THE INHIBITORY MGLUR AGONIST, S-4-CARBOXY-3-HYDROXY-PHENYLGLYCINE SELECTIVELY ATTENUATES NMDA NEUROTOXICITY AND OXYGEN GLUCOSE DEPRIVATION-INDUCED NEURONAL DEATH

We examined the effect of two novel phenylglycine derivative drugs on excitotoxicity in murine cortical cell cultures: s-4-carboxy-3-hydroxy-phenylglycine (4C3HPG), a selective agonist of mGluRs 2/3 and an antagonist at mGluRs 1/5, and s-3 hydroxy-phenylglycine (3HPG), an agonist of mGluRs 1/5. 4C3HPC attenuated slowly-triggered NMDA-induced excitotoxic neuronal death, as well as the death induced by combined oxygen-glucose deprivation, but did not affect slowly-triggered excitotoxicity induced by AMPA or kainate. As expected, 4C3HPG also reduced NMDA-induced increases in cAMP in near-pure neuronal cultures, and the protective effect of 4C3HPG on NMDA toxicity could be reversed by adding 8-(4-chlorophenylthio)adenosine 3':5'-cyclic-monophosphate (CPT cAMP) to the exposure medium. In contrast, 3HPG did not did not have any protective effects in these paradigms; in fact, slowly-triggered NMDA-induced excitotoxicity and the neuronal cell death induced by oxygen-glucose deprivation were potentiated. These results are consistent with the idea that the ''inhibitory'' mGluRs 2/3 exert a negative modulatory action on NMDA receptor-mediated excitotoxicity via reduction in neuronal cAMP levels.