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Vol. 296, Issue 1, 99-105, January 2001

Adenosine Kinase Inhibitor GP515 Improves Experimental Colitis in Mice

Britta Siegmund, Florian Rieder, Stefan Albrich, Katrin Wolf, Christoph Bidlingmaier, Gary S. Firestein, David Boyle, Hans-Anton Lehr, Florian Loher, Gunther Hartmann, Stefan Endres and Andreas Eigler

Division of Clinical Pharmacology, Medizinische Klinik Innenstadt of the Ludwig-Maximilians-University, Munich, Germany (B.S., F.R., S.A., K.W., C.B., F.L., G.H., S.E., A.E.); Division of Rheumatology, University of California San Diego School of Medicine, La Jolla, California (G.S.F., D.B.); and Institute of Pathology, University of Mainz, Mainz, Germany (H-A.L.)

Adenosine is a potent anti-inflammatory mediator. Through elevation of endogenous adenosine concentrations the adenosine kinase inhibitor GP515 might serve to down-regulate local inflammatory responses. In the present study we investigated the effect of systemic GP515 in the nonacute model of dextran sulfate sodium (DSS)-induced colitis. The clinical score, colon length, histologic score, colon cytokine production, and spleen weight from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving GP515 treatment were determined and compared with untreated control mice. Splenocytes were analyzed for phenotype, interferon-gamma (IFNgamma ) production, and CD69 expression. First, GP515 treatment resulted in a significant improvement of clinical score (weight loss, stool consistency, and bleeding) and of histologic score. Second, colon shortening, an indirect parameter for the degree of inflammation, was decreased, consistent with a decreased IFNgamma concentration in the colonic tissue. Third, spleen weight was reduced in GP515-treated DSS mice. And fourth, IFNgamma synthesis and CD69 expression, as a marker for early cell activation, of ex vivo-stimulated splenocytes were suppressed in the GP515-treated DSS mice. These studies show that GP515 is effective in the therapy of DSS-induced colitis. One potential mechanism of action is the suppression of IFNgamma synthesis and CD69 expression. Adenosine kinase inhibition forms a pharmacologic target that should be further investigated for chronic inflammatory bowel disease.

0022-3565/01/2961-0099$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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