The intestinal anti-inflammatory activity of UR-12746S on reactivated experimental colitis is mediated through downregulation of cytokine production.

Abstract

UR-12746S (dersalazine sodium) is cleaved by colonic bacteria delivering the PAF antagonist UR-12715 and 5-ASA. This study describes the anti-inflammatory activity of UR-12746S in an experimental model of reactivated colitis and its effects on cytokine production. Rats were initially rendered colitic by a colonic instillation of 10 mg of trinitrobenzenesulphonic acid (TNBS) dissolved in 0.25 ml of 50 % ethanol, and colitis was reactivated two weeks after by a second administration of the same dose of TNBS. Two groups of colitic rats received UR-12746S (25 and 50 mg/kg daily, p.o.) and colonic damage was evaluated every week for 4 weeks. Different biochemical markers of colonic inflammation were assayed: MPO activity and cytokine (IL-1beta and TNFalpha) levels. Also, the in vitro effects of UR-12715 and 5-ASA on cytokine production were assayed. UR-12746S showed anti-inflammatory effect in reactivated colitis in rats, as evidenced by a significant reduction in MPO activity. Both doses of UR-12746S decreased IL-1beta production, while only the highest dose assayed inhibited TNFalpha production. In vitro studies revealed that UR-12715 or 5-ASA (from 10(-6) to 10(-4) M) inhibited IL-8 production (30-40%) in HT-29 cells when incubated with LPS. This inhibitory effect was enhanced when both compounds were administered simultaneously at 10(-4) M. In addition, UR-12715 inhibited IL-1beta or TNFalpha production in THP-1 or U937 cells, respectively, when these cells were stimulated by PMA and LPS; whereas 5-ASA only showed a weak effect in inhibiting IL-1beta production. UR-12746S was able to prevent relapse in experimental colitis and inhibition of proinflammatory cytokine production participates in the intestinal anti-inflammatory activity exerted by this compound.