Specific type IV phosphodiesterase inhibitor rolipram mitigates experimental colitis in mice

The specific type IV phosphodiesterase inhibitor rolipram is a potent suppr essor of tumor necrosis factor-alpha (TNF) synthesis. We examined the effic acy of rolipram for the prevention and treatment of experimental colitis. T o induce colitis, BALB/c mice received 5% dextran sulfate sodium in their d rinking water continuously for up to 11 days. Colitis was quantified by a c linical activity score assessing weight loss, stool consistency, and rectal bleeding (range from 0 to 4); by colon length; by a semiquantitative histo logic score (range from 0 to 6); and by detecting TNF concentration in colo nic tissue by enzyme-linked immunosorbent assay. In a first protocol, rolip ram (10 mg/kg b.wt./day i.p.) was started on the same day as dextran sulfat e sodium. Rolipram reduced the clinical activity of colitis (score 1.1 +/- 0.3) compared with mice that did not receive rolipram (2.4 +/- 0.4; P = .04 1). Rolipram also partially reversed the reduction of colon length (without rolipram, 12.4 +/- 0.3 cm; with rolipram, 15.4 +/- 0.7 cm; P = .004) and i mproved the histologic score (1.5 +/- 0.6 in rolipram-treated mice versus 4 .6 +/- 0.5; P = .020). Rolipram suppressed colonic tissue TNF concentration s. The beneficial effect of rolipram was confirmed in a second protocol in which dextran sulfate sodium exposure was discontinued on day 7 and rolipra m was administered from day 8 through day 15. These three series of experim ents on a total of 153 mice documented the efficacy of rolipram in both the prevention and treatment of experimental colitis.