Adenosine kinase inhibitor GP515 improves experimental colitis in mice.
Details
Serval ID
serval:BIB_1262003532C8
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Adenosine kinase inhibitor GP515 improves experimental colitis in mice.
Journal
Journal of Pharmacology and Experimental Therapeutics
ISSN
0022-3565 (Print)
ISSN-L
0022-3565
Publication state
Published
Issued date
2001
Volume
296
Number
1
Pages
99-105
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
Abstract
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.
Keywords
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
Pubmed
Create date
26/11/2011 14:08
Last modification date
20/08/2019 13:40