Selective blockade of metabotropic glutamate receptor subtype 5 is neuroprotective

We have used potent and selective non-competitive antagonists of metabotrop ic glutamate receptor subtype 5 (mGlu5) - 2-methyl-6-phenylethenylpyridine (MPEP), [6-methyl-2-(phenylazo)-3-pyridinol] (SIB-1757) and [(E)-2-methyl-6 -(2-phenylethenyl)pyridine] (SIB-1893) - to examine whether endogenous acti vation of this particular metabotropic glutamate receptor subtype contribut es to neuronal degeneration. In cortical cultures challenged with N-methyl- D-aspartate (NMDA), all three mGlu5 receptor antagonists were neuroprotecti ve. The effect of MPEP was highly specific because the close analogue, 3-me thyl-6-phenylethynylpyridine (iso-MPEP), which did not antagonize heterolog ously expressed mGlu5 receptors, was devoid of activity on NMDA toxicity. N europrotection by mGlu5 receptor antagonists was also observed in cortical cultures challenged with a toxic concentration of P-amyloid peptide. We hav e also examined the effect of mGlu5 receptor antagonists in in vivo models of excitotoxic degeneration. MPEP and SIB-1893 were neuroprotective against neuronal damage induced by intrastriatal injection of NMDA or quinolinic a cid. These results indicate that mGlu5 receptors represent a suitable targe t for novel neuroprotective agents of potential application in neurodegener ative disorders. (C) 2000 Elsevier Science Ltd. All rights reserved.