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 III mGlu receptors exerts neuroprotective activity against excitotoxic neuronal death. At least one of the two major group III mGlu receptor subtypes, i.e. mGlu 4 receptor, is expressed by cultured cortical neurons, as shown by immunocytochemical analysis with specific polyclonal antibodies.