title: Beneficial effects of GW274150 treatment on the development of experimental colitis induced by dinitrobenzene sulfonic acid.
abstract: Inflammatory bowel disease is associated with inducible nitric oxide synthase (iNOS) expression, oxidative and nitrosative stress, and leukocyte infiltration in the colon. Here, we investigate the effects of the selective iNOS-inhibitor (S)-2-amino-(1-iminoethylamino)-5-thiopentanoic acid (GW274150) on the development of experimental colitis induced by dinitrobenzene sulfonic acid. When compared to dinitrobenzene sulfonic acid-treated mice, GW274150 (5 mg/kg i.p.)-treated mice subjected to dinitrobenzene sulfonic ACID-induced colitis experienced a significantly lower rate of the extent and severity of the histological signs of colon injury. Dinitrobenzene sulfonic acid-treated mice experienced hemorrhagic diarrhoea and weight loss. At 4 days after the administration of dinitrobenzene sulfonic acid, the mucosa of the colon exhibited large areas of necrosis. Immunohistochemistry for nitrotyrosine and poly (ADP-ribose) (PAR) showed an intense staining in the inflamed colon. Treatment of dinitrobenzene sulfonic acid-treated mice with GW274150 significantly reduced the degree of hemorrhagic diarrhoea and weight loss caused by administration of dinitrobenzene sulfonic acid. GW274150 also caused a substantial reduction of (i) the degree of colon injury, (ii) the rise in myeloperoxidase (MPO) activity (mucosa), (iii) the increase in staining (immunohistochemistry) for nitrotyrosine, as well as (iv) PARP activation caused by dinitrobenzene sulfonic acid in the colon. Thus, GW274150 treatment reduced the degree of colitis caused by dinitrobenzene sulfonic acid. We propose that selective inhibition of iNOS activity with GW274150 may be useful in the treatment of inflammatory bowel disease.
authors.affiliation: Department of Clinical and Experimental Medicine and Pharmacology, School of Medicine, University of Messina Torre Biologica, Policlinico Universitario, 98123 Messina, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Paola
authors.forename: Emanuela
authors.initials: E
authors.lastname: Mazzon
authors.forename: Nimesh S A
authors.initials: NS
authors.lastname: Patel
authors.forename: Tiziana
authors.initials: T
authors.lastname: Genovese
authors.forename: Carmelo
authors.initials: C
authors.lastname: Muià
authors.forename: Christoph
authors.initials: C
authors.lastname: Thiemermann
authors.forename: Angelina
authors.initials: A
authors.lastname: De Sarro
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000818:Animals; D001557:Benzenesulfonates / Q000633:toxicity*; D003092:Colitis / Q000139:chemically induced* / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D013440:Sulfides / Q000627:therapeutic use*
chemical_list: D001557:Benzenesulfonates; D013440:Sulfides; C409004:GW 274150; C007488:dinitrobenzenesulfonic acid