Mechanism of kainate toxicity to cerebellar neurons in vitro is analogous to reperfusion tissue injury.
The neuroexcitotoxin kainate has been used as a selective lesioning agent to model the etiology of a number of neurodegenerative disorders. Although excitotoxins cause susceptible neurons to undergo prolonged or repeated depolarization, the proximate metabolic pathology responsible for neuronal necrosis has remained elusive. We report here that kainate-induced death of cerebellar neurons in culture is prevented by inhibiting the enzyme xanthine oxidase, a cellular source of cytotoxic superoxide radicals (O2-.). Moreover, neurons are also protected from excitotoxin-induced death by the addition to the culture medium of either superoxide dismutase or mannitol, which scavenge superoxide and hydroxyl radicals, respectively, or serine protease inhibitor, which forestalls formation of xanthine oxidase. These findings indicate that excitotoxin-induced neuronal degeneration is mediated by superoxide radicals generated by xanthine oxidase, a mechanism partially analogous to that proposed for tissue damage seen upon reperfusion of ischemic tissues.
D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology*; D010450:Endopeptidases; D006878:Hydroxides / Q000378:metabolism; D017665:Hydroxyl Radical; D007511:Ischemia; D007608:Kainic Acid / Q000494:pharmacology*; D008353:Mannitol / Q000494:pharmacology; D051379:Mice; D009252:NADPH Dehydrogenase / Q000378:metabolism; D009422:Nervous System Diseases / Q000209:etiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010477:Perfusion; D011480:Protease Inhibitors; D012697:Serine Endopeptidases; D013482:Superoxide Dismutase / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism
D006878:Hydroxides; D011480:Protease Inhibitors; D013481:Superoxides; D017665:Hydroxyl Radical; D008353:Mannitol; D000493:Allopurinol; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; D009252:NADPH Dehydrogenase; D010450:Endopeptidases; D012697:Serine Endopeptidases; D007608:Kainic Acid