The Selective Phosphodiesterase 4 Inhibitor Roflumilast and Phosphodiesterase 3/4 Inhibitor Pumafentrine Reduce Clinical Score and TNF Expression in Experimental Colitis in Mice
et al. (2013) The Selective Phosphodiesterase 4 Inhibitor Roflumilast and Phosphodiesterase 3/
4 Inhibitor Pumafentrine Reduce Clinical Score and TNF Expression in Experimental Colitis in Mice. PLoS ONE 8(2): e56867. doi:10.1371/journal.pone.0056867
The Selective Phosphodiesterase 4 Inhibitor Roflumilast and Phosphodiesterase 3/4 Inhibitor Pumafentrine Reduce Clinical Score and TNF Expression in Experimental Colitis in Mice
Florian Rieder 0
Britta Siegmund 0
Daniela S. Bundschuh 0
Hans-Anton Lehr 0
Stefan Endres 0
Andreas Eigler 0
Stefan Bereswill, Charite-University Medicine Berlin, Germany
0 1 Division of Clinical Pharmacology and Section of Gastroenterology, University of Munich , Munich, Germany , 2 Department of Internal Medicine I, University of Regensburg , Regensburg, Germany, 3 Medical Department I, Charite Universita tsmedizin , Campus Benjamin Franklin, Berlin, Germany , 4 Takeda Pharmaceuticals International GmbH, Zurich, Switzerland, 5 Institut Universitaire de Pathologie, Centre Hospitalier Universitaire Vaudois , Lausanne , Switzerland
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 pumafentrinetreated animals, splenocytes were analyzed for interferon-c (IFNc) 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-a (TNFa) 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 TNFa production. In vitro stimulated splenocytes after in vivo treatment with pumafentrine showed a significantly lower state of activation and production of IFNc 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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Funding: This study was partly supported by Takeda Pharmaceuticals International GmbH (formerly Nycomed GmbH), the employer of Daniela S. Bundschuh.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing Interests: This study was partly supported by Takeda Pharmaceuticals International GmbH (formerly Nycomed GmbH), the employer of Daniela S.
Bundschuh. Roflumilast and pumafentrine are products of Nycomed and were synthesized by the Department of Chemistry at the Nycomed GmbH, Konstanz,
Germany, a member of the Takeda Group. There are no further patents, products in development or marketed products to declare. This does not alter the
authors adherence to all the PLOS ONE policies on sharing data and materials.
. These authors contributed equally to this work.
Inflammatory bowel disease (IBD) is characterized by a
disturbed balance of pro- and anti-inflammatory cytokines. Tumor
necrosis factor-a (TNFa), which is elevated in the intestinal
mucosa of both of its entities Crohns disease (CD) and ulcerative
colitis (UC) [1] plays a crucial role in the pathogenesis of IBD [2],
a fact further underlined by the efficacious treatment of patients
with CD and UC with anti-TNFa antibodies [3,4,5]. However,
repeated administration of infliximab results in the production of
auto-antibodies and antibodies against double-stranded DNA
[3,4]. In addition, patients treated with infliximab are at an
increased risk of concomitant infectious complications secondary
to the sustained immune suppression [6].
Among the agents known to inhibit pro-inflammatory cytokine
production rather than to block its biological function are cyclic
adenosine-39,59-monophosphate (cAMP)-elevating PDE
inhibitors. A major PDE isoenzyme family in mononuclear
inflammatory cells, the main source of TNFa production, is PDE4 [7]. The
specific inhibition of PDE4 with rolipram is 500-fold more potent
in suppressing TNFa synthesis in human mononuclear cells
compared to pentoxifylline [8]. PDE4 inhibitors have shown
efficacy in the treatment of several chronic inflammatory
disorders, including experimental colitis [9,10,11]. Unfortunately,
the clinical use of rolipram a (...truncated)