EXCITOTOXICITY AND OXIDATIVE STRESS DURING INHIBITION OF ENERGY-METABOLISM

Glutamate receptor involvement and oxidative stress have both been imp licated in damage to neurons due to impairment of energy metabolism. U sing two different neuronal in vitro model systems, an ex vivo chick r etinal preparation and dopamine neurons in mesencephalic culture, the involvement and interaction of these events as early occurring contrib utors to irreversible neuronal damage have been examined. Consistent w ith previous reports, the early acute changes in the retinal preparati on, as well as irreversible loss of dopamine neurons due to inhibition of metabolism, can be prevented by blocking NMDA receptors during the time of energy inhibition. Oxidative stress was suggested to be a dow nstream consequence and contributor to neuronal cell loss due to eithe r glutamate receptor overstimulation or metabolic inhibition since tra pping of free radicals with the cyclic nitrone spin-trapping agent MDL 102,832 (1 mM) attenuated acute excitotoxicity in the retinal prepara tion or loss of mesencephalic dopamine neurons due to either metabolic inhibition by the succinate dehydrogenase inhibitor, malonate, or exp osure to excitotoxins. In mesencephalic culture, malonate caused an en hanced efflux of both oxidized and reduced glutathione into the medium , a significant reduction in total reduced glutathione and a significa nt increase in total oxidized glutathione at time points that preceded those necessary to cause toxicity. These findings provide direct evid ence for early oxidative events occurring following malonate exposure and suggest that the glutathione system is important for protecting ne urons during inhibition of energy metabolism. Consistent with this, lo wering of glutathione by buthionine sulfoxamine (BSO) pretreatment gre atly potentiated malonate toxicity in the mesencephalic dopamine popul ation. In contrast. BSO pretreatment did not potentiate glutamate toxi city. This latter finding indicates dissimilarities in the type of oxi dative stress that is generated by the two insults and suggests that t he oxidative challenge during energy inhibition is not solely a downst ream consequence of glutamate receptor overstimulation.