Inhibition of matrix metalloproteinase-9 by a barbiturate-nitrate hybrid ameliorates dextran sulphate sodium-induced colitis: effect on inflammation-related genes.

BACKGROUND AND
PURPOSE: Matrix metalloproteinase-9 (MMP-9) is up-regulated in ulcerative colitis and implicated in the pathology of the disease. In this study, we have examined the effects of a barbiturate-based MMP inhibitor incorporating a nitric oxide donor/mimetic group (dinitrate-barbiturate) on the intestinal injury induced by dextran sulphate sodium (DSS). EXPERIMENTAL APPROACH: In vivo experiments were carried out using male Wistar rats given 5% DSS ad libitum in drinking water. The dinitrate-barbiturate, non-nitrate equivalent, nitrate side chains alone or vehicle were administered rectally, twice daily. MMP-9 release was measured by gelatin zymography, and analysis of gene expression was carried out using RT-qPCR. TaqMan low density arrays were used to evaluate the expression of 91 inflammatory genes in the rat colon. KEY
RESULTS: The dinitrate-barbiturate inhibited the induction and activity of MMP-9 during DSS colitis in the rat. This occurred in association with significant reductions in the colitic response to DSS as assessed by an established clinical disease activity index and a pathological colitis grade score. The compound modified expression rates of numerous inflammation-related genes in the colon. CONCLUSIONS AND IMPLICATIONS: This study demonstrated the efficacy of the dinitrate-barbiturate in DSS-induced colitis. Therefore, barbiturate-nitrate hybrids may be developed as a promising anti-inflammatory approach to the treatment of inflammatory bowel disease.