Article: article from journal or magazin.
Adenosine kinase inhibitor GP515 improves experimental colitis in mice.
Journal of Pharmacology and Experimental Therapeutics
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
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.
Adenosine Kinase/antagonists & inhibitors, Animals, Antigens, CD/biosynthesis, Antigens, Differentiation, T-Lymphocyte/biosynthesis, Cells, Cultured, Colitis/chemically induced, Colitis/drug therapy, Colon/metabolism, Colon/pathology, Dextran Sulfate, Enzyme Inhibitors/therapeutic use, Female, Flow Cytometry, Gastrointestinal Agents/therapeutic use, Interferon-gamma/biosynthesis, Lectins, C-Type, Mice, Mice, Inbred BALB C, Organ Size, Ribonucleosides/therapeutic use, Spleen/pathology, Tetradecanoylphorbol Acetate/pharmacology
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