Abstract
The α7 pentamer nicotinic acetylcholine receptors (nAChRs) are a target in transduction of anti-inflammatory signals from the central nervous system to the gastrointestinal (GI) tract. The aim of this study was to investigate the anti-inflammatory action of the novel α7 nAChR partial agonist encenicline and to determine the mechanism underlying its activity. Anti-inflammatory activity of encenicline was evaluated using trinitrobenzenesulfonic acid (TNBS)- and dextran sulfate sodium (DSS)-induced models of colitis. Macroscopic score, ulcer score, colon length and thickness, as well as myeloperoxidase (MPO) activity were recorded. Immunohistochemistry (IHC) was used to measure the infiltration of immune cells in the colon. Furthermore, we employed flow cytometry to determine the effect of encenicline on frequencies of FoxP3+ and interleukin (IL)-17A+ T cells in the mouse colon. Encenicline attenuated TNBS- and DSS-induced colitis in mice via α7 nAChRs, as indicated by significantly reduced macroscopic parameters and MPO activity. Treatment with encenicline significantly reduced the infiltration of macrophages, neutrophils, and B cells in the colon of TNBS-treated animals, as indicated by IHC. In the TNBS model encenicline reduced the frequency of FoxP3+ IL-17A+ T cells in the colon. In the DSS-model treatment encenicline increased the frequency of FoxP3+ T cells and reduced IL-17A+ T cells. Stimulation of α7 nAChR with partial agonist encenicline alleviates colitis via alteration of the number and/or activation status of the immune cells in the gut, emphasizing a potential role of α7 nAChRs as a target for anticolitic drugs.
Footnotes
- Received July 30, 2015.
- Accepted September 24, 2015.
Supported by the Iuventus Plus program of the Polish Ministry of Science and Higher Education [No. 0107/IP1/2013/72 to J.F.] and the grants from the Medical University of Lodz [502-03/1-156-02/502-14-140 to MS and #503/1-156-04/503-01 to J.F.] and National Science Centre [No. UMO-2013/11/N/NZ7/02354 to M.S., No. UMO-2013/11/B/NZ7/01301 and No. UMO-2014/13/B/NZ4/01179 to J.F.]. L.V.B. and J.D.M. are supported by grants from the Danish Research Council for Strategic Research [COGNITO] and the Novo Nordisk Foundation. Study sponsored by a Polpharma Scientific Foundation scholarship to M.S.
- Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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