Therapeutic Effect of Sildenafil in Experimental Colitis through Anti-Oxidative Stress and Inhibition of Adhesion Molecules

Inflammatory bowel disease is a progressive inflammatory intestinal disease characterized by colon tissue edema and increased epithelial permeability of colon and extensive infiltration of leukocytes in the colon . Failure of current treatment strategies and the adverse effects of currently used drugs , it is crucial to investigate new drugs with more favourable therapeutic profiles. The aim of the present study was to evaluate possible therapeutic effects of sildenafil against acetic acid – induced colitis in a rat model and to found out correlation between severity index with oxidative stress parameters and inflammatory markers. Experimental colitis was induced in rats by rectal administration of 4% acetic acid (vol/vol) . Rats with colitis were received either sildenafil 10mg/kg or sulfasalazine 100mg/kg orally for 7days.Macroscopical and microscopical assessment and the measurement of the colonic cytokines (IL-6 and TNF-α) , oxidative stress markers ; myeloperoxidase (MPO) and malondialdehyde (MDA) , and adhesion molecules (E-Selectin and ICAM-1) . Our findings had shown that both macroscopical lesion area and histological colonic injury induced by acetic acid were significantly reduced by both sildenafil and sulfasalazine . These were accompanied by attenuation of the elevated colonic MPO activity , MDA and proinflammatory cytokines . Besides downregulation of the adhesion molecules . These results demonstrated that sildenafil possesses therapeutic potential in experimental colitis . The anti-inflammatory actions involve antioxidant effect along with inhibition of adhesion molecule synthesis in the colonic tissues. Key Word : Sildenafil , ulcerative colitis , Oxidative stress , Adhesion molecules INTRODUCTION Inflammatory bowel disease (IBD) is a chronic inflammatory disease. It is of two different types; ulcerative colitis and Crohn’s disease [1] . They are characterized by immune-mediated chronic relapsing intestinal disorders, associated with rectal bleeding and diarrhea resulting in damage of the epithelial barrier and the formation of epithelial ulceration[2]. Despite the fact that little is known about etiology of these diseases, it is believed to involve an abnormal host response to endogenous or environmental or immunological factors, causing initial tissue damage followed by amplification of this response [3]. IBD are also associated with extensive inflammatory infiltrates in the lamina propria characterized by extensive inflammatory infiltrates consisting of poly morphnuclear neutrophils , eosinophils and plasma cells , leading to a remarkable production of unstable chemical species such as nitrogen and reactive oxygen species , significantly involved in injury[4,5] . Activation of these infiltrating cells results in the release of different pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), interleukin-1 β (IL-1 β), an IL-6 , plays a crucial role in tissue disruption and ulceration [6]. Although extensive development has been made in the treatment of ulcerative colitis, adverse effects and incomplete efficacy of currently used medications is a continuous challenge[7] For this reason, there is a need to develop new strategies that in could restore the altered immune response that emerges in the inflamed intestine . One of the important strategies is targeting adhesion molecules that expressed on the surface of endothelial cells and lymphocyte; which in fact recruits immune and inflammatory cells from the periphery into site of inflammation. On the other hand there is evidence that nitric oxide ( NO) inhibits the expression of adhesion molecules on endothelial cells, which is an important step in neutrophil migration[8]. Sildenafil is one of the drugs that have nitric oxide modulating activity[9]. This effect of sildenafil is attributable to inhibition of phosphodiesterase-type 5 enzyme that catalyze the hydrolysis of cGMP[10] , and has vascular smooth muscle relaxant effect and inhibition of platelets aggregation by preventing the breakdown of nitric oxide –dependant cGMP[11] . Moreover sildenafil has antioxidative stress potential (12) and prevent lipid peroxidation and cytokine release[13]. MATERIAL AND METHODS Materials Animals : Adult male albino rats (200-220g) were purchased from animal house of the national center for drug control and researches (NCDCR) . Animal were housed five per cage for one week prior to the experiment and had access to laboratory chow pellet and were allowed to drink tap water ad libitum. All animal experiments were performed after getting prior approval from the institutional animal ethics committee college of medicine Al-Nahrain university. Mohammed J Manna et al /J. Pharm. Sci. & Res. Vol. 9(9), 2017, 1615-1623