Hot Topics in Neural Membrane Lipidology (eBook)

About the Author: Akhlaq A. Farooqui is a leader in the field of brain phospholipases A2, bioactive ether lipid metabolism, and glutamate-mediated neurotoxicity. He has discovered the stimulation of plasmalogen-selective phospholipase A2 activity in brains from patients with Alzheimer disease, and published cutting edge research on the generation and identification of glycerophospholipid, sphingolipid, and cholesterol-derived lipid mediators in kainic acid neurotoxicity. He has authored three monographs: Glycerophospholipids in Brain: Phospholipase A2 in Neurological Disorders (2007); Neurochemical Aspects of Excitotoxicity (2008); and Metabolism and Functions of Bioactive Ether Lipids in Brain (2008). All monographs are published by Springer, New York.

Preface 6
Acknowledgments 9
Contents 10
List of Abbreviations 18
About the Author 19
1 Neural Membranes: A Pandora’s Box of Lipid Mediators 20
1.1 Lipid Composition of Neural Membranes 20
1.2 Glycerophospholipids and Their Metabolism in Brain 22
1.3 Arachidonic Acid and Its Enzymically Derived Oxidation Products 23
1.3.1 Arachidonic Acid and Lyso-glycerophospholipids 24
1.3.2 Lysophosphatidylcholine (lyso-PtdCho) 24
1.3.3 Eicosanoids 27
1.3.4 Lipoxins 29
1.4 Non-enzymic Oxidation of Arachidonic Acid 29
1.4.1 4-Hydroxynonenal (4-HNE) 30
1.4.2 Isoprostanes 32
1.4.3 Isoketals 33
1.4.4 Isofurans 33
1.5 Enzymic and Non-enzymic Oxidation of DHA 34
1.5.1 Enzymically Derived Lipid Mediators of DHA 34
1.5.2 Resolvins 34
1.5.3 Protectins and Neuroprotectins 35
1.6 Non-enzymic Oxidation of Docosahexaenoic Acid 36
1.6.1 4-Hydroxyhexenal 37
1.6.2 Neuroprostanes 37
1.6.3 Neuroketals (NK) 38
1.7 Sphingolipid Metabolism in Brain 38
1.7.1 Ceramide and Ceramide 1-Phosphate 39
1.7.2 Sphingosine and Sphingosine 1-Phosphate 41
1.8 Cholesterol Metabolism in Brain 42
1.9 Association of Lipid Mediators with Neurological Disorders 44
1.10 Conclusion 44
References 45
2 Interplay Among Glycerophospholipid, Sphingolipid, and Cholesterol-Derived Lipid Mediators in Brain: A Matter of Life and Death 56
2.1 Introduction 56
2.2 Generation of Glycerophospholipid-Derived Lipid Mediators 57
2.3 Enzymically-Derived AA Metabolites and Neuroinflammation 57
2.4 Platelet-Activating Factor in Brain 64
2.5 Metabolism of Sphingolipid-Derived Lipid Mediators in Brain 65
2.6 Neurochemical Effects and Roles of Ceramides 69
2.7 Generation of Cholesterol-Derived Metabolites in Brain 70
2.8 Interactions Among Phospholipid, Sphingolipid, and Cholesterol-Derived Lipid Mediators 72
2.8.1 Interactions Between Glycerophospholipid and Sphingolipid Metabolism 72
2.8.2 Interactions Between Glycerophospholipid and Sphingolipid-Derived Lipid Mediators 73
2.8.3 Interactions Between Glycerophospholipid and Cholesterol-Derived Lipid Mediators 76
2.8.4 Interactions Between Sphingolipid and Cholesterol-Derived Lipid Mediators 77
2.9 Conclusion 79
References 80
3 Janus Face of Phospholipase A2: Role of Phospholipase A2 in Neural Cell Survival and Death 90
3.1 Introduction 90
3.2 Multiplicity of PLA2 in Brain Tissue 91
3.2.1 Cytosolic Phospholipase A2 (cPLA2) 91
3.2.2 Calcium Independent Phospholipase A2(iPLA2) 95
3.2.3 Secretory Phospholipase A2 (sPLA2) 98
3.2.4 Plasmalogen Selective Phospholipase A2 (PlsEtn-PLA2) 99
3.3 Role of Multiple Forms of PLA2 in Brain 100
3.3.1 Multiple Forms of PLA2 and Neurotransmitter Release 100
3.3.2 Multiple Forms of PLA2 in Long-Term Potentiation and Long-Term Depression 102
3.3.3 Multiple Forms of PLA2 in Membrane Repair 104
3.3.4 Multiple Forms of PLA2 in Modulation of Neurite Outgrowth and Regeneration 105
3.3.5 Multiple Forms of PLA2 in Tubule Formation and Membrane Trafficking 106
3.3.6 Multiple Forms of PLA2 in the Cell Cycle 107
3.3.7 Multiple Forms of PLA2 in Neuroinflammation 108
3.3.8 Multiple Forms of PLA2 in Nociception and Vacuous Chewing Movements 110
3.3.9 Multiple Forms of PLA2 in Oxidative Stress 111
3.3.10 Multiple Forms of PLA2 in Apoptotic and Necrotic Cell Death 112
3.3.11 Multiple Forms of PLA2 in Chemotaxis 114
3.4 Regulation of Multiple Forms of PLA2 Activity in Brain 115
3.4.1 Regulation of cPLA2 115
3.4.2 Regulation of iPLA2 116
3.4.3 Regulation of sPLA2 117
3.5 Conclusion 117
References 118
4 Glycerophospholipid Metabolism in the Nucleus: Cross Talk Among Phospholipase A2, Phospholipase C and Phospholipase D 130
4.1 Introduction 130
4.2 Phospholipid Metabolism in the Nucleus 132
4.3 Importance of Phospholipases and Glycerophospholipid Metabolism in the Nucleus 133
4.4 Occurrence of Isoforms of Phospholipase A2, Phospholipase C, and Phospholipase D in Nucleus 135
4.4.1 PLA2 Activities in the Nucleus 137
4.4.2 Nuclear PLC Activities 144
4.4.3 Nuclear PLD Activities 148
4.5 Interplay Among Nuclear and Non-Nuclear PLA2, PLC, and PLD Activities 149
4.6 Nuclear PLA2, PLC, and PLD and Nuclear Inclusions in Neurological Disorders 150
4.7 Conclusion 151
References 152
5 Ether Glycerophospholipids: The Workhorse Lipids of Neural Membranes 160
5.1 Introduction 160
5.2 Plasmalogens in Brain 162
5.3 Biosynthesis of Plasmalogens 162
5.4 Degradation of Plasmalogens 164
5.4.1 Plasmalogen-Selective Phospholipase A2 (PlsEtn-PLA2) 164
5.4.2 Receptor-Mediated Degradation of Plasmalogens 166
5.5 Roles of Plasmalogens in Brain 168
5.6 Platelet-Activating Factor (PAF) 170
5.7 Biosynthesis of PAF 170
5.7.1 Remodeling Pathway 171
5.7.2 De Novo Synthesis of PAF 172
5.7.3 Oxidative Fragmentation Pathway for PAF Synthesis 172
5.8 Catabolism of PAF 172
5.8.1 Mammalian Brain Type I PAF-Acetyl Hydrolases 173
5.8.2 Type II PAF-Acetyl Hydrolases in Mammalian Tissues 174
5.8.3 PAF-Acetyl Hydrolases in Mammalian Plasma 174
5.9 Roles of PAF in Brain 175
5.10 Involvement of Plasmalogens in Neurological Disorders 177
5.10.1 Plasmalogens in Ischemic Injury 178
5.10.2 Plasmalogens in Alzheimer Disease 178
5.10.3 Plasmalogens in Spinal Cord Injury 178
5.10.4 Plasmalogens in Peroxisomal Disorders 179
5.11 Involvement of Platelet-Activating Factor in Neurological Disorders 179
5.12 Conclusion 180
References 181
6 Excitotoxicity-Mediated Neurochemical Changes in Neurological Disorders 192
6.1 Introduction 192
6.2 Glutamate-Mediated Neurochemical Changes in Brain 193
6.2.1 Glutamate-Mediated Changes in Arachidonic Acid and Lysophosphatidylcholine Metabolism 193
6.2.2 Glutamate-Mediated Changes in Platelet-Activating Factor Metabolism 197
6.2.3 Glutamate-Mediated Alterations in Eicosanoid Metabolism 198
6.2.4 Glutamate-Mediated Generation of Reactive Oxygen Species 199
6.2.5 Glutamate-Mediated Depletion of Reduced Glutathione 199
6.2.6 Glutamate-Mediated Alterations in Nuclear Transcription Factor kappaB (NF-kappaB) 200
6.2.7 Glutamate-Mediated Changes in Enzymic Activities 201
6.2.8 Glutamate-Mediated Expression of Cytokines 204
6.2.9 Glutamate-Mediated Changes in Growth Factors 205
6.2.10 Glutamate-Mediated Changes in Heat Shock Protein Expression 206
6.2.11 Glutamate-Mediated Upregulation of Genes 207
6.2.12 Glutamate and Apoptotic Neural Cell Death 208
6.3 Mechanism of Glutamate-Mediated Neural Cell Injury in Neurological Disorders 208
6.4 Involvement of Excitotoxicity in Neurological Disorders 210
6.4.1 Glutamate in Ischemic Injury 211
6.4.2 Glutamate in Spinal Cord Injury 212
6.4.3 Glutamate in Head Injury 212
6.4.4 Glutamate in Epilepsy 213
6.4.5 Glutamate in Alzheimer Disease 213
6.4.6 Glutamate in Amyotrophic Lateral Sclerosis (ALS) 214
6.4.7 Glutamate in Huntington Disease 215
6.4.8 Glutamate in AIDS Dementia Complex 216
6.4.9 Glutamate in Creutzfeldt-Jakob Disease (CJD) 217
6.4.10 Glutamate in Multiple Sclerosis (MS) 218
6.4.11 Domoic Acid Neurotoxicity 219
6.5 Conclusion 220
References 220
7 Recent Developments on Kainate-Mediated Neurotoxicity and Their Association with Generation of Lipid Mediators 233
7.1 Introduction 233
7.2 KA Receptor-Mediated Ion Fluxes in Neural Cells 234
7.3 KA-Mediated Alterations in Neural Membrane Glycerophospholipids 237
7.4 KA-Mediated Alterations in Sphingolipid Metabolism 242
7.5 Cholesterol Metabolism in Brain 245
7.5.1 KA-Mediated Changes in Cholesterol and Its Metabolites 245
7.5.2 KA-Mediated Alterations in Oxycholesterols 247
7.5.3 KA-Mediated Changes in Steroid Hormones 248
7.6 Consequences of Interactions Among Glycerophospholipid, Sphingolipid, and Cholesterol-Derived Lipid Mediators in KA-Mediated Neurotoxicity 250
7.7 Interactions Between Ceramide and Cholesterol Metabolism in KA-Mediated Toxicity 252
7.8 Interactions Between Glycerophospholipid and Cholesterol Metabolism in KA-Mediated Neurotoxicity 253
7.9 Conclusion 254
References 254
8 Beneficial Effects of Docosahexaenoic Acid on Health of the Human Brain 260
8.1 Introduction 260
8.2 Synthesis of DHA in Brain 262
8.3 Transport and Incorporation of Docosahexaenoic Acid in Brain 263
8.4 Release and Catabolism of DHA in Brain 264
8.5 Role of DHA in Brain Tissue 268
8.5.1 Modulation of Gene Expression by DHA 270
8.5.2 Modulation of Enzymic Activities by DHA 271
8.5.3 Modulation of Inflammation and Immunity by DHA 271
8.5.4 Modulation of Learning and Memory by DHA 272
8.5.5 Modulation of Apoptotic Cell Death by DHA 273
8.5.6 DHA and Generation of Docosanoids 274
8.5.7 DHA and Neurite Outgrowth 274
8.5.8 DHA in Visual Function 275
8.5.9 DHA in Nociception (Pain) 276
8.6 Alterations in DHA Levels in Aging and Neurological Disorders 277
8.6.1 DHA Levels in Normal Aging Brain 277
8.6.2 DHA Levels in Neurological Disorders 278
8.6.3 Dietary DHA and Cancer 280
8.7 The Adverse Effects of DHA 282
8.8 Conclusion 283
References 284
9 Effects of Statins and n-3 Fatty Acids on Heart and Brain Tissues: The Clash of the Titans 294
9.1 Introduction 294
9.2 Properties, Metabolic Sites and Mechanism of Action of Statins 295
9.3 Composition of Fish Oil and Its Importance in Human Nutrition 300
9.4 Biochemical Effects of Statins on Cardiovascular System 302
9.5 Biochemical Effects of Statins on Brain 306
9.5.1 Cholesterol-Independent Effects of Statins 307
9.5.2 Cholesterol-Dependent Effects of Statins 309
9.6 Biochemical Effects of Fish Oil on Heart 311
9.7 Biochemical Effects of Fish Oil on Brain 313
9.8 Therapeutic Value of Statins and DHA in Cardiovascular and Cerebrovascular Systems Disorders 314
9.8.1 Statins in Cardiovascular System 314
9.8.2 Stains in Cerebrovascular System 315
9.8.3 n-3 Fatty Acids in Cardiovascular System 319
9.8.4 n-3 Fatty Acids in Cerebrovascular System 319
9.9 Effects of Combination of Statin and Fish Oil in Cardiovascular and Neurological Disorders 321
9.10 Adverse Effects of Statins and n-3 Fatty Acids 322
9.11 Conclusions 323
References 324
10 Apoptosis and Necrosis in Brain: Contribution of Glycerophospholipid, Sphingolipid, and Cholesterol-Derived Lipid Mediators 336
10.1 Introduction 336
10.2 Apoptosis and Necrosis Death in Brain 338
10.2.1 Mechanisms Associated with the Activation of Caspases 339
10.2.2 Biochemical Changes Associated with Apoptosis 343
10.2.3 Biochemical Changes Associated with Necrosis 344
10.3 Apoptosis and Necrosis-Mediated Alterations in Glycerophospholipid, Sphingolipid, and Cholesterol Metabolism 345
10.3.1 Apoptosis and Necrosis-Mediated Changes in Glycerophospholipid Metabolism 347
10.3.2 Apoptosis and Necrosis-Mediated Changes in Sphingolipid Metabolism 351
10.3.3 Apoptosis and Necrosis-Mediated Changes in Cholesterol Metabolism 353
10.4 Interactions Among Glycerophospholipid, Sphingolipid, and Cholesterol Metabolism in Apoptosis and Necrosis 354
10.5 Apoptotic and Necrotic Cell Death in Neurological Disorders 356
10.6 Association of Mitochondrial Dysfunction with Apoptotic and Necrotic Cell Death in Neurological Disorders 358
10.7 Prevention of Apoptotic Cell Death by Inhibitors of Enzymes Associated with Exicitoxicity, Inflammation, and Oxidative Stress 360
10.7.1 Glutamate Receptor Antagonists 361
10.7.2 Antioxidants and Anti-inflammatory Agents 363
10.7.3 Prevention of Apoptosis by Inhibitors of Caspases, Calpains, PLA2, Nitric Oxide Synthase, and SMase 364
10.8 Conclusion 368
References 369
11 Perspective and Directions for Future Developments on Glycerophospholipid-, Sphingolipid-, and Cholesterol-Derived Lipid Mediators 382
11.1 Introduction 382
11.2 Association of Lipid Mediators with Neural Cell Death 384
11.3 Detection and Levels of Lipid Mediators in Neurological Disorders by Lipidomics 387
11.4 Detection of Lipid Mediators by Positron Emission Tomography 388
11.5 Proteomics, Enzymes of Lipid Metabolism, and Neurodegenerative Diseases 390
11.6 Antisense and RNAi as Neuroprotective Agents 391
11.7 Significance of Developing Early Detection Procedures and Treatment for Neurodegenerative Diseases 392
11.8 Conclusion 393
References 394
Index 400