ACTIVATION OF METABOTROPIC GLUTAMATE RECEPTORS PROTECTS CULTURED NEURONS AGAINST APOPTOSIS INDUCED BY BETA-AMYLOID PEPTIDE

Prolonged exposure of cultured cortical cells or cultured cerebellar g ranule cells to the residue 25-35 fragment of beta-amyloid peptide (be ta AP), beta AP((25-35)), induced neuronal apoptosis, as revealed by m orphological analysis, fluorescent chromatin staining, and immunodetec tion of oligonucleosomes released from the nucleus into the cytoplasm. beta AP((25-35))-induced apoptosis was insensitive to ionotropic glut amate receptor antagonists but was substantially attenuated by the met abotropic glutamate receptor (mGluR) agonist (1S,3R)-1-aminocyclopenta ne-1,3-dicarboxylic acid. The neuroprotective action of (1S,3R)-1-amin ocyclopentane-1 ,3-dicarboxylic acid was antagonized by (RS)-alpha-met hyl-4-carboxyphenylglycine and was mimicked by (2S,1'R,2'R,3'R)-2-(2,3 -dicarboxycyclopropyl) (a selective agonist of mGluR2 and -3 subtypes) and by L-2-amino-4-phosphobutanoate and L-serine-0-phosphate (selecti ve agonists of mGluR4, -6, and -7 subtypes). However, whereas all of t hese drugs behaved as neuroprotectants in cultured cortical cells, onl y L-2-amino-4-phosphobutanoate and L-serine-0-phosphate [and not ,1'R, 2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine] reduced beta AP((25-35)) -induced apoptosis in cultured cerebellar granule cells. The neuroprot ective activity of mGluR agonists may be related to their ability to i nhibit membrane Ca2+ conductance, because drugs that block voltage-sen sitive Ca2+ channels, such as nimodipine or Co2+, could also attenuate beta AP((25-35))-induced apoptosis.