THE 21-AMINOSTEROID TIRILAZAD MESYLATE CAN AMELIORATE INFLAMMATORY BOWEL-DISEASE IN RATS

The 21-aminosteroid tirilazad mesylate (U74006F) is a lipophilic antio xidant and free radical scavenger that has been reported to attenuate brain or spinal cord injury caused by trauma, stroke, ischemia and rep erfusion injury. In this study, we have examined the effect of U74006F in reducing the inflammatory parameters of trinitrobenzene sulfonic a cid (TNBS)-induced inflammatory bowel disease (IBD) in rats, To induce IBD, rats were given ethanolic TNBS intracolonically. Rats received e ither 1)TNBS and U74006F 2) TNBS and vehicle or 3) saline and vehicle, Rats were sacrificed 1, 2 and 3 weeks after IBD induction. Colon to b ody weight ratio (an index of tissue edema) was markedly increased in the vehicle-treated IBD rats after 1 week of administration of TNBS, T he ratio was significantly lower after U74006F treatment and the trend remained even after 3 weeks of chronic inflammation. Myeloperoxidase (MPO) activity in vehicle-treated IBD rats was substantially increased compared with controls during the entire 3 weeks of the experiment. U 74006F-treated animals had significantly reduced MPO activity (60% low er) when compared with vehicle-treated animals at the end of the secon d and third weeks. These observations were confirmed by histopathology studies showing reduced granulocyte infiltration after drug treatment . U74006F treatment decreased basal (by 70%) and fMLP stimulated (by 7 5%) superoxide generation from colonic tissue from IBD rats compared w ith vehicle treatment after 2 weeks, but there was no apparent differe nce in superoxide generation among all three groups after 3 weeks. The results of this study suggested that administration of U74006F effect ively reduces the inflammatory parameters in this chronic rat model of IBD. As such, U74006F may be therapeutically beneficial for the treat ment of IBD in humans.