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Metals and Oxidative Damage in Neurological Disorders
Metals and Oxidative Damage in Neurological Disorders
Edited by
James R. Connor Pennsylvania State University Hershey, Pennsylvania
Springer Science+Business Media, LLC
The Library of Congress Cataloging-in-Publication Data
On file
Cover micrographs: Astrocytes loaded with two dyes: Fura 2, which tluoresces green upon coupling with calcium, and a yellow dye that is an indicator of mitochondrial membrane potential. Front cover: Normal astrocytes showing dye localized to normally polarized mitochondria. Back cover: Astrocytes treated with an oxidizing agent causing loss ofmitochondrial membrane potential, thus almost no yellow fluorescence is visible; the calcium indicator, however,is still prominent. The photomicrographs were prepared by Sara Robb-Gaspers and James Connor with assistance from Greg Y oung.
ISBN 978-1-4899-0199-6 ISBN 978-1-4899-0197-2 (eBook) DOI 10.1007/978-1-4899-0197-2
© 1997 Springer Science+Business Media New York
Origina11y pub1ished by Plenum Press, New York in 1997. Softcover reprint ofthe hardcover 1st edition 1997
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All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microfilming, recording, or otherwise, without written permission from the Publisher
The pleasure of an accomplishment is magnified when it can be shared with people you love. I am blessed that the joys I
have known have been magnified three-fold. As such, I lovingly and gratefully dedicate this book to my wife Judy,
my daughter Jennifer, and my son Jonathan.
Contributors
Michael Aschner Department of Physiology and Pharmacology, Bowman Gray School of Medicine, Winston-Salem, North Carolina 27157
George Bartzokis Department of Psychiatry, UCLA, Los Angeles, Califomia 90024; and the Research Service and the Psychiatry Service, West Los Angeles Veterans Affairs Medical Center, Los Angeles, Califomia 90073
M. Flint Beal Neurology Service, Massachusetts General Hospital, Boston, Mas-sachusetts 02114
Mark W. Becher Department of Pathology and the Neuropathology Laboratory, The Johns Hopkins University School of Medicine and School of Hygiene and Public Health, Baltimore, Maryland 21205
David R. Borchelt Department of Pathology and the Neuropathology Laboratory, The Johns Hopkins University School of Medicine and School of Hygiene and Public Health, Baltimore, Maryland 21205
Lucie I. Bruijn Department of Biological Chemistry, The Johns Hopkins Univer-sity School of Medicine and School of Hygiene and Public Health, Baltimore, Maryland 21205; current address: Departments of Neurology and Neuroscience, the Ludwig Institute, University of Califomia at San Diego, La Jolla, Califomia 92093
Jean Lud Cadet Molecular Neuropsychiatry Section, NIH/NIDA, Intramural Re-search Program, Baltimore, Maryland 21224
Elsbeth G. Chikhale Neurochemistry and Brain Transport Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892
Don W. Cleveland Department of Biological Chemistry, The Johns Hopkins Uni-versity School of Medicine and School of Hygiene and Public Health, Baltimore,
vii
viii Contributors
Maryland 21205; current address: Departments of Neurology and Neuroscience, the Ludwig Institute, University of Califomia at San Diego, La Jolla, Califomia 92093
James R. Connor George M. Leader Family Laboratory far Alzheimer's Disease Research, Department of Neuroscience and Anatomy, Pennsylvania State University College of Medicine, M. S. Hershey Medical Center, Hershey, Pennsylvania 17033
Neal G. Copeland Mammalian Genetics Laboratory, ABL-Basic Research Pro-gram, NCI-Frederick Cancer Center Research and Development, Frederick, Maryland 21702
Valeria C. Cnlotta Departments of Biochemistry and Environmental Health Sci-ences, The Johns Hopkins University School of Medicine and School of Hygiene and Public Health, Baltimore, Maryland 21205
Deborah A. Dawson Stroke Branch, NINDS, National Institutes of Health, Be-thesda, Maryland 20892
Michael Gassen Department of Pharmacology, Bruce Rappaport Family Research Institute, Faculty of Medicine, Technion, Haifa 31096, Israel
Yelena Glinka Department of Pharmacology, Bruce Rappaport Family Research Institute, Faculty of Medicine, Technion, Haifa 31096, Israel
Pani F. Good Department of Pathology and Fishberg Research Center for Neuro-biology, Mount Sinai School of Medicine, New York, New York 10029
Edward D. Hall CNS Diseases Research, Pharmacia and Upjohn, Inc., Kala-mazoo, Michigan 49001
Nancy A. Jenkins Mammalian Genetics Labaratory, ABL-Basic Research Pro-gram, NCI-Frederick Cancer Center Research and Development, Frederick, Maryland 21702
J. G. Joshi Department of Biochemistry, University of Tennessee, Knoxville, Tennessee 37996
Michael K. Lee Department of Pathology and the Neuropathology Labaratory, The Johns Hopkins University School of Medicine and School of Hygiene and Public Health, Baltimore, Maryland 21205
C. Warren Olanow Department of Neurology, Mount Sinai School of Medicine, New York, New York 10029
Charles Palmer Division of Newbom Medicine, Department of Pediatrics, Penn-sylvania State University College of Medicine, M. S. Hershey Medical Center, Hershey, Pennsylvania 17033
Contributors ix
Carlos A. Pardo Department of Pathology and the Neuropathology Laboratory, The Johns Hopkins University School of Medicine and School of Hygiene and Public Health, Baltimore, Maryland 21205
Daniel P. Perl Department of Pathology and Fishberg Research Center for Neuro-biology, Mount Sinai School of Medicine, New York, New York 10029
Ananda S. Prasad Division of Hematology-Oncology, Department of Internal Medicine, Wayne State University School of Medicine, and Harper Hospital, Detroit, Michigan 48201
Donald L. Price Departments of Pathology,Neurology, and Neuroscience, and the Neuropathology Laboratory, The Johns Hopkins University School of Medieine and School of Hygiene and Public Health, Baltimore, Maryland 21205
Joseph R. Prohaska Department of Biochemistry and Molecular Biology, School of Medicine, University of Minnesota-Duluth, Duluth, Minnesota 55812
Olivier Rabin Neurochemistry and Brain Transport Seetion, Laboratory of Neuro-sciences, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892
George V. Rebec Program in Neural Science, Department of Psychology, Indiana University, Bloomington, Indiana 47405
Sara J. Robb-Gaspers George M. Leader Family Laboratory for Alzheimer's Disease Research, Department of Neuroscience and Anatomy, Pennsylvania State University College of Medicine, M. S. Hershey Medical Center, Hershey, Pennsylvania 17033
Leslie A. Shinobu Neurology Service, Massachusetts General Hospital, Boston, Massachusetts 02114
Sangram S. Sisodia Departments of Pathology and Neuroscience and the Neuro-pathology Laboratory, The Johns Hopkins University School of Medicine and School of Hygiene and Public Health, Baltimore, Maryland 21205
Quentin R. Smith Neurochemistry and Brain Transport Seetion, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892; current address: Department of Pharmaceutical Sciences, Texas Tech University HSC, Amarillo, Texas 79106
G. T. Vatassery Research Service and the Geriatrie Research Education and Clini-cal Center (GRECC), Veterans Affairs Medical Center, Minneapolis, Minnesota 55417; and Department of Psychiatry, University of Minnesota, Minneapolis, Minnesota 55455
Philip C. Wong Department of Pathology and the Neuropathology Laboratory, The Johns Hopkins University School of Medicine and School of Hygiene and Public Health, Baltimore, Maryland 21205
x Contributors
Zhou-Shang Xu Department ofBiological Chemistry, The Johns Hopkins Univer-sity School of Medicine and School of Hygiene and Public Health, Baltimore, Maryland 21205; current address: The Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts 01545
Moussa B. H. Youdim Department of Pharmacology, Bruce Rappaport Family Research Institute, Faculty of Medicine, Technion, Haifa 31096, Israel
Preface
The purpose of this book is to bring together scientists and clinicians interested in oxidative injury in the nervous system but whose approaches to investigation and treatment design vary widely. Indeed the goal of this book is to show that the investigative approaches and potential therapeutic interventions perhaps do not vary as widely as some may think. I think that the readers of this book will not read it from front to back, but will pick chapters of interest. Thus, the chapters are organized to contain information that is essential to understanding basic aspects of oxidative injury, and thus have some redundancy. However, within the context of each chapter the reader should hopefully find impetus and direction to go on to another chapter.
The book is divided into three seetions. The first section contains reviews of metals and their role in generating oxidative injury. lron is considered in three of these chapters because of its relative abundance in the brain and its potency in inducing free radicals. The second section focuses on mechanisms by which the brain attempts to protect itself from oxidative injury. Some of these mechanisms have the potential to be protective in some situations and potentiaIly damaging in others. The third section contains the clinicaI diseases in which oxidative injury is known to contribute to the pathogenic process. This seetion ends with a chapter on antioxidant therapeutic strategies in neurological disorders. Finally, a common pathway is proposed for oxidative injury in the brain. We have argued that whatever the mechanism by which the oxidative stress is triggered, eventually a cascade will be initiated that will result in cell death. This cascade would be consistent in each of the disease processes and would be independent of the metal(s) that induced the process.
We hope this book serves as a reference for those entering the field and brings together individuals already working in the field from seemingly disparate approaches. We hope it serves as a catalyst to clinicians to consider oxidative stress as a component of many neurological diseases and consider metal regulation as an important component in their patients' diets.
J ames R. Connor Hershey, Pennsylvania
xi
Contents
Chapter 1 Iron and Neurotransmitter Function in tbe Brain Yelena Glinka, Michael Gassen, and Moussa B. H. Youdim
1.1. Introduetion ............................................... . 1.2. Biosynthesis and Metabolism of Neurotransmitters. . . . . . . . . . . . . . . . . 3
1.2.1. Cateeholamine Neurotransmitters ........................ 3 1.2.2. GABA.............................................. 3 1.2.3. Serotonin (5-HT) .................. ;.................. 4
1.3. The Regulation ofAxonal Growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 1.4. Axonal Transport and Iron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 1.5. Transloeation of Neurotransmitters: Storage, Release,
Reuptake. . . . .... . . .. . . . . . . ... . . . . . . ..... . .. . . ..... .. . . . . . .. 6 1.5.1. Uptake of Neurotransmitters into Vesicles . . . . . . . . . . . . . . . . . 6 1.5.2. Neurotransmitter Release. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 1.5.3. Neurotransmitter Reuptake. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
1.6. Reeeptors, Metabolie Consequenees of the Reeeption, Baekward Signaling. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
1.6.1. Regulation of Reeeptor Expression. . . . . . . . . . . . . . . . . . . . . . . 9 1.6.2. Influenee of Iron on Seeond Messenger Systems. . . . . . . . . . . . 10 1.6.3. Iron Interaetion with Protein Phosphorylation .............. 11 1.6.4. Allosterie Control of Receptor Sensitivity and Desensitization
of Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 1.7. Influence of Neural Signaling on the Iron Regulation in the
Cello . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13 1.8. Intercellular Interactions in the CNS ............................ 14 1.9. Conclusion................................................. 15
1.10. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
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xiv
Chapter 2 Evidence for Iron Mismanagement in the Brain in Neurological Disorders James R. Connor
Contents
2.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 2.2. Regional and Cellular Distribution of Iron in the Brain . . . . . . . . . . . . . 24
2.2.1. Aging and Alzheimer's Disease. . . . . . . . . . . . . . . . . . . . . . . . . . 25 2.2.2. Parkinson's Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.3. Acquisition of Iron. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 2.4. Iron Mobilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29 2.5. Intracellular Iron Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30 2.6. Iron Regulatory Proteins (IRPs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 2.7. Iron and Multiple Sclerosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 2.8. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 2.9. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
Chapter 3 Magnetic Resonance Imaging of Brain Iron George Bartzokis
3.1. Introduction . . . . . . . . . . . . .. . . . . . . . . . . .. . . . . . . . . .... . . .. .. . . . . 41 3.2. MRI Evaluation of Tissue lron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.2.1. T2 Is a Nonspecific Measure of Iron . . . . . . . . . . . . . . . . . . . . . . 43 3.2.2. Specific MRI Measures of Ferritin . . . . . . . . . . . . . . . . . . . . . . . 44 3.2.3. Initial Clinical Research Applications of the FDRI Method . . . 45 3.2.4. Future Directions of in Vivo Evaluation of Tissue Iron with
MR........................... ..................... 51 3.3. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 3.4. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
Chapter 4 Neurochemical Roles of Copper as Antioxidant or Prooxidant Joseph R. Prohaska
4.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57 4.2. Copper Distribution. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58 4.3. Neurochemical Functions of Copper. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
4.3.1. Cuproenzymes........................................ 60
Contents xv
4.3.2. Copper Complexes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 4.3.3. Prooxidant Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 4.3.4. Antioxidant Roles. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
4.4. Copper Deficiency . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 4.4.1. Dietary Copper Deficiency. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 4.4.2. Genetic Copper Deficiency ............................. 66
4.5. Copper Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 4.5.1. CNS Toxicity ...... . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . 67 4.5.2. Genetic Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
4.6. Cu,Zn-Superoxide Dismutase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70 4.7. Summary.................................................. 70 4.8. References .... ". . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
Chapter 5 Manganese Neurotoxicity and Oxidative Damage Michael Aschner
5.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 5.2. Manganese Transport in the CNS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78 5.3. Manganese Neurotoxicity: What Possible Mechanisms? . . . . . . . . . . . . 80
5.3.1. Manganese Neurotoxicity-A Dual Spectrum . . . . . . . . . . . . . . 80 5.3.2. Mechanisms Associated with Manganese-Induced
Neurotoxicity ........................................ 81 5.3.3. Manganese as an Antioxidant and Brain Protectant . . . . . . . . . . 87
5.4. Summary and Future Directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88 5.5. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
Chapter 6 Tbe Role of Zine in Brain and Nerve Functions Ananda S. Prasad
6.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. "95 6.2. Zinc and Cell Division . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 6.3. Transport of Zinc .............. ". . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 6.4. Biochemical Role of Zinc . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 6.5. Zinc and Free Radicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 6.6. Zinc and Brain Function in Animals and Humans. . . . . . . . . . . . . . . . . . 100 6.7. Zinc and Epilepsy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101 6.8. Zinc and Nerve Functions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
xvi Contents
6.9. Summary.................................................. 107 6.10. Referenees . .. . . . . . . . . . . . . . . . . . .. . . . . . . . . . .. . . . . . . . . . . . . . . . . 108
Chapter 7 Delivery of Metals to Brain and the Role of the Blood-Brain Barrier Quentin R. Smith, Olivier Rabin, and E1sbeth G. Chikha1e
7.1. Introduetion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 7.2. Cireu1ation in Serum and Blood . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 114 7.3. Blood-Brain Barrier . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 7.4. Transport Methods and Kinetie Analysis. . . . . . . . . . . . . . . . . . . . . . . . . 116 7.5. Rates of Metal Transport into Brain and CSF . . . . . . . . . . . . . . . . . . . . . 119 7.6. Transport Meehanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
7.6.1. Iron . . . . . . .. . . . . . . . . .. . . . . . . . .. .. . . . . .. . . . . . . . . .. .. . 121 7.6.2. Manganese .................. . . . . . . . . . . . . . . . . . . . . . . . . 124 7.6.3. Zine................................................ 124 7.6.4. Calcium.............. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 7.6.5. Toxie Metals (Aluminum, Lead, Mereury) . . . . . . . . . . . . . . . . . 126
7.7. Changes with Diet, Disease, and Development . . . . . . . . . . . . . . . . . . . . 126 7.8. Conc1usions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 7.9. Referenees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Chapter 8 Ferritin: Intracellular Regulator of Metal Availability J. G. Joshi
8.1. Introduetion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131 8.2. Formation of Holoferritin and Loading of Iron into Apoferritin. . . . . . . 133 8.3. Reduetive Release of Iron. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133 8.4. Ferritin and Binding of Nonferrous Metal Ions. . . . . . . . . . . . . . . . . . . . 134
8.4.1. Ferritin and Beryllium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 8.4.2. Ferritin and Zine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137 8.4.3. Ferritin and Cadmium ................................. 138 8.4.4. Ferritin and Manganese . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 8.4.5. Ferritin and Arsenie . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 8.4.6. Ferritin and Aluminum. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 8.4.7. Aluminum and Free Radieals. . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
8.5. Aluminum, Iron, Free Radieals, and the Formation of Amyloid Plaques Charaeteristic for AD. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
8.6. The Role for Novel Ferritin H-Chain mRNAs. . . . . . . . . . . . . . . . . . . . . 142 8.7. Referenees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Contents
Chapter 9 Ascorbate: An Antioxidant Neuroprotectant and Extracellular Neuromodulator George V. Rebec
xvii
9.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149 9.2. Uptake into Brain Tissue. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150 9.3. Release into Extracellular Fluid. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
9.3.1. Modulation by Dopamine. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152 9.3.2. The Nigro-Thalamo-Cortical System. .. . . . . .. . . . . . . .. . . . . . 153 9.3.3. Heteroexchange at the Glutamate Transporter. . . . . . . . . . . . . . 154 9.3.4. Other Considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
9.4. Neuroprotectant Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 9.4.1. Degeneration of Dopaminergic Neurons. . . . . . . . . . . . . . . . . . . 155 9.4.2. Glutamate-Induced Neurotoxic Effects . . . . . . . . . . . . . . . . . . . . 159 9.4.3. Neurotoxic Mechanisms in Schizophrenia and Tardive
Dyskinesia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 9.5. Clinical and Functional Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161
9.5.1. Dopaminergic Modulation. . . ... . . . . . . .. . . .. .. . . . . . . . ... 161 9.5.2. Glutamatergic Modulation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164
9.6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 164 9.7. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
Chapter 10 Vitamin E: Neurochemical Aspects and Relevance to Nervous System Disorders G. T. Vatassery
10.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 10.2. Familial Ataxia with Vitamin E Deficiency . . . . . . . . . . . . . . . . . . . . . . . 176 10.3. Peripheral Nerve Damage . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 177 10.4. Abetalipoproteinemia......................................... 177 10.5. Aging . . . .. .. .. . . . . . . . .. . . .... . . .. . .. . . . . . . . . .. .. . . . . ... .. . 178 10.6. Parkinson's Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 10.7. Alzheimer's Disease .............................. . . . . . . ... . . 179 10.8. Alteration of Neurotoxicity by Vitamin E . . . . . . . . . . . . . . . . . . . . . . . . 180 10.9. Tardive Dyskinesia and Vitamin E. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180
10.10. Vitamin E in Other Neurological Conditions. . . . . . . . . . . . . . . . . . . . . . 181 10.11. Vitamin E in Cell Proliferation and Growth in the Nervous System . . . 182 10.12. Neurobiology of Vitamin E: Experimental Data from Animals . . . . . . . 182 10.13. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184 10.14. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
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Chapter 11 Nitric Oxide and Oxidative Damage in the CNS Deborah A. Dawson
11.1. Nitric Oxide: Synthesis and Inhibition. . . . . . . . . . . . . . . . . . . . . . . . . . . 189 11.1.1. NO Synthases: Constitutive and Inducible Enzymes . . . . . . . . . 189 11.1.2. NO Synthases: Localization within the CNS ... . . . . . . . . . . . . 190 11.1.3. NO Synthases: Inhibition of NO Production. . . . . . . . . . . . . . . . 190
11.2. Mechanisms of NO Toxicity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 11.2.1. Oxidative Damage: Direct and by Combination with
Superoxide .......................................... 191 11.2.2. Oxidative Damage: Alterations in Iron Homeostasis . . . . . . . . . 192 11.2.3. Inhibition of Respiration and DNA Synthesis. . . . . . . . . . . . . . . 193
11.3. Role of NO in CNS Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 11.3.1. NO and Glutamate Toxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 11.3.2. Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 11.3.3. Neurodegenerative Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196
11.4. Summary and Conc1usions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199 11.5. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 199
Chapter 12 lron and Oxidative Stress in Neonatal Hypoxic-Ischemic Brain Injury: Directions for Therapeutic Intervention Charles Palmer
12.1. Introduction to Oxidant Stress and Secondary Brain Injury . . . . . . . . .. 205 12.2. Reactive Oxygen Species (ROS): An Overview . . . . . . . . . . . . . . . . . .. 206 12.3. Vascular Injury. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 209
12.3.1. The Primary Insult. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209 12.3.2. Reperfusion: Sources of ROS ...... . . . . . . . . . . . . . . . . . . . . . 209 12.3.3. Effects of ROS on the Microvasculature. . . . . . . . . . . . . . . . . . . 210 12.3.4. Neutrophils . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 210 12.3.5. Antioxidants and Microvascular Injury . . . . . . . . . . . . . . . . . . .. 211
12.4. Free-Radical-Mediated Injury to Brain Parenchyma . . . . . . . . . . . . . . . . 212 12.4.1. Actions on Cellular Function. . . . . . . . . . . . . . . . . . . . . . . . . . . . 213 12.4.2. Impaired Energy Metabolism and ROS. . . . . . . . . . . . . . . . . . . . 214 12.4.3. Elevated Intracellular Calcium and ROS. . . . . . . . . . . . . . . . . . . 214 12.4.4. Excitotoxic Injury and ROS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 12.4.5. Mitochondrlal Dysfunction and ROS ..................... 215 12.4.6. Hydroxyl Radicals: From Iron or Nitric Oxide? . . . . . . . . . . . . 216 12.4.7. Oxidant Stress in Young Neurons and Oligodendrocytes. . . . .. 216
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12.4.8. Microglia as Souree of ROS . . . . . . . . . . . . . . . . . . . . . . . . . . . . 216 12.4.9. Apoptosis and ROS ................................... 217
12.5. Iron....................................................... 217 12.5.1. Suseeptibility ofImmature Brain to Iron-Mediated Injury. . . .. 217 12.5.2. Sourees of Iron in Cerebral Isehemia . . . . . . . . . . . . . . . . . . . .. 218 12.5.3. Iron Aeeumulation in the Post-Isehemie Brain. . . . . . . . . . . . .. 219
12.6. Nitrie Oxide and the Immature Brain. . . . . . . . . . . . . . . . . . . . . . . . . . .. 220 12.6.1. NO: Injury Meehanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 220 12.6.2. NO and Regulation of Iron Metabolism. . . . . . . . . . . . . . . . . .. 221 12.6.3. NO Synthase Inhibition and Neuroproteetion . . . . . . . . . . . . . .. 222
12.7. Appendix: Reseue Therapies. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 223 12.8. Referenees . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225
Chapter 13 The Role of Oxidative Processes and Metal Ions in Aging and Alzheimer's Disease Leslie A. Shinobu and M. Flint Beal
13.1. Age-Related Changes in Cellular Energy Metabolism. . . . . . . . . . . . . . . 237 13.1.1. Introduetion..... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 237 13.1.2. The Mitoehondria and Oxidative Phosphorylation . . . . . . . . . .. 238 13.1.3. Age-Related Changes in Mitoehondrial DNA Strueture. . . . . .. 240 13.1.4. Age-Related Changes in Mitoehondrial Funetion. . . . . . . . . . . . 242
13.2. Oxidative Damage and Alzheimer's Disease . . . . . . . . . . . . . . . . . . . . .. 244 13.2.1. Introduetion............ . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 244 13.2.2. Risk Faetors for Alzheimer's Disease . . . . . . . . . . . . . . . . . . . .. 244 13.2.3. Evidenee for Impaired Energy Metabolism in Alzheimer's
Disease .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 245 13.2.4. Evidenee of Mitoehondrial Dysfunetion in Alzheimer's
Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 245 13.2.5. Evidenee for Oxidative Stress in Alzehimer's Disease. . . . . . .. 247 13.2.6. Peripheral Markers of Oxidative Damage in Alzheimer's
Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 250 13.2.7. Speeifie Roles for Reaetive Oxygen Speeies in the
Pathogenesis of Alzheimer's Disease . . . . . . . . . . . . . . . . . . . .. 251 13.3. The Role of Metal Ions in Aging and Alzheimer's Disease . . . . . . . . .. 255
13.3.1. Aluminum........................................... 256 13.3.2. Copper. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 257 13.3.3. Iron . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 257 13.3.4. Zine................................................ 259
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13.4. Summary ... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 260 13.5. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 261
Chapter 14 Oxidative Stress with Emphasis on the Role of LAMMA in Parkinson's Disease Paul F. Good, Daniel P. Perl, and C. Warren Olanow
14.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 277 14.2. Oxidative Stress. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 278 14.3. Evidence of Oxidative Stress and Oxidative Damage in Parkinson's
Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 280 14.4. Microprobe Studies of Trace Elements in Parkinson's Disease. . . . . . .. 283
14.4.1. The Laser Mieroprobe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 283 14.4.2. Laser Microprobe Studies in Parkinson's Disease . . . . . . . . . .. 284
14.5. Parkinsonism Associated with Accumulation of Trace Metals . . . . . . .. 287 14.6. Therapeutic Implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 289 14.7. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 290
Chapter 15 Perspectives on the Mechanisms of Familial Amyotrophic Lateral Sclerosis Caused by Mutations in Superoxide Dismutase 1 David R. Borchelt, Philip C. Wong, Mark W. Becher, Lucie I. Bruijn, Don W. Cleveland, Neal G. Copeland, Valeria C. Culotta, Nancy A. Jenkins, Michael K. Lee, Carlos A. Pardo, Donald L. Price, Sangram S. Sisodia, and Zhou-Shang Xu
15.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 295 15.2. Clinical and Neuropathological Phenotypes of FALS . . . . . . . . . . . . . .. 296 15.3. Etiological Factors/Mechanisms in ALS and FALS . . . . . . . . . . . . . . .. 298 15.4. Functions of Cu/Zn SODI .................................... 300 15.5. Properties of FALS Mutant SODI . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 302 15.6. Transgenic Models of SODI-Linked FALS . . . . . . . . . . . . . . . . . . . . . . . 303 15.7. Nature of the Toxie Property. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 305 15.8. Factors Goveming the Severity of Disease . . . . . . . . . . . . . . . . . . . . . .. 307 15.9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 307
15.10. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 308
Contents
Chapter 16 Tardive Dyskinesia and Oxidative Stress Jean Lud Cadet
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16.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 16.2. Description................ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 315 16.3. Neuropathological Findings Associated with Neuroleptic Use . . . . . . . . 316 16.4. Models of Tardive Dyskinesia. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 317 16.5. Free-Radical Hypothesis of Tardive Dyskinesia. . . . . . . . . . . . . . . . . . . . 318 16.6. Clinical Implications of the Free-Radical Hypothesis . . . . . . . . . . . . . . . 320 16.7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 320 16.8. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 321
Chapter 17 Antioxidant Therapeutic Strategies in CNS Disorders Edward D. Hall
17.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325 17.2. Chemistry of Lipid Peroxidation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 17.3. Potential Mechanisms of Lipid Peroxidation Inhibition. . . . . . . . . . . . . . 327
17.3.1. Inhibition of Oxygen Radical Formation. . . . . . . . . . . . . . . . . . . 327 17.3.2. Enzymatic Radical Scavenging . . . . . . . . . . . . . . . . . . . . . . . . . . 328 17.3.3. Chemical Radical Scavenging . . . . . . . . . . . . . . . . . . . . . . . . . .. 328 17.3.4. Peroxynitrite Scavenging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 17.3.5. Peroxyl Radical Scavenging. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 17.3.6. Iron Chelation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 17.3.7. Membrane Stabilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330
17.4. Tirilazad: An Example of a Multi-Mechanistic Antioxidant Neuroprotective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 330 17.4.1. Tirilazad Lipid Peroxidation-Inhibiting Mechanisms . . . . . . . . . 332 17.4.2. Proteetion of Endothelial Function . . . . . . . . . . . . . . . . . . . . . .. 333 17.4.3. Proteetion of Calcium Homeostatic Mechanisms . . . . . . . . . . . . 333 17.4.4. Tirilazad Clinical Neuroprotection Trials . . . . . . . . . . . . . . . . .. 334
17.5. 2-Methy1aminochromans...................................... 334 17.6. Pyrrolopyrimidines........................................... 335 17.7. References . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336
Chapter 18 Oxidative Stress-Induced Cell Damage in the CNS: A Proposal for a Final Common Pathway Sara J. Robb-Gaspers and James R. Connor
18.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341 18.2. Chemistry of Free Radicals. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 341
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18.3. Unique Vulnerability of the Brain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 342 18.4. Mitochondria as Mediators of Oxidative Damage in Astrocytes. . . . . .. 344 18.5. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 347 18.6. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349
Appendix Accepted Biomarkers of Oxidative Damage in Tissues Leslie A. Shinobu and M. Flint Beal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 353
Index. .. . . . . .... . . . .... . . . . . ..... . . . . .. . . . . . . . . . . .. . . ..... . . . . .. 357