Effects of tumour necrosis factor-alpha synthesis inhibitors on rat trinitrobenzene sulphonic acid-induced chronic colitis

The fact that turnout necrosis factor-alpha (TNF-alpha) is clearly involved in the pathogenesis of intestinal bowel disease, especially Crohn's diseas e, suggests that TNF-alpha synthesis inhibitors could be beneficial for tre atment. The present study assessed the effect of chronic oral gavage of two in vitro TNF-alpha synthesis inhibitors, JM 34 maleate or [N-(4,6-dimethyl pyridin-2-yl)-furane-2-carboxamide)] maleate and XC 21 or (N-beta -picolyl- tetrafluorophtalimide), on colonic inflammation in trinitrobenzene sulphoni c acid-induced colitis in rats. Rats received JM 34 maleate (100 mg/kg) and XC 21 (50 mg/kg) 1 h before colitis induction and then daily for 8 days by oral gavage. The colon was removed on day 8 and processed for clinical sco re. myeloperoxidase activity, and soluble TNF-alpha release. Treatment with XC 21, as well as dexamethasone and sulphasalazine, reduced colonic damage and decreased (except with dexamethasone) the incidence of diarrhoea. JM 3 4 maleate failed to improve the clinical signs of chronic colitis. After tr initrobenzene sulphonic acid-induced colitis, myeloperoxidase activity and TNF-alpha colonic mucosal production were substantially increased compared to the control (saline instillation). Both of these inflammatory indicators were then significantly decreased (P less than or equal to 0.05) after the four chronic treatments (JM 34 maleate, XC 21, sulphasalazine, and dexamet hasone). XC 21 appeared to be as efficient as sulphasalazine in improving c olonic inflammation. (C) 2001 Published by Elsevier Science B.V.