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Journal of Neuroscience, Vol 13, 1441-1453, Copyright © 1993 by Society for Neuroscience
Vulnerability of oligodendroglia to glutamate: pharmacology, mechanisms, and prevention
A Oka, MJ Belliveau, PA Rosenberg and JJ Volpe
Department of Neurology and Program in Neuroscience, Children's Hospital, Boston, Massachusetts 02115.
Periventricular white matter injury, the principal variety of brain injury
of the human premature infant, involves differentiating oligodendroglia.
Nothing is known of the biochemical mechanism of oligodendroglial death in
this disorder. Because an early event in periventricular white matter
injury is ischemia-induced axonal disruption and because such axonal
destruction could lead to a marked increase in local concentrations of
glutamate, we evaluated the vulnerability of differentiating
oligodendroglia to glutamate in a culture model. Oligodendroglia were
isolated from mixed-glial primary cultures by a selective detachment
technique and grown in a primary culture under conditions that lead to
differentiation. These oligodendroglia were found to be highly vulnerable
to glutamate-induced cell death. The EC50 for glutamate for a 24 hr
exposure was approximately 200 microM, comparable to the value reported for
neurons in conventional cerebral cortical cultures. Astrocytes, in
contrast, were shown to be resistant to as much as 5 mM glutamate. Study of
glutamate receptor antagonists and glutamate transport substrates showed
that the glutamate-induced oligodendroglial death was not related to a
receptor mechanism, as operates in neurons, but rather was secondary to
glutamate uptake by the oligodendroglia. Glutamate transport by
high-affinity, sodium-dependent and by sodium-independent systems was
shown. The central importance of glutamate uptake for the toxic effect of
glutamate was shown by total prevention of the oligodendroglial toxicity by
the simultaneous inhibition of glutamate uptake by the specific inhibitor
D,L-threo-beta-hydroxyaspartate. Subsequent observations showed that the
toxicity of glutamate was mediated by free radical attack, the consequence
of glutathione depletion, apparently caused by the action of a
glutamate-cystine exchange mechanism that results in cystine and thereby
glutathione depletion. Thus, addition of cystine or cysteine totally
prevented the glutamate toxicity to oligodendroglia. Second, glutamate
exposure led to cystine efflux. Third, glutathione levels decreased
markedly in cells exposed to glutamate, and this marked decrease preceded
the loss of cell viability. Fourth, glutamate toxicity could be prevented
totally by exposure to different free radical scavengers, vitamin E and
idebenone. The data thus show that glutamate is highly toxic to
oligodendroglia. Moreover, the findings raise the possibilities that such
glutamate toxicity is operative in the oligodendroglial cell death
associated with ischemic processes that disrupt axons, such as
periventricular white matter injury of the premature infant, and that novel
therapies directed against glutamate transport, glutathione depletion, and
free radical attack might be beneficial in prevention of that injury.
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