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The selective phosphodiesterase 4 inhibitor roflumilast and phosphodiesterase 3/4 inhibitor pumafentrine reduce clinical score and TNF expression in experimental colitis in mice.

Rieder F, Siegmund B, Bundschuh DS, Lehr HA, Endres S, Eigler A - PLoS ONE (2013)

Bottom Line: Roflumilast treatment resulted in dose-dependent improvements of clinical score (weight loss, stool consistency and bleeding), colon length, and local tumor necrosis factor-α (TNFα) production in the colonic tissue.These findings, however, were not associated with an improvement of the histologic score.In vitro stimulated splenocytes after in vivo treatment with pumafentrine showed a significantly lower state of activation and production of IFNγ compared to no treatment in vivo.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Pharmacology and Section of Gastroenterology, University of Munich, Munich, Germany.

ABSTRACT

Objective: The specific inhibition of phosphodiesterase (PDE)4 and dual inhibition of PDE3 and PDE4 has been shown to decrease inflammation by suppression of pro-inflammatory cytokine synthesis. We examined the effect of roflumilast, a selective PDE4 inhibitor marketed for severe COPD, and the investigational compound pumafentrine, a dual PDE3/PDE4 inhibitor, in the preventive dextran sodium sulfate (DSS)-induced colitis model.

Methods: The clinical score, colon length, histologic score and colon cytokine production from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving either roflumilast (1 or 5 mg/kg body weight/d p.o.) or pumafentrine (1.5 or 5 mg/kg/d p.o.) were determined and compared to vehicle treated control mice. In the pumafentrine-treated animals, splenocytes were analyzed for interferon-γ (IFNγ) production and CD69 expression.

Results: Roflumilast treatment resulted in dose-dependent improvements of clinical score (weight loss, stool consistency and bleeding), colon length, and local tumor necrosis factor-α (TNFα) production in the colonic tissue. These findings, however, were not associated with an improvement of the histologic score. Administration of pumafentrine at 5 mg/kg/d alleviated the clinical score, the colon length shortening, and local TNFα production. In vitro stimulated splenocytes after in vivo treatment with pumafentrine showed a significantly lower state of activation and production of IFNγ compared to no treatment in vivo.

Conclusions: These series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice.

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Effect of roflumilast on clinical score and colon length. A. Mitigation of DSS-induced colitis by roflumilast.Mice were exposed to 3.5% DSS in drinking water for 11 days. Either 1 mg/kg/d roflumilast, 5 mg/kg/d roflumilast or 4% methocel were administered orally once daily for 11 days (n = 8). Non-DSS-treated mice received 5 mg/kg/d roflumilast (n = 8) or 4% methocel (n = 5). The degree of colitis was quantified by the clinical score assessing weight loss, stool consistency and rectal bleeding (range from 0 =  healthy to 4 =  maximal disease activity). Scores are depicted as mean ± SEM; *p<0.05, **p<0.01 versus DSS+methocel. B. Effect of roflumilast on colon length shortening in DSS-induced colitis. Mice were exposed to 3.5% DSS in drinking water for an 11 day period. Roflumilast treatment (either 1 mg/kg/d or 5 mg/kg/d orally, once daily for eleven days) or 4% methocel were started on the same day as DSS administration (n = 8). Non-DSS mice received 5 mg/kg/d roflumilast (n = 8) or 4% methocel (n = 5). Values are depicted as mean ± SEM. **p<0.01, ***p<0.001 versus DSS+methocel.
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pone-0056867-g001: Effect of roflumilast on clinical score and colon length. A. Mitigation of DSS-induced colitis by roflumilast.Mice were exposed to 3.5% DSS in drinking water for 11 days. Either 1 mg/kg/d roflumilast, 5 mg/kg/d roflumilast or 4% methocel were administered orally once daily for 11 days (n = 8). Non-DSS-treated mice received 5 mg/kg/d roflumilast (n = 8) or 4% methocel (n = 5). The degree of colitis was quantified by the clinical score assessing weight loss, stool consistency and rectal bleeding (range from 0 =  healthy to 4 =  maximal disease activity). Scores are depicted as mean ± SEM; *p<0.05, **p<0.01 versus DSS+methocel. B. Effect of roflumilast on colon length shortening in DSS-induced colitis. Mice were exposed to 3.5% DSS in drinking water for an 11 day period. Roflumilast treatment (either 1 mg/kg/d or 5 mg/kg/d orally, once daily for eleven days) or 4% methocel were started on the same day as DSS administration (n = 8). Non-DSS mice received 5 mg/kg/d roflumilast (n = 8) or 4% methocel (n = 5). Values are depicted as mean ± SEM. **p<0.01, ***p<0.001 versus DSS+methocel.

Mentions: Mice exposed to 3.5% DSS developed signs of colitis as expressed by a clinical score higher than 0.5 starting on day 2 (Figure 1A). Treatment with 5 mg/kg/d roflumilast halted the progression of colitis as expressed by a lower clinical score versus the roflumilast 1 mg/kg/d group and the control group, respectively, starting from day 10. The difference persisted illustrating no further progression of colitis at the point of the last measure on day 11 for the roflumilast 5 mg/kg/d group (p<0.01). On day 11, the difference was also significant for the roflumilast 1 mg/kg/d group (p<0.05; n = 8 per group; Figure 1A). In the animals exposed to DSS, each of the three clinical parameters was independently improved by administration of 5 mg/kg/d roflumilast (data not shown). Mice not exposed to DSS and treated with either 5 mg/kg/d roflumilast or 4% methocel did not show any signs of colitis (n = 5).


The selective phosphodiesterase 4 inhibitor roflumilast and phosphodiesterase 3/4 inhibitor pumafentrine reduce clinical score and TNF expression in experimental colitis in mice.

Rieder F, Siegmund B, Bundschuh DS, Lehr HA, Endres S, Eigler A - PLoS ONE (2013)

Effect of roflumilast on clinical score and colon length. A. Mitigation of DSS-induced colitis by roflumilast.Mice were exposed to 3.5% DSS in drinking water for 11 days. Either 1 mg/kg/d roflumilast, 5 mg/kg/d roflumilast or 4% methocel were administered orally once daily for 11 days (n = 8). Non-DSS-treated mice received 5 mg/kg/d roflumilast (n = 8) or 4% methocel (n = 5). The degree of colitis was quantified by the clinical score assessing weight loss, stool consistency and rectal bleeding (range from 0 =  healthy to 4 =  maximal disease activity). Scores are depicted as mean ± SEM; *p<0.05, **p<0.01 versus DSS+methocel. B. Effect of roflumilast on colon length shortening in DSS-induced colitis. Mice were exposed to 3.5% DSS in drinking water for an 11 day period. Roflumilast treatment (either 1 mg/kg/d or 5 mg/kg/d orally, once daily for eleven days) or 4% methocel were started on the same day as DSS administration (n = 8). Non-DSS mice received 5 mg/kg/d roflumilast (n = 8) or 4% methocel (n = 5). Values are depicted as mean ± SEM. **p<0.01, ***p<0.001 versus DSS+methocel.
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pone-0056867-g001: Effect of roflumilast on clinical score and colon length. A. Mitigation of DSS-induced colitis by roflumilast.Mice were exposed to 3.5% DSS in drinking water for 11 days. Either 1 mg/kg/d roflumilast, 5 mg/kg/d roflumilast or 4% methocel were administered orally once daily for 11 days (n = 8). Non-DSS-treated mice received 5 mg/kg/d roflumilast (n = 8) or 4% methocel (n = 5). The degree of colitis was quantified by the clinical score assessing weight loss, stool consistency and rectal bleeding (range from 0 =  healthy to 4 =  maximal disease activity). Scores are depicted as mean ± SEM; *p<0.05, **p<0.01 versus DSS+methocel. B. Effect of roflumilast on colon length shortening in DSS-induced colitis. Mice were exposed to 3.5% DSS in drinking water for an 11 day period. Roflumilast treatment (either 1 mg/kg/d or 5 mg/kg/d orally, once daily for eleven days) or 4% methocel were started on the same day as DSS administration (n = 8). Non-DSS mice received 5 mg/kg/d roflumilast (n = 8) or 4% methocel (n = 5). Values are depicted as mean ± SEM. **p<0.01, ***p<0.001 versus DSS+methocel.
Mentions: Mice exposed to 3.5% DSS developed signs of colitis as expressed by a clinical score higher than 0.5 starting on day 2 (Figure 1A). Treatment with 5 mg/kg/d roflumilast halted the progression of colitis as expressed by a lower clinical score versus the roflumilast 1 mg/kg/d group and the control group, respectively, starting from day 10. The difference persisted illustrating no further progression of colitis at the point of the last measure on day 11 for the roflumilast 5 mg/kg/d group (p<0.01). On day 11, the difference was also significant for the roflumilast 1 mg/kg/d group (p<0.05; n = 8 per group; Figure 1A). In the animals exposed to DSS, each of the three clinical parameters was independently improved by administration of 5 mg/kg/d roflumilast (data not shown). Mice not exposed to DSS and treated with either 5 mg/kg/d roflumilast or 4% methocel did not show any signs of colitis (n = 5).

Bottom Line: Roflumilast treatment resulted in dose-dependent improvements of clinical score (weight loss, stool consistency and bleeding), colon length, and local tumor necrosis factor-α (TNFα) production in the colonic tissue.These findings, however, were not associated with an improvement of the histologic score.In vitro stimulated splenocytes after in vivo treatment with pumafentrine showed a significantly lower state of activation and production of IFNγ compared to no treatment in vivo.

View Article: PubMed Central - PubMed

Affiliation: Division of Clinical Pharmacology and Section of Gastroenterology, University of Munich, Munich, Germany.

ABSTRACT

Objective: The specific inhibition of phosphodiesterase (PDE)4 and dual inhibition of PDE3 and PDE4 has been shown to decrease inflammation by suppression of pro-inflammatory cytokine synthesis. We examined the effect of roflumilast, a selective PDE4 inhibitor marketed for severe COPD, and the investigational compound pumafentrine, a dual PDE3/PDE4 inhibitor, in the preventive dextran sodium sulfate (DSS)-induced colitis model.

Methods: The clinical score, colon length, histologic score and colon cytokine production from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving either roflumilast (1 or 5 mg/kg body weight/d p.o.) or pumafentrine (1.5 or 5 mg/kg/d p.o.) were determined and compared to vehicle treated control mice. In the pumafentrine-treated animals, splenocytes were analyzed for interferon-γ (IFNγ) production and CD69 expression.

Results: Roflumilast treatment resulted in dose-dependent improvements of clinical score (weight loss, stool consistency and bleeding), colon length, and local tumor necrosis factor-α (TNFα) production in the colonic tissue. These findings, however, were not associated with an improvement of the histologic score. Administration of pumafentrine at 5 mg/kg/d alleviated the clinical score, the colon length shortening, and local TNFα production. In vitro stimulated splenocytes after in vivo treatment with pumafentrine showed a significantly lower state of activation and production of IFNγ compared to no treatment in vivo.

Conclusions: These series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice.

Show MeSH
Related in: MedlinePlus