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To evaluate the mechanism of the cytotoxicity, the effects of cyanide on intracellular glutathione (GSH) pools and inducible nitric oxide synthase (iNOS)\u2010mediated reactive nitrogen species (RNS) generation were studied. Cyanide rapidly depleted intracellular GSH. Restoration of GSH blocked cell death, whereas depletion of GSH by synthesis inhibition increased the necrosis. Selective depletion of mitochondrial GSH (mtGSH) increased oxidative stress and enhanced cell death, whereas the cytoplasmic pool was not critical to cell survival. These actions were accompanied by increased iNOS expression as determined by Western blot analysis, RT\u2010PCR and immunohistochemistry. Up\u2010regulation of iNOS led to increased generation of NO as reflected by elevated nitrite levels (an end product of NO metabolism). It was determined by use of a selective inhibitor that up\u2010regulation of iNOS expression was transcriptionally regulated by activation of nuclear factor\u2010\u03baB, a redox\u2010sensitive transcription factor. It was concluded that, in cyanide\u2010mediated neurotoxicity, mtGSH is a vital component of the cellular antioxidant defense, and its depletion can lead to oxidative stress\u2010mediated iNOS up\u2010regulation, thus enhancing RNS generation and necrosis. \u00a9 2006 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jnr.20998","type":"journal-article","created":{"date-parts":[[2006,8,24]],"date-time":"2006-08-24T23:48:36Z","timestamp":1156463316000},"page":"1003-1011","source":"Crossref","is-referenced-by-count":11,"title":["Inducible nitric oxide synthase up\u2010regulation and mitochondrial glutathione depletion mediate cyanide\u2010induced necrosis in mesencephalic 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