Journal of neuroscience research
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Glutamate transporters are coupled with cystine/glutamate antiporters to supply cystine as a component of glutathione, an important antioxidant. We sought evidence that L-trans-pyrrolidine-2,4-dicarboxylate (PDC) enhances glutamate-induced neuronal damage not only via the N-methyl-D-aspartate (NMDA) receptor mediated pathway, but also through induction of oxidative stress. Cultured hippocampal cells were exposed to glutamate (100 microM) for 5 min, washed and incubated for 18 hr with PDC (200 microM). ⋯ The NMDA receptor antagonist MK-801, although partially effective in reducing PDC toxicity, slightly recovered glutathione level but did not reduce the reactive oxygen species even at a high concentration (100 microM). N-acetylcysteine, dimethylsulfoxide, alpha-phenyl-N-butyl nitrone and glutathione ethylester prevented neuronal death enhanced by PDC, but superoxide dismutase and catalase did not. Our study provides evidence that the block of glutamate uptake by PDC exerts toxicity on glutamate-pretreated neurons not only through the accumulation of extracellular glutamate and subsequent activation of the NMDA receptor but also through depletion of glutathione and generation of reactive oxygen species.