Adenosine kinase inhibitor GP515 improves experimental colitis in mice

Adenosine is a potent anti-inflammatory mediator. Through elevation of endo genous adenosine concentrations the adenosine kinase inhibitor GP515 might serve to down-regulate local inflammatory responses. In the present study w e investigated the effect of systemic GP515 in the nonacute model of dextra n sulfate sodium (DSS)-induced colitis. The clinical score, colon length, h istologic score, colon cytokine production, and spleen weight from mice wit h DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving GP 515 treatment were determined and compared with untreated control mice. Spl enocytes were analyzed for phenotype, interferon-gamma (IFN gamma) producti on, and CD69 expression. First, GP515 treatment resulted in a significant i mprovement of clinical score (weight loss, stool consistency, and bleeding) and of histologic score. Second, colon shortening, an indirect parameter f or the degree of inflammation, was decreased, consistent with a decreased I FN gamma concentration in the colonic tissue. Third, spleen weight was redu ced in GP515-treated DSS mice. And fourth, IFN gamma synthesis and CD69 exp ression, as a marker for early cell activation, of ex vivo-stimulated splen ocytes were suppressed in the GP515-treated DSS mice. These studies show th at GP515 is effective in the therapy of DSS-induced colitis. One potential mechanism of action is the suppression of IFN gamma synthesis and CD69 expr ession. Adenosine kinase inhibition forms a pharmacologic target that shoul d be further investigated for chronic inflammatory bowel disease.