Brain Hypoxia and Ischemia (eBook)

Brain Hypoxia and Ischemia 2
Title Page 3
Copyright Page 4
Preface 5
Contents 7
Contributors 9
Part I: Ion Channels, Transporters and Excitotoxicity 12
Chapter 1 13
Regulation of Vulnerability to NMDA Excitotoxicity During Postnatal Maturation 13
1.1 Postnatal Maturation Alters the Vulnerability of the Brain to Acute Injury 13
1.1.1 Vulnerability to Hypoxia-Ischemia Changes During Postnatal Development 13
1.1.2 Vulnerability to Excitotoxicity During Postnatal Development 15
1.1.3 Increases in Vulnerability of Cultured Neurons with Increasing Time In Vitro 17
1.2 Developmental Regulation of NMDA Receptor Expression 18
1.2.1 NMDA Receptor Subunits and Functional Properties 18
1.2.2 Developmental Regulation of NMDA Receptor Subunit Expression 19
1.2.3 Contribution of NR2A and NR2B Subunits to Excitotoxicity 20
1.2.4 Role of NR2A and NR2B Subunits in Regulating Developmental Regulation of Vulnerabilityto Excito toxicity 21
1.2.5 Role of Synaptic and Extrasynaptic NMDA Receptors 22
1.2.6 NMDA Receptor Desensitization During Development 23
1.3 Role of Ongoing Synaptic Activity and NMDA Release 24
1.4 Nitric Oxide 25
1.4.1 Nitric Oxide as a Neurotoxin 25
1.4.2 Developmental Regulation of NOS Expression and NO Production 25
1.4.3 Mitochondrial Nitric Oxide Production: A Mediator of Decreased Vulnerability in the Neonatal Period 26
References 28
Chapter 2 35
Acidosis, Acid-Sensing Ion Channels, and Glutamate Receptor-Independent Neuronal Injury 35
2.1 Glutamate Excitotoxicity 36
2.2 Brain Acidosis Activates Acid-Sensing Ion Channels 36
2.2.1 Brain Acidosis 36
2.2.2 Acidosis Induces Neuronal Injury 37
2.2.3 Acid-Sensing Ion Channels 37
2.2.4 Tissue Distribution and Electrophysiological Properties of ASICs 38
2.3 Pharmacology of ASICs 39
2.3.1 Amiloride 39
2.3.2 A-317567 40
2.3.3 Psalmotoxin 1 (PcTX1) 40
2.3.4 APETx2 40
2.3.5 Nonsteroid Anti-inflammatory Drugs (NSAIDs) 41
2.4 Modulation of ASIC Activity by Ischemia-Related Signals 41
2.4.1 Proteases 41
2.4.2 Arachidonic Acid 42
2.4.3 Lactate 42
2.4.4 Glucose 43
2.5 Activation of ASICs Induces Neuronal Excitation and Increased Intracellular Ca2+ 43
2.6 ASIC1a Activation Plays an Important Role in Acidosis-Induced Neuronal Injury 44
2.7 Evidence of a Developmental Change of ASICs 45
References 45
Chapter 3 52
Brain Ischemia and Neuronal Excitability 52
3.1 Excitatory Neurotransmission After Ischemia 53
3.2 Voltage-Dependent Potassium Currents After Ischemia 56
3.3 Conclusion 58
References 59
Chapter 4 62
Critical Roles of the Na+/K+-ATPase in Apoptosis and CNS Diseases 62
4.1 Introduction 62
4.1.1 Molecular Structure of the Na+/K+-ATPase 63
4.1.1.1 Structure and Function of alpha Subunit 63
4.1.1.2 Structure and Function of beta Subunit 64
4.1.1.3 Structure and Function of gamma Subunit (FXYD Proteins) 64
4.1.2 Physiological Function of the Na+/K+-ATPase 65
4.1.3 Physiologic Regulation of the Na+/K+-ATPase 66
4.1.3.1 Dual Effects of Ouabain and Cardiac Glycosides 66
4.1.3.2 Ouabain-Mediated Signal Transduction 66
4.1.3.3 Protein Kinase Regulation of the Na+/K+-ATPase 67
4.1.3.4 Src Family Kinases as Regulators of the Na+, K+-ATPase 67
4.1.3.5 AMP-Kinase Regulation of Na+/K+-ATPase 68
4.2 The Na+/K+-ATPase and Cell Death 68
4.2.1 Regulation of the Na+/K+-ATPase Under Pathological Conditions 68
4.2.1.1 Hypoxic and Ischemic Regulation of the Na+/K+-ATPase 68
4.2.2 K+ Homeostasis and Apoptosis 70
4.2.3 Na+/K+-ATPase, Apoptosis, and Hybrid Cell Death 72
4.2.3.1 Synergistic Effects of Low Concentrations of Ouabain and Sublethal Apoptotic Insults 73
4.2.3.2 Blocking Na+/K+-ATPase Induces Hybrid Cell Death with Both Apoptotic and Necrotic Features 73
4.3 Neuronal Function of the Na+/K+-ATPase and Roles in CNS Diseases 74
4.3.1 Emerging Neuronal Functions of the Na+/K+-ATPase 74
4.3.1.1 The Na+/K+-ATPase as a Receptor for Agrin 74
4.3.1.2 Na+/K+-ATPase alpha Subunit Knockout Phenotypes 75
4.3.2 The Na+/K+-ATPase and CNS Diseases 75
4.3.2.1 Stroke 75
4.3.2.2 Alzheimer Disease/Alzheimer’s Disease? 76
4.3.2.3 Parkinson’s Disease 76
4.3.2.4 Rapid Onset Dystonia-Parkinsonism 77
4.3.2.5 Bipolar Disorder 77
4.3.2.6 Familial Hemiplegic Migraine Type II 78
4.4 Na+/K+-ATPases as Drug Targets 78
4.4.1 Naturally Occurring Na+/K+-ATPase Inhibitors 78
4.4.2 Na+/K+-ATPase as Therapeutics for Cancer 79
4.4.3 Targeting the Na+/K+-ATPase for Cytoprotection 79
4.5 Conclusion 80
References 80
Chapter 5 88
Emerging Role of Water Channels in Regulating Cellular Volume During Oxygen Deprivation and Cell Death 88
5.1 Volume Regulatory Mechanisms 88
5.2 Properties of AQP and Their Neuronal Expression 89
5.2.1 AQP in the Brain 91
5.3 Changes in Aquaporin Expression During Hypoxia and Ischemia 92
5.3.1 Nonapoptotic Roles for AQP During Hypoxia/Ischemia 92
5.4 AVD: Role and Significance of AQP 94
5.5 Regulation of Aquaporin Expression and Function After (and Before) the AVD 95
5.6 Colocalization of AQP and Potassium Channels 97
5.7 Concluding Remarks 99
References 99
Chapter 6 106
A Zinc–Potassium Continuum in Neuronal Apoptosis 106
6.1 Introduction 106
6.2 Role of Zn2+ in Neuronal Injury 107
6.3 Mechanism of Zn2+ Neurotoxicity 108
6.4 Intracellular Release of Zn2+ 108
6.5 Cell Death Signaling Events Following Liberation of Intracellular Zn2+ 109
6.6 Potassium Efflux and Apoptosis 112
6.7 The Zinc–Potassium Continuum in Ischemia 113
6.8 Alternative Zn2+ Signaling Pathways 114
6.9 Intracellular Zn2+ Release in Chronic Models of Neurodegeneration 115
6.10 Concluding Remarks 116
References 117
Chapter 7 125
Mitochondrial Ion Channels in Ischemic Brain 125
7.1 Introduction 126
7.2 Role of VDAC in Mitochondrial Function 126
7.3 Biophysical Characteristics of VDAC 127
7.4 Control of Metabolism by VDAC 128
7.5 BCL-2 Family Ion Channels: Role in Programmed Cell Death in Neurons 129
7.6 Actions of BCL-2 Family Proteins Are Regulated by Binding Partners 130
7.7 BCL-2 Family Proteins Function as Ion Channels 131
7.8 Recordings of BCL-2 Family Proteins In Vivo 132
7.9 Endogenous Death Channels Produced by BAX-Containing Protein Complexes 134
7.10 Interaction of VDAC with BCL-2 Family Proteins 134
7.11 VDAC and Apoptosis 135
7.12 Interaction of VDAC with BCL-2 Family Members 135
7.13 Interactions of VDAC with BCL-xL 135
7.14 BCL-xL Interaction with VDAC in Mitochondria of Live Neurons 137
7.15 VDAC2 Inhibits Apoptosis 137
7.16 Mitochondrial Inner Membrane Channels 138
7.17 Energy dependence of Mitochondrial Calcium Accumulation 138
7.18 Voltage-Dependent Inner Membrane Channels: The Calcium Uniporter 139
7.19 Other Inner Membrane Conductances: Mitoplast Recording Technique 140
7.20 Channel Activity Correlated with Permeability Transition: The Mitochondrial Permeability Pore (mPTP) 140
7.21 Complex of Channels Exists at Contact Points Between Outer and Inner Membranes 142
7.22 Fundamental Events During Ischemia 143
7.23 Cellular Events During Ischemia-Excitotoxicity 144
7.24 Role of Oxygen-Free Radicals in Ischemic Neuronal Damage 145
7.25 BCL-2 Family Proteins in Ischemic Neuronal Damage 146
7.26 Large Channels of Mitochondria from Postischemic Hippocampal CA1 Neurons 147
7.27 Large Channel Activity Associated with VDAC 148
7.28 Large Zn2+-Activated Channels in Postischemic Mitochondria 148
7.29 Ischemic Tolerance and Mitochondrial Ion Channel Activity 149
7.30 Mito K ATP 150
7.31 Mito KCa 150
7.32 Conclusions 151
References 151
Part II: Reactive Oxygen Species, and Gene Expression to Behavior 159
Chapter 8 160
Perinatal Panencephalopathy in Premature Infants: Is It Due to Hypoxia-Ischemia? 160
8.1 Introduction 160
8.2 The Neuropathology of PPPI 161
8.3 Strategy Toward Establishing the Causative Role for Hypoxia-Ischemia in PPPI 170
8.4 Evidence for the Causative Role for Hypoxia-Ischemia in PVL Based upon Human Clinical Studies 173
8.5 Evidence for the Causative Role for Hypoxia-Ischemia in PVL Based upon Human Pathologic Studies 176
8.6 Evidence for the Causative Role for Hypoxia-Ischemia in PVL Based upon Pathologic Studies in Animal Models 179
8.7 Intrinsic Vulnerability of the Cerebral White Matter of the Premature Newborn to Hypoxia-Ischemia 180
8.8 The Causative Role of Synergistic Factors in PVL 181
8.9 The Potential Role of Cumulative Hypoxic-Ischemic Insults in PPPI 184
8.10 Conclusions 184
References 185
Chapter 9 193
Effects of Intermittent Hypoxia on Neurological Function 193
9.1 Intermittent Hypoxia 193
9.2 OSA and Cognition 194
9.3 Cognitive and Behavioral Effects of IH 195
9.4 Pathophysiology of IH-Induced Cognitive Deficits 198
9.5 Environmental and Lifestyle Modulation of End-Organ Susceptibility 203
9.6 Effects of Sustained and Intermittent Hypoxia on Respiratory Control 204
9.6.1 Sustained Hypoxia and Control of Breathing 204
9.6.2 Effects of Intermittent Hypoxia on Respiratory Control 205
9.7 Effects of Acute Intermittent Hypoxia on Respiratory Plasticity 206
9.8 Effects of Chronic Intermittent Hypoxia on Respiratory Plasticity 208
9.9 Summary 209
References 210
Chapter 10 219
Brainstem Sensitivity to Hypoxia and Ischemia 219
10.1 Introduction 219
10.2 The Acute Response to Hypoxia 220
10.2.1 Cerebral Vasodilation and Blood Flow 220
10.2.2 Brain Stem 221
10.3 Global Ischemia 223
10.4 Chronic Hypoxia 223
10.4.1 Adaptation to Prolonged Mild Hypoxia 223
10.4.2 The Ventilatory Response 223
10.4.3 Cerebral Blood Flow 224
10.4.4 Angiogenesis 226
10.5 Conclusions 227
References 228
Chapter 11 230
Matrix Metalloproteinases in Cerebral Hypoxia-Ischemia 230
11.1 Introduction 231
11.2 Crystal Structure Model of S-Nitrosylation of MMPs 232
11.3 Neuronal NOS-Associated Activation of MMP During Cerebral Hypoxia/Ischemia 233
11.4 S-Nitrosylation of Recombinant MMP Leads to Its Activation 234
11.5 MMP Proteolysis-Mediated Neuronal Apoptosis in Cerebrocortical Cultures 235
11.6 Oxidative Modification Following S-Nitrosylation of MMP In Vitro and In Vivo 236
11.7 Increased MMP Gelatinolytic Activity Spatially Associated with Neuronal Laminin in the Ischemic Brain 238
11.8 Inhibition of MMP Proteolysis Prevents Laminin Degradation and Rescues Neurons from Ischemia 238
11.9 Summary 240
References 241
Chapter 12 244
Oxidative Stress in Hypoxic-Ischemic Brain Injury 244
12.1 Reactive Oxygen Species: Overview 244
12.2 Sources of ROS in Hypoxia-Ischemia 247
12.2.1 Mitochondria 247
12.2.2 The NADPH Oxidase (Nox) Family of Superoxide-Generating Enzymes in Hypoxia-Ischemia 249
12.2.3 Nitric Oxide Synthase (NOS) 251
12.2.4 Other Sources of ROS 252
12.3 Effects of ROS on Blood–Brain Barrier Integrity and Cerebral Microvasculature 253
12.4 Effects of ROS on Neuronal Circuits and Synaptic Function in Hypoxia-Ischemia 254
12.5 Antioxidant Strategies to Test the Contribution of ROS to CNS Alterations and Injury After HI 255
12.6 Summary 255
References 255
Chapter 13 260
Postnatal Hypoxia and the Developing Brain: Cellular and Molecular Mechanisms of Injury 260
13.1 Introduction 260
13.2 Normal Brain Development 261
13.3 Altered Brain Development During Hypoxia 262
13.4 Hypoxia and the Stage of Development 262
13.5 Neurocognitive Effects of Postnatal Hypoxia 263
13.6 Hypoxia and Altitude: Lessons from Life at High Altitude 263
13.7 Cellular and Molecular Mechanisms of Hypoxic Cell Injury and Death 264
13.7.1 Cell Type-Specific Responses 265
13.7.2 Brain Region-Specific Responses 265
13.7.3 Ion Channel and Transporter Mechanisms 266
13.7.4 Hypoxia and Metabolic Arrest 266
13.7.5 Hypoxia and Apoptosis: Glutamate Excitotoxicity 267
13.7.6 Hypoxia and ROS 268
13.7.7 Hypoxia and the Immune System 270
13.7.8 Hypoxia and Gene Transcription 271
13.8 Summary 273
References 273
Chapter 14 282
Hypoxia-Inducible Factor 1 282
14.1 Oxygen Homeostasis and Its Impact on Evolution, Development, and Disease 282
14.2 Molecular Mechanisms of Oxygen Sensing 283
14.3 Regulation of Erythropoietin Production by HIF-1 285
14.4 Regulation of Angiogenesis by HIF-1 285
14.5 HIF-1 Is Required for Carotid Body-Mediated Responses to Continuous Hypoxia 286
14.6 HIF-1 Is Required for Carotid Body-Mediated Responses to Intermittent Hypoxia 287
14.7 Role of HIF-1 In Cerebral Preconditioning Phenomena 288
References 289
Chapter 15 294
Transcriptional Response to Hypoxia in Developing Brain 294
15.1 Introduction 294
15.2 Hypoxia-Responsive Transcription Factors in the Brain 295
15.3 Transcriptional Response to Hypoxia in Developing Brain 298
15.4 Summary 306
References 306
Chapter 16 312
Acute Stroke Therapy: Highlighting the Ischemic Penumbra 312
16.1 Introduction 312
16.2 The Concept of Ischemic Penumbra 313
16.3 The Existence and the Evolution of Ischemic Penumbra 314
16.4 Possible Mechanisms of the Penumbral Cell Death 316
16.4.1 Cell Death in the Infarct Core 317
16.4.2 Challenges of Penumbral Cells by Direct Exposure to the Core Milieu 317
16.4.2.1 Acidosis 317
16.4.2.2 Ionic Disturbances 318
16.4.2.3 Glutamate Toxicity 322
16.5 Penumbra and the Acute Stroke Therapy 322
16.6 Conclusion 324
References 324
Chapter 17 328
Genes and Survival to Low O2 Environment: Potential Insights from Drosophila 328
17.1 Introduction: Why Flies? 328
17.2 Strategies for Understanding Hypoxic Injury in the CNS 329
17.3 Our Specific Focus: Insights from Microarray Analysis 329
17.4 Role of Single Genes in an Inherited Complex Trait 331
17.5 Is Hypoxia Survival Related to Various Genetic Pathways? 333
17.6 Single Gene Vs. Multigenic Diseases 334
17.7 Fly Genes and Relevance to Mammalian Hypoxic Brain Injury 335
17.8 Summary 336
References 337
Index 339
Color Plates 348