Activation of group III metabotropic glutamate receptors is neuroprotective in cortical cultures

(RS)-α-Methyl-4-phosphonophenylglycine (MPPG) and (S)-α-methyl-3-carboxyphenylalanine (M3CPA), two novel preferential antagonists of group III metabotropic glutamate (mGlu) receptors, antagonized the neuroprotective activity of L-2-amino-4-phosphonobutanoate (L-AP4) or L-serine-O-phosphate in mice cultured cortical cells exposed to a toxic pulse of N-methyl-D-aspartate. In contrast, MPPG did not influence the neuroprotective activity of the selective group II mGlu receptors agonist, (2(S),1'(R),2'(R),3'(R))-2-(2,3-dicarboxycyclopropyl) glycine (DCG-IV). These results indicate that activation of group m mGlu receptors exerts neuroprotective activity against excitotoxic neuronal death. At least one of the two major group III mGlu receptor subtypes, i.e. mGlu₄ receptor, is expressed by cultured cortical neurons, as shown by immunocytochemical analysis with specific polyclonal antibodies.