Acute Neuronal Injury (eBook)

Dr. Denson Fujikawa is an Adjunct Professor of Neurology at the David Geffen School of Medicine at UCLA, a member of the Brain Research Institute at UCLA and a Staff Neurologist at the Department of Veterans Affairs Greater Los Angeles Healthcare System. His interest in mechanisms of nerve cell death in the brain began during a two-year epilepsy research fellowship with Dr. Claude Wasterlain, from 1981 to 1983. He is a Fellow of the American Academy of Neurology and is a member of the American Epilepsy Society, American Neurological Association, International Society for Cerebral Blood Flow and Metabolism and the Society for Neuroscience.

Contents 6
Introduction 11
References 13
Contributors 8
Chapter 2 18
Caspase-Independent Cell Death Mechanisms in Simple Animal Models 18
2.1 Introduction 18
2.2 Advantages of Invertebrate Model Organisms 21
2.3 Cell Death by Mitotic Catastrophe 23
2.4 Autophagic Cell Death 27
2.5 Necrotic Cell Death 30
2.6 Novel Programs of Caspase-Independent Cell Death 33
2.7 Concluding Remarks 34
References 35
Chapter 3 43
Programmed Necrosis: A “New” Cell Death Outcome for Injured Adult Neurons? 43
3.1 Cell Death Outcomes: General Considerations 43
3.2 Programmed Necrosis 47
3.2.1 General Considerations 47
3.2.2 Definition 47
3.2.3 Effectors of Programmed Necrosis 48
3.2.3.1 AIF 49
3.2.3.2 Bax 50
3.2.3.3 Calpains 53
3.2.3.4 PARP-1 54
3.2.4 Mechanism of Programmed Necrosis Induction 55
3.2.4.1 Decreased ATP Production/Energy Failure 55
3.2.4.2 Increase in Intracellular Ca2+ Concentration 56
3.2.4.3 DNA Damage 57
3.3 Neuronal Death Outcomes 58
3.3.1 General Considerations 58
3.4 AIF-Dependent Alternative PCD Phenotypes in Neurons 59
3.4.1 Apoptosis-Like PCD 59
3.4.2 Necrotic PCDs 60
3.5 Excitotoxic Neuronal Death and Programmed Necrosis in Acute Injuries 61
3.5 Conclusion 64
References 65
Chapter 4 75
Age-Dependence of Neuronal Apoptosis and of Caspase Activation 75
4.1 Morphological Classification of Cell Death 75
4.2 Programmed Cell Death 76
4.2.1 Caspase-Dependent Programmed Cell Death 77
4.2.2 Caspase-Independent Programmed Cell Death 79
References 83
Chapter 5 86
Excitotoxic Programmed Cell Death Involves Caspase-Independent Mechanisms 86
.1 Introduction 86
5.2 Excitotoxicity 87
5.3 Role of PARP-1 and PAR Polymer in Excitotoxicity 87
5.4 Role of PARG in Excitotoxicity and PAR-Mediated Cell Death 90
5.5 Mitochondria in PAR-Induced Cell Death: Role of AIF 92
5.6 Conclusion 93
References 93
Chapter 6 97
Significant Role of Apoptosis-Inducing Factor (AIF) for Brain Damage Following Focal Cerebral Ischemia 97
6.1 Introduction 97
6.2 Mechanisms of Delayed Cell Death Following Focal Cerebral Ischemia 98
References 105
Chapter 7 108
The Role of Poly(ADP-Ribose) Polymerase-1 (PARP-1) Activation in Focal Cerebral Ischemia 108
7.1 PARP-1 and Poly(ADP-ribosyl)ation 108
7.2 PARP-1 in the Pathobiology of Ischemic Stroke 109
7.3 Molecular Mechanism of PARP-1 Activation-Induced Cell Death 110
7.3.1 PARP-1 Activation-Induced Energy Failure: The Suicide Hypothesis 110
7.3.2 PARP-1 Induced Changes in Gene Expression: The Transcriptional Hypothesis 112
7.3.3 PARP-1 Activation of Neuronal Death: The Signaling Hypothesis 114
7.4 Suppression of Par Neo-Synthesis and Its Effects on Ischemic Brain Injury 115
7.5 Future Perspectives 117
Bibliography 118
Chapter 8 125
Transient Global Cerebral Ischemia Produces Morphologically Necrotic, Not Apoptotic Neurons 125
8.1 Introduction 125
8.2 Animal Models of Global Ischemia 126
8.3 Cell Death Modes 127
8.4 Morphological Features of Ischemic Neuronal Death 128
8.5 Summary, Limitations and Future Directions 131
References 132
Chapter 9 135
Apoptosis-Inducing Factor Translocation to Nuclei After Transient Global Ischemia 135
9.1 Introduction 135
9.1.1 Physiological Functions of AIF 137
9.2 AIF Translocation Mechanism and Therapeutic Targets 138
9.2.1 The Time Course of AIF Translocation 138
9.2.2 Mechanism of AIF Release 138
9.2.2.1 PARP-1 and AIF 138
9.2.2.2 Direct Activation of AIF: Truncation by Calpain 140
9.2.2.3 Release of AIF from Mitochondria: Formation of the Mitochondrial Outer Membrane Pore 141
9.2.3 Regulation of AIF Activity in the Cytoplasm 143
9.2.3.1 AIF Function is Inhibited by Hsp70 143
9.2.3.2 Ubiquitination of AIF via XIAP 143
9.2.4 AIF-Induced DNA Fragmentation 143
9.2.4.1 Cyclophilins 144
9.3 Conclusions 144
References 145
Chapter 10 149
Role of µ-Calpain I and Lysosomal Cathepsins in Hippocampal Neuronal Necrosis After Transient Global Ischemia in Primates 149
10.1 The Actors: Calpain I and Cathepsins B and L 149
10.2 The Scene: Modes of Neuronal Demise in DND 150
10.3 The Play: Calpain–Cathepsin Cascade in Primate DND 153
10.4 The Future: Calpain–Cathepsin Cascade at the Core of Cell Death Machinery? 155
References 155
Chapter 11 159
Mitochondrial Damage in Traumatic CNS Injury 159
11.1 Traumatic Brain Injury 159
11.2 Mitochondria 162
11.3 Role of Ca2+ in Neurons and Mitochondrial Ca2+ Sequestration 164
11.4 Free Radicals, Dy, Mitochondria and Neuronal Cell Death 165
11.5 Mitochondria & TBI
11.6 Closing Remarks 168
References 168
Chapter 12 171
Programmed Neuronal Cell Death Mechanisms in CNS Injury 171
12.1 Introduction 171
12.2 Cell Death Phenotypes: Morphological-Based Classification 172
12.3 Cell Death Programs: Molecular Pathways that Participate in Cell Death 179
12.3.1 Caspase-Dependent Pathways 181
12.3.1.1 Regulation of Caspase Activation 183
12.3.2 Caspase-Independent Cell Death and Its Regulators 185
12.3.2.1 Heat Shock Proteins 189
12.3.2.2 Endonuclease G 191
12.4 Cooperation of Cell Death Programs 191
12.5 Cell Death Mechanisms: Implications for Treatment 192
References 192
Chapter 13 204
Hypoglycemic Brain Damage 204
13.1 Historical and Clinical Aspects 204
13.2 Gross Features 206
13.3 Light Microscopy 207
13.4 Electron Microscopy 207
13.5 Biochemical Features 208
References 210
Chapter 14 212
Hypoglycemic Neuronal Death 212
14.1 Hypoglycemic Brain Injury: Epidemiology and Background 212
14.2 Hypoglycemia and Brain Energetics 213
14.3 Anatomical Distribution of Neuronal Injury After Severe Hypoglycemia 215
14.4 The Hypoglycemic Neuronal Cell Death Pathway 215
14.4.1 Glutamate Receptor Activation 216
14.4.2 Superoxide Production is Triggered by Glucose Reperfusion 217
14.4.3 PARP-1 Activation 220
14.4.4 Role of Zinc and Nitric Oxide 222
14.5 Summary of Hypoglycemia-Induced Neuronal Cell Death 224
References 224
Chapter 15 231
Tumor Suppressor p53: A Multifunctional Protein Implicated in Seizure-Induced Neuronal Cell Death 231
15.1 Tumor Suppressor p53: A Major Regulator of Cell Growth and Death 231
15.2 p53 Is Regulated Through Multiple Pathways 232
15.3 Transcription-Independent Functions of p53 234
15.4 p53 and Seizure-Induced Neuronal Cell Death 234
15.5 Seizures Activate Key Downstream Effectors in the p53 Pathway 237
15.6 Summary 238
References 238
Chapter 16 242
DNA Damage and Repair in the Brain: Implications for Seizure-Induced Neuronal Injury, Endangerment, and Neuroprotection 242
16.1 Introduction 242
16.2 DNA Damage and Repair in the Brain 245
16.2.1 What Are the Sources of DNA Damage in the Brain? 245
16.2.2 Oxidative Stress Yields DNA Damage 247
16.2.3 DNA Repair Counters DNA Damage 248
Base Excision Repair 248
Nucleotide Excision Repair 249
Mismatch Repair 250
Double-Strand Break Repair 251
Early Events 251
Delayed Events 256
Ku70 Protein Levels Increase Following Continuous Seizures 258
Ku70 Protein Levels Are Not Affected by ECS Treatment 258
Preexposure to ECS Prevents Seizure-Induced Upregulation of Ku70 Protein 258
16.3 Concluding Remarks 263
References 264
Chapter 17 275
Activation of Caspase-Independent Programmed Pathways in Seizure-Induced Neuronal Necrosis 275
17.1 Excitotoxicity and Seizure-Induced Neuronal Death 275
17.1.1 Verification of the Excitotoxic Hypothesis with Respect to Seizures 275
17.2 The Morphology of Cell Death 276
17.2.1 The Morphology of Seizure-Induced Neuronal Death 277
17.3 The Time Course of the Appearance of Necrotic Neurons Following Seizure Onset 278
17.4 Apoptosis and the Caspase-Dependent Pathways of Cell Death 278
17.5 Caspase-Independent Programmed Mechanisms in Necrotic Cell Death 279
17.5.1 Caspase-Independent Programmed Mechanisms in Seizure-Induced Neuronal Necrosis 280
PARP-1, AIF, Calpain I, Cytochrome c and Endonuclease G 280
Lysosomal Cathepsins, DNase II, Calpain I, and Reactive Oxygen Species 285
p53 in Status Epilepticus 285
Autophagy in Status Epilepticus 286
17.6 Translating an Understanding of Mechanisms to a Neuroprotective Strategy in Refractory Human Status Epilepticus 286
References 287
Concluding Remarks 292
Personal Blurb for Springer Book 294
References 294
Index 296