GLUTAMATE NEUROTOXICITY IS ASSOCIATED WITH NITRIC OXIDE-MEDIATED MITOCHONDRIAL DYSFUNCTION AND GLUTATHIONE DEPLETION

The role of mitochondrial energy metabolism in glutamate mediated neur otoxicity was studied in rat neurones in primary culture. A brief (15 min) exposure of the neurones to glutamate caused a dose-dependent (0. 01-1 mM) increase in cyclic GMP levels together with delayed (24 h) ne urotoxicity and ATP depletion. These effects were prevented by either the nitric oxide ((NO)-N-.) synthase (NOS) inhibitor Nw-nitro-L-argini ne methyl ester (NAME; 1 mM) or by the N-methyl-D-aspartate (NMDA) glu tamate-subtype receptor antagonist D-(-)-2-amino-5-phosphonopentanoate (APV; 0.1 mM). Glutamate exposure (0.1 mM and 1 mM) followed by 24 h of incubation caused the inhibition of succinate-cytochrome c reductas e (20-25%) and cytochrome c oxidase (31%) activities in the surviving neurones, without affecting NADH-coenzyme-Q(1) reductase activity. The rate of oxygen consumption was impaired in neurones exposed to 1 mM g lutamate, either with glucose (by 26%) or succinate (by 39%) as substr ates. These effects on the mitochondrial respiratory chain and neurona l respiration, together with the observed glutathione depletion (20%) by glutamate exposure were completely prevented by NAME or APV. Our re sults suggest that mitochondrial dysfunction and impairment of antioxi dant status may account for glutamate-mediated neurotoxicity via a mec hanism involving (NO)-N-. biosynthesis. (C) 1998 Elsevier Science B.V.