THE ACTION OF CGS-19755 ON THE REDOX ENHANCEMENT OF NMDA TOXICITY IN RAT CORTICAL-NEURONS INVITRO

The effects of the competitive N-methyl-D-aspartate receptor antagonist CGS-19755 (cis-4-phosphonomethyl-2-piperidine carboxylic acid) were studied in cultures of rat cerebral cortex under normal and altered redox conditions. CGS-19755 was effective in preventing delayed neuronal death produced by an acute exposure to either glutamate (500-mu-M) or NMDA (200-mu-M), but was ineffective in protecting neurons against the toxicity induced by a prolonged exposure to kainate (500-mu-M). We observed that the reducing agent dithiothreitol (DTT, 500-mu-M), could dramatically enhance toxicity and electrophysiological responses produced by 50-mu-M NMDA. CGS-19755 (100-mu-M) could effectively block both of these effects of DTT. Any toxicity produced by DTT alone was also antagonized by CGS-19755. In contrast, oxidized DTT did not enhance NMDA toxicity nor was it toxic when added alone. These results indicate that CGS-19755 is an effective and specific neuroprotectant acting at the NMDA receptor in vitro, and that the enhancement in NMDA toxicity induced by DTT is mediated by an increase in activity at this receptor complex.