An inhibitor of inducible nitric oxide synthase and scavenger of peroxynitrite prevents diabetes development in NOD mice
Suarez-Pinzon, W.L., Mabley, J.G., Strynadka, K., Power, R.F., Szabo, C. and Rabinovitch, A. (2001) An inhibitor of inducible nitric oxide synthase and scavenger of peroxynitrite prevents diabetes development in NOD mice Journal of Autoimmunity, 16 (4). pp. 449-455. ISSN 0896-8411
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Peroxynitrite (ONOO−) is a highly reactive oxidant produced by the interaction of the free radicals superoxide (O•−2) and nitric oxide (NO•). In a previous study, we found that peroxynitrite is formed in islet β-cells of nonobese diabetic (NOD) mice. Here, we report that guanidinoethyldisulphide (GED), a selective inhibitor of inducible nitric oxide synthase (iNOS) and scavenger of peroxynitrite prevents diabetes in NOD mice. GED treatment of female NOD mice, starting at age 5 weeks, delayed diabetes onset (from age 12 to 22 weeks) and significantly decreased diabetes incidence at 30 weeks (from 80% to 17%). GED did not prevent pancreatic islet infiltration by leukocytes; however, β-cells that stained positive for nitrotyrosine (a marker of peroxynitrite) were significantly decreased in islets of GED-treated mice (1±1%) compared with vehicle-treated mice (30±9%). In addition, GED significantly inhibited nitric oxide and nitrotyrosine formation and decreased destruction of β-cells in NOD mouse islets incubated in vitro with the combination of proinflammatory cytokines interleukin 1-beta (IL-1β), tumour necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ). These findings indicate that both superoxide and nitric oxide radicals contribute to islet β-cell destruction in autoimmune diabetes via peroxynitrite formation in the β-cells.
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