An inhibitor of inducible nitric oxide synthase and scavenger of peroxynitrite prevents diabetes development in NOD mice.
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 beta-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, beta-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 beta-cells in NOD mouse islets incubated in vitro with the combination of proinflammatory cytokines interleukin 1-beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). These findings indicate that both superoxide and nitric oxide radicals contribute to islet beta-cell destruction in autoimmune diabetes via peroxynitrite formation in the beta-cells.
Suarez-Pinzon
W L
WL
Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
Mabley
J G
JG
Strynadka
K
K
Power
R F
RF
Szabó
C
C
Rabinovitch
A
A
D000818:Animals; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology*; D006146:Guanidines / Q000008:administration & dosage / Q000494:pharmacology*; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D016877:Oxidants / Q000378:metabolism*; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D030421:Peroxynitrous Acid / Q000378:metabolism*
D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D006146:Guanidines; D016877:Oxidants; C014363:bis(2-guanidinoethyl)disulfide; D030421:Peroxynitrous Acid; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse