Neurochemical Aspects of Excitotoxicity (eBook)

Note 5
Preface 6
Acknowledgments 9
Contents 10
1 Glutamate and Aspartate in Brain 15
Introduction 15
Glutamate Synthesis and Release in Brain 16
Glutamate-Related Metabolic Interactions Between Neurons and Glial Cells 20
Roles of Glutamate in Brain 22
Glutamate and Intermediary Energy Metabolism 23
Glutamate as a Putative Neurotransmitter 24
Glutamate as a Metabolic Precursor of GABA 24
Glutamate and Detoxification of Ammonia 25
Glutamate as a Constituent of Proteins 26
Glutamate as a Constituent of Small Peptides 26
Glutamate and Intracellular Osmotic and Ionic Homeostasis 27
Glutamate in Learning and Memory 27
Aspartate Metabolism in Brain 28
References 31
2 Excitatory Amino Acid Receptors in Brain 35
Ionotropic Receptors 36
NMDA Receptors 36
NMDA Receptor Agonists and Antagonists 39
Kainic Acid Receptors 39
Agonists and Antagonists of KAR 40
AMPA Receptors 42
Agonists and Antagonists of AMPA Receptors 42
Metabotropic Glutamate Receptors 43
Glutamate Receptors and Glutamate-Mediated Neural Cell Death 45
References 46
3 Multiplicity of Glutamate Receptors in Brain 50
Structure and Distribution of NMDA Receptor Subunits in Brain 50
Structure and Distribution of KA Receptor Subunits in Brain 53
Structure and Distribution of AMPA Receptor Subunits in Brain 56
Structure and Distribution of Metabotropic Glutamate Receptor Subunits in Brain 59
References 60
4 Glutamate Transporters and Their Role in Brain 63
Astrocytic Glutamate Transporters 64
Neuronal Glutamate Transporters 70
EAAT3 in Brain 70
EAAT4 in Brain 72
EAAT5 in Brain 73
Vesicular Glutamate Transporters 74
Glutamate Transporters in Neurological Disorders 76
Conclusions 79
References 80
5 Excitatory Amino Acid Receptors and Their Association with Neural Membrane Glycerophospholipid Metabolism 87
Effects of Glutamate on Glycerophospholipid Synthesis 89
Effects of Glutamate on Glycerophospholipid Degradation 90
Physiological and Pathophysiological Effects of Released AA in Brain 100
Physiological Effects of AA 100
Pathophysiological Effects of AA 101
Physiological and Pathophysiological Effects of Lyso-Glycerophospholipids 102
Physiological Effects of Lyso-Glycerophospholipids 102
Pathophysiological Effects of Lyso-Glycerophospholipids 103
Physiological and Pathophysiological Effects of PAF 104
Physiological Effects of PAF 104
Pathophysiological Effects of PAF 105
Physiological and Pathophysiological Effects of Eicosanoids 106
Neurotrophic Effects 106
Pathophysiological Effects of Eicosanoids 107
Neuroprotective Effects of NMDA Receptors 108
References 109
6 Glutamate Receptors and Their Association with Other Neurochemical Parameters in Excitotoxicity 116
Glutamate Toxicity and Production of Free Radicals and Lipid Peroxides 117
Glutathione Levels in Neurotoxicity Mediated by Glutamate 118
4-Hydroxynonenal Generation in Neurotoxicity Mediated by Glutamate 120
NF-B in Glutamate Neurotoxicity 122
Protein Kinase C in Neurotoxicity Mediated by Glutamate 123
Ornithine Decarboxylase and Polyamines in Neurotoxicity Mediated by Glutamate 125
MAP Kinases in Neurotoxicity Mediated by Glutamate 126
Nitric Oxide Synthase in Neurotoxicity Mediated by Glutamate 126
Expression of Apolipoproteins D and E in Neurotoxicity Mediated by Glutamate 127
Growth Factor Expression in Neurotoxicity Mediated by Glutamate 129
Cytokine Expression in Neurotoxicity Mediated by Glutamate 130
Regulation of NMDA and GABA Receptors in Neurotoxicity Mediated by Glutamate 131
Heat Shock Protein Expression in Neurotoxicity Mediated by Glutamate 133
Cholesterol and Its Oxidation Products in Neurotoxicity Mediated by KA 135
Ceramide in Neurotoxicity Mediated by KA 136
Uptake of Toxic Divalent Metal Ions in Neurotoxicity Induced by Kainate 138
Other Neurochemical Changes in Neurotoxicity Mediated by Glutamate 139
References 140
7 Possible Mechanisms of Neural Injury Caused by Glutamate and Its Receptors 148
Excitotoxicity 148
Glutamate-Mediated Inflammation and Neural Cell Injury 150
Glutamate-Mediated Oxidative Stress in Brain 157
Glutamate-Mediated Energy Status of Degenerating Neurons 161
Glutamate-Mediated Alterations in Cellular Redox Status 162
Glutamate-Mediated Alterations in Gene Expression 163
References 165
8 Glutamate Receptors and Neurological Disorders 172
Glutamate in Ischemic Injury 173
Glutamate in Spinal Cord Injury 176
Glutamate in Head Injury 178
Glutamate in Epilepsy 180
Glutamate in Alzheimer Disease 181
Glutamate in Amyotrophic Lateral Sclerosis (ALS) 183
Glutamate in Huntington Disease 185
Glutamate in AIDS Dementia Complex 187
Glutamate in Creutzfeldt-Jakob Disease (CJD) 189
Glutamate in Parkinson Disease 191
Guam-Type Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia 192
Glutamate in Multiple Sclerosis (MS) 193
Domoic Acid Neurotoxicity 195
Glutamate in Schizophrenia 196
Mechanism of Glutamate-Mediated Neural Cell Injury in Neurological Disorders 198
Conclusion 199
References 200
9 Endogenous Antioxidant Mechanisms and Glutamate Neurotoxicity 215
Introduction 215
Effects of Oxidative Stress on Neural Cell Membrane Components 216
Brain Oxidant and Antioxidant Proteins in Glutamate-Mediated Neurotoxicity 219
Multiple Forms of PLA2, COX, LOX in Glutamate Neurotoxicity 219
Superoxide Dismutase in Glutamate Neurotoxicity 221
Catalase and Glutathione Peroxidase in Glutamate Neurotoxicity 222
Heme Oxygenase in Glutamate Neurotoxicity 223
Ferritin in Glutamate Neurotoxicity 223
Apolipoprotein D in Glutamate Neurotoxicity 225
Low Molecular Weight Endogenous Antioxidants in Glutamate Neurotoxicity 228
Plasmalogens and Glutamate Neurotoxicity 228
Gangliosides and Glutamate Neurotoxicity 230
Vitamins C and E and Glutamate Neurotoxicity 231
Melatonin and Glutamate Neurotoxicity 233
Glutathione and Glutamate Neurotoxicity 234
Lipoic Acid and Glutamate Neurotoxicity 234
Antioxidant Coenzyme Q10 and Glutamate Neurotoxicity 235
Antioxidants and Clinical Trials in Ischemic Injury 236
Antioxidant Strategies and Therapeutic Aspects of Neurodegenerative Diseases 237
References 238
10 Glutamate Receptor Antagonists and the Treatment of Neurological Disorders 251
NMDA Antagonists for the Treatment of Neurological Disorders 251
NMDA Antagonists for the Treatment of Ischemic Injury 255
Selfotel (CGS 19755) 255
Dextrorphan 256
Aptiganel (Cerestat) 256
Gavestinel 257
Ifenprodil and Eliprodil 257
YM872 258
NMDA Antagonists for the Treatment of Alzheimer Disease 259
NMDA Receptor Antagonists for the Treatment of Huntington Disease 262
NMDA Antagonists for the Treatment of Epilepsy 262
NMDA Antagonists for the Treatment of Head Injury 263
NMDA Receptor Antagonists for the Treatment of Chronic Pain 263
Conclusion 264
References 265
11 Future Perspectives: New Strategies for Antagonism of Excitotoxicity, Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases 271
Sources and Mechanism of Glutamate Release 272
Interplay Among Excitotoxicity, Oxidative Stress, and Neuroinflammation 273
NMDA Receptor Antagonists, Antioxidants, and Anti-Inflammatory 277
n-3 Fatty Acids as Anti-Excitotoxic, Antioxidant, and Anti-Inflammatory Agents 278
References 282
Index 290