Depletion of intracellular glutathione increases susceptibility to nitric oxide in mesencephalic dopaminergic neurons.
Using primary neuronal cultures, we investigated the effects of GSH depletion on the cytotoxic effects of glutamate and NO in dopaminergic neurons. Intracellular GSH was depleted by 24-h exposure to L-buthionine-[S,R]-sulfoximine (BSO), an irreversible inhibitor of GSH synthase. BSO exposure caused concentration-dependent reduction of the viability of both dopaminergic and nondopaminergic neurons. In contrast, 24-h exposure of cultures to glutamate or NOC18, an NO-releasing agent, significantly reduced the viability of nondopaminergic neurons without affecting that of dopaminergic neurons. Pretreatment with N-acetyl-L-cysteine for 24 h ameliorated the NOC18-induced toxicity in nondopaminergic neurons. In dopaminergic neurons, sublethal concentrations of BSO reduced intracellular GSH content and markedly potentiated glutamate- and NOC18-induced toxicity. These results suggested that glutamate toxicity was enhanced in dopaminergic neurons by suppression of defense mechanisms against NO toxicity under conditions of GSH depletion. Under such conditions, free iron plays an important role because BSO-enhanced NO toxicity was ameliorated by the iron-chelating agent, deferoxamine. These results suggest that GSH plays an important role in the expression of NO-mediated glutamate cytotoxicity in dopaminergic neurons. Free iron may be related to enhanced NO cytotoxicity under GSH depletion.
Ibi
M
M
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Japan.
Sawada
H
H
Kume
T
T
Katsuki
H
H
Kaneko
S
S
Shimohama
S
S
Akaike
A
A
D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology; D005333:Fetus; D018698:Glutamic Acid / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D008636:Mesencephalon / Q000166:cytology* / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000633:toxicity*; D009603:Nitroso Compounds / Q000633:toxicity*; D051381:Rats
C093285:NOC 18; D009498:Neurotoxins; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D018698:Glutamic Acid; D019328:Buthionine Sulfoximine; D005978:Glutathione; D003676:Deferoxamine; D004298:Dopamine