Glutathione efflux induced by NMDA and kainate: implications in neurotoxicity?
Neurotoxicity in acute as well as chronic neurological diseases may be partly mediated by oxidative stress caused by overactivation of glutamate receptors. A key component of the cellular defense against oxidative stress is reduced glutathione. In our earlier work, we have shown that ischemia in brain induces increased efflux, elevated metabolism, and decreased tissue concentrations of glutathione. In this study, we have evaluated the effect of glutamate receptor activation on the efflux of glutathione from hippocampus in vitro. NMDA and kainate induced a delayed increase in glutathione, taurine, and phosphoethanolamine efflux. Extracellular glutathione was recovered mainly in the reduced form (85-95%); the efflux was dependent on extracellular calcium but unrelated to dantrolene-sensitive intracellular calcium release and independent of glutathione or NO synthesis. The NMDA-induced efflux of glutathione was enhanced by blockage of gamma-glutamyl transpeptidase, indicating an increased transpeptidation of glutathione after NMDA receptor activation. Our results suggest that increased efflux of glutathione could be a factor in initiating nerve cell death via a change in intracellular redox potential and/or a decrease in the intracellular capacity for inactivation of reactive oxygen species.
Wallin
C
C
Department of Anatomy and Cell Biology, University of Göteborg, Sweden.
Weber
S G
SG
Sandberg
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D003620:Dantrolene / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004983:Ethanolamines / Q000378:metabolism; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D009498:Neurotoxins; D051381:Rats; D017207:Rats, Sprague-Dawley; D013654:Taurine / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000037:antagonists & inhibitors
D004791:Enzyme Inhibitors; D004983:Ethanolamines; D007555:Isoxazoles; D009498:Neurotoxins; D013654:Taurine; D016202:N-Methylaspartate; C005448:phosphorylethanolamine; D005723:gamma-Glutamyltransferase; D003620:Dantrolene; D005978:Glutathione; C006303:acivicin; D007608:Kainic Acid; D002118:Calcium; D019803:Glutathione Disulfide