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Table of Contents
                            Front Matter
Glutamate and Aspartate in Brain
Excitatory Amino Acid Receptors in Brain
Multiplicity of Glutamate Receptors in Brain
Glutamate Transporters and Their Role in Brain
Excitatory Amino Acid Receptors and Their Association with Neural Membrane Glycerophospholipid Metabolism
Glutamate Receptors and Their Association with Other Neurochemical Parameters in Excitotoxicity
Possible Mechanisms of Neural Injury Caused by Glutamate and Its Receptors
Glutamate Receptors and Neurological Disorders
Endogenous Antioxidant Mechanisms and Glutamate Neurotoxicity
Glutamate Receptor Antagonists and the Treatment of Neurological Disorders
Future Perspectives: New Strategies for Antagonism of Excitotoxicity, Oxidative Stress and Neuroinflammation in Neurodegenerative Diseases
Back Matter
Document Text Contents
Page 1

Neurochemical Aspects
of Excitotoxicity

Page 2

Neurochemical Aspects
of Excitotoxicity

Akhlaq A. Farooqui
The Ohio State University
Columbus, Ohio

Wei-Yi Ong
National University of Singapore


Lloyd A. Horrocks
The Ohio State University
Columbus, Ohio

Page 151

138 7 Mechanisms of Neural Injury Caused by Glutamate and Its Receptors

Table 7.1 Excitotoxicity-mediated alterations in enzymic activities in brain tissues

Enzyme Effect Reference

Phospholipase A2 Increased (Bartolomeo et al., 1997; Kim et al., 1995)
Phospholipase D Increased (Kim et al., 2004)
Lipoprotein lipase Increased (Paradis et al., 2004)
Cyclooxygenase Increased (Adams et al., 1996)
Lipoxygenase Increased (Manev et al., 1998)
Nitric oxide synthase Increased (Milatovic et al., 2002)
Calpain Increased (Ong et al., 1997)
Diacylglycerol lipase Increased (Farooqui et al., 1993)
Monoacylglycerol lipase Increased (Farooqui et al., 1993)
Protein kinases Increased (Vaccarino et al., 1987; Manev et al., 1989)
Endonucleases Increased (Siesjö, 1990)

arachidonic acid metabolites along with abnormal ion homeostasis, activation of
NOS, and protein kinases, alterations in cellular redox, and lack of energy genera-
tion, is associated with neural cell injury.

Glutamate-mediated damage to glial cells does not involve the activation of
glutamate receptors, but rather glutamate uptake (Oka et al., 1993; Matute et al.,
2006). Glutamate uptake from the extracellular space by specific glutamate trans-
porters is essential for maintaining excitatory postsynaptic currents (Auger and
Attwell, 2000) and for blocking excitotoxic death due to overstimulation of glu-
tamate receptors (Rothstein et al., 1996) (Chapter 4). Exposure of astroglial, oligo-
dendroglial, and microglial cell cultures to glutamate produces glial cell demise by
a transporter-related mechanism involving the inhibition of cystine uptake, which
causes a decrease in glutathione and makes glial cells vulnerable to toxic free radi-
cals (Oka et al., 1993; Matute et al., 2006). The accumulation of extracellular glu-
tamate at the synapse is toxic to neurons. Astrocytes protect neurons by removing
glutamate from the extracellular space through glutamate transporters. If removal of
glutamate from the synapse does not keep pace with accumulation, neuronal damage
may occur. Thus, by regulating the levels of extracellular glutamate that have access
to these receptors, glutamate uptake systems have the potential to affect both normal
synaptic signaling and the abnormal over-activation of the receptors that can trigger
excitotoxic cell death.

Neural injury mediated by glutamate involves two important components: neu-
roinflammation, a neuroprotective mechanism whose prolonged presence is inju-
rious to neurons, and oxidative stress, cytotoxic consequences produced by oxy-

Table 7.2 Excitotoxicity-mediated changes in neurochemical parameters involved in oxidative

Neurochemical parameter Effect Reference

Free radicals and lipid peroxides Increased (Wang et al., 2005)
4-Hydroxynonenal Increased (Ong et al., 2001)
Glutathione Increased (Ong et al., 2001)
Cytochrome c Increased (Garrido et al., 2001)
F2-isoprostane Increased (Pepicelli et al., 2005)

Page 152

7.2 Glutamate-Mediated Inflammation and Neural Cell Injury 139

gen free radicals. Although neuroinflammation and oxidative stress may occur
independently, growing evidence indicates that ROS formation may be a specific
consequence of glutamate receptor activation, and may partly mediate excitotoxic
neuronal injury (Olney et al., 1979; Choi, 1988). Neuroinflammation and oxidative
stress are interrelated processes that may bring about neural cell demise indepen-
dently or synergistically.

It remains controversial whether inflammation and oxidative stress are the cause
or consequence of neural injury (Andersen, 2004; Juranek and Bezek, 2005). Sim-
ilarly, very little information is available on neural injury and clinical expression
of inflammation and oxidative stress with trauma and neurodegenerative diseases
involving neural cell death mediated by glutamate through apoptosis as well as
necrosis (Farooqui et al., 2004). Thus discovering the molecular mechanisms of
brain damage in acute neural trauma, ischemia, and the neurodegenerative diseases
AD and PD remains a most challenging area of neuroscience research (Graeber and
Moran, 2002).

7.2 Glutamate-Mediated Inflammation and Neural Cell Injury

Inflammation is a protective mechanism that isolates the damaged brain tissue
from uninjured areas, destroys affected cells, and repairs the extracellular matrix
(Correale and Villa, 2004). Inflammation is a “double-edged sword”. On one hand
the continuous antigenic challenge, duration, and intensity of inflammation dam-
ages neural cells through the synthesis of pro-inflammatory lipid mediators. On the
other hand immune-mediated processes induce neuroprotection and repair through
the generation of anti-inflammatory lipid mediators and repair proteins. Without a
strong inflammatory response, brain tissue would be highly susceptible to acute neu-
ral trauma, neurodegenerative diseases, and microbial, viral, and prion infections.

All neural cells, including microglia, astrocytes, neurons, and oligodendrocytes,
participate in inflammatory responses. Morphologically in brain tissue, major hall-
marks of inflammatory reaction are phenotypic changes of glial cells, mainly acti-
vation and transformation of microglial cells into phagocytic cells, and to a lesser
extent, reactive astrocytosis. Although the chemical nature of signals that initiate
the activation of microglial cells responding to inflammation remains unknown,
neuronal depolarization following injury combined with extracellular ion changes,
metabolic perturbations, and alterations in acid-base balance may be the major stim-
uli (Block and Hong, 2005).

The identity of factors released from damaged neurons to signal microglial cell
activation may depend upon which type of neural cell is damaged, neuron ver-
sus glial, and on the the toxin or stimulus, glutamate versus β-amyloid versus α-
synuclein, and the nature of cellular death, apoptosis versus necrosis. Similarly, the
molecular mechanisms and internal and external factors that modulate the dynamic
aspects of acute and chronic inflammation in cell injury mediated by glutamate
remain unclear. It also remains unclear to what extent inflammation is beneficial

Page 302

Index 289

NMDA receptor antagonists
aptiganel, 248
chronic pain, 255–256
dextrorphan, 248
efficacy of, 255
gavestinel (GV150526), 249
Huntington disease, 254
selfotel (CGS19755), 247

NMDA receptors, 22–24

production of ROS, 149
agonists and antagonists, 25
Ca2+ influx, opening, 107
domain, 22–23
effects of

on cPLA2, 82
diacylglycerol lipase and monoacyl-

glycerol lipase, 87
importance of, in ischemia, 243
physiological activity, 251
stimulation of, 167
structures of

competitive antagonists, 23
noncompetitive antagonists, 24

subunits, 37
in brain, 37–40

NR1, 37
subunit of brain tissue, 39

glutamate binding subunit, 38

NR3 subunit, 40

OmacorTM, 271
Oncomodulin, 148
Ornithine decarboxylase, 116
Oxaloacetate, 1
Oxidative glutamate toxicity, 207
Oxidative stress, 140–141, 148, 177, 208

involvement in pathogenesis of
ischemia, 208

2-oxoglutarate, 1

Parkinson disease (PD), 147, 181–182
role of glutamate in, 181–182

Phencyclidine, 251
Phosphatidylcholine (PtdCho)

degradation of, see PtdCho-specific PLC
inhibition of, 79

Phosphatidylserine (PtdSer), 80
Phospholipase A2 (PLA2), 81
Phosphorylation, 45
PKCγ phosphorylates, 115
PLA2, 45

brain oxidant and antioxidant proteins in,

Plasmalogens (PlsEtn), 211, 220
glutamate neurotoxicity, 220–222

Platelet-activating factor (PAF), 94
Positron emission tomography

(PET), 268
Priming, 4

synaptic transmission, 4–5
Prostaglandin H2 synthase-1 (PGHS-1), 209
Prostaglandins, 108
PtdCho-specific PLC, 88
Purkinje cells, 47, 59

Quinacrine, 82, 93–94

Radical and non-radical oxygen
species, 148

Reactive oxygen species (ROS), 109
chemical reactivity, 149, 209
damage to neural membranes

induced by, 150
effect of, on cellular components, 150
excess generation, cell injury, 188
generation of, 150
glutamate-mediated generation,

142, 145, 149
low and high concentration, 91–93
reaction between proteins and, 151
roles of, 209
synthesis in mitochondria, 139

Remacemide hydrochloride, 254
Resolution (inflammation), 146

docosanoids, 146
lipoxins, 146
molecular mechanism, 146
role of, generation of oxidized

glycerophospholipids, 146–147
defense strategies, 147

Resolvins, 146, 212
internal neuroprotective mechanism for

preventing brain damage, 271
structures of, 147

Resynthesis of intramitochondrial
glutamate, 1

ROS, see Reactive oxygen species (ROS)

Schizophrenia, 187–188
role of glutamate in, 187–188

Selfotel (CGS19755), 247
highest tolerated level, 247
neuropsychiatric symptoms, 247

Serine palmitoyltransferase (SPT), 128
Spinal chord injury, 167–168
Superoxide dismutase (SOD), 213–214

Page 303

290 Index

Synapses, 4
Synaptic plasticity

forms, 172
Synaptic transmission, 4–5

Thioredoxin (Trx), 153
reactions associated with, 153

Thromboxanes, 108

Toxicity, mediated by KA
neurochemical consequences, 108

Traumatic injury, 167
components, 167

Ubiquinol, see Coenzyme Q10 (CoQ10)

YM872, 250–251

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