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.
Kim
W K
WK
Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, South Korea. won_k@mm.ewha.ac.kr
Pae
Y S
YS
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