Group I metabotropic glutamate receptors participate in homocysteine‐evoked neurotoxicity

Abstract

Homocysteine (HCY) neurotoxicity is known to be mediated by disturbances in methylation processes and by the NMDA receptor‐mediated excitotoxicity. In this study we examined the role of group I metabotropic glutamate receptors (mGlyRs) in HCY‐induced toxicity in cultured rat cerebellar granule neurons exhibited for 30 min, or cultured in the presence of HCY for 3 days. Acute neurodegeneration induced by >10 mm D,L‐HCY, or subchronic damage evoked by 75–500 µm HCY were enhanced by 50 µm glycine and moderately inhibited by 0.5 µm MK‐801, revealing the NMDA receptor‐mediated portion of HCY neurotoxicity. Also group I mGluRs antagonists 25 µm LY367385 or MPEP given alone only moderately inhibited acute and subchronic HCY neurotoxicity, but given together with MK‐801 completely prevented neurotoxicity. These results demonstrate that acute homocysteine‐induced neurotoxicity is mediated cooperatively by group I mGluRs and NMDA receptors.