novel role of pravastatin in experimental colitis and their mechanisms in rats

ABSTRACT

Inflammatory bowel diseases [IBDs] are multifactorial processes in which enhanced free radical production in mucosal cells has been implicated in the pathogenesis of these diseases. Free radicals are highly reactive species that have been accused in the pathogenesis of many diseases that can initiate lipid peroxidation. Malondialdehyde [MDA] synthesis and Nitric oxide [NO] are used as markers for increased oxidative and nitrosative stress of tissues in IBD. This study was undertaken to investigate the ameliorative effects of pravastatin on acetic acid-induced colitis and its mechanisms in rats. The colitis model of albino rats was induced by intracolon enema with 8 % of acetic acid. The experimental animals were randomly divided into normal control, model control, 5-aminosalicylic acid [5-ASA] therapy group and pravastatin therapy group. The 4 groups were treated intraperitonealy with normal saline, normal saline, 5-aminosalicylic acid [100 mg/kg] and pravastatin [1 mg/kg] respectively and daily [8 am] for 7 days 24 h following the induction of colitis. At the end of the experiment, animals were sacrificed by decapitation and coionic mucosa was sampled for some tissue biochemical events associated with colitis. Pathological changes of the colonic mucosa were evaluated by the colon mucosa damage index [CMDI] and the histopathological score[HS]. To evaluate the level of oxidative damage in colonic mucosa, colonic levels of malondialdehyde [MDA] and nitric oxide [NO] were measured in colon homogenate using ultraviolet spectrophotometry. Also, colonic contents of prostaglandin E2 [PGE2] was determined by enzyme immunoassay [ELISA] method to assess the level of participation of abnormal arachidonic acid metabolism in the pathogenesis of IBD. Enhanced colonic mucosal injury, inflammatory response and oxidative stress were observed in the animals clystered with acetic acid. Estimation of colonic mucosal injury has revealed significant increase of CMDI, HS activities, MDA and NO levels as well as PGE2 contents compared with the normal control [CMDI 2.9 +/- 0.6 vs 0.0 +/- 0.0; HS 4.3 +/- 0.9 vs 0.7 +/- 1.1; MDA 57.53 +/- 12.36 vs 9.21 +/- 3.85; NO 331 +/- 92 vs 176 +/- 045; PGE2 186.2 +/- 96.2 vs 42.8 +/- 32.8 P<0.01]. However, these parameters Were found to be significantly ameliorated in rats treated with pravastatin [1mg/ kg] [CMDI 1.6 + 0.9, HS 3.1 +/- 1.0; MDA 37.34+8.58,NO 216 +/- 33; PGE2 58.4 +/- 23.9 [P<0.01]. Moreover, a therapeutic dose protocol of pravastatin was observed as effective as 100 mg/kg of 5-ASA in the amelioration of colonic mucosal injury as evaluated by CMDI and HS In conclusion, these findings indicate that administration of pravastatin may have significant therapeutic effects on the rat model of colitis induced by acetic acid enema, which was probably due to antioxidant effect, and inhibition of arachidonic acid metabolism