Specific Type IV Phosphodiesterase Inhibitor Rolipram Mitigates Experimental Colitis in Mice1
- Gunther Hartmann2,
- Christoph Bidlingmaier2,
- Britta Siegmund,
- Stefan Albrich,
- Johannes Schulze,
- Katharina Tschoep,
- Andreas Eigler,
- Hans Anton Lehr3 and
- Stefan Endres
- Division of Clinical Pharmacology, Medizinische Klinik, Klinikum Innenstadt, University of Munich, Germany
Abstract
The specific type IV phosphodiesterase inhibitor rolipram is a potent suppressor of tumor necrosis factor-α (TNF) synthesis. We examined the efficacy of rolipram for the prevention and treatment of experimental colitis. To induce colitis, BALB/c mice received 5% dextran sulfate sodium in their drinking water continuously for up to 11 days. Colitis was quantified by a clinical activity score assessing weight loss, stool consistency, and rectal bleeding (range from 0 to 4); by colon length; by a semiquantitative histologic score (range from 0 to 6); and by detecting TNF concentration in colonic tissue by enzyme-linked immunosorbent assay. In a first protocol, rolipram (10 mg/kg b.wt./day i.p.) was started on the same day as dextran sulfate 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 = .041). 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 improved the histologic score (1.5 ± 0.6 in rolipram-treated mice versus 4.6 ± 0.5;P = .020). Rolipram suppressed colonic tissue TNF concentrations. The beneficial effect of rolipram was confirmed in a second protocol in which dextran sulfate sodium exposure was discontinued on day 7 and rolipram was administered from day 8 through day 15. These three series of experiments on a total of 153 mice documented the efficacy of rolipram in both the prevention and treatment of experimental colitis.
Footnotes
-
Send reprint requests to: Stefan Endres, M.D., Clinical Pharmacology, Medizinische Klinik, University of Munich, Ziemssenstraße 1, 80336 München, Germany. E-mail:EndresS{at}lrz.uni-muenchen.de
-
↵1 This work was supported by the Deutsche Forschungsgemeinschaft (En 169/3), the German-Israeli Foundation for Scientific Research and Development (021-203.05/96), and the Wilhelm Sander-Stiftung (93.042.3). These data are part of the dissertation of Christoph Bidlingmaier, cand. med. and Stefan Albrich, cand. med. (Medizinische Klinik, Klinikum Innenstadt, Ludwig-Maximilians-University of Munich, in preparation). Parts of these studies have been presented in abstract form during the American Gastroenterology Association meeting, New Orleans, May 17–20, 1998.
-
↵2 G.H. and C.B. contributed equivalently to the work.
-
↵3 Current address: Department of Pathology, University of Mainz, Germany.
- Abbreviations:
- TNF
- tumor necrosis factor-α
- PDE
- phosphodiesterase
- DSS
- dextran sulfate sodium
- ELISA
- enzyme-linked immunosorbent assay
- IL
- interleukin
-
- Received December 7, 1998.
- Accepted September 13, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
