title: Inhibition of matrix metalloproteinase-9 by a barbiturate-nitrate hybrid ameliorates dextran sulphate sodium-induced colitis: effect on inflammation-related genes.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Shane
authors.initials: S
authors.lastname: O'Sullivan
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Maria T
authors.initials: MT
authors.lastname: Pigott
authors.affiliation: Department of Physiology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Neil
authors.initials: N
authors.lastname: Docherty
authors.affiliation: Department of Physiology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Noreen
authors.initials: N
authors.lastname: Boyle
authors.affiliation: Department of Physiology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Samuel Kana
authors.initials: SK
authors.lastname: Lis
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: John F
authors.initials: JF
authors.lastname: Gilmer
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
authors.forename: Carlos
authors.initials: C
authors.lastname: Medina
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000494:pharmacology*; D001463:Barbiturates / Q000008:administration & dosage / Q000494:pharmacology*; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D016264:Dextran Sulfate / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009566:Nitrates / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D001463:Barbiturates; D004791:Enzyme Inhibitors; D009566:Nitrates; D016264:Dextran Sulfate; D020780:Matrix Metalloproteinase 9