ATTENUATION OF EXCITATORY AMINO-ACID TOXICITY BY METABOTROPIC GLUTAMATE-RECEPTOR AGONISTS AND ANIRACETAM IN PRIMARY CULTURES OF CEREBELLAR GRANULE CELLS

Activation of glutamate ionotropic receptors represents the primary ev ent in the neurotoxicity process triggered by excitatory amino acids. We demonstrate here that the concentration-dependent stimulation of me tabotropic glutamate receptor (mGluR) by the selective agonist trans-1 -aminocyclopentane-1,3-dicarboxylate or by quisqualate counteracts bot h glutamate- and kainate-induced neurotoxicity in primary cultures of rat cerebellar granule cells. The mGluR-evoked responses are potentiat ed by aniracetam, which per se also elicits neuroprotection. Aniraceta m concentration-dependently counteracted glutamate-, kainate-, or a-am ino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-induced cell death an d greatly facilitated neuroprotective response achieved by different c oncentrations of both quisqualate and trans-1-aminocy-clopentane-1,3-d icarboxylate. In addition, aniracetam potentiated the mGluR-coupled st imulation of phospholipase C, as revealed by the measurement of H-3-in ositol phosphate formation. Thus, mGluRs could be a suitable target fo r novel pharmacological strategies pointing to the treatment of neurod egenerative diseases.