Neurochemical Aspects of Excitotoxicity

298 Pages·2008·3.09 MB·English

by  Akhlaq A. Farooqui, Wei-Yi Ong, Lloyd A. Horrocks (auth.)

Neurochemical Aspects
of Excitotoxicity
Neurochemical Aspects
of Excitotoxicity
Akhlaq A. Farooqui
The Ohio State University
Columbus, Ohio
Wei-Yi Ong
National University of Singapore
Singapore
and
Lloyd A. Horrocks
The Ohio State University
Columbus, Ohio
Akhlaq Farooqui Wei-Yi Ong
Department of Molecular Department of Anatomy
and Cellular Biochemistry Faculty of Medicine
The Ohio State University National University of Singapore
3120 Herrick Road Singapore
Columbus, Ohio
Note
We regret to note that Dr. Lloyd A. Horrocks passed away on August 18, 2007.
Dr. Horrocks grew up in Cincinnati, Ohio, and attended school at Ohio Wesleyan
University before earning a Ph.D. in Physiological Chemistry from The Ohio State
University in 1960. He served as a Project Engineer in the United States Air Force
from 1955–1958, and as a Research Associate at the Cleveland Psychiatric Institute
from 1960–1968 before joining the Department of Physiological Chemistry (now
Molecular Cellular Biochemistry) at The Ohio State University as an Assistant
Professor. He became full Professor in 1973, mentoring many graduate and post-
graduate students during his tenure. Dr. Horrocks retired in 1992, serving thereafter
as Professor Emeritus.
Dr. Horrocks is best known for his research on plasmalogen metabolism and
phospholipases A2 in the brain. He authored over 300 research papers, book chap-
ters, and reviews. He edited seven books, and published two monographs. He served
as the Editor-in-Chief of Neurochemical Pathology and was a member of numerous
journal editorial advisory boards, including those of the Journal of Neurochemistry,
the Journal of Lipid Research, Lipids, and Neurochemical Research. Dr. Horrocks
was dedicated to his family and the field of scientific research and writings. He was
a gentleman who will be greatly missed by his friends, students, and colleagues.
v
Preface
About 40% of central nervous system synapses use glutamate as the neurotransmit-
ter. It acts through ionotropic (NMDA, AMPA, and KA) and metabotropic types
of glutamate receptors and plays crucial roles in developmental synaptogenesis,
plasticity, long-term potentiation, and learning memory. Our understanding of the
diversity, structure, and functions of various glutamate receptors has advanced sig-
nificantly. Several splice variants of NMDA, AMPA, KA and metabotropic recep-
tors exist in brain tissue. Over-stimulation of glutamate receptors produces neuronal
injury or death by a mechanism called excitotoxicity. Excitotoxicity is closely asso-
ciated with neurochemical and neuropathological changes involved in acute neural
trauma (stroke, spinal cord trauma, and head injury) and neurodegenerative diseases
such as Alzheimer disease (AD), Parkinson disease (PD), Huntington disease (HD),
amyotrophic lateral sclerosis (ALS), Creutzfeldt-Jakob disease (CJD), Guam-type
amyotrophic lateral sclerosis/Parkinson dementia (ALS/PDC), and multiple sclero-
sis (MS).
In the past decade, our understanding of the biochemistry, molecular biology,
and neuropathology of the glutamate transporters and receptors has exploded. This
is also true for the signal transduction mechanisms involved in the production of
oxygen radicals, cytokines, and lipid mediators associated with neurodegenerative
process. It is becoming increasingly evident that molecular mechanisms, which
govern the transfer of the death signal from the neural cell surface to the nucleus,
depend on lipid mediators and on cross talk among excitotoxicity, oxidative stress,
and neuroinflammation. Thus, interactions among excitotoxicity, oxidative stress,
and neuroinflammation play a major role in neuronal cell death during acute neural
trauma and neurodegenerative disease. These processes may be primary initiating
points in neurodegeneration or they may be the end result of the neurodegenerative
process itself.
We are now empowered by technological advances in lipidomics, proteomics,
and genomics. Using these techniques, investigators characterize splice variants
of glutamate transporters and receptors and levels of lipid mediators and develop
diagnostic tests for neurodegenerative diseases associated with glutamate-mediated
toxicity. Moreover, the development of quantitative immunochemical localiza-
tion techniques allows us to characterize neurodegeneration in kainate-induced
model of neurotoxicity. Targeting molecular mechanisms of glutamate-mediated
cell death in neurological disorders for therapeutic interventions with glutamate
vii
viii Preface
receptor antagonists has become a realistic objective of studies on neurodegen-
erative diseases, stroke, and mechanical neural trauma. This objective is sup-
ported by the constantly expanding innovative biotechnological approaches to drug
design.
The purpose of this monograph is to present readers with a coherent overview
of cutting edge information on glutamate metabolism in brain, the role of glu-
tamate transporters, the involvement of glutamate receptors in the pathogenesis
of acute neural trauma and neurodegenerative diseases (AD, PD, HD, and ALS),
the treatment of these diseases with endogenous and exogenous antioxidants and
glutamate receptor antagonists in a manner that is useful to students and teach-
ers and also to researchers and physicians. Graduate students, neuroscientists and
physicians will refer to this monograph in their professional writing. The mono-
graph is user-friendly and designed in a way that graduate students in neuroscience
will benefit to have this book as a reference. A dedicated graduate course on
glutamate metabolism and toxicity in brain could use this monograph as a text-
book.
The monograph has eleven chapters. The first three chapters describe the
metabolism of glutamate in brain, cutting edge information on structure and
function of glutamate receptors, and properties of agonists and antagonists of
NMDA, AMPA, KA and metabotropic types of glutamate receptor in the cen-
tral nervous system. Chapter 4 is devoted to glutamate transporters and their
role in brain tissue. Chapter 5 describes the association of glutamate with neu-
ral membrane glycerophospholipid metabolism in brain. Chapter 6 covers the
effect of glutamate on neurochemical parameters other than neural membrane
glycerophospholipids. Chapter 7 deals with neurochemical mechanisms involved
in glutamate-mediated neuronal injury. Chapter 8 describes the association of
glutamate with neurological disorders (stroke, AD, PD, HD, ALS, MS, CJD,
AIDS dementia, and schizophrenia). Chapter 9 is devoted to the effects of
endogenous antioxidants and anti-inflammatory agents on glutamate toxicity in
brain. Chapter 10 describes the use of glutamate receptor antagonists for the
treatment of acute neural trauma and neurodegenerative diseases and Chapter 11
presents readers with future directions that should be followed to solve unre-
solved problems of glutamate-related neurological disorders and also discusses
new strategies for the antagonism of the NMDA type of glutamate receptors and
anti-inflammatory nutraceuticals. The chosen topics presented in this monograph
are personal. They are based on our interest on glutamate metabolism in neu-
rological disorders and in areas where major progress has been made. We have
tried to ensure uniformity and mode of presentation as well as a logical progres-
sion from one topic to another and have provided extensive referencing. For the
sake of simplicity and uniformity a large number of figures and line diagrams
of signal transduction pathways are also included. Our attempt to integrate and
consolidate knowledge of glutamate metabolism and glutamate-mediated signal
transduction processes in brain will provide the basis for more dramatic advances
and developments in the involvement of glutamate receptors in neurological
disorders and in new strategies for the antagonism of excitotoxicity, oxidative
Preface ix
stress, and inflammation using endogenous and exogenous glutamate receptor
antagonists, antioxidants, and anti-inflammatory agents in the central nervous
system.
Akhlaq A. Farooqui
Wei-Yi Ong
Lloyd A. Horrocks
Acknowledgments
We would like to thank a number of publishers who have granted us permission
to reproduce figures from our earlier papers published by them. These include
Springer-Verlag, Heidelberg, Germany; Elsevier Ltd, Oxford, U.K.; Blackwell Pub-
lishing, Oxford, U.K.; and Lippincott William and Wilkins, Baltimore, USA. We
would also like to thank Tahira Farooqui, Siew-Mei Lim, and Marjorie Horrocks for
their patience, understanding, and moral support during preparation of this mono-
graph and Siraj A. Farooqui for drawing chemical structures of glutamate receptor
agonists and antagonists.
Akhlaq A. Farooqui
Wei-Yi Ong
Lloyd A. Horrocks
xi
Contents
1 Glutamate and Aspartate in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.2 Glutamate Synthesis and Release in Brain . . . . . . . . . . . . . . . . . . . . . . 2
1.3 Glutamate-Related Metabolic Interactions Between Neurons and
Glial Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
1.4 Roles of Glutamate in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
1.4.1 Glutamate and Intermediary Energy Metabolism . . . . . . . . . . 9
1.4.2 Glutamate as a Putative Neurotransmitter . . . . . . . . . . . . . . . . . 10
1.4.3 Glutamate as a Metabolic Precursor of GABA . . . . . . . . . . . . 10
1.4.4 Glutamate and Detoxification of Ammonia . . . . . . . . . . . . . . . 11
1.4.5 Glutamate as a Constituent of Proteins . . . . . . . . . . . . . . . . . . . 12
1.4.6 Glutamate as a Constituent of Small Peptides . . . . . . . . . . . . . 12
1.4.7 Glutamate and Intracellular Osmotic and Ionic Homeostasis . 13
1.4.8 Glutamate in Learning and Memory . . . . . . . . . . . . . . . . . . . . . 13
1.5 Aspartate Metabolism in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2 Excitatory Amino Acid Receptors in Brain . . . . . . . . . . . . . . . . . . . . . . . . . 21
2.1 Ionotropic Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.1.1 NMDA Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.1.2 NMDA Receptor Agonists and Antagonists . . . . . . . . . . . . . . . 25
2.1.3 Kainic Acid Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.1.4 Agonists and Antagonists of KAR. . . . . . . . . . . . . . . . . . . . . . . 26
2.1.5 AMPA Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.1.6 Agonists and Antagonists of AMPA Receptors . . . . . . . . . . . . 28
2.2 Metabotropic Glutamate Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.3 Glutamate Receptors and Glutamate-Mediated Neural Cell Death . . 31
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3 Multiplicity of Glutamate Receptors in Brain . . . . . . . . . . . . . . . . . . . . . . . 37
3.1 Structure and Distribution of NMDA Receptor Subunits in Brain . . . 37
3.2 Structure and Distribution of KA Receptor Subunits in Brain . . . . . . 40
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xiv Contents
3.3 Structure and Distribution of AMPA Receptor Subunits in Brain . . . 43
3.4 Structure and Distribution of Metabotropic Glutamate Receptor
Subunits in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
4 Glutamate Transporters and Their Role in Brain . . . . . . . . . . . . . . . . . . . 51
4.1 Astrocytic Glutamate Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52
4.2 Neuronal Glutamate Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
4.2.1 EAAT3 in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
4.2.2 EAAT4 in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
4.2.3 EAAT5 in Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61
4.3 Vesicular Glutamate Transporters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
4.4 Glutamate Transporters in Neurological Disorders . . . . . . . . . . . . . . . 64
4.5 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
5 Excitatory Amino Acid Receptors and Their Association with Neural
Membrane Glycerophospholipid Metabolism . . . . . . . . . . . . . . . . . . . . . 75
5.1 Effects of Glutamate on Glycerophospholipid Synthesis . . . . . . . . . . 77
5.2 Effects of Glutamate on Glycerophospholipid Degradation . . . . . . . . 78
5.3 Physiological and Pathophysiological Effects of Released AA in
Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
5.3.1 Physiological Effects of AA . . . . . . . . . . . . . . . . . . . . . . . . . . . . 88
5.3.2 Pathophysiological Effects of AA . . . . . . . . . . . . . . . . . . . . . . . 89
5.4 Physiological and Pathophysiological Effects of Lyso-
Glycerophospholipids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
5.4.1 Physiological Effects of Lyso-Glycerophospholipids . . . . . . . 90
5.4.2 Pathophysiological Effects of Lyso-Glycerophospholipids . . . 91
5.5 Physiological and Pathophysiological Effects of PAF . . . . . . . . . . . . . 92
5.5.1 Physiological Effects of PAF . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
5.5.2 Pathophysiological Effects of PAF . . . . . . . . . . . . . . . . . . . . . . 93
5.6 Physiological and Pathophysiological Effects of Eicosanoids . . . . . . 94
5.6.1 Neurotrophic Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 94
5.6.2 Pathophysiological Effects of Eicosanoids . . . . . . . . . . . . . . . . 95
5.7 Neuroprotective Effects of NMDA Receptors . . . . . . . . . . . . . . . . . . . 96
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
6 Glutamate Receptors and Their Association with Other
Neurochemical Parameters in Excitotoxicity . . . . . . . . . . . . . . . . . . . . . . 105
6.1 Glutamate Toxicity and Production of Free Radicals and Lipid
Peroxides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
6.2 Glutathione Levels in Neurotoxicity Mediated by Glutamate . . . . . . . 107
6.3 4-Hydroxynonenal Generation in Neurotoxicity Mediated
by Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 109
6.4 NF-κB in Glutamate Neurotoxicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111
6.5 Protein Kinase C in Neurotoxicity Mediated by Glutamate . . . . . . . . 112