Contents
1 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
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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
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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
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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
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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