Involvement of N-methyl-d-aspartate receptor and free radical in homocysteine-mediated toxicity on rat cerebellar granule cells in culture.
The present study investigates the possible mechanism responsible for the neurotoxicity of D,L-homocysteine in primary culture of rat cerebellar granule cells. Neurotoxicity was assessed by measuring the amount of lactate dehydrogenase released from the cells following homocysteine treatment. D,L-Homocysteine (> 300 microM; 16-22 h) induced the release of lactate dehydrogenase from the cells in a concentration-dependent manner. The N-methyl-D-aspartate (NMDA) antagonist (+/-)-2-amino-5-phosphonopentanoic acid (APV) partially blocked the homocysteine-mediated neurotoxicity. However, the non-NMDA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) did not block the homocysteine-mediated toxicity. The homocysteine-mediated neurotoxicity was mostly prevented by the co-administration of superoxide dismutase and catalase or catalase alone. The results suggest that homocysteine induces neuronal cell death by stimulating NMDA receptor as well as by producing free radicals.
Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, South Korea. won_k@mm.ewha.ac.kr
W K
WK
Kim
Y S
YS
Pae
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002374:Catalase / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology*; D004234:Diuretics, Osmotic / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005609:Free Radicals; D006710:Homocysteine / Q000633:toxicity*; D006861:Hydrogen Peroxide / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008353:Mannitol / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000201:enzymology; D017397:Prefrontal Cortex / Q000166:cytology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology*; D013482:Superoxide Dismutase / Q000494:pharmacology
D000975:Antioxidants; D004234:Diuretics, Osmotic; D018691:Excitatory Amino Acid Antagonists; D005609:Free Radicals; D016194:Receptors, N-Methyl-D-Aspartate; D006710:Homocysteine; D008353:Mannitol; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D015763:2-Amino-5-phosphonovalerate; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D002374:Catalase; D013482:Superoxide Dismutase; D002118:Calcium