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Journal of Neuroscience, Vol 14, 2924-2932, Copyright © 1994 by Society for Neuroscience
Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes
A Volterra, D Trotti, C Tromba, S Floridi and G Racagni
Center of Neuropharmacology, Institute of Pharmacological Sciences, University of Milan, Italy.
Formation of reactive oxygen species and disfunction of the excitatory
amino acid (EAA) system are thought to be key events in the development of
neuronal injury in several acute and long-term neurodegenerative diseases.
Recent evidence suggests that the two phenomena may be interdependent. The
present study is aimed at exploring possible molecular mechanisms
underlying oxygen radical-EAA interaction. Exposure of cortical astrocytic
cultures to either xanthine + xanthine oxidase (X/XO), a free
radical-generating system, or hydrogen peroxide (H2O2) results in a marked
decrease of high-affinity glutamate transport. Within 10 min of X/XO
application, uptake falls to approximately 60% of its control value. In
parallel no detectable release of lactate dehydrogenase occurs. X/XO effect
is abolished in the presence of a mixture of scavenger enzymes (superoxide
dismutase+catalase) or by the disulfide-reducing agents glutathione and
dithiothreitol (DTT), but not by lipophilic antioxidants or ascorbate. The
time course of inhibition shows an almost linear decline of glutamate
transport during cell exposure to free radicals, while upon their
inactivation the decline stops but established inhibition persists for at
least 1 hr. In this situation, application of DTT significantly restores
transport function. These data suggest that free radicals inhibit glutamate
uptake primarily by long-lasting oxidation of protein sulfhydryl (SH)
groups. Chemical modifiers of free SH groups, such as
p-chloromercuribenzoate and N-ethylmaleimide, also induce uptake
inhibition. Na+/K+ ATPase is a known target of oxygen radicals and may be
involved in glutamate uptake inhibition. Indeed, ouabain, a blocker of the
pump, reduces uptake in astrocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
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