vii

Contents

1 Introduction ............................................................................................. 1

Definitions ................................................................................................. 1Historical Development of Neuroprotection ............................................. 1Intrinsic Neuroprotective Factors .............................................................. 3

Neuroprotective Gene Expression ........................................................ 4Neurotrophic Factors ............................................................................ 5Intrinsic Nonenzymatic Antioxidants ................................................... 6Intrinsic Neuroprotective Proteins ........................................................ 6Stem Cell Factor ................................................................................... 9Role of the Immune System in Neuroprotection .................................. 9Induction of DNA Repair Enzymes for Neuroprotection ..................... 10

Pathomechanisms of CNS Injury as Basis for Neuroprotection ............... 11Biomarkers of Neurological Disorders and Neuroprotection ................... 12

CNS Biomarker Identification Using Proteomics ................................. 12Brain Imaging for Detection of Biomarkers ......................................... 13

Role of Neuroprotection in Various Neurological Disorders .................... 13Neuroprotection and Neuroregeneration ................................................... 14Acute Versus Chronic Neuroprotection .................................................... 15Discovery and Evaluation of Neuroprotective Agents .............................. 15 Neuroprotective Drug Discovery .......................................................... 15

Discovery of CNS Drugs that Penetrate the Blood–Brain Barrier ........ 16In Vitro Assays for the Evaluation of Neuroprotective Agents ............ 17Oxidative Injury Model to Test Neuroprotective Drugs ....................... 18Apoptosis Model for Designing Neuroprotective Drugs ...................... 18Transgenic Mouse Models of Neurological Disorders ......................... 18Evaluating Effects of Neuroprotective Drugs on Living Brain Slices ........................................................................................... 19Role of Brain Imaging in Neuroprotective Drug Discovery and Development ......................................................................................... 20Application of Nanotechnology in Neuroprotection ............................. 22Evaluation Criteria for Potential Neuroprotective Agents .................... 22

References ................................................................................................. 23

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2 Neuroprotective Agents .......................................................................... 25

Classification of Neuroprotective Agents ................................................. 25Activity-Dependent Neuroprotective Protein ........................................... 25Adenosine Analogs ................................................................................... 32

Propentofylline ...................................................................................... 32Antidepressants ......................................................................................... 33

Antidepressant-Induced Neurogenesis .................................................. 33Neurogenesis Induced by Electroconvulsive Therapy .......................... 33Neuroprotective Effect of Selective Serotonin Reuptake Inhibitors ..... 34

Antiepileptic Drugs as Neuroprotectives .................................................. 34Phenytoin .............................................................................................. 35Valproic Acid ........................................................................................ 36Levetiracetam ........................................................................................ 36

Anti-inflammatory Agents ........................................................................ 37Aspirin ................................................................................................... 37Interleukin-1 Antagonists ...................................................................... 37COX-2 Inhibitors .................................................................................. 38Gold Microparticles as Anti-neuroinflammatory Agents ..................... 39Minocycline .......................................................................................... 40

Anti-apoptosis Agents ............................................................................... 40Activated Protein C ............................................................................... 41Calpain Inhibitors .................................................................................. 42Caspase Inhibitors ................................................................................. 43DNA-Binding Drugs ............................................................................. 43Lithium .................................................................................................. 43Olesoxime ............................................................................................. 44Omega-3 Fatty Acids ............................................................................ 44Poly(ADP-Ribose) Polymerase Inhibitors ............................................ 45Prevention of Apoptosis by Binding of proNGF to Sortilin ................. 46

Antioxidants/Free Radical Scavengers ..................................................... 47 Free Radical Generation ....................................................................... 47

Natural Defenses Against Oxidative Stress .......................................... 47Effects of Oxidative Damage ................................................................ 48Measures to Control Oxidative Stress ................................................... 49Translation of Antioxidant Neuroprotection from Preclinical to Clinical ............................................................................ 55

Carbon Monoxide and Heme Oxygenase ................................................. 55 Cell Transplants ............................................................................................ 55

Cells Secreting Neuroprotective Substances ......................................... 56Stem Cells ............................................................................................. 57Stem Cell Activation for Neuroprotection/Regeneration by Glucocorticoids ................................................................................ 57

Cytokines ........................................................................................................ 57 Erythropoietin ....................................................................................... 57

Granulocyte Colony-Stimulating Factor ............................................... 60

ixContents

Delta-Opioid Receptor Agonists ............................................................... 61FK960 ....................................................................................................... 61Gene Therapy ............................................................................................ 62Glucagon-Like Peptide ............................................................................. 63Glatiramer Acetate .................................................................................... 63Glutamate Antagonists .............................................................................. 64

Neuroprotection by Scavenging Blood Glutamate ............................... 65N-Acylethanolamines for Protection Against Glutamatergic Excitotoxicity ........................................................................................ 66Glutamate Transporters ......................................................................... 66Glutamate Transporter-Mediated Neuroprotective Effect of Drugs ..... 67Neuroprotection by Targeting KAI Subunit of Kainate Receptor ........ 67

Glycine-Proline-Glutamate Analogs ......................................................... 68Herbal Preparations ................................................................................... 68

Flavonoid Wogonin ............................................................................... 68Ginseng ................................................................................................. 69

Hydrogen Sulfide ...................................................................................... 69NMDA Receptor Ion Channel Complex ................................................... 70

NMDA Receptor Antagonists ............................................................... 71AMPA Receptor Modulators ................................................................ 74Metabotropic Glutamate Receptor Modulators .................................... 74Cannabinoids ......................................................................................... 75Dexanabinol .......................................................................................... 76

Glutathione ................................................................................................ 77Heat Shock Proteins .................................................................................. 77Hormones .................................................................................................. 78

Estrogen and Neuroprotection .............................................................. 78Insulin ................................................................................................... 80

Ion Channel Modulators ........................................................................... 81Calcium Channel Blockers ................................................................... 81Na+ Channel Blockers ........................................................................... 82Neuroprotective Potassium Channel Inhibitors .................................... 83

Kynurenine Inhibitors ............................................................................... 83Leukocyte Adhesion Inhibitors ................................................................. 84Modafinil ................................................................................................... 85Neural Regeneration Protein ..................................................................... 85Neurite Outgrowth-Promoting Prostaglandin Compounds ....................... 86Neuroimmunophilins ................................................................................ 86

Cyclosporin-A ....................................................................................... 87FK506 ................................................................................................... 87Rapamycin ............................................................................................ 88

Neurotrophic Factors ................................................................................ 88Activity-Dependent Neurotrophic Factor ............................................. 89Bone Morphogenetic Proteins ............................................................... 89Brain-Derived Neurotrophic Factor ...................................................... 90Ciliary Neurotrophic Factor .................................................................. 90

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Fibroblast Growth Factors .................................................................... 91Glial Cell Line-Derived Neurotrophic Factor ....................................... 92Insulin-Like Growth Factor................................................................... 92Nerve Growth Factor ............................................................................. 93Neurotrophins ....................................................................................... 94Osteogenic Protein-1 ............................................................................. 94Pigment Epithelium-Derived Factor ..................................................... 95Transforming Growth Factor-b1 ........................................................... 95Vascular Endothelial Growth Factor ..................................................... 95Neurotrophic Factor-Related Neuroprotective Agents ......................... 96

Nicotine and Nicotinic Receptor Agonists ............................................... 99Nitric Oxide-Based Neuroprotection ........................................................ 100

Nitric Oxide Synthase Inhibitors .......................................................... 101Nitric Oxide Mimetics .......................................................................... 101

Nootropics ................................................................................................. 102Piracetam ............................................................................................... 103

Nutraceuticals and Food Constituents ...................................................... 103Creatine ................................................................................................. 103Curcumin/Curry .................................................................................... 104Glyceryltriacetate .................................................................................. 106Green Tea .............................................................................................. 106Nicotinamide ......................................................................................... 107Resveratrol ............................................................................................ 107

Osmotic Diuretics ..................................................................................... 108Mannitol ................................................................................................ 108Osteopontin ........................................................................................... 109

Oxygen Therapeutics ................................................................................ 109Oxygen Carriers .................................................................................... 110Hemoglobin-Based Oxygen Carriers .................................................... 110Perfluorocarbons as Oxygen Carriers ................................................... 111Hyperbaric Oxygen Therapy ................................................................. 112

Peptides ..................................................................................................... 112C3-Derived Peptide for Neuroprotection and Neuroregeneration ........ 113Corticotropin-Releasing Hormone ........................................................ 113Thyrotropin-Releasing Hormone .......................................................... 113Vasoactive Intestinal Peptide ................................................................ 114

Pharmacological Preconditioning ............................................................. 115PPARs as Drug Targets for Neuroprotection ............................................ 115Riluzole ..................................................................................................... 116Role of RNA Interference in Neuroprotection .......................................... 116Sigma Receptor Agonists as Neuroprotective Agents .............................. 117SIRT Group of Proteins ............................................................................ 117Statins ........................................................................................................ 118Steroids ..................................................................................................... 119

Dehydroepiandrosterone ....................................................................... 119

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HF0220 ................................................................................................. 120Sulforaphane ............................................................................................. 120Tauroursodeoxycholic Acid ...................................................................... 121Tetanus Toxin as a Neuroprotective Agent ............................................... 121Thrombolytic Agents as Neuroprotective Agents ..................................... 122Uncoupling Protein 2 ................................................................................ 122Vaccines as Neuroprotectives .................................................................... 123Vitamins as Neuroprotective Agents ......................................................... 123

Vitamin B12 .......................................................................................... 123Nonpharmacological Approaches to Neuroprotection .............................. 124

Environmental Enrichment ................................................................... 124Mental Training ..................................................................................... 125Physical Exercise .................................................................................. 125Hypothermia ......................................................................................... 125Hibernation Induced by Hydrogen Sulfide ........................................... 127Ketogenic Diet ...................................................................................... 128Nonpharmacological Preconditioning for Neuroprotection .................. 128Transcranial Magnetic Stimulation ....................................................... 129Electrical Fields for Improvement of Cerebral Function in Neurodegeneration ................................................................................ 130Neuroprotective Effect of Exercise ....................................................... 131Hibernation and Neuroprotection ......................................................... 132Suspended Animation and Neuroprotection ......................................... 132

References ................................................................................................. 132

3 Neuroprotection in Cerebrovascular Disease ...................................... 141

Introduction ............................................................................................... 141Pathophysiology of Cerebral Ischemia ..................................................... 141

Calcium Overload ................................................................................. 143Ion Channel Dysfunction in Stroke ....................................................... 143Role of Oxygen Free Radicals in Cerebral Ischemia ............................ 143Role of Nitric Oxide in Cerebral Ischemia ........................................... 144Glutamate as a Biomarker of Stroke ..................................................... 144Cerebral Edema in Stroke ..................................................................... 144Gene Expression in Response to Cerebral Ischemia ............................. 145Induction of Heat Shock Proteins in Stroke .......................................... 145Role of Cytokines and Adhesion Molecules in Stroke ......................... 146DNA Damage and Repair in Cerebral Ischemia ................................... 147Role of Neurotrophic Factors in Stroke ................................................ 147Role of Poly(ADP-Ribose) Polymerase Gene ...................................... 148Role of Protease-Activated Receptor 1 ................................................. 149

Reperfusion Injury after Cerebral Ischemia .............................................. 149Neuroprotection According to Zones in Cerebral Infarction .................... 149

Zone of Ischemic Infarction .................................................................. 150Penumbra .............................................................................................. 150

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Current Management of Stroke ................................................................. 151Neuroprotection in Stenosis of Intracranial Arteries ............................ 152Neuroprotection in Transient Ischemic Attacks .................................... 152

Neuroprotective Therapies for Stroke ....................................................... 152Acid-Sensing Ion Channel Blockers ..................................................... 153AMPA Receptor Antagonists as Neuroprotectives for Stroke .............. 154Anti-apoptotic Neuroprotectives ........................................................... 154Antiepileptic Drugs as Neuroprotectives in Stroke ............................... 156Anti-HMGB1 Monoclonal Antibody .................................................... 157Antioxidant Approaches ....................................................................... 158Anti-glutamate Compounds .................................................................. 160Arimoclomol for Stroke ........................................................................ 161Cardiac Glycosides as Neuroprotectives in Stroke ............................... 162Clenbuterol ............................................................................................ 162Cox-2 Inhibitors for Ischemic Stroke ................................................... 162Enoxaparin ............................................................................................ 163Estrogen for Stroke ............................................................................... 163Flavones for Neuroprotection in Stroke ................................................ 165Granulocyte-Macrophage Colony-Stimulating Factor for Cerebral Ischemia ............................................................................ 166Modulation of Histamine H

2 Receptors ................................................ 166

Inosine for Stroke .................................................................................. 167Insulin-Like Growth Factor-I ................................................................ 167Ischemic Preconditioning for Neuroprotection in Stroke ..................... 168Ketone Bodies for Neuroprotection in Stroke ....................................... 169Mineralocorticoid Receptor Blockade for Neuroprotection ................. 169Multifunctional Neuroprotective Agents .............................................. 169Neuroserpin as a Neuroprotective in Stroke ......................................... 170N-2-Mercaptopropionyl Glycine........................................................... 171NeuroAid ............................................................................................... 171Neurotrophic Factors as Neuroprotectives for Stroke ........................... 171NO-Based Strategies for Neuroprotection in Cerebral Ischemia .......... 174Peroxisome Proliferator-Activated Receptor-g Agonists ...................... 175PGE2 EP2 Receptor Activation ............................................................ 175Pioglitazone for Reduction of Stroke Risk in Diabetes ........................ 175Progesterone .......................................................................................... 176Proteosome Inhibitors ........................................................................... 176Statins for Prevention of and Neuroprotection in Stroke ...................... 176Sildenafil ............................................................................................... 177Src Receptor Blockade .......................................................................... 178Stroke Vaccine ...................................................................................... 178SUN-N4057 .......................................................................................... 179Thrombosis Inhibitors ........................................................................... 179Neuroprotectives in Reperfusion Injury ................................................ 180Prevention of Hemorrhage Following Ischemic Stroke ........................ 181

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Nonpharmacological Neuroprotective Therapies for Stroke ................ 181Cell Therapy for Stroke......................................................................... 186Neuroprotective Vaccines for Stroke .................................................... 188Gene Therapy for Neuroprotection in Cerebrovascular Disease .......... 188Regulation of microRNAs for Neuroprotection in Cerebral Ischemia ................................................................................. 192Neuroprotective Therapies for Cerebral Ischemia: Clinical Trials ....... 192Failed Clinical Trials of Neuroprotection in Stroke .............................. 197

Design of Acute Stroke Trial to Facilitate Drug Approval ....................... 208The Ideal Neuroprotective Agent for Stroke ............................................. 208Future Prospects for Neuroprotection in Stroke ....................................... 209References ................................................................................................. 210

4 Neuroprotection in Traumatic Brain Injury ........................................ 217

Introduction ............................................................................................... 217Cerebral Hypoxia/Ischemia as a Complication of Trauma ....................... 217Traumatic Brain Injury .............................................................................. 218

Pathophysiology of TBI ........................................................................ 218Management of TBI .............................................................................. 225Neuroprotection in TBI ......................................................................... 226Biological Approaches to Neuroprotection in TBI ............................... 241Nonpharmaceutical Approaches to Neuroprotection in TBI ................ 243Prophylactic Neuroprotection Against TBI .......................................... 245Clinical Trials of Neuroprotective Agents in TBI ................................. 245Failed Clinical Trials in TBI ................................................................. 247Concluding Remarks and Future Prospects of Neuroprotection in TBI ......................................................................... 249

References ................................................................................................. 250

5 Neuroprotection in Spinal Cord Injury ................................................ 255

Introduction ............................................................................................... 255Pathophysiology of SCI ............................................................................ 255

Secondary Mechanisms of SCI ............................................................. 256Neurotrophic Factor Changes in SCI .................................................... 257

Management of SCI .................................................................................. 258Pharmacological Neuroprotective Agents for SCI .................................... 259

4-Aminopyridine ................................................................................... 259Antibodies as Neurite Growth Inhibitors in SCI ................................... 259Bacterial Enzyme Chondroitinase ABC ............................................... 260Docosahexaenoic Acid as Neuroprotective in SCI ............................... 260Erythropoietin as a Neuroprotective in SCI .......................................... 261Free Radical Scavengers for Neuroprotection in SCI ........................... 261Gacyclidine ........................................................................................... 262GYKI 52466 .......................................................................................... 262

xiv Contents

Immunosuppressants as Neuroprotectants in SCI ................................. 262Interleukin-10 for Neuroprotection in SCI ........................................... 263Matrix Metalloproteinase Inhibitors for SCI ........................................ 263Methylprednisolone .............................................................................. 264Minocycline as Neuroprotective in SCI ................................................ 264Neurotrophic Factors for Neuroprotection After SCI ........................... 265Rho Pathway and Rho Antagonists in SCI ........................................... 266Selenium as a Neuroprotective for SCI ................................................. 266Sialidase for Enhancing Recovery After SCI ....................................... 267Targeting the Inflammatory Response for Neuroprotection in SCI ...... 267Uric Acid as Neuroprotective in SCI .................................................... 268

Nonpharmacological Approaches to SCI .................................................. 268Hyperbaric Oxygen Therapy ................................................................. 268Hypothermia for SCI ............................................................................. 268

Cell Therapy for SCI ................................................................................. 269Autoimmune T Cells Against CNS Myelin-Associated Peptide .......... 269Fetal Neural Grafts for SCI ................................................................... 269Olfactory Ensheathing Cells for SCI .................................................... 269Oligodendrocyte Precursor Cells for Treatment of SCI ........................ 270Schwann Cell Transplants for SCI ........................................................ 271Transplantation of Glial Cells for SCI .................................................. 271Stem Cells for SCI ................................................................................ 271

Gene Therapy for SCI ............................................................................... 275Combined Approaches to SCI .................................................................. 276Discovery of New Targets for Neuroprotective Therapies in SCI ............ 277Clinical Trials in SCI ................................................................................ 277References ................................................................................................. 279

6 Neuroprotection in Neurodegenerative Disorders ............................... 281

Introduction ............................................................................................... 281Pathomechanism of Neurodegeneration ................................................... 281

Dual Role of a-Synuclein in Neuroprotection and Neurodegeneration ................................................................................ 282Lack of Neurotrophic Factors ............................................................... 282Neuroinflammation in Neurodegenerative Disorders ........................... 283Neurodegeneration Associated with Protein Misfolding ...................... 283TDP-43 Proteinopathy and Neurodegenerative Diseases ..................... 285Role of Apoptosis in Neurodegenerative Disorders .............................. 286Role of Glia in Neurodegeneration ....................................................... 286Role of Metals in Neurodegeneration ................................................... 286Viral Infections and Neurodegeneration ............................................... 287

Genetic Disorders with Neurodegeneration .............................................. 289Batten Disease ....................................................................................... 289Friedreich Ataxia .................................................................................. 290

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Niemann–Pick Type C Disease ............................................................. 291Creutzfeldt–Jakob Disease .................................................................... 292

Approaches to Neuroprotection in Neurodegenerative Disorders ............ 293Glutamate-Based Therapies for Neurodegenerative Disorders ............. 294Mitochondria Permeability Transition Pore Complex and Neuroprotection .................................................................................... 294

References ................................................................................................. 295

7 Neuroprotection in Parkinson’s Disease ............................................... 297

Introduction ............................................................................................... 297Pathophysiology of Parkinson’s Disease .................................................. 297

Oxidative Stress .................................................................................... 297Excitotoxicity ........................................................................................ 299Asynchronous Neuronal Activity.......................................................... 299Apoptosis .............................................................................................. 299Role of Neurotrophic Factors ................................................................ 299Role of Misfolding Proteins .................................................................. 300Genetic Factors in PD ........................................................................... 300Alteration of Dopamine Homeostasis ................................................... 302

Neuroprotective Strategies for PD Based on Pathomechanism ................ 302RNAi Screening to Identify Neuroprotective Genes in a PD Model ........................................................................................... 303

Management of Parkinson’s Disease ........................................................ 304Limitation of Conventionally Administered Dopamine Therapy ......... 305Treatment of Dementia Associated with PD ......................................... 306

Neuroprotective Therapy in PD ................................................................ 306Neuroprotective Effect of Currently Used Drugs for PD .......................... 307

Pramipexole .......................................................................................... 307Rasagiline Mesylate .............................................................................. 308Ropinirole ............................................................................................. 309Selegiline ............................................................................................... 309

Nonpharmacological Strategies for Neuroprotection in PD ..................... 310Preventive Effect of Exercise and Environmental Enrichment ............. 310Low-Calorie Diet .................................................................................. 311

Development of Neuroprotective Therapies for PD ................................. 311Adenosine A

2A Receptor Antagonists ................................................... 311

Anti-apoptotic Strategies for PD ........................................................... 312Calcium Channel Blockers for PD ........................................................ 312Cell Therapies for PD ........................................................................... 313Cogane .................................................................................................. 315Creatine and Minocycline ..................................................................... 315Conserved Dopamine Neurotrophic Factor for PD ............................... 316Free Radical Scavengers for Neuroprotection in Parkinson’s Disease .............................................................................. 316Gene Therapy for PD ............................................................................ 318

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Heat Shock Protein 70 .......................................................................... 321Neuroprotective Effect of DJ-1 Protein ................................................ 321Neurotrophic Factors ............................................................................ 322Nrf2-Mediated Neuroprotection in PD ................................................. 324Omega-3 Polyunsaturated Fatty Acids ................................................. 325RAB3B Overexpression ........................................................................ 325RNAi Therapy for PD ........................................................................... 326Safinamide ............................................................................................ 326Sirtuin 2 Inhibitors for Neuroprotection in PD ..................................... 327Statins and PD ....................................................................................... 328Targeting Bax ........................................................................................ 328Vitamin D for Neuroprotection in PD ................................................... 328Vaccine for PD ...................................................................................... 329

Clinical Trials of Neuroprotection in Parkinson’s Disease ....................... 329Evaluation of Neuroprotective Therapies for PD ...................................... 330Current Status and Future Challenges for Neuroprotection in PD ........... 331References ................................................................................................. 333

8 Neuroprotection in Alzheimer’s Disease ............................................... 337

Introduction ............................................................................................... 337Pathomechanism of Alzheimer’s Disease ................................................. 337

Role of Glutamate Transport Dysfunction in AD ................................. 338Role of Neurotrophic Factors in the Pathomechanism of AD .............. 339

Management of Alzheimer’s Disease ....................................................... 339Neuroprotection in Alzheimer’s Disease .................................................. 339Inhibition of Ab Aggregation ................................................................... 340

Secretase Inhibitors ............................................................................... 340AN-1792 ............................................................................................... 342Monoclonal Antibody m266 ................................................................. 342Clioquinol ............................................................................................. 342FKBP52 for Neuroprotection from Cu Toxicity in AD ........................ 343Phenserine ............................................................................................. 344Colostrinin............................................................................................. 345

Inhibition of Neuroinflammation .............................................................. 345Etanercept ............................................................................................. 345

Neurotrophic Factors/Gene Therapy ......................................................... 346NGF Gene Therapy ............................................................................... 346AL-108 .................................................................................................. 348Targeting Plasminogen Activator Inhibitor Type-1 Gene ..................... 348

Estrogen and AD ....................................................................................... 348Antioxidants .............................................................................................. 349

NSAIDS ................................................................................................ 349Memantine ................................................................................................ 349Dimebon .................................................................................................... 350Cerebrolysin .............................................................................................. 351

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Ginkgo biloba ............................................................................................ 352Tetrahydrocannabinol for Neuroprotection in AD .................................... 353Ladostigil Tartrate ..................................................................................... 354Phosphodiesterase Inhibitors as Neuroprotectives .................................... 354PPAR-g Agonists ....................................................................................... 354Role of Statins in Reducing the Risk of AD ............................................. 355Combined Therapeutic Approaches to AD ............................................... 356Clinical Trials in AD ................................................................................. 356Future Prospects of Neuroprotection in AD ............................................. 356Mild Cognitive Impairment ...................................................................... 356

Relation of MCI to AD ......................................................................... 364Neuroprotection in MCI ........................................................................ 365

References ................................................................................................. 365

9 Neuroprotection in Huntington’s Disease ............................................. 369

Introduction ............................................................................................... 369Pathophysiology of HD ............................................................................. 369Management of Huntington’s disease ....................................................... 371Neuroprotection in Huntington’s disease .................................................. 371

Antipsychotic D2 and 5-HT1A

Antagonists ........................................... 372Caspase Inhibitors ................................................................................. 373Clioquinol for HD ................................................................................. 373Creatine for Stabilizing Bioenergetic Defects ...................................... 373Cysteamine ............................................................................................ 374Drugs that Block Inappropriate Calcium Release from Neurons ......... 374Enhancing Protease Activity for Clearance of mHtt ............................. 375Eicosapentaenoic Acid .......................................................................... 375Free Radical Scavengers ....................................................................... 375Histone Deacetylase Inhibitors ............................................................. 376Inhibitors of Polyglutamine Aggregation in HD................................... 376Pridopidine ............................................................................................ 377Simvastatin as a Neuroprotective in HD ............................................... 377Single-Chain Fv Antibodies .................................................................. 378SIRT2 Inhibitors for Neuroprotection in HD ........................................ 378Synaptic Activation of NMDA Receptors ............................................ 379Tetrabenazine ........................................................................................ 379Combinatorial Therapy and Targeting Multiple Pathways in HD ........ 379Cell Transplants .................................................................................... 380Neurotrophic Factors and Gene Therapy .............................................. 381RNAi Therapy for Huntington’s Disease .............................................. 382

References ................................................................................................. 382

10 Neuroprotection in Amyotrophic Lateral Sclerosis ............................. 385

Introduction ............................................................................................... 385Pathophysiology of ALS ........................................................................... 385

xviii Contents

Neuroprotective Therapies for ALS .......................................................... 388Activated Protein C ............................................................................... 389AEOL 10150 ......................................................................................... 390AIMSPRO ............................................................................................. 390Arimoclomol for ALS ........................................................................... 391Antisense Therapy ................................................................................ 391Creatine for ALS ................................................................................... 391Ceftriaxone for ALS ............................................................................. 392Coenzyme Q10 for ALS ....................................................................... 393COX-2 Inhibitors for ALS .................................................................... 393Dexpramipexole .................................................................................... 393Diallyl Trisulfide ................................................................................... 394Erythropoietin for ALS ......................................................................... 394Gene Therapy for ALS .......................................................................... 394Glatiramer Acetate ................................................................................ 395Insulin-Like Growth Factor................................................................... 396Ketogenic Diet for Neuroprotection in ALS ......................................... 396Lenalidomide ........................................................................................ 397Lithium for Neuroprotection in ALS .................................................... 398Methylcobalamin .................................................................................. 398Minocycline for ALS ............................................................................ 399Olesoxime as a Neuroprotective for ALS ............................................. 399ONO-2506 for ALS .............................................................................. 399Riluzole ................................................................................................. 400RNAi-Based Therapy for ALS.............................................................. 400Sodium Phenylbutyrate ......................................................................... 401Stem Cell Therapy ................................................................................ 401Talampanel ............................................................................................ 402Tamoxifen ............................................................................................. 402Vaccination for ALS Caused by SOD1 Mutations ............................... 402Vascular Endothelial Growth Factor for ALS ....................................... 403

Clinical Trials of Neuroprotective Therapies for ALS.............................. 403Concluding Remarks and Future Prospects .............................................. 406References ................................................................................................. 406

11 Neuroprotection in Miscellaneous Neurological Disorders ................. 409

Introduction ............................................................................................... 409Age-Related Dementia .............................................................................. 409

Enhancing Endogenous Neurotrophic Support of the Aging Brain ...... 410Pharmacological Approaches for Treatment of Age-Related Dementia .......................................................................... 410Physical Exercise to Prevent Decline of Mental Function with Aging ............................................................................. 412

Vascular Dementia .................................................................................... 412Prediction of Dementia in Persons with Vascular Risk Factors ............ 413

xixContents

Management of Subcortical Vascular Dementia ................................... 413Dementia with Lewy Bodies ..................................................................... 414Neuroprotection in AIDS Dementia ......................................................... 415Multiple System Atrophy .......................................................................... 416Epilepsy ..................................................................................................... 416

Mechanisms of Neuronal Damage in Epilepsy ..................................... 417Strategies for Neuroprotection in Epilepsy ........................................... 418Control of Seizures and Neuroprotection ............................................. 418Cell Therapy for Neuroprotection in Epilepsy ...................................... 420Gene Therapy for Neuroprotection in Epilepsy .................................... 422

Spinal and Bulbar Muscular Atrophy ....................................................... 423Multiple Sclerosis ..................................................................................... 423 Introduction ........................................................................................... 423

Epidemiology of Multiple Sclerosis ..................................................... 424Pathophysiology .................................................................................... 424Current Management of Multiple Sclerosis .......................................... 425Specific Therapies for MS Based on Pathomechanism ........................ 426Neuroprotection in Multiple Sclerosis .................................................. 426Clinical Trials of Neuroprotective Therapies for MS ........................... 427Neuroprotection by Control of Progressive Forms of Multiple Sclerosis ................................................................................. 428Neuroprotection by Controlling Autoimmune Inflammation in the Brain ............................................................................................ 428Remyelination for Neuroprotection in Multiple Sclerosis .................... 430Agents for Neuroprotection in Multiple Sclerosis ................................ 430

Neuroprotection in Transverse Myelitis.................................................... 444Neuroprotection in Decompression Sickness ........................................... 445Neuroprotection in Hydrocephalus ........................................................... 446

Neuroprotection in Normal Pressure Hydrocephalus ........................... 446Neuroprotection in Infections of the CNS ................................................ 447

Neuroprotection in Bacterial Meningitis .............................................. 447Neuroprotective Approach to Rabies .................................................... 448Neuroprotection in Cerebral Malaria .................................................... 449

Neuroprotection in Hypertensive Encephalopathy ................................... 449Neuroprotection in Toxic Encephalopathies ............................................. 450

Hepatic Encephalopathy ....................................................................... 450Encephalopathy Due to Organophosphorus Poisoning ......................... 451Neuroprotection Against Chemotherapy-Induced Brain Damage ........ 452Neuroprotection Against Alcohol ......................................................... 453

Neuroprotection in Hypoxia-Ischemia ...................................................... 455Neuroprotection in Neonatal Hypoxic-Ischemic Brain Injury .............. 455Neuroprotection in Carbon Monoxide Poisoning ................................. 457Syndrome of Delayed Post-hypoxic Leukoencephalopathy ................. 459

Neuroprotection in Sleep Apnea ............................................................... 460Neuroprotection in Hypoglycemic Coma ................................................. 461Neuroprotection in Mitochondrial Dysfunction ........................................ 462

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Mitochondrial Permeability Transition ................................................. 462Mitochondrial Approaches for Neuroprotection ................................... 463Methylene Blue ..................................................................................... 463Role of Nanolasers in Evaluation of Mitochondrial Neuroprotectants ................................................................................... 465Neuroprotection in Mitochondrial Encephalopathies ........................... 465

Schizophrenia ............................................................................................ 466Cognitive Impairment in Schizophrenia ............................................... 466Neuroprotection in Schizophrenia ........................................................ 466

Neuroprotection in Hearing Loss .............................................................. 467Causes of Hearing Loss ........................................................................ 467Pathomechanism of Hearing Loss ........................................................ 467Prevention and Treatment of Hearing Loss........................................... 468

Neuroprotection of Peripheral Nerves ...................................................... 471Neuroprotective Agents for Peripheral Nerves ..................................... 471Neuroprotection in Peripheral Nerve Injuries ....................................... 473Peripheral Neuropathy .......................................................................... 475Chronic Inflammatory Demyelinating Polyradiculoneuropathy .......... 477

References ................................................................................................. 478

12 Neuroprotection of the Optic Nerve and the Retina ............................ 485

Introduction ............................................................................................... 485Neuroprotection in Optic Neuropathy ...................................................... 485

Neuroprotection in Optic Neuritis ........................................................ 485Neuroprotection in Optic Nerve Trauma .................................................. 487

Potential Regeneration of the Optic Nerve ........................................... 487Subthreshold Transpupillary Thermotherapy for Protection of RGCs ............................................................................... 488

Neuroprotection of Optic Nerve in Glaucoma .......................................... 488Aminoguanidine as a Neuroprotective in Glaucoma ............................ 489Antiglutamate Agents for Neuroprotection of Optic Nerve.................. 490Betaxolol ............................................................................................... 491NGF Eye Drops ..................................................................................... 491Targeting Ab in Glaucoma Treatment .................................................. 492TNF-a Blockers for Neuroprotection in Glaucoma.............................. 492Concluding Remarks About Neuroprotection in Glaucoma ................. 492

Neuroprotection in Retinal Ischemia ........................................................ 493Endogenous Neuroprotection in the Retina .......................................... 493b-Adrenoceptor Antagonists ................................................................. 494Brimonidine as a Neuroprotective is Ischemic Retinopathy ................. 494Thioredoxin as a Neuroprotective Agent in Retinal Ischemia .............. 495Erythropoietin for Neuroprotection of Retinal Ischemia ...................... 495Gene therapy for Retinal Neuroprotection ............................................ 496Hyperbaric Oxygen for Central Retinal Artery Occlusion ................... 496

Protection Against Oxygen-Induced Retinopathy .................................... 496

xxiContents

Neuroprotection in Macular Degeneration ............................................... 497 Epidemiology ........................................................................................ 497

Pathomechanism of AMD ..................................................................... 497Current Treatment of AMD .................................................................. 497Novel Neuroprotective Strategies Against Retinal Degeneration ......... 499Antiangiogenic Agents .......................................................................... 499Protection of Retinal Cells from Oxidative Stress-Induced Apoptosis . 500Nutritional Protection Against AMD .................................................... 501Cell therapy for Macular Degeneration ................................................ 501Gene Therapy for Retinal Degeneration ............................................... 502RNAi-Based Treatments for AMD ....................................................... 503

Neuroprotection in Proliferative Diabetic Retinopathy ............................ 504Strategies for Neuroprotection in Diabetic Retinopathy ....................... 504RNAi-Based Approaches to Diabetic Retinopathy ............................... 505

Clinical Trials for Optic Nerve and Retinal Neuroprotection ................... 505References ................................................................................................. 507

13 Neuroprotection During Anesthesia and Surgery ................................ 509

Introduction ............................................................................................... 509Anesthetic Agents as Neuroprotectives .................................................... 509

Barbiturates ........................................................................................... 510Etomidate .............................................................................................. 511Propofol ................................................................................................. 512Ketamine ............................................................................................... 512Gaseous Anesthetics ............................................................................. 513Local Anesthetics .................................................................................. 514

Monitoring of CNS Function During Anesthesia and Surgery ................. 514 Monitoring of Cerebral Function .......................................................... 514

Monitoring of Spinal Cord Function During Spinal Surgery ............... 515Neuroprotection During Cardiovascular Procedures ................................ 516 CNS Complications of Cardiac Surgery ............................................... 516

Neuroprotective Strategies During Cardiac Surgery ............................. 516Surgery on the Aorta ............................................................................. 520

Spinal Cord Protection During Cardiovascular Surgery ........................... 521Cerebral Protection During Organ Transplantation Surgery..................... 521Cerebral Protection During Neurosurgery ................................................ 521

Cerebral Angiography and Endovascular Surgery ................................ 522Cerebral Protection During Surgery for Arteriovenous Malformations ....................................................................................... 522Cerebral Protection During Surgery of Intracranial Aneurysms .......... 522Management of Subarachnoid Hemorrhage ......................................... 523Cerebral Protection During Carotid Endarterectomy ........................... 525Neuroprotective Measures Prior to Surgery .......................................... 526Neuroprotection Following Surgery ..................................................... 527

References ................................................................................................. 527

xxii Contents

14 Future Prospects of Neuroprotective Therapies .................................. 529

Introduction ............................................................................................... 529Challenges in Neuroprotective Drug Development .................................. 529Promising Areas of Research in Neuroprotection .................................... 530

Autoreactive Antibodies ....................................................................... 530Biological Therapies for Neuroprotection ............................................ 531Multidisciplinary Approaches to Neuroprotection ............................... 531

Index ................................................................................................................. 533

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