Table Of ContentNEUROSCIENCE
INTELLIGENCE
UNIT
The Role
of Oxidative Stress
in Neuronal Death
Irène Ceballos-Picot
Hôpital Necker
Paris, France
Springer-Verlag
Berlin Heidelberg GmbH AusTIN, TEXAS
U.S.A.
NEUROSCIENCE INTELLIGENCE UNIT
The Role of Oxidative Stress in Neuronal Death
LANDES BIOSCIENCE
Austin, Texas, U.S.A.
International Copyright © 1997 Springer-Verlag Berlin Heidelberg
Originally published by Springer-Verlag, Heidelberg, Germany in 1997
Softcover reprint of the hardcover 1st edition 1997
All rights reserved.
No part of this book may be reproduced or transmitted in any form or by any
means, electronic or mechanical, including photocopy, recording, or any informa
tion storage and retrieval system, without permission in writing from the publisher.
Springer
International ISBN 978-3-662-22518-9
While the authors, editors and publisher believe that drug selection and dosage and the
specifications and usage of equipment and devices, as set forth in this book, are in accord
with current recommendations and practice at the time of publication, they make no
warranty, expressed or implied, with respect to material described in this book. In view of
the ongoing research, equipment development, changes in governmental regulations and
the rapid accumulation of information relating to the biomedical sciences, the reader is
urged to carefully review and evaluate the information provided herein.
Library of Congress Cataloging-in-Publication Data
Ceballos-Picot, Irene, 1957-
0xidative stress in neuronal death I Irene Ceballos-Picot.
p. em.-(Neuroscience intelligence unit)
Includes bibliographical references and index.
ISBN 978-3-662-22518-9 ISBN 978-3-662-22516-5 (eBook)
DOI 10.1007/978-3-662-22516-5
1. Nervous system--Pathophysiology. 2. Neurons. 3. Apoptosis. 4. Active oxygen
in the body. 5. Nervous system--Degeneration. 6. Oxidation, Physiological. 7. Stress
(Physiology) I. Title. II. Series.
[DNLM: l. Nervous System Diseases--physiopathology. 2. Oxidative stress-
physiology. 3. Neurons--physiology. 4. Cell Death--physiology. WL 140 C387o 1997]
RC347.C43 1997
616.8'047-dc21
DNLM/DLC 97-19204
for Library of Congress CIP
PuBLISHER's NoTE
Landes Bioscience produces books in six Intelligence Unit se
ries: Medical, Molecular Biology, Neuroscience, Tissue Engineering,
Biotechnology and Environmental. The authors of our books are
acknowledged leaders in their fields. Topics are unique; almost
without exception, no similar books exist on these topics.
Our goal is to publish books in important and rapidly
changing areas of bioscience for sophisticated researchers and
clinicians. To achieve this goal, we have accelerated our
publishing program to conform to the fast pace at which
information grows in bioscience. Most of our books are
published within 90 to 120 days of receipt of the manuscript.
We would like to thank our readers for their continuing interest
and welcome any comments or suggestions they may have for
future books.
Shyamali Ghosh
Publications Director
Landes Bioscience
DEDICATION
To Jean-Patrice and Antoine
To my parents
To my teachers and co-workers
CONTENTS
1. Introduction ................................................................................. 1
2. Biology of Oxidative Stress .......................................................... 5
Introduction to Oxygen Chemistry
and Reactive Oxygen Species .................................................. 5
Reactive Oxygen Species: Biochemistry ..................................... 6
The Oxygen Paradox ................................................................... 7
Sources of Reactive Oxygen Species in the Brain .................... 10
Nitric Oxide: Biological Mediator, Modulator
and Effector ............................................................................ 11
Antioxidant Defense Systems in the Brain ............................... 13
Heterogeneous Cellular Localization of Antioxidants
Governs the Susceptibility of Neurons
to Oxidative Stress ................................................................. 16
Excitotoxicity and Oxidative Stress .......................................... 23
Mitochondria and Oxidative Stress .......................................... 26
Cell Responses to Oxidative Damage ....................................... 26
The Oxidant Stress: The Molecular Targets in the Brain ........ 28
3. Oxidative Stress in Neuronal Death and Apoptosis ................ 39
Introduction .............................................................................. 39
Reactive Oxygen Species as Common Mediators
of Neuronal Apoptosis .......................................................... 40
Sources of Reactive Oxygen Species
in Neuronal Apoptosis .......................................................... 41
Oxidants/A ntioxidants in the Modulation
of Neuronal Apoptosis .......................................................... 43
Oxidative Stress and Calcium Homeostasis
in the Development of Neuronal Apoptosis ........................ 52
Oxidative Stress, Immediate Early Genes
and Neuronal Apoptosis ....................................................... 53
Alterations of Cell Signaling Processes by Oxidants:
Implication in Neuronal Death ............................................ 56
Role of Apoptosis in Disease-Related Neural Cell Death ........ 58
Oxidative Stress, Transcription Factors and Redox
Regulation of Gene Transcription:
Role in Neuronal Death ........................................................ 58
Oxidative Stress and Mitochondria in Neuronal Death ......... 65
Reactive Oxygen Species in Neuronal Differentiation ............ 68
4. Oxidative Stress, Cerebral Aging and Longevity ..................... 83
Introduction .............................................................................. 83
The "Free-Radical" Theory of Aging ........................................ 83
Oxidative Stress and Genes in Aging and Longevity ............... 86
Oxidative Processes and Antioxidant Defense
Mechanisms in the Aging Brain ............................................ 87
Mitochondria, Oxidative Stress and Aging .............................. 91
Conclusions ............................................................................... 93
5. Oxidative Stress in Alzheimer's Disease .................................. 99
Introduction and Neuropathology ........................................... 99
Genetic Heterogeneity ............................................................ 101
Risk Factors ............................................................................. 102
The "Oxidative Stress" Hypothesis
in Alzheimer's Disease ..... .. .. . . . . . . . . . . . ................. ....... .. .. . . . . . . . .. 104
Antioxidant Defense Mechanisms in Alzheimer's Disease ... 107
Amyloid Precursor Protein in the Pathogenesis
of Alzheimer's Disease ......................................................... 112
Glycated Tau in the Neuropathogenesis
of Alzheimer's disease ................... .................. ................. ... 115
Amyloid Peptide in the Pathogenesis
of Alzheimer's disease ......................................................... 116
Oxidative Stress in Amyloid Peptide Toxicity ....................... 119
Conclusion ............................................................................... 127
6. Oxidative Stress in Down's Syndrome ................................... 141
Down's Syndrome, Alzheimer's Disease,
and Their Relationships ...................................................... 141
Copper-Zinc Superoxide Dismutase Overexpression
in Down's Syndrome ........................................................... 142
Cellular Models Overexpressing Copper-Zinc
Superoxide Dismutase ......................................................... 143
Transgenic Mice Expressing the Human CuZnSOD Gene ... 146
Genetic Manipulations of Other Superoxide Dismutases .... 153
Conclusions ............................................................................. 153
7. Oxidative Stress in Amyotrophic Lateral Sclerosis ............... 159
Introduction and Clinical Pathology ..................................... 159
Etiology: Possible Causes of Motor Neuron Disease ............. 160
CuZnSOD Gene Mutations in FALS ...................................... 160
The Peroxynitrite Nitration Hypothesis of ALS .................... 161
A Gain-of-Function ofCuZnSOD in FALS? ......................... 162
Cellular and Animal Models with Downregulation
or Mutation of Copper-Zinc Superoxide Dismutase ........ 163
N eurofilaments and ALS ......................................................... 167
Oxidative Stress, Excitotoxicity and Motor Neuron
Selectivity in ALS ................................................................. 167
Concluding Questions ............................................................ 169
8. Oxidative Stress in Parkinson's Disease ................................. 175
Introduction and Neuropathology ......................................... 175
Etiology of Parkinson's Disease .............................................. 175
The 'Free Radical' Hypothesis ................................................ 176
Evidence of Oxidant Stress in the Substantia Nigra .............. 176
Mitochondrial Dysfunction in Parkinson's Disease .............. 180
Neuronal Consequences of a Selective Depletion
of Glutathione in Experimental Models ............................. 181
New "Radical" Directions in Parkinson's Disease ................. 185
Preventive or Therapeutic Implications ................................ 186
9. Conclusions .............................................................................. 195
Index ........................................................................................ 199
PREFACE
O
xidative stress refers to the cytotoxic consequences of reactive oxy
gen species (ROS) which are generated as by-products of normal or
aberrant metabolic processes that utilize molecular oxygen, or changes
in protection systems. Thus, generation of ROS is a part of normal life
and their interaction with host defense systems appears to exert a sig
nificant influence on the normal and abnormal functioning of the cen
tral nervous system. Oxidative stress could also be a secondary conse
quence of defects in energy metabolism involving mitochondria. A
subbtle shift toward the prooxidant status that occurs in brain aging
could contribute to the pathogenesis and neuropathology of
neurodegenerative disorders exemplified by Alzheimer's disease,
Parkinson's disease and amyotrophic lateral sclerosis. The attractive fea
ture of the oxidative stress hypothesis is that it can account for cumula
tive damage associated with the delayed onset and the progressive na
ture of these conditions. Oxidative damage may constitute a common
pathogenic link between these seemingly diverse neurodegenerative dis
orders.
This book examines current knowledge and recent advances of
fundamental processes involved in neuronal death, particularly oxida
tive stress as a causal, or at least an ancillary, factor in neuronal death.
This book also presents an up-to-date account of the current state of
knowledge about of oxidative stress in neuronal apoptosis and its role in
the neuropathogenesis of age-related neurodegenerative diseases. The
first chapters are devoted to the biology of oxidative stress, biochemical
consequences of damaging free radical reactions in the brain, and their
participation in neurodegenerative processes. Another part of the book
will describe the role of ROS in activation of transcription factors and
its oxidative influence on gene expression, with links to alterations in
cell signalling processes and to neuronal death. Some chapters will ad
dress recent progress in understanding the relationships between its oxi
dative stress, excitotoxicity, mitochondria in neuronal apoptosis and the
potential role for apoptosis in neurodegeneration. The central role of
oxidative stress in the major age-related neurodegenerative disorders is
critically reviewed and potential prevention and therapy by antioxidants
is examined.
====ABBREVIATIONS====
AA: arachidonic acid
Ap: amyloid peptide
AD: Alzheimer's disease
AGE: advanced glycated end products
ALS: amyotrophic lateral sclerosis
AMPA: a.-amino-3-hydro:xy-5-methyl-4-isoxasole
AP-I: Activator protein 1
ApoE: apolipoprotein E
APP: amyloid peptide precursor
ARE: antioxidant response element
ATP: adenosine triphosphate
ATPases: adenosine triphosphatases
BDNF: brain-derived neurotrophic factor
bFGF; basic fibroblast factor
BHA: butylated hydroxyanisole
CI: complex I
CII: complex II
CIV: cytochrome oxidase
CA: cornu ammonis
CAT: catalase
Cdk: cyclin-dependent kinase
ChAT: choline acetyl transferase
CK: creatine kinase
CNS: central nervous system
Cox: cytochrome oxidase
CSF: cerebrospinal fluid
CS: citrate synthase
CuZnSOD: copper-zinc superoxide dismutase
DA: dopamine
DCF: dichlorofluorescin
DMPO: 5,5-dimethyl-1 pyrroline-N-oxide
DOPAC: dihydroxyphenylacetic acid
DS: Down's syndrome
e-: electron
EAA: Excitatory amino-acids
EC-SOD: extracellular superoxide dismutase
EPR: electron paramagnetic resonance
EpRE: electrophile response element
ERK2: extracellular signal-regulated protein kinase
ETC: electron transport chain
