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

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.

• Authors: Florian Rieder, Britta Siegmund, Daniela S Bundschuh, Hans-Anton Lehr, Stefan Endres, Andreas Eigler
• Journal: PloS one (PLoS One) Vol. 8 Issue 2 Pg. e56867 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23468885 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aminopyridines
• Antigens, CD
• Antigens, Differentiation, T-Lymphocyte
• Benzamides
• CD69 antigen
• Cyclopropanes
• Lectins, C-Type
• Naphthyridines
• Phosphodiesterase 3 Inhibitors
• Phosphodiesterase 4 Inhibitors
• Tumor Necrosis Factor-alpha
• pumafentrine
• Roflumilast
• Interferon-gamma
• Dextran Sulfate
• Cyclic Nucleotide Phosphodiesterases, Type 4

Topics

• Aminopyridines (administration & dosage, pharmacology)
• Animals
• Antigens, CD (metabolism)
• Antigens, Differentiation, T-Lymphocyte (metabolism)
• Benzamides (administration & dosage, pharmacology)
• Colitis (chemically induced, drug therapy, metabolism)
• Colon (drug effects, metabolism, pathology)
• Cyclic Nucleotide Phosphodiesterases, Type 4 (metabolism)
• Cyclopropanes (administration & dosage, pharmacology)
• Dextran Sulfate (adverse effects)
• Disease Models, Animal
• Female
• Interferon-gamma (biosynthesis)
• Intestinal Mucosa (metabolism)
• Lectins, C-Type (metabolism)
• Mice
• Naphthyridines (administration & dosage, pharmacology)
• Phosphodiesterase 3 Inhibitors (administration & dosage, pharmacology)
• Phosphodiesterase 4 Inhibitors (administration & dosage, pharmacology)
• Spleen (cytology, metabolism)
• Tumor Necrosis Factor-alpha (metabolism)