Partial involvement of group I metabotropic glutamate receptors in the neurotoxicity of 3-N-oxalyl-L-2,3-diaminopropanoic acid (L-beta-ODAP).
Neurolathyrism is a human motoneuron disease caused by the overconsumption of grass pea (Lathyrus sativus) that contains a toxic non-protein amino acid, 3-N-oxalyl-L-2,3-diaminopropanoic acid (L-beta-ODAP). The preventive activities of various glutamatergic agents from acute neuronal death caused by L-beta-ODAP were studied using rat primary cortical neuron/glia culture. Nearly 80% of the rat primary cortical neurons were killed by 300 microM L-beta-ODAP within 24 h. Though antagonists acting on the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor prevented most of the toxicity, antagonists acting on group I metabotropic glutamatergic receptors (mGluRs), including (RS)-1-aminoindan-1,5-dicarboxylic acid (AIDA), (S)-alpha-methyl-4-carboxyphenylglycine (MCPG), and 2-methyl-6-(2-phenylethenyl)pyridine (SIB1893) partially and significantly prevented neuronal death due to L-beta-ODAP. These antagonists, within limited concentrations, did not have any inhibitory effects on the currents through AMPA receptors expressed in Xenopus oocytes. L-beta-ODAP itself did not induce the currents through group I mGluRs expressed in Xenopus oocytes. These results suggest that the neurotoxicity induced by L-beta-ODAP is partially mediated by the activation of group I mGluRs by an indirect mechanisms.
Kusama-Eguchi
Kuniko
K
Laboratory of Biology, College of Pharmacy, Nihon University, Japan. kusamak@pha.nihon-u.ac.jp
Kusama
Tadashi
T
Suda
Atsuhiro
A
Masuko
Takashi
T
Yamamoto
Makoto
M
Ikegami
Fumio
F
Igarashi
Kazuei
K
Kuo
Yu-Haey
YH
Lambein
Fernand
F
Watanabe
Kazuko
K
D000599:Amino Acids, Diamino / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D009498:Neurotoxins / Q000633:toxicity*; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000502:physiology*; D014982:Xenopus laevis
D000599:Amino Acids, Diamino; D018691:Excitatory Amino Acid Antagonists; D009498:Neurotoxins; D018094:Receptors, Metabotropic Glutamate; C104077:metabotropic glutamate receptor type 1; C100126:oxalyldiaminopropionic acid