HOME HELP CONTACT US SUBSCRIPTIONS ARCHIVE SEARCH		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Accepted manuscript (PDF) All Versions of this Article: JOE-07-0511v1 198/3/581    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Mabley, J. Articles by Szabo, C. Search for Related Content PubMed PubMed Citation Articles by Mabley, J. Articles by Szabo, C.

J Mabley, School of Pharmacy and Biomolecular Sciences, University of Brighton, Brighton, United Kingdom
P Pacher, Section on Oxidative Stress Tissue injury, Laboratory of Physiological Studies, National Institutes of Health/NIAAA, Bethesda, United States
K Murthy, Inotek Pharmaceuticals Corporation, Beverly, United States
W Williams, Boston, United States
G Southan, Boston, United States
A Salzman, Boston, United States
C Szabo, Department of Surgery, University of Medicine and Dentistry of New Jersey - New Jersey Medical School, Newark, United States

Correspondence: Jon Mabley, Email: j.g.mabley{at}brighton.ac.uk

Abstract

Endogenous purines including inosine have been shown to exert immunomodulatory and anti-inflammatory effects in a variety of disease models. The dosage of inosine required for protection is very high because of the rapid metabolism of inosine in vivo. The aim of this study was to determine whether a metabolic resistant purine analogue, INO-2002, exerts anti-inflammatory effects in two animal models of Type I diabetes. Type 1 diabetes was induced chemically with streptozotocin or genetically using the non-obese diabetic female mouse model. Mice were treated with INO-2002 or inosine as required at 30, 100 or 200 mg/kg/day while blood glucose and diabetes incidence was monitored. The effect of INO-2002 on the pancreatic cytokine profile was also determined. INO-2002 reduced both the hyperglycaemia and incidence of diabetes in both streptozotocin-induced diabetes and spontaneous diabetes in NOD mice. INO-2002 proved to be more effective in protecting against diabetes than the naturally occurring purine, inosine, when administered at the same dose. INO-2002 treatment decreased pancreatic levels of IL-12 and TNF-?, while increasing levels of IL-4 and IL-10. INO-2002 also reduced pancreatic levels of the chemokine MIP-1?. The inosine analogue, INO-2002, protected more effectively than the naturally occurring purine, inosine, against development of diabetes in two separate animal models. INO-2002 exerts protective effects by changing the pancreatic cytokine expression from a destructive Th1 to a protective Th2 profile. The use of analogues of inosine such as INO-2002 should be considered as a potential preventative therapy in individuals susceptible to developing Type 1 diabetes.