The role of group I metabotropic glutamate (mGlu) receptors in neurodegeneration is controversial because of the contradictory effects of mGlu1/5 agonists in in vitro models of neuronal cell death. In this study, novel and selective antagonists of mGlu1 and mGlu5: LY367385 and LY367366 were found to show consistent neuroprotective effects against N-methyl-D-aspartate (NMDA)-induced excitotoxicity in vitro and in vivo. Furthermore, intraventricular administration of LY367385 reduced hippocampal cell death in gerbils subjected to transient global ischemia, Previous studies have also shown that activation of group II mGlu receptors may contribute to neuroprotective mechanisms in vitro and in vivo. Three potent group II mGlu agonists-LY354740, LY379268 and LY389775-were found to attenuate both NMDA excitotoxicity and staurosporine-induced neuronal cell death. LY354740 and LY379268 were protective against transient global Ischemia in gerbils when dosed Intraperitoneally. These results support the view that antagonists of mGlu1 and mGlu5 and agonists of group II mGlu receptors may be useful agents in the therapeutic treatment of neurodegenerative disease.