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Specific type IV phosphodiesterase inhibitor rolipram mitigates experimental colitis in mice
G Hartmann1, C Bidlingmaier, B Siegmund
1Division 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-alpha (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.
Insights
Rolipram, a tumor necrosis factor-alpha (TNF) inhibitor, effectively prevents and treats experimental colitis in mice. This phosphodiesterase inhibitor reduced disease severity and inflammation, showing therapeutic potential.
Area of Science:
- Gastroenterology and Immunology
- Pharmacology and Therapeutics
Background:
- Tumor necrosis factor-alpha (TNF) plays a key role in inflammatory conditions like colitis.
- Rolipram, a type IV phosphodiesterase inhibitor, is known to suppress TNF synthesis.
- The therapeutic potential of rolipram in inflammatory bowel disease, specifically experimental colitis, requires investigation.
Purpose of the Study:
- To evaluate the efficacy of rolipram in preventing and treating experimental colitis.
- To assess rolipram's impact on clinical, macroscopic, and histological markers of colitis.
- To determine rolipram's effect on colonic TNF concentrations in an experimental colitis model.
Main Methods:
- Experimental colitis was induced in BALB/c mice using 5% dextran sulfate sodium (DSS) in drinking water.
- Rolipram was administered intraperitoneally at 10 mg/kg/day in two protocols: simultaneous with DSS (prevention) and after DSS discontinuation (treatment).
- Colitis severity was assessed using clinical activity scores, colon length, histological scoring, and colonic TNF levels measured by ELISA.
Main Results:
- Rolipram significantly reduced the clinical activity score of colitis compared to controls (1.1 vs. 2.4).
- Rolipram treatment partially reversed colon length reduction and improved histological scores (1.5 vs. 4.6).
- Rolipram suppressed TNF concentrations in colonic tissue and demonstrated efficacy in both preventive and treatment models.
Conclusions:
- Rolipram is effective in both preventing and treating experimental colitis induced by DSS in mice.
- The therapeutic benefits of rolipram are associated with reduced inflammation and suppressed TNF production.
- Rolipram shows promise as a potential therapeutic agent for inflammatory bowel diseases.