Abstract
BACKGROUND AND PURPOSE: Hydrogen sulfide (H(2) S) and polysulfides (H(2) S(n) ) are signalling molecules that mediate various physiological responses including cytoprotection. Their oxidized metabolite sulfite (SO(3) (2-) ) is found in blood and tissues. However, its physiological role remains unclear. In this study, we investigated the cytoprotective effect of sulfite on neurons exposed to oxidative stress caused by high concentrations of the neurotransmitter glutamate, known as oxytosis. EXPERIMENTAL APPROACH: Concentrations of sulfite as well as those of cysteine and GSH in rats were measured by HPLC. Cytoprotective effects of sulfite on primary cultures of rat neurons against oxytosis was examined by WST-8 cytoprotective and LDH cytotoxicity assays and compared with that of H(2) S, H(2) S(n) and thiosulfate. KEY RESULTS: Free sulfite, present at approximately 2 μM in the rat brain, converts cystine to cysteine more efficiently than H(2) S and H(2) S(n) and facilitates transport of cysteine into cells. Physiological concentrations of sulfite protected neurons from oxytosis and were accompanied by increased intracellular concentrations of cysteine and GSH probably due to converting extracellular cystine to cysteine, more efficiently than H(2) S and H(2) S(n) . In contrast, thiosulfate only slightly protected neurons from oxytosis. CONCLUSIONS AND IMPLICATIONS: Our present data have shown sulfite to be a novel cytoprotective molecule against oxytosis, through maintaining cysteine levels in the extracellular milieu, leading to increased intracellular cysteine and GSH. Although there may be adverse clinical effects in sensitive individuals, our results provide a new insight into the therapeutic application of sulfite to neuronal diseases caused by oxidative stress. LINKED ARTICLES: This article is part of a themed section on Chemical Biology of Reactive Sulfur Species. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.4/issuetoc.