Reportlinker Adds Neuroprotection - Drugs, Markets and Companies

NEW YORK, Nov. 9, 2010 /PRNewswire/ -- Reportlinker.com announces that a new market research report is available in its catalogue:

Neuroprotection - Drugs, Markets and Companies

http://www.reportlinker.com/p0203546/Neuroprotection---Drugs-Markets-and-Companies.html

Summary

This report describes the role of neuroprotection in acute disorders such as stroke and injuries of the nervous system as well as in chronic diseases such as neurodegenerative disorders because many of the underlying mechanisms of damage to neural tissues are similar in all these conditions and several products are used in more than one disorder. Over 500 products have been investigated for neuroprotective effects including those from the categories of free radical scavengers, anti-excitotoxic agents, apoptosis (programmed cell death) inhibitors, anti-inflammatory agents, neurotrophic factors, metal ion chelators, ion channel modulators and gene therapy. Some of the agents are old established pharmaceuticals whereas others are new biotechnology products.

Pathomechanisms of diseases are described with steps at which neuroprotective therapies are directed. Diseases covered include cerebrovascular disorders, traumatic brain injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, epilepsy and ischemic optic neuropathy as well as retinal degeneration. Although anesthetics such as propofol are neuroprotective as well, neuroprotection during surgery and anesthesia is discussed with the aim of preventing and treating complications that result in CNS damage.

The report contains a profile of 140 companies that have a neuroprotective product or products along with 100 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 800 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 are analyzed with suggestions for improving the selection of drugs and design of trials. The report is supplemented with 66 tables and 11 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 24

1. Introduction .. 28

Definitions . 28

Historical development of neuroprotection 28

Intrinsic neuroprotective factors 29

Neuroprotective gene expression 30

Upregulation of GADD34 . 30

Induction of NR4A proteins by CREB in neurons .. 31

Neurotrophic factors 31

Intrinsic nonenzymatic antioxidants .. 31

Intrinsic neuroprotective proteins 32

Excitatory amino acid transporters .. 32

Extracellular serine protease thrombin 32

Galanin . 32

Neuroglobin 32

Nuclear factor I-A . 33

Prion protein .. 33

Rai adaptor protein .. 33

Stem cell factor 34

Role of the immune system in neuroprotection .. 34

Induction of DNA repair enzymes for neuroprotection .. 35

Pathomechanisms of CNS injury as basis for neuroprotection . 35

Biomarkers of neurological disorders and neuroprotection 36

CNS biomarker identification using proteomics .. 36

Brain imaging for detection of biomarkers 36

Role of neuroprotection in various neurological disorders . 36

Neuroprotection and neuroregeneration . 38

Acute versus chronic neuroprotection . 38

Discovery and evaluation of neuroprotective agents 38

Neuroprotective drug discovery .. 38

Discovery of CNS drugs that penetrate the blood-brain barrier . 39

In vitro assays for the evaluation of neuroprotective agents .. 39

Oxidative injury model to test neuroprotective drugs 40

Apoptosis model for designing neuroprotective drugs .. 40

Transgenic mouse models of neurological disorders .. 40

Evaluating effects of neuroprotective drugs on living brain slices .. 41

Role of brain imaging in neuroprotective drug discovery and development 41

Positron emission tomography .. 42

Role of single photon emission computed tomography .. 42

Functional CT scanning to evaluate cerebrovascular protection .. 42

Magnetic resonance imaging for the evaluation of neuroprotectives .. 43

Application of nanotechnology to neuroprotection . 43

Evaluation criteria for potential neuroprotective agents 43

2. Neuroprotective Agents 44

Classification of neuroprotective agents . 44

Activated protein C 48

Activity-dependent neuroprotective protein . 48

Adenosine analogs . 49

Propentofylline . 49

Antidepressants .. 50

Antidepressant-induced neurogenesis 50

Neurogenesis induced by electroconvulsive therapy . 50

Neuroprotective effect of selective serotonin reuptake inhibitors .. 50

Antiepileptic drugs as neuroprotectives .. 52

Phenytoin .. 53

Valproic acid.. 53

Levetiracetam .. 53

Antiinflammatory agents 54

Aspirin . 54

Interleukin-1 antagonists .. 54

COX-2 inhibitors .. 55

Nimesulide .. 55

Gold microparticles as anti-neuroinflammatory agents . 55

Minocycline 56

Anti-apoptosis agents .. 57 - 6 -

Activated protein C . 57

Calpain inhibitors . 58

Caspase inhibitors 58

DNA binding drugs .. 58

Lithium 58

Olesoxime .. 59

Omega-3 fatty acids 59

Docosahexaenoic acid .. 59

Poly(ADP-ribose) polymerase inhibitors 60

Prevention of apoptosis by binding of proNGF to sortilin .. 60

Antioxidants/free radical scavengers .. 61

Free radical generation .. 61

Natural defenses against oxidative stress . 61

Effects of oxidative damage . 61

Oxidative damage and aging . 61

Neuronal damage by free radicals 62

Oxidative damage and neurodegenerative disorders .. 62

Measures to control oxidative stress .. 63

Categories of therapeutic antioxidants 63

Alpha-phenyl-tert-butylnitrone . 63

Coenzyme Q10 .. 64

Dihydroergocryptine . 64

Flavonoids 65

Mitochondria-targeted antioxidants . 65

Nanoparticles as neuroprotective antioxidants . 65

Neuroleptics as antioxidants .. 66

Nitrones 66

Translation of antioxidant neuroprotection from preclinical to clinical .. 67

Carbon monoxide and heme oxygenase .. 67

Cell transplants 67

Cells secreting neuroprotective substances .. 67

Stem cells .. 68

Stem cell activation for neuroprotection/regeneration by glucocorticoids 68

Cytokines 68

Erythropoietin .. 68

Non-erythropoietic EPO variants and mimics 70

Granulocyte colony-stimulating factor 71

Delta-opioid receptor agonists . 71

FK960 . 71

Gene therapy 72

Glucagon-like peptide .. 73

Glatiramer acetate . 73

Glutamate antagonists . 73

Neuroprotection by scavenging blood glutamate 74

N-acylethanolamines for protection against glutamatergic excitotoxicity 75

Glutamate transporters .. 75

Glutamate transporter-mediated neuroprotective effect of drugs.. 75

Neuroprotection by targeting KAI subunit of kainate receptor 76

Glycine-proline-glutamate analogs 76

Herbal preparations .. 76

Flavonoid wogonin .. 77

Ginseng .. 77

Hydrogen sulfide. 77

NMDA receptor ion channel complex. 78

NMDA receptor antagonists .. 79

NMDA NR2B subunit receptor antagonists . 79

Ifenprodil . 79

Memantine as a neuroprotective agent .. 79

Magnesium . 80

NAALADase inhibitors .. 80

Gacyclidine . 80

N-alkylglycines .. 80

AMPA receptor modulators 81

Metabotropic glutamate receptor modulators .. 81

Cannabinoids . 82

Dexanabinol .. 82

Glutathione 83

Heat shock proteins .. 83

Hormones .. 84

Estrogen and neuroprotection .. 84

Neuroprotective effect of estrogen receptor ligands 84 - 7 -

Selective estrogen receptor modulators . 84

Mitochondrial mechanisms of estrogen neuroprotection 85

Insulin . 85

Ion Channel modulators . 86

Calcium channel blockers. . 86

Ziconotide 86

Na+ channel blockers. . 87

Neuroprotective potassium channel inhibitors . 87

Kynurenine inhibitors .. 88

Leukocyte adhesion inhibitors . 88

Modafinil . 89

Neural regeneration protein . 89

Neurite outgrowth-promoting prostaglandin compounds .. 89

Neuroimmunophilins . 90

Cyclosporin-A 90

FK506 . 91

Rapamycin . 91

Neurotrophic factors . 91

Activity-dependent neurotrophic factor . 92

Bone morphogenetic proteins .. 92

Brain-derived neurotrophic factor 92

Ciliary neurotrophic factor . 93

Fibroblast growth factors .. 93

Glial cell line-derived neurotrophic factor . 94

Insulin-like growth factor .. 94

Nerve growth factor 94

Neurotrophins .. 95

Osteogenic protein-1 .. 96

Pigment epithelium-derived factor .. 96

Transforming growth factor-?1 96

Vascular endothelial growth factor . 96

Neurotrophic factor-related neuroprotective agents .. 97

Amitriptyline as a TrkA and TrkB receptor agonist .. 97

Colivelin 97

Gambogic amide 97

Inosine . 98

Meteorin .. 98

Oxygen-regulated protein 150 kD 98

Prosaptide 98

Siagoside . 98

Small molecule activators of the Trk receptors . 99

Nicotine and nicotinic receptor agonists . 99

Nitric oxide-based neuroprotection 100

Nitric oxide synthase inhibitors . 100

Nitric oxide mimetics 101

Nootropics .. 101

Piracetam . 102

Nutraceuticals and food constituents . 102

Creatine.. 102

Curcumin/curry . 103

Curcumin as a neuroprotectant in Alzheimer disease .. 103

Curcumin as a neuroprotectant in stroke . 103

Curcumin as a neuroprotectant in multiple sclerosis 104

Mechanism of neuroprotective effect of curcumin . 104

Glyceryltriacetate .. 104

Green tea 104

Nicotinamide .. 105

Resveratrol . 105

Osmotic diuretics . 106

Mannitol .. 106

Osteopontin 106

Oxygen therapeutics .. 106

Oxygen carriers . 107

Hemoglobin-based oxygen carriers .. 107

Perfluorocarbons as oxygen carriers 108

Hyperbaric oxygen therapy 109

Peptides 109

C3-derived peptide for neuroprotection and neuroregeneration .. 109

Corticotropin-releasing hormone .. 109

Thyrotropin-releasing hormone . 109

Vasoactive intestinal peptide . 110 - 8 -

Pharmacological preconditioning . 110

PPARs as drug targets for neuroprotection . 111

Riluzole . 111

Role of RNA interference in neuroprotection . 111

Sigma receptor agonists as neuroprotective agents .. 112

SIRT group of proteins .. 112

Statins .. 113

Steroids 113

Dehydroepiandrosterone . 114

HF0220 114

Sulforaphane . 114

Tauroursodeoxycholic acid . 115

Tetanus toxin as a neuroprotective agent 115

Thrombolytic agents as neuroprotective agents .. 115

Uncoupling protein 2 . 116

Vaccines as neuroprotectives 116

Vitamins as neuroprotective agents 116

Vitamin B12 116

Non-pharmacological approaches to neuroprotection 117

Environmental enrichment . 117

Mental training .. 117

Physical exercise 117

Hypothermia .. 118

Limitations of hypothermia .. 118

Hypothermic neuroprotection in hypoxia-ischemia 119

Hibernation induced by hydrogen sulfide 119

Ketogenic diet 120

Nonpharmacological preconditioning for neuroprotection .. 120

Transcranial magnetic stimulation 121

Electrical fields for improvement of cerebral function in neurodegeneration 121

Neuroprotective effect of exercise 122

Hibernation and neuroprotection .. 122

Suspended animation and neuroprotection 123

3. Neuroprotection in Cerebrovascular Disease .. 124

Introduction .. 124

Pathophysiology of cerebral ischemia 124

Calcium overload .. 125

Ion channel dysfunction in stroke . 125

Role of oxygen free radicals in cerebral ischemia 126

Role of nitric oxide in cerebral ischemia . 126

Glutamate as a biomarker of stroke 126

Cerebral edema in stroke 126

Gene expression in response to cerebral ischemia .. 127

Induction of heat shock proteins in stroke . 127

Role of cytokines and adhesion molecules in stroke 127

Tumor necrosis factor-? 127

Interleukin-1 and IL-6 .. 128

Adhesion molecules 128

DNA damage and repair in cerebral ischemia 128

Role of neurotrophic factors in stroke . 129

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 . 130

Reperfusion injury after cerebral ischemia . 130

Neuroprotection according to zones in cerebral infarction .. 130

Zone of ischemic infarction . 130

Penumbra 131

Current management of stroke . 131

Neuroprotection in stenosis of intracranial arteries . 132

Neuroprotection in transient ischemic attacks .. 132

Neuroprotective therapies for stroke . 132

Acid-sensing ion channel blockers 133

AMPA receptor antagonists as neuroprotectives for stroke 133

Zonampanel . 133

Antiapoptotic neuroprotectives . 134

NIM811 . 134

Creatine as neuroprotective in stroke .. 134

Lithium as a neuroprotective in stroke . 134

TUDCA as a neuroprotective in stroke .. 135

Antiepileptic drugs as neuroprotectives in stroke . 135 - 9 -

Tiagabine .. 135

Topiramate .. 135

Zonisamide .. 136

Anti-HMGB1 monoclonal antibody 136

Antioxidant approaches .. 136

Carnosine as a neuroprotective in stroke. 137

Dehydroascorbic acid. 137

Tocotrienols . 138

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 . 140

Cox-2 inhibitors for ischemic stroke . 140

Enoxaparin .. 140

Estrogen for stroke .. 140

Flavones for neuroprotection in stroke 142

Granulocyte-macrophage colony-stimulating factor for cerebral ischemia 142

Modulation of histamine H2-receptors . 142

Inosine for stroke . 143

Intravenous immunoglobulin as neuroprotective in stroke . 143

Insulin-like growth factor-I . 143

Ischemic preconditioning for neuroprotection in stroke . 143

Ketone bodies for neuroprotection in stroke . 144

Minalocorticoid receptor blockade for neuroprotection 145

Multifunctional neuroprotective agents 145

Nasal delivery of neuroprotective agents in stroke 145

Neuroserpin as a neuroprotective in stroke .. 145

N-2-mercaptopropionyl glycine . 146

NeuroAid . 146

Neurotrophic factors as neuroprotectives for stroke 146

AX200 146

Brain-derived neurotrophic factor .. 147

Fibroblast growth factor 147

Glial cell line-derived neurotrophic factor 147

Insulin-like growth factor-1 . 148

Neuregulin-1 148

NO-based strategies for neuroprotection in cerebral ischemia . 148

Peroxisome proliferator-activated receptor-? agonists 149

PGE2 EP2 receptor activation . 149

Pioglitazone for reduction of stroke risk in diabetes 149

Progesterone .. 149

Proteosome inhibitors .. 150

Statins for prevention and neuroprotection in stroke . 150

Sildenafil . 151

Src receptor blockade .. 151

Stroke vaccine 151

SUN N4057 . 152

Thrombosis inhibitors .. 152

Aspirin 152

Clopidogrel 152

Dipyridamole 153

Neuroprotectives in reperfusion injury 153

Prevention of hemorrhage following ischemic stroke .. 153

Non-pharmacological neuroprotective therapies for stroke .. 154

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 intrinsic stem cells for repair of brain in stroke 158

Neuroprotective vaccines for stroke . 159

Gene therapy for neuroprotection in cerebrovascular disease . 159

Regulation of microRNAs for neuroprotection in cerebral ischemia . 161 - 10 -

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 .. 165

Ancrod 166

Aptiganel .. 166

Cerovive 167

Citicoline 168

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 .. 178

Introduction .. 178

Cerebral hypoxia/ischemia as a complication of trauma.. 178

Traumatic brain injury .. 178

Pathophysiology of TBI 178

Immediate damage following TBI .. 179

Cerebral edema following TBI . 179

Delayed damage following TBI 180

Mechanism of axonal damage after TBI .. 180

Role of neuroinflammation in TBI .. 180

Molecular events following TBI 180

BBB damage after TBI .. 181

Chronic traumatic encephalopathy 181

Neurocognitive sequelae of TBI .. 182

Changes in neurotrophic factors following TBI 182

Changes in neurotransmitters following TBI 183

Proteomics of TBI 183

Genetic influences on outcome following TBI . 183

Management of TBI .. 184

Control of intracranial pressure and cerebral edema 184

Corticosteroids 185

Neuroprotection in TBI. 185

Antiepileptic drugs for prevention of seizures and neuroprotection . 186

Antioxidants . 187

Barbiturates . 187

?- and ?-secretase inhibitors .. 187

Beta blockers .. 187

Bradykinin B2 antagonists 188

Branched chain amino acids to ameliorate cognitive impairment in TBI . 188

Cell cycle inhibitors for TBI .. 188

Creatine for neuroprotection in TBI .. 189

COX-2 inhibitors for neuroprotection in TBI 189

Cyclosporin for neuroprotection in TBI . 189

Dexanabinol for TBI .. 190

Erythropoietin for neuroprotection in TBI 190

Gold implants for neuroprotection in focal TBI .. 190

KN 38-7271 . 191

Magnesium sulfate . 191

Minocycline for TBI . 191

Neurotrophic factors for TBI 191

Neurosteroids as neuroprotective agents for TBI .. 192

Nicotinamide for neuroprotection in TBI .. 193

NMDA receptor antagonists . 193

Nogo-A inhibitor . 194 - 11 -

NP-1 .. 194

Omega 3 fatty acids as neuroprotectives in TBI 194

Oxygen carriers for TBI . 194

Polyethylene glycol for neuroprotection in TBI .. 195

Propofol for neuroprotection in TBI 195

Rapamycin as neuroprotective in TBI 196

Simvastatin as neuroprotective in TBI . 196

Thyrotropin-releasing hormone analogs .. 196

Traxoprodil 196

Biological approaches to neuroprotection in TBI .. 197

Antisense approaches to TBI .. 197

Cell therapy for TBI 197

Gene therapy for TBI . 197

Vaccine for TBI 198

Non-pharmaceutical approaches to neuroprotection in TBI .. 198

Hyperbaric oxygen therapy for TBI 198

Hypothermia 198

Reduction of microglial migration after TBI . 199

Deep brain stimulation for TBI 199

Prophylactic neuroprotection against TBI .. 199

Role of physical exercise in protection against TBI 199

Clinical trials of neuroprotective agents in TBI . 200

Failed clinical trials in TBI 201

Differences between clinical trials and studies in animal models of TBI . 201

Subgroup analysis .. 202

Improving the clinical trial design .. 202

Clinical trials combining multiple treatment strategies 202

Shortening the trial time .. 203

Concluding remarks and future prospects of neuroprotection in TBI.. 203

5. Neuroprotection in Spinal Cord Injury 206

Introduction .. 206

Pathophysiology of SCI . 206

Secondary mechanisms of SCI 207

Neurotrophic factor changes in SCI .. 208

Management of SCI 209

Pharmacological neuroprotective agents for SCI . 210

4-aminopyridine 210

Antibodies as neurite growth inhibitors in SCI .. 210

Bacterial enzyme chondroitinase ABC . 210

Docosahexaenoic acid as neuroprotective in SCI . 211

Erythropoietin as a neuroprotective in SCI 211

Free radical scavengers for neuroprotection in SCI . 211

Gacyclidine . 212

GYKI 52466 212

Immunosuppressants as neuroprotectants in SCI 212

Interleukin-10 for neuroprotection in SCI .. 212

Matrix metalloproteinase inhibitors for SCI 213

Methylprednisolone .. 213

Minocycline as neuroprotective in SCI . 213

Neurotrophic factors for neuroprotection after SCI . 214

Promotion of regeneration of neurons in SCI . 214

Rho pathway and Rho antagonists in SCI .. 215

Selenium as a neuroprotective for SCI 215

Sialidase for enhancing recovery after SCI 215

Targeting the inflammatory response for neuroprotection in SCI 216

Uric acid as neuroprotective in SCI .. 216

Non-pharmacological approaches to SCI . 216

Hyperbaric oxygen therapy 216

Hypothermia for SCI 216

Cell therapy for SCI 217

Autoimmune T cells against CNS myelin-associated peptide 217

Fetal neural grafts for SCI .. 217

Olfactory-ensheathing cells for SCI . 217

Oligodendrocyte precursor cells for treatment of SCI . 218

Schwann cell transplants for SCI .. 218

Transplantation of glial cells for SCI 218

Stem cells for SCI . 218

Bone marrow stem cells for SCI . 218

Embryonic stem cells for SCI .. 219

Transplantation of induced pluripotent stem cells in SCI 219 - 12 -

Transplantation of MSCs for SCI 220

Transplantation of NSCs for SCI . 220

Transdifferentiation of stem cells into cholinergic neurons for SCI .. 221

Gene therapy for SCI . 221

Combined approaches to spinal cord injury 222

Discovery of new targets for neuroprotective therapies in SCI . 222

Clinical trials in SCI. 223

6. Neuroprotection in Neurodegenerative Disorders . 224

Introduction .. 224

Pathomechanism of neurodegeneration .. 224

Dual role of ?-synuclein in neuroprotection and neurodegeneration .. 224

Lack of neurotrophic factors .. 225

Neuroinflammation in neurodegenerative disorders 225

Neurodegeneration associated with protein misfolding .. 225

Modulation of neurodegeneration by molecular chaperones .. 225

Intrabodies targeting protein misfolding in neurodegeneration . 226

Targeting in proteins aggregation to prevent amyloid formation .. 226

Tau and neurodegeneration . 226

TDP-43 proteinopathy and neurodegenerative diseases 227

Role of apoptosis in neurodegenerative disorders 227

Role of glia in neurodegeneration . 227

Role of metals in neurodegeneration .. 228

Viral infections and neurodegeneration .. 228

AIDS and the nervous system 228

Avian influenza as cause of neurodegeneration . 229

Genetic disorders with neurodegeneration . 230

Batten disease 230

Friedrich ataxia .. 231

Pathomechanism of FA . 231

Neuroprotection in FA 231

Niemann-Pick type C disease . 231

Creutzfeldt-Jakob disease 232

Approaches to neuroprotection in neurodegenerative disorders .. 233

Glutamate-based therapies for neurodegenerative disorders .. 233

Mitochondria permeability transition pore complex and neuroprotection .. 234

7. Neuroprotection in Parkinson Disease 236

Introduction .. 236

Epidemiology of Parkinson's disease . 236

Pathophysiology of Parkinson's disease .. 236

Oxidative stress . 237

Excitotoxicity .. 238

Asynchronous neuronal activity 238

Apoptosis . 238

Role of neurotrophic factors .. 238

Role of misfolding proteins . 238

Genetic factors in PD 239

Alteration of dopamine homeostasis 240

Neuroprotective strategies for PD based on pathomechanism .. 240

RNAi screening to identify neuroprotective genes in a PD model 241

Management of Parkinson's disease .. 241

Limitation of conventionally administered dopamine therapy .. 243

Treatment of dementia associated with PD 243

Neuroprotective therapy in PD .. 244

Neuroprotective effect of currently used drugs for PD .. 244

Pramipexole 244

Rasagiline mesylate . 245

Ropinirole 246

Selegiline . 246

Non-pharmacological strategies for neuroprotection in PD . 247

Preventive effect of exercise and environmental enrichment 247

Low-calorie diet . 247

Development of neuroprotective therapies for PD .. 247

Adenosine AA2 receptor antagonists 247

Antiapoptotic strategies for PD . 248

Calcium channel blockers for PD .. 248

Cell therapies for PD . 248

Stem cells for PD 249

Activation of endogenous stem cells and neural precursors .. 249

Cogane . 250 - 13 -

Creatine and minocycline 250

Conserved dopamine neurotrophic factor for PD.. 251

Free radical scavengers for neuroprotection in Parkinson's disease 251

Antioxidants . 251

Melatonin .. 251

Tea extracts as neuroprotectives 252

Nicotine as a neuroprotective in PD .. 252

Gene therapy for PD . 252

Implantation of genetically engineered cells .. 253

Gene therapy using GDNF and neurturin . 253

Glutamic acid decarboxylase gene therapy . 254

Parkin gene therapy .. 254

Concluding remarks about gene therapy for PD. 254

Heat shock protein 70 . 255

Neuroprotective effect of DJ-1 protein 255

Neurotrophic factors . 255

GDNF for PD . 256

Neurturin for PD . 256

BDNF for PD . 256

Basic fibroblast growth factor for PD . 257

Platelet derived growth factor . 257

Clinical trials with NTFs . 257

Nrf2-mediated neuroprotection in PD .. 257

Omega-3 polyunsaturated fatty acids . 258

RAB3B overexpression . 258

RNAi therapy for PD . 258

Safinamide .. 259

Sirtuin 2 inhibitors for neuroprotection in PD 259

Statins and PD 260

Targeting Bax . 260

Vitamin D for neuroprotection in PD 260

Vaccine for PD 260

Clinical trials of neuroprotection in Parkinson's disease .. 261

Evaluation of neuroprotective therapies for PD 263

Current status and future challenges for neuroprotection in PD .. 264

8. Neuroprotection in Alzheimer Disease 266

Introduction .. 266

Pathomechanism of Alzheimer's disease . 266

Role of glutamate transport dysfunction in AD . 267

Role of neurotrophic factors in the pathomechanism of AD . 267

Management of Alzheimer's disease .. 267

Neuroprotection in Alzheimer's disease 268

Inhibition of A? aggregation .. 269

Secretase inhibitors .. 269

AN-1792 .. 270

Monoclonal antibody m266 . 270

Clioquinol . 270

FKBP52 for neuroprotection from Cu toxicity in AD . 271

Phenserine .. 271

Colostrinin .. 272

Inhibition of neuroinflammation .. 272

Etanercept .. 272

Neurotrophic factors/ gene therapy .. 273

NGF gene therapy . 273

AL-108 . 274

Targeting plasminogen activator inhibitor type-1 gene .. 274

Estrogen and AD .. 274

Antioxidants .. 275

NSAIDS 275

Memantine .. 275

Dimebon .. 276

Cerebrolysin .. 277

Ginko biloba 277

Tetrahydrocannabinol for neuroprotection in AD . 278

Ladostigil tartrate 278

Phosphodiesterase inhibitors as neuroprotectives .. 279

PPAR-? agonists .. 279

Role of statins in reducing the risk of AD . 279

Combined therapeutic approaches to AD . 280

Clinical trials in AD.. 280 - 14 -

Future prospects of neuroprotection in AD . 287

Mild cognitive impairment .. 287

Relation of MCI to AD .. 287

Neuroprotection in MCI 288

9. Neuroprotection in Huntington Disease . 290

Introduction .. 290

Pathophysiology of HD .. 290

Management of Huntington's disease 291

Neuroprotection in Huntington's disease . 292

Antipsychotic D2 and 5-HT1A antagonists 293

Caspase inhibitors . 293

Clioquinol for HD 293

Creatine for stabilizing bioenergetic defects .. 293

Cysteamine . 294

Drugs that block inappropriate calcium release from neurons . 294

Enhancing protease activity for clearance of mHtt .. 294

Eicosapentaenoic acid .. 294

Free radical scavengers .. 295

Histone deacetylase inhibitors .. 295

Inhibitors of polyglutamine aggregation HD .. 295

Pridopidine .. 296

Simvastatin as a neuroprotective in HD . 296

Single chain Fv antibodies .. 297

SIRT2 inhibitors for neuroprotection in HD 297

Synaptic activation of NMDA receptors 297

Tetrabenazine 297

Combinatorial therapy and targeting multiple pathways in HD 298

Cell transplants.. 298

Neurotrophic factors and gene therapy .. 299

RNAi therapy for Huntington's disease 299

10. Neuroprotection in Amyotrophic Lateral Sclerosis . 302

Introduction .. 302

Pathophysiology of ALS 302

Neuroprotective therapies for ALS .. 304

Activated protein C .. 305

AEOL 10150 306

AIMSPRO . 306

Arimoclomol for ALS . 306

Antisense therapy . 306

Creatine for ALS 307

Ceftriaxone for ALS .. 307

Coenzyme Q10 for ALS 308

COX-2 inhibitors for ALS . 308

Dexpramipexole . 308

Diallyl trisulfide .. 308

Erythropoietin for ALS . 309

Gene therapy for ALS .. 309

Glatiramer acetate 310

Insulin-like growth factor 310

Ketogenic diet for neuroprotection in ALS.. 310

Lenalidomide .. 311

Lithium for neuroprotection in ALS .. 311

Methylcobalamin 312

Minocycline for ALS .. 312

Olesoxime as neuroprotective for ALS. 312

ONO-2506 for ALS 312

Riluzole 313

RNAi-based therapy for ALS .. 313

Sodium phenylbutyrate 313

Stem cell therapy .. 314

Talampanel . 314

Tamoxifen 314

Vaccination for ALS caused by SOD1 mutations .. 314

Vascular endothelial growth factor for ALS 315

Clinical trials of neuroprotective therapies for ALS 315

Concluding remarks and future prospects 318

11. Neuroprotection in Miscellaneous Neurological Disorders . 320

Introduction .. 320 - 15 -

Age-related dementia 320

Enhancing endogenous neurotrophic support of the aging brain . 320

Pharmacological approaches for treatment of age-related dementia . 321

Physical exercise to prevent decline of mental function with aging 322

Vascular dementia .. 322

Prediction of dementia in persons with vascular risk factors. 322

Management of subcortical vascular dementia . 323

Dementia with Lewy bodies 324

Neuroprotection in AIDS dementia . 324

Multiple system atrophy .. 325

Epilepsy 325

Mechanisms of neuronal damage in epilepsy 325

Strategies for neuroprotection in epilepsy . 326

Control of seizures and neuroprotection . 327

Cell therapy for neuroprotection in epilepsy .. 328

Cell therapy of posttraumatic epilepsy . 329

Cell therapy for temporal lobe epilepsy 329

Cell therapy for pharmacoresistant epilepsies 329

Gene therapy for neuroprotection in epilepsy .. 330

Spinal and bulbar muscular atrophy .. 331

Multiple sclerosis . 331

Introduction 331

Epidemiology of multiple sclerosis 331

Pathophysiology 332

Current management of multiple sclerosis . 332

Specific therapies for MS based on pathomechanism . 333

Neuroprotection in multiple sclerosis .. 333

Clinical trials of neuroprotective therapies for MS 334

Neuroprotection by control of progressive forms of multiple sclerosis .. 337

Neuroprotection by controlling autoimmune inflammation in the brain . 337

Remyelination for neuroprotection in multiple sclerosis . 337

Agents for neuroprotection in multiple sclerosis .. 338

Angiotensin-II inhibitors .. 338

Antiglutamate agents 338

Antioxidants for neuroprotection in MS 338

Antisense and RNAi approaches to MS . 338

Cell therapy for multiple sclerosis .. 339

Cladribine . 341

Dalfampridine in MS .. 342

DNA vaccine for MS 342

Erythropoietin as a neuroprotective in MS .. 342

Fingolimod (FTY720) . 342

Fusokine composed of GM-CSF and IL-15 for immune suppression . 343

Gene therapy for MS . 344

Ibudilast for MS .. 344

IVIG for MS .. 344

Laquinimod .. 344

MBP8298 .. 345

Monoclonal antibodies for MS . 345

Natalizumab . 345

Natural human antibodies for repair of myelin .. 346

Neurotrophic factors for multiple sclerosis .. 346

Recombinant T-cell ligands .. 347

Statins for MS.. 347

Concluding remarks on neuroprotection in MS .. 348

Neuroprotection in transverse myelitis . 348

Neuroprotection in decompression sickness .. 349

Neuroprotection in hydrocephalus .. 350

Neuroprotection in normal pressure hydrocephalus 350

Neuroprotection in infections of the CNS . 350

Neuroprotection in bacterial meningitis .. 351

Mechanism of neural injury in bacterial meningitis .. 351

Strategies for neuroprotection 351

Neuroprotective approach to rabies . 352

Neuroprotection in cerebral malaria . 352

Neuroprotection in hypertensive encephalopathy 352

Neuroprotection in toxic encephalopathies . 353

Hepatic encephalopathy .. 353

Management of hepatic encephalopathy.. 353

Encephalopathy due to organophosphorus poisoning . 354

Neuroprotection against chemotherapy-induced brain damage .. 354 - 16 -

Neuroprotection against alcohol 355

Alcoholic neurologic disorders . 355

Fetal alcohol syndrome . 355

Pathogenesis of alcohol-induced damage to the nervous system . 356

Neuroprotection against neurotoxicity of alcohol .. 356

Neuroprotection in hypoxia-ischemia 356

Neuroprotection in neonatal hypoxic-ischemic brain injury .. 357

Neuroprotection in carbon monoxide poisoning 358

Pathomechanism of CO poisoning as a basis for neuroprotection . 359

Management of CO poisoning . 359

Syndrome of delayed post-hypoxic leukoencephalopathy . 360

Neuroprotection in sleep apnea 360

Neuroprotection in hypoglycemic coma 361

Neuroprotection in mitochondrial dysfunction .. 362

Mitochondrial permeability transition .. 362

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