期刊
NEUROPHARMACOLOGY
卷 39, 期 12, 页码 2223-2230出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/S0028-3908(00)00079-4
关键词
excitotoxicity; beta-amyloid toxicity; neuroprotection; mGlu5 receptors; non-competitive antagonists; MPEP; SIB-1757; SIB-1893
We have used potent and selective non-competitive antagonists of metabotropic 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 activation of this particular metabotropic glutamate receptor subtype contributes to neuronal degeneration. In cortical cultures challenged with N-methyl-D-aspartate (NMDA), all three mGlu5 receptor antagonists were neuroprotective. The effect of MPEP was highly specific because the close analogue, 3-methyl-6-phenylethynylpyridine (iso-MPEP), which did not antagonize heterologously expressed mGlu5 receptors, was devoid of activity on NMDA toxicity. Neuroprotection by mGlu5 receptor antagonists was also observed in cortical cultures challenged with a toxic concentration of P-amyloid peptide. We have 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 acid. These results indicate that mGlu5 receptors represent a suitable target for novel neuroprotective agents of potential application in neurodegenerative disorders. (C) 2000 Elsevier Science Ltd. All rights reserved.
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