Neurotoxicity of (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine, a potent agonist for class II metabotropic glutamate receptors, in the rat.
Neurotoxicity of (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), a potent agonist for metabotropic glutamate receptors negatively coupled to adenylyl cyclase, was investigated in vivo by the intraventricular administration in the rat, compared with that of (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I) and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD]. Neither L-CCG-I nor (1S,3R)-ACPD caused any apparent pathological change in the brain at an intraventricular dose of 1 mumol, whereas DCG-IV induced selective neuronal damage in some rats at higher doses than 3 nmol. The neurotoxicity was intensified in a dose-dependent manner, and at a dose of 50 nmol DCG-IV caused repetitive seizures and selective neuronal damage in all cases. Neuronal damage was pronounced in the cingulate cortex, lateral septum and hippocampus, and a few degenerating neurons were observed also 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 competitive antagonist for N-methyl-D-aspartate receptors, 3-[(RS)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (CPP), was examined on the neurotoxicity of DCG-IV. Although a combined treatment with CPP (0.1 nmol) completely 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 neuronal damage induced by DCG-IV, although a direct participation of metabotropic glutamate receptors in glutamate neurotoxicity is not deniable.
Kwak
S
S
Department of Pharmacology, Tokyo Metropolitan Institute of Medical Science, Japan.
Miyamoto
M
M
Ishida
M
M
Shinozaki
H
H
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D003521:Cyclopropanes / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005998:Glycine / Q000031:analogs & derivatives* / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects; D008297:Male; D009410:Nerve Degeneration / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*
D003521:Cyclopropanes; D018094:Receptors, Metabotropic Glutamate; C082313:2-(2,3-dicarboxycyclopropyl)glycine; D005998:Glycine