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Journal of Neuroscience, Vol 14, 4385-4392, Copyright © 1994 by Society for Neuroscience
Macromolecular synthesis inhibitors prevent oxidative stress-induced apoptosis in embryonic cortical neurons by shunting cysteine from protein synthesis to glutathione
RR Ratan, TH Murphy and JM Baraban
Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Although macromolecular synthesis inhibitors have been demonstrated to
prevent neuronal apoptosis in a number of paradigms, their mechanisms of
protection remains unclear. Recently, we found that neuronal death
resulting from cystine deprivation, glutathione loss, and oxidative stress
is apoptotic and is prevented by inhibitors of macromolecular synthesis. We
now report that protection is associated with enhanced availability of
acid-soluble cyst(e)ine and restoration of cellular glutathione levels.
N-acetylcysteine, an agent that delivers exogenous cysteine intracellularly
and raises glutathione, is also protective, while buthionine sulfoximine,
an inhibitor of glutathione synthesis, prevents protection by inhibitors of
macromolecular synthesis. These results suggest that protection provided by
these agents, in this paradigm, derives from shunting of the amino acid
cysteine from global protein synthesis into the formation of the
antioxidant glutathione.
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