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Depletion of Intracellular Glutathione Increases Susceptibility to Nitric Oxide in Mesencephalic Dopaminergic Neurons
Author(s) -
Ibi Masakazu,
Sawada Hideyuki,
Kume Toshiaki,
Katsuki Hiroshi,
Kaneko Shuji,
Shimohama Shun,
Akaike Akinori
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.731696.x
Subject(s) - dopaminergic , glutathione , buthionine sulfoximine , glutamate receptor , toxicity , intracellular , neurotoxicity , pharmacology , chemistry , biochemistry , nitric oxide , dopamine , biology , endocrinology , enzyme , receptor , organic chemistry
: 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 non‐dopaminergic 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 NOC‐18‐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.