Activation of multiple metabotropic glutamate receptor subtypes prevents NMDA-induced excitotoxicity in rat hippocampal slices

Metabotropic glutamate receptors (mGluRs) belong to a relative large receptor family consisting of multiple members with important roles in a number of brain functions. We report here that activation of mGluRs prevents the neurotoxic effect induced by N-methyl-D-aspartate (NMDA) in slices from the rat hippocampus. Neuroprotection was elicited when slices were simultaneously exposed to both the selective mGluR agonist (+/-)-1-aminocyclopentane-trans-1,3-dicarboxylic acid (tACPD) and NMDA. Persisting stimulation of mGluRs after the toxic exposure did not improve the survival of pyramidal or granular cells. The neuroprotection elicited by tACPD toxic exposure did not improve the survival of pyramidal or granular cells. The neuroprotection elicited by tACPD was also evoked by its active isomer, (1S, 3R)-ACPD, and was prevented by the selective mGluR antagonist (+)-alpha-methyl-4-carboxyphenyl-glycine (500 microM), confirming that mGluR activation is involved in the mechanism of action of tACPD. The effect of 100 microM tACPD was reproduced by 100 microM quisqualate, an agonist of mGluR2 and mGluR3 subtypes. No neuroprotection was induced by L-2-amino-4-phosphonobutyrate, a selective agonist for mGluR4, mGluR6, mGluR7 and mGluR8, at 500 microM. Since the NMDA-mediated cell death in hippocampal slices is considered relevant to ischaemia-induced brain injury, these results indicate that mGluRs may be important safety devices used by neurons to decrease their sensitivity to excitotoxic stimuli and increase their chance of survival.