutations 315

Vascular endothelial growth factor for ALS 316

Clinical trials of neuroprotective therapies for ALS 316

Concluding remarks and future prospects 319

11. Neuroprotection in Miscellaneous Neurological Disorders 321

Introduction 321

Age-related dementia 321

Enhancing endogenous neurotrophic support of the aging brain 321

Pharmacological approaches for treatment of age-related dementia 322

Physical exercise to prevent decline of mental function with aging 323

Vascular dementia 323

Prediction of dementia in persons with vascular risk factors 323

Management of subcortical vascular dementia 324

Dementia with Lewy bodies 325

Neuroprotection in AIDS dementia 325

Multiple system atrophy 326

Epilepsy 326

Mechanisms of neuronal damage in epilepsy 326

Strategies for neuroprotection in epilepsy 327

Control of seizures and neuroprotection 328

Cell therapy for neuroprotection in epilepsy 329

Cell therapy of posttraumatic epilepsy 330

Cell therapy for temporal lobe epilepsy 330

Cell therapy for pharmacoresistant epilepsies 330

Gene therapy for neuroprotection in epilepsy 331

Spinal and bulbar muscular atrophy 332

Multiple sclerosis 332

Introduction 332

Epidemiology of multiple sclerosis 332

Pathophysiology 333

Current management of multiple sclerosis 333

Specific therapies for MS based on pathomechanism 334

Neuroprotection in multiple sclerosis 334

Clinical trials of neuroprotective therapies for MS 335

Neuroprotection by control of progressive forms of multiple sclerosis 338

Neuroprotection by controlling autoimmune inflammation in the brain 338

Remyelination for neuroprotection in multiple sclerosis 339

Agents for neuroprotection in multiple sclerosis 339

Angiotensin-II inhibitors 339

Antiglutamate agents 339

Antioxidants for neuroprotection in MS 339

Antisense and RNAi approaches to MS 340

Cell therapy for multiple sclerosis 340

Cladribine 342

Dalfampridine in MS 343

Dimethyl fumarate 343

DNA vaccine for MS 343

Erythropoietin as a neuroprotective in MS 344

Fingolimod (FTY720) 344

Fusokine composed of GM-CSF and IL-15 for immune suppression 345

Gene therapy for MS 345

Ibudilast for MS 345

IVIG for MS 346

Laquinimod 346

MBP8298 346

Monoclonal antibodies for MS 346

Natalizumab 347

Natural human antibodies for repair of myelin 347

Neurotrophic factors for multiple sclerosis 348

Recombinant T-cell ligands 349

Statins for MS 349

Concluding remarks on neuroprotection in MS 349

Neuroprotection in transverse myelitis 350

Neuroprotection in decompression sickness 350

Neuroprotection in hydrocephalus 351

Neuroprotection in normal pressure hydrocephalus 352

Neuroprotection in infections of the CNS 352

Neuroprotection in bacterial meningitis 352

Mechanism of neural injury in bacterial meningitis 352

Strategies for neuroprotection 353

Neuroprotective approach to rabies 353

Neuroprotection in cerebral malaria 353

Neuroprotection in hypertensive encephalopathy 354

Neuroprotection in toxic encephalopathies 354

Hepatic encephalopathy 354

Management of hepatic encephalopathy 355

Encephalopathy due to organophosphorus poisoning 355

Neuroprotection against chemotherapy-induced brain damage 356

Neuroprotection against alcohol 356

Alcoholic neurologic disorders 356

Fetal alcohol syndrome 357

Pathogenesis of alcohol-induced damage to the nervous system 357

Neuroprotection against neurotoxicity of alcohol 357

Neuroprotection in hypoxia-ischemia 358

Neuroprotection in neonatal hypoxic-ischemic brain injury 358

Neuroprotection in carbon monoxide poisoning 360

Pathomechanism of CO poisoning as a basis for neuroprotection 360

Management of CO poisoning 361

Syndrome of delayed post-hypoxic leukoencephalopathy 361

Neuroprotection in sleep apnea 362

Neuroprotection in hypoglycemic coma 362

Neuroprotection in mitochondrial dysfunction 363

Mitochondrial permeability transition 364

Mitochondrial approaches for neuroprotection 364

Methylene blue 365

Role of nanolasers in evaluation of mitochondrial neuroprotectants 365

Neuroprotection in mitochondrial encephalopathies 365

Schizophrenia 366

Cognitive impairment in schizophrenia 366

Neuroprotection in schizophrenia 366

Neuroprotection in hearing loss 367

Causes of hearing loss 367

Pathomechanism of hearing loss 368

Prevention and treatment of hearing loss 368

Hyperbaric oxygen for hearing loss 369

Stem cell therapy for hearing loss 369

Auditory hair cell replacement by gene therapy 369

Pharmaceutical approaches to hearing loss 370

Neuroprotection of peripheral nerves 370

Neuroprotective agents for peripheral nerves 371

Acetyl-L-carnitine for peripheral nerve injuries 371

Atorvastatin for peripheral nerve injuries 371

Erythropoietin for neuroprotection in peripheral nerve injuries 372

Neuroprotection in peripheral nerve injuries 372

Role of hyperbaric oxygen in peripheral nerve injuries 372

Role of neurotrophic factors in peripheral nerve injuries 373

Pharmacological approaches to Schwann cells 373

Role of gene therapy in neuroprotection of injured peripheral nerves 373

Schwann cell transplantation for peripheral nerve injury

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Nicolas Bombourg



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