Neuroprotection has been placed on a firm scientific basis during the past decade due to an improved understanding of the molecular basis of neurological diseases and the knowledge that treatment of neurological disorders should not be merely symptomatic but preventative against the progression of the underlying disease, as well as regenerative. The Handbook of Neuroprotection serves as a comprehensive review of neuroprotection based on knowledge of the molecular basis of neurological disorders. Neuroprotective effects of older, established drugs, as well as new drugs in development, are well documented in this detailed volume, featuring the most cutting-edge and innovative methods currently in use.

Introduction.............................................................................................. 1
Definitions.................................................................................................. 1
Historical Development of Neuroprotection.............................................. 1
Intrinsic Neuroprotective Factors............................................................... 3
Neuroprotective Gene Expression......................................................... 4
Neurotrophic Factors............................................................................. 5
Intrinsic Nonenzymatic Antioxidants.................................................... 6
Intrinsic Neuroprotective Proteins......................................................... 6
Stem Cell Factor.................................................................................... 9
Role of the Immune System in Neuroprotection................................... 9
Induction of DNA Repair Enzymes for Neuroprotection...................... 10
Pathomechanisms of CNS Injury as Basis for Neuroprotection................ 11
Biomarkers of Neurological Disorders and Neuroprotection.................... 12
CNS Biomarker Identification Using Proteomics.................................. 12
Brain Imaging for Detection of Biomarkers.......................................... 13
Role of Neuroprotection in Various Neurological Disorders..................... 13
Neuroprotection and Neuroregeneration.................................................... 14
Acute Versus Chronic Neuroprotection..................................................... 15
Discovery and Evaluation of Neuroprotective Agents............................... 15
Neuroprotective Drug Discovery........................................................... 15
Discovery of CNS Drugs that Penetrate the Blood Brain Barrier......... 16
In Vitro Assays for the Evaluation of Neuroprotective Agents............. 17
Oxidative Injury Model to Test Neuroprotective Drugs........................ 18
Apoptosis Model for Designing Neuroprotective Drugs....................... 18
Transgenic Mouse Models of Neurological Disorders.......................... 18
Evaluating Effects of Neuroprotective Drugs on Living
Brain Slices............................................................................................ 19
Role of Brain Imaging in Neuroprotective Drug Discovery and
Development.......................................................................................... 20
Application of Nanotechnology in Neuroprotection.............................. 22
Evaluation Criteria for Potential Neuroprotective Agents..................... 22
References.................................................................................................. 23
viii Contents
2 Neuroprotective Agents........................................................................... 25
Classification of Neuroprotective Agents.................................................. 25
Activity-Dependent Neuroprotective Protein............................................ 25
Adenosine Analogs.................................................................................... 32
Propentofylline....................................................................................... 32
Antidepressants.......................................................................................... 33
Antidepressant-Induced Neurogenesis................................................... 33
Neurogenesis Induced by Electroconvulsive Therapy........................... 33
Neuroprotective Effect of Selective Serotonin Reuptake Inhibitors...... 34
Antiepileptic Drugs as Neuroprotectives................................................... 34
Phenytoin............................................................................................... 35
Valproic Acid......................................................................................... 36
Levetiracetam......................................................................................... 36
Anti-inflammatory Agents......................................................................... 37
Aspirin.................................................................................................... 37
Interleukin-1 Antagonists....................................................................... 37
COX-2 Inhibitors................................................................................... 38
Gold Microparticles as Anti-neuroinflammatory Agents...................... 39
Minocycline........................................................................................... 40
Anti-apoptosis Agents................................................................................ 40
Activated Protein C................................................................................ 41
Calpain Inhibitors................................................................................... 42
Caspase Inhibitors.................................................................................. 43
DNA-Binding Drugs.............................................................................. 43
Lithium................................................................................................... 43
Olesoxime.............................................................................................. 44
Omega-3 Fatty Acids............................................................................. 44
Poly(ADP-Ribose) Polymerase Inhibitors............................................. 45
Prevention of Apoptosis by Binding of proNGF to Sortilin.................. 46
Antioxidants/Free Radical Scavengers...................................................... 47
Free Radical Generation........................................................................ 47
Natural Defenses Against Oxidative Stress........................................... 47
Effects of Oxidative Damage................................................................. 48
Measures to Control Oxidative Stress.................................................... 49
Translation of Antioxidant Neuroprotection from
Preclinical to Clinical............................................................................. 55
Carbon Monoxide and Heme Oxygenase.................................................. 55
Cell Transplants............................................................................................. 55
Cells Secreting Neuroprotective Substances.......................................... 56
Stem Cells.............................................................................................. 57
Stem Cell Activation for Neuroprotection/Regeneration
by Glucocorticoids................................................................................. 57
Cytokines......................................................................................................... 57
Erythropoietin........................................................................................ 57
Granulocyte Colony-Stimulating Factor................................................ 60
Contents ix
Delta-Opioid Receptor Agonists................................................................ 61
FK960........................................................................................................ 61
Gene Therapy............................................................................................. 62
Glucagon-Like Peptide.............................................................................. 63
Glatiramer Acetate..................................................................................... 63
Glutamate Antagonists............................................................................... 64
Neuroprotection by Scavenging Blood Glutamate................................ 65
N-Acylethanolamines for Protection Against Glutamatergic
Excitotoxicity......................................................................................... 66
Glutamate Transporters.......................................................................... 66
Glutamate Transporter-Mediated Neuroprotective Effect of Drugs...... 67
Neuroprotection by Targeting KAI Subunit of Kainate Receptor......... 67
Glycine-Proline-Glutamate Analogs.......................................................... 68
Herbal Preparations.................................................................................... 68
Flavonoid Wogonin................................................................................ 68
Ginseng.................................................................................................. 69
Hydrogen Sulfide....................................................................................... 69
NMDA Receptor Ion Channel Complex.................................................... 70
NMDA Receptor Antagonists................................................................ 71
AMPA Receptor Modulators................................................................. 74
Metabotropic Glutamate Receptor Modulators..................................... 74
Cannabinoids.......................................................................................... 75
Dexanabinol........................................................................................... 76
Glutathione................................................................................................. 77
Heat Shock Proteins................................................................................... 77
Hormones................................................................................................... 78
Estrogen and Neuroprotection............................................................... 78
Insulin.................................................................................................... 80
Ion Channel Modulators............................................................................ 81
Calcium Channel Blockers.................................................................... 81
Na+ Channel Blockers............................................................................ 82
Neuroprotective Potassium Channel Inhibitors..................................... 83
Kynurenine Inhibitors................................................................................ 83
Leukocyte Adhesion Inhibitors.................................................................. 84
Modafinil.................................................................................................... 85
Neural Regeneration Protein...................................................................... 85
Neurite Outgrowth-Promoting Prostaglandin Compounds........................ 86
Neuroimmunophilins................................................................................. 86
Cyclosporin-A........................................................................................ 87
FK506.................................................................................................... 87
Rapamycin............................................................................................. 88
Neurotrophic Factors................................................................................. 88
Activity-Dependent Neurotrophic Factor.............................................. 89
Bone Morphogenetic Proteins................................................................ 89
Brain-Derived Neurotrophic Factor....................................................... 90
Ciliary Neurotrophic Factor................................................................... 90
x Contents
Fibroblast Growth Factors..................................................................... 91
Glial Cell Line-Derived Neurotrophic Factor........................................ 92
Insulin-Like Growth Factor................................................................... 92
Nerve Growth Factor.............................................................................. 93
Neurotrophins........................................................................................ 94
Osteogenic Protein-1.............................................................................. 94
Pigment Epithelium-Derived Factor...................................................... 95
Transforming Growth Factor-b1............................................................ 95
Vascular Endothelial Growth Factor...................................................... 95
Neurotrophic Factor-Related Neuroprotective Agents.......................... 96
Nicotine and Nicotinic Receptor Agonists................................................ 99
Nitric Oxide-Based Neuroprotection......................................................... 100
Nitric Oxide Synthase Inhibitors........................................................... 101
Nitric Oxide Mimetics........................................................................... 101
Nootropics.................................................................................................. 102
Piracetam................................................................................................ 103
Nutraceuticals and Food Constituents....................................................... 103
Creatine.................................................................................................. 103
Curcumin/Curry..................................................................................... 104
Glyceryltriacetate................................................................................... 106
Green Tea............................................................................................... 106
Nicotinamide.......................................................................................... 107
Resveratrol............................................................................................. 107
Osmotic Diuretics...................................................................................... 108
Mannitol................................................................................................. 108
Osteopontin............................................................................................ 109
Oxygen Therapeutics................................................................................. 109
Oxygen Carriers..................................................................................... 110
Hemoglobin-Based Oxygen Carriers..................................................... 110
Perfluorocarbons as Oxygen Carriers.................................................... 111
Hyperbaric Oxygen Therapy.................................................................. 112
Peptides...................................................................................................... 112
C3-Derived Peptide for Neuroprotection and Neuroregeneration......... 113
Corticotropin-Releasing Hormone......................................................... 113
Thyrotropin-Releasing Hormone........................................................... 113
Vasoactive Intestinal Peptide................................................................. 114
Pharmacological Preconditioning.............................................................. 115
PPARs as Drug Targets for Neuroprotection............................................. 115
Riluzole...................................................................................................... 116
Role of RNA Interference in Neuroprotection........................................... 116
Sigma Receptor Agonists as Neuroprotective Agents............................... 117
SIRT Group of Proteins............................................................................. 117
Statins......................................................................................................... 118
Steroids...................................................................................................... 119
Dehydroepiandrosterone........................................................................ 119
Contents xi
HF0220.................................................................................................. 120
Sulforaphane.............................................................................................. 120
Tauroursodeoxycholic Acid....................................................................... 121
Tetanus Toxin as a Neuroprotective Agent................................................ 121
Thrombolytic Agents as Neuroprotective Agents...................................... 122
Uncoupling Protein 2................................................................................. 122
Vaccines as Neuroprotectives..................................................................... 123
Vitamins as Neuroprotective Agents.......................................................... 123
Vitamin B12........................................................................................... 123
Nonpharmacological Approaches to Neuroprotection............................... 124
Environmental Enrichment.................................................................... 124
Mental Training...................................................................................... 125
Physical Exercise................................................................................... 125
Hypothermia.......................................................................................... 125
Hibernation Induced by Hydrogen Sulfide............................................ 127
Ketogenic Diet....................................................................................... 128
Nonpharmacological Preconditioning for Neuroprotection................... 128
Transcranial Magnetic Stimulation........................................................ 129
Electrical Fields for Improvement of Cerebral Function in
Neurodegeneration................................................................................. 130
Neuroprotective Effect of Exercise........................................................ 131
Hibernation and Neuroprotection.......................................................... 132
Suspended Animation and Neuroprotection.......................................... 132
References.................................................................................................. 132
3 Neuroprotection in Cerebrovascular Disease ....................................... 141
Introduction................................................................................................ 141
Pathophysiology of Cerebral Ischemia...................................................... 141
Calcium Overload.................................................................................. 143
Ion Channel Dysfunction in Stroke........................................................ 143
Role of Oxygen Free Radicals in Cerebral Ischemia............................. 143
Role of Nitric Oxide in Cerebral Ischemia............................................ 144
Glutamate as a Biomarker of Stroke...................................................... 144
Cerebral Edema in Stroke...................................................................... 144
Gene Expression in Response to Cerebral Ischemia.............................. 145
Induction of Heat Shock Proteins in Stroke........................................... 145
Role of Cytokines and Adhesion Molecules in Stroke.......................... 146
DNA Damage and Repair in Cerebral Ischemia.................................... 147
Role of Neurotrophic Factors in Stroke................................................. 147
Role of Poly(ADP-Ribose) Polymerase Gene....................................... 148
Role of Protease-Activated Receptor 1.................................................. 149
Reperfusion Injury after Cerebral Ischemia............................................... 149
Neuroprotection According to Zones in Cerebral Infarction..................... 149
Zone of Ischemic Infarction................................................................... 150
Penumbra............................................................................................... 150
xii Contents
Current Management of Stroke.................................................................. 151
Neuroprotection in Stenosis of Intracranial Arteries............................. 152
Neuroprotection in Transient Ischemic Attacks..................................... 152
Neuroprotective Therapies for Stroke........................................................ 152
Acid-Sensing Ion Channel Blockers...................................................... 153
AMPA Receptor Antagonists as Neuroprotectives for Stroke............... 154
Anti-apoptotic Neuroprotectives............................................................ 154
Antiepileptic Drugs as Neuroprotectives in Stroke................................ 156
Anti-HMGB1 Monoclonal Antibody..................................................... 157
Antioxidant Approaches........................................................................ 158
Anti-glutamate Compounds................................................................... 160
Arimoclomol for Stroke......................................................................... 161
Cardiac Glycosides as Neuroprotectives in Stroke................................ 162
Clenbuterol............................................................................................. 162
Cox-2 Inhibitors for Ischemic Stroke.................................................... 162
Enoxaparin............................................................................................. 163
Estrogen for Stroke................................................................................ 163
Flavones for Neuroprotection in Stroke................................................. 165
Granulocyte-Macrophage Colony-Stimulating Factor
for Cerebral Ischemia............................................................................. 166
Modulation of Histamine H2 Receptors................................................. 166
Inosine for Stroke................................................................................... 167
Insulin-Like Growth Factor-I................................................................. 167
Ischemic Preconditioning for Neuroprotection in Stroke...................... 168
Ketone Bodies for Neuroprotection in Stroke........................................ 169
Mineralocorticoid Receptor Blockade for Neuroprotection.................. 169
Multifunctional Neuroprotective Agents............................................... 169
Neuroserpin as a Neuroprotective in Stroke.......................................... 170
N-2-Mercaptopropionyl Glycine........................................................... 171
NeuroAid................................................................................................ 171
Neurotrophic Factors as Neuroprotectives for Stroke............................ 171
NO-Based Strategies for Neuroprotection in Cerebral Ischemia........... 174
Peroxisome Proliferator-Activated Receptor-g Agonists....................... 175
PGE2 EP2 Receptor Activation............................................................. 175
Pioglitazone for Reduction of Stroke Risk in Diabetes......................... 175
Progesterone........................................................................................... 176
Proteosome Inhibitors............................................................................ 176
Statins for Prevention of and Neuroprotection in Stroke....................... 176
Sildenafil................................................................................................ 177
Src Receptor Blockade........................................................................... 178
Stroke Vaccine....................................................................................... 178
SUN-N4057........................................................................................... 179
Thrombosis Inhibitors............................................................................ 179
Neuroprotectives in Reperfusion Injury................................................. 180
Prevention of Hemorrhage Following Ischemic Stroke......................... 181
Contents xiii
Nonpharmacological Neuroprotective Therapies for Stroke................. 181
Cell Therapy for Stroke......................................................................... 186
Neuroprotective Vaccines for Stroke..................................................... 188
Gene Therapy for Neuroprotection in Cerebrovascular Disease........... 188
Regulation of microRNAs for Neuroprotection in
Cerebral Ischemia.................................................................................. 192
Neuroprotective Therapies for Cerebral Ischemia: Clinical Trials........ 192
Failed Clinical Trials of Neuroprotection in Stroke............................... 197
Design of Acute Stroke Trial to Facilitate Drug Approval........................ 208
The Ideal Neuroprotective Agent for Stroke.............................................. 208
Future Prospects for Neuroprotection in Stroke........................................ 209
References.................................................................................................. 210
4 Neuroprotection in Traumatic Brain Injury......................................... 217
Introduction................................................................................................ 217
Cerebral Hypoxia/Ischemia as a Complication of Trauma........................ 217
Traumatic Brain Injury............................................................................... 218
Pathophysiology of TBI......................................................................... 218
Management of TBI............................................................................... 225
Neuroprotection in TBI.......................................................................... 226
Biological Approaches to Neuroprotection in TBI................................ 241
Nonpharmaceutical Approaches to Neuroprotection in TBI................. 243
Prophylactic Neuroprotection Against TBI........................................... 245
Clinical Trials of Neuroprotective Agents in TBI.................................. 245
Failed Clinical Trials in TBI.................................................................. 247
Concluding Remarks and Future Prospects of
Neuroprotection in TBI.......................................................................... 249
References.................................................................................................. 250
5 Neuroprotection in Spinal Cord Injury................................................. 255
Introduction................................................................................................ 255
Pathophysiology of SCI............................................................................. 255
Secondary Mechanisms of SCI.............................................................. 256
Neurotrophic Factor Changes in SCI..................................................... 257
Management of SCI................................................................................... 258
Pharmacological Neuroprotective Agents for SCI..................................... 259
4-Aminopyridine.................................................................................... 259
Antibodies as Neurite Growth Inhibitors in SCI.................................... 259
Bacterial Enzyme Chondroitinase ABC................................................ 260
Docosahexaenoic Acid as Neuroprotective in SCI................................ 260
Erythropoietin as a Neuroprotective in SCI........................................... 261
Free Radical Scavengers for Neuroprotection in SCI............................ 261
Gacyclidine............................................................................................ 262
GYKI 52466........................................................................................... 262
xiv Contents
Immunosuppressants as Neuroprotectants in SCI.................................. 262
Interleukin-10 for Neuroprotection in SCI............................................ 263
Matrix Metalloproteinase Inhibitors for SCI......................................... 263
Methylprednisolone............................................................................... 264
Minocycline as Neuroprotective in SCI................................................. 264
Neurotrophic Factors for N