Neurochemical Aspects of Excitotoxicity

Glutamate and Aspartate in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.2 Glutamate Synthesis and Release in Brain . . . . . . . . . . . . . . . . . . . . . . 2 1.3 Glutamate-Related Metabolic Interactions Between Neurons and Glial Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 1.4 Roles of Glutamate in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 1.4.1 Glutamate and Intermediary EnergyMetabolism . . . . . . . . . . 9 1.4.2 Glutamate as a Putative Neurotransmitter . . . . . . . . . . . . . . . . . 10 1.4.3 Glutamate as aMetabolic Precursor of GABA . . . . . . . . . . . . 10 1.4.4 Glutamate and Detoxification of Ammonia . . . . . . . . . . . . . . . 11 1.4.5 Glutamate as a Constituent of Proteins . . . . . . . . . . . . . . . . . . . 12 1.4.6 Glutamate as a Constituent of Small Peptides . . . . . . . . . . . . . 12 1.4.7 Glutamate and Intracellular Osmotic and Ionic Homeostasis . 13 1.4.8 Glutamate in Learning andMemory . . . . . . . . . . . . . . . . . . . . . 13 1.5 AspartateMetabolismin Brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 2 Excitatory Amino Acid Receptors in Brain . . . . . . . . . . . . . . . . . . . . . . . . . 21 2.1 Ionotropic Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 2.1.1 NMDA Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 2.1.2 NMDA Receptor Agonists and Antagonists . . . . . . . . . . . . . . . 25 2.1.3 Kainic Acid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25 2.1.4 Agonists and Antagonists of KAR. . . . . . . . . . . . . . . . . . . . . . . 26 2.1.5 AMPA Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 2.1.6 Agonists and Antagonists of AMPA Receptors . . . . . . . . . . . . 28 2.2 Metabotropic Glutamate Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.3 Glutamate Receptors and Glutamate-Mediated Neural Cell Death . . 31 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 3 Multiplicity of Glutamate Receptors in Brain . . . . . . . . . . . . . . . . . . . . . . . 37 3.1 Structure and Distribution of NMDA Receptor Subunits in Brain . . . 37 3.2 Structure and Distribution of KA Receptor Subunits in Brain . . . . . . 40 xiii xiv Contents 3.3 Structure and Distribution of AMPA Receptor Subunits in Brain . . . 43 3.4 Structure and Distribution of Metabotropic Glutamate Receptor Subunits in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 4 Glutamate Transporters and Their Role in Brain . . . . . . . . . . . . . . . . . . . 51 4.1 AstrocyticGlutamate Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 4.2 Neuronal Glutamate Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 4.2.1 EAAT3 in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 4.2.2 EAAT4 in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 4.2.3 EAAT5 in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61 4.3 VesicularGlutamate Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62 4.4 Glutamate Transporters in NeurologicalDisorders . . . . . . . . . . . . . . . 64 4.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68 5 Excitatory Amino Acid Receptors and Their Association with Neural Membrane Glycerophospholipid Metabolism . . . . . . . . . . . . . . . . . . . . . 75 5.1 Effects of Glutamate on Glycerophospholipid Synthesis . . . . . . . . . . 77 5.2 Effects of Glutamate on Glycerophospholipid Degradation . . . . . . . . 78 5.3 Physiological and Pathophysiological Effects of Released AA in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 5.3.1 Physiological Effects ofAA. . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 5.3.2 Pathophysiological Effects of AA . . . . . . . . . . . . . . . . . . . . . . . 89 5.4 Physiological and Pathophysiological Effects of Lyso- Glycerophospholipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90 5.4.1 Physiological Effects of Lyso-Glycerophospholipids . . . . . . . 90 5.4.2 Pathophysiological Effects of Lyso-Glycerophospholipids . . . 91 5.5 Physiological and Pathophysiological Effects of PAF . . . . . . . . . . . . . 92 5.5.1 Physiological Effects of PAF . . . . . . . . . . . . . . . . . . . . . . . . . . . 92 5.5.2 Pathophysiological Effects of PAF . . . . . . . . . . . . . . . . . . . . . . 93 5.6 Physiological and Pathophysiological Effects of Eicosanoids . . . . . . 94 5.6.1 Neurotrophic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94 5.6.2 Pathophysiological Effects of Eicosanoids . . . . . . . . . . . . . . . . 95 5.7 Neuroprotective Effects of NMDA Receptors . . . . . . . . . . . . . . . . . . . 96 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 6 Glutamate Receptors and Their Association with Other Neurochemical Parameters in Excitotoxicity . . . . . . . . . . . . . . . . . . . . . . 105 6.1 Glutamate Toxicity and Production of Free Radicals and Lipid Peroxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 6.2 Glutathione Levels in NeurotoxicityMediated by Glutamate . . . . . . . 107 6.3 4-Hydroxynonenal Generation in Neurotoxicity Mediated byGlutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109 6.4 NF-κB in Glutamate Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111 6.5 ProteinKinase C in NeurotoxicityMediated by Glutamate . . . . . . . . 112 Contents xv 6.6 Ornithine Decarboxylase and Polyamines in Neurotoxicity Mediated by Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 6.7 MAP Kinases in NeurotoxicityMediated by Glutamate . . . . . . . . . . . 115 6.8 Nitric Oxide Synthase in Neurotoxicity Mediated by Glutamate . . . . 115 6.9 Expression of Apolipoproteins D and E in Neurotoxicity Mediated byGlutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 6.10 Growth Factor Expression in Neurotoxicity Mediated by Glutamate 118 6.11 Cytokine Expression in NeurotoxicityMediated by Glutamate . . . . . 119 6.12 Regulation of NMDA and GABA Receptors in Neurotoxicity Mediated by Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120 6.13 Heat Shock Protein Expression in Neurotoxicity Mediated by Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122 6.14 Cholesterol and Its Oxidation Products in Neurotoxicity Mediated byKA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 6.15 Ceramide in NeurotoxicityMediated by KA . . . . . . . . . . . . . . . . . . . . 125 6.16 Uptake of Toxic Divalent Metal Ions in Neurotoxicity Induced by Kainate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 6.17 Other Neurochemical Changes in Neurotoxicity Mediated by Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 7 Possible Mechanisms of Neural Injury Caused by Glutamate and Its Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 7.1 Excitotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 7.2 Glutamate-Mediated Inflammation andNeural Cell Injury. . . . . . . . . 139 7.3 Glutamate-MediatedOxidative Stress in Brain . . . . . . . . . . . . . . . . . . 146 7.4 Glutamate-Mediated Energy Status of Degenerating Neurons . . . . . . 150 7.5 Glutamate-MediatedAlterations in Cellular Redox Status . . . . . . . . . 151 7.6 Glutamate-MediatedAlterations in Gene Expression . . . . . . . . . . . . . 152 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154 8 Glutamate Receptors and Neurological Disorders . . . . . . . . . . . . . . . . . . . 161 8.1 Glutamate in Ischemic Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 162 8.2 Glutamate in Spinal Cord Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165 8.3 Glutamate in Head Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167 8.4 Glutamate in Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 8.5 Glutamate in AlzheimerDisease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 170 8.6 Glutamate in Amyotrophic Lateral Sclerosis (ALS) . . . . . . . . . . . . . . 172 8.7 Glutamate in HuntingtonDisease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 174 8.8 Glutamate in AIDS Dementia Complex . . . . . . . . . . . . . . . . . . . . . . . . 176 8.9 Glutamate in Creutzfeldt-JakobDisease (CJD) . . . . . . . . . . . . . . . . . . 178 8.10 Glutamate in ParkinsonDisease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 8.11 Guam-Type Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia 181 8.12 Glutamate in Multiple Sclerosis (MS) . . . . . . . . . . . . . . . . . . . . . . . . . . 182 8.13 DomoicAcid Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 8.14 Glutamate in Schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185 xvi Contents 8.15 Mechanism of Glutamate-Mediated Neural Cell Injury in NeurologicalDisorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 8.16 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 188 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 189 9 Endogenous Antioxidant Mechanisms and Glutamate Neurotoxicity . . 205 9.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 9.2 Effects of Oxidative Stress on Neural Cell Membrane Components . 206 9.3 Brain Oxidant and Antioxidant Proteins in Glutamate-Mediated Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 9.3.1 Multiple Forms of PLA2, COX, LOX in Glutamate Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 9.3.2 SuperoxideDismutase in Glutamate Neurotoxicity. . . . . . . . . 211 9.3.3 Catalase and Glutathione Peroxidase in Glutamate Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212 9.3.4 Heme Oxygenase in Glutamate Neurotoxicity . . . . . . . . . . . . . 213 9.3.5 Ferritin in Glutamate Neurotoxicity . . . . . . . . . . . . . . . . . . . . . 213 9.3.6 Apolipoprotein D in Glutamate Neurotoxicity . . . . . . . . . . . . . 215 9.4 Low Molecular Weight Endogenous Antioxidants in Glutamate Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 218 9.4.1 Plasmalogens andGlutamate Neurotoxicity . . . . . . . . . . . . . . . 218 9.4.2 Gangliosides andGlutamate Neurotoxicity . . . . . . . . . . . . . . . 220 9.4.3 Vitamins C and E andGlutamate Neurotoxicity . . . . . . . . . . . 221 9.4.4 Melatonin and Glutamate Neurotoxicity. . . . . . . . . . . . . . . . . . 223 9.4.5 Glutathione and GlutamateNeurotoxicity . . . . . . . . . . . . . . . . 224 9.4.6 Lipoic Acid and GlutamateNeurotoxicity . . . . . . . . . . . . . . . . 224 9.4.7 Antioxidant Coenzyme Q10 and Glutamate Neurotoxicity . . . 225 9.5 Antioxidants and Clinical Trials in Ischemic Injury . . . . . . . . . . . . . . 226 9.6 Antioxidant Strategies and Therapeutic Aspects of NeurodegenerativeDiseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 227 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 228 10 Glutamate Receptor Antagonists and the Treatment of Neurological Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 10.1 NMDA Antagonists for the Treatment of Neurological Disorders . . . 241 10.2 NMDA Antagonists for the Treatment of Ischemic Injury . . . . . . . . . 245 10.2.1 Selfotel (CGS 19755) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 10.2.2 Dextrorphan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 10.2.3 Aptiganel (Cerestat) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 246 10.2.4 Gavestinel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 10.2.5 Ifenprodil and Eliprodil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247 10.2.6 YM872 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 248 10.3 NMDA Antagonists for the Treatment of Alzheimer Disease . . . . . . . 249 10.4 NMDA Receptor Antagonists for the Treatment of Huntington Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 10.5 NMDA Antagonists for the Treatment of Epilepsy . . . . . . . . . . . . . . . 252 Contents xvii 10.6 NMDA Antagonists for the Treatment of Head Injury . . . . . . . . . . . . 253 10.7 NMDA Receptor Antagonists for the Treatment of Chronic Pain . . . 253 10.8 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 255 11 Future Perspectives: New Strategies for Antagonism of Excitotoxicity, Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261 11.1 Sources andMechanismof Glutamate Release . . . . . . . . . . . . . . . . . . 262 11.2 Interplay Among Excitotoxicity, Oxidative Stress, and Neuroinflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 11.3 NMDA Receptor Antagonists, Antioxidants, and Anti-Inflammatory 267 11.4 n-3 Fatty Acids as Anti-Excitotoxic, Antioxidant, and Anti- InflammatoryAgents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 272 Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 281