An inhibitor of inducible nitric oxide synthase and scavenger of peroxynitrite prevents diabetes development in NOD mice

Wilma L. Suarez-Pinzon, Jon G. Mabley, Ken Strynadka, Robert F. Power, Csaba Szabó, Alex Rabinovitch

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

Peroxynitrite (ONOO-) is a highly reactive oxidant produced by the interaction of the free radicals superoxide (O2·-) 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.

Original languageEnglish (US)
Pages (from-to)449-455
Number of pages7
JournalJournal of Autoimmunity
Volume16
Issue number4
DOIs
StatePublished - 2001
Externally publishedYes

Keywords

  • Free radicals
  • Insulitis
  • NOD mice
  • Nitric oxide
  • Peroxynitrite

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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