ANTAGONISTS FOR GROUP-I MGLURS ATTENUATE EXCITOTOXIC NEURONAL DEATH IN CORTICAL CULTURES

Activation of ion channel-linked glutamate receptors, especially N-met hyl-D-aspartate (NMDA) receptors, mediates the excitotoxic effects of glutamate upon central neurons. We examined the hypothesis that activa tion of group I metabotropic glutamate receptors (mGluRs) would increa se NMDA receptor-mediated cortical neuronal death. Addition of the sel ective group I mGluR agonists, dihydroxyphenylglycine (DHPG) or trans- azetidine-2,4-dicarboxylic acid (t-ADA) potentiated NMDA-induced neuro nal death, and application of the group I mGluR-selective antagonist, aminoindan-1,5-dicarboxylic acid (AIDA), as well as the non-selective antagonists methyl-4-carboxyphenylglycine (MCPG) or 4-carboxyphenylgly cine (4CPG) reduced NMDA- and kainate-induced neuronal death in murine cortical cultures. The pro-excitotoxic effect of group I mGluR activa tion may be mediated largely by enhancement of glutamate release, as D HPG potentiated high potassium-stimulated glutamate release, and the p rotective effects of both AIDA and MCPG were abolished when NMDA and a lpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) recep tors were blocked immediately after toxic NMDA receptor overstimulatio n. The present data support the possibility that antagonizing group I mGluRs may be a useful strategy for attenuating excitotoxic neuronal d eath in certain disease states.