NEUROTOXICITY OF ,1'R,2'R,3'R)-2-(2,3-DICARBOXYCYCLOPROPYL)GLYCINE, APOTENT AGONIST FOR CLASS-II METABOTROPIC GLUTAMATE RECEPTORS, IN THE RAT

Neurotoxicity of S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (D CG-IV), a potent agonist for metabotropic glutamate receptors negative ly coupled to adenylyl cyclase, was investigated in vivo by the intrav entricular administration in the rat, compared with that of (2S,1'S,2' S)-2-(carboxycyclopropyl)glycine (L-CCG-I) and (1S,3R)-1-aminocyclopen tane-1,3-dicarboxylic acid [(IS,3R)-ACPD]. Neither L-CCG-I nor (1S,3R) -ACPD caused any apparent pathological change in the brain at an intra ventricular dose of 1 mu mol, whereas DCG-IV induced selective neurona l damage in some rats at higher doses than 3 nmol. The neurotoxicity w as intensified in a dose-dependent manner, and at a dose of 50 nmol DC G-IV caused repetitive seizures and selective neuronal damage in all c ases. Neuronal damage was pronounced in the cingulate cortex, lateral septum and hippocampus, and a few degenerating neurons were observed a lso in other brain areas, such as the striatum, thalamus or neocortex. Since DCG-IV activates N-methyl-D-aspartate-type receptors as well at relatively high concentrations, the protective effect of a competitiv e antagonist for N-methyl-D-aspartate receptors, -[(RS)-2-carboxypiper azin-4-yl]propyl-1-phosphonic acid (CPP), was examined on the neurotox icity of DCG-IV. Although a combined treatment with CPP (0.1 nmol) com pletely blocked the neurotoxicity of N-methyl-D-aspartate (100 nmol), at least 3 nmol of CPP was necessary to decrease the neurotoxicity of DCG-IV (50 nmol) to a considerable extent. The synergistic activation of metabotropic glutamate receptors and N-methyl-D-aspartate receptors is suggested as a possible mechanism underlying the selective neurona l damage induced by DCG-IV, although a direct participation of metabot ropic glutamate receptors in glutamate neurotoxicity is not deniable. Copyright (C) 1996 IBRO.