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Encenicline, an A7 Nicotinic Acetylcholine Receptor Partial Agonist, Reduces Immune Cell Infiltration in the Colon and Improves Experimental Colitis in Mice

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Encenicline, an A7 Nicotinic Acetylcholine Receptor Partial Agonist, Reduces Immune Cell Infiltration in the Colon and Improves Experimental Colitis in Mice 1521-0103/356/1/157–169$25.00 http://dx.doi.org/10.1124/jpet.115.228205 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 356:157–169, January 2016 Copyright ª 2015 by The American Society for Pharmacology and Experimental Therapeutics Encenicline, an a7 Nicotinic Acetylcholine Receptor Partial Agonist, Reduces Immune Cell Infiltration in the Colon and Improves Experimental Colitis in Mice M. Salaga, L.V. Blomster, A. Piechota-Polanczyk, M. Zielinska, D. Jacenik, A.I. Cygankiewicz, W.M. Krajewska, J.D. Mikkelsen, and Jakub Fichna Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland (M.S., A.P.-P., M.Z., J.F.); Neurobiology Research Unit, University Hospital Rigshospitalet, Copenhagen, Denmark (L.V.B., J.D.M.); Department of Cytobiochemistry, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland (D.J., A.I.C., W.M.K.) Received July 30, 2015; accepted September 24, 2015 Downloaded from ABSTRACT The a7 pentamer nicotinic acetylcholine receptors (nAChRs) are a of FoxP31 and interleukin (IL)-17A1 T cells in the mouse colon. target in transduction of anti-inflammatory signals from the central Encenicline attenuated TNBS- and DSS-induced colitis in mice via nervous system to the gastrointestinal (GI) tract. The aim of this a7 nAChRs, as indicated by significantly reduced macroscopic jpet.aspetjournals.org study was to investigate the anti-inflammatory action of the novel parameters and MPO activity. Treatment with encenicline signifi- a7 nAChR partial agonist encenicline and to determine the cantly reduced the infiltration of macrophages, neutrophils, and mechanism underlying its activity. Anti-inflammatory activity of B cells in the colon of TNBS-treated animals, as indicated by IHC. encenicline was evaluated using trinitrobenzenesulfonic acid In the TNBS model encenicline reduced the frequency of FoxP31 (TNBS)- and dextran sulfate sodium (DSS)-induced models of IL-17A1 T cells in the colon. In the DSS-model treatment colitis. Macroscopic score, ulcer score, colon length and thickness, encenicline increased the frequency of FoxP31 T cells and reduced as well as myeloperoxidase (MPO) activity were recorded. Immu- IL-17A1 T cells. Stimulation of a7 nAChR with partial agonist nohistochemistry (IHC) was used to measure the infiltration of encenicline alleviates colitis via alteration of the number and/or at ASPET Journals on October 1, 2021 immune cells in the colon. Furthermore, we employed flow activation status of the immune cells in the gut, emphasizing a cytometry to determine the effect of encenicline on frequencies potential role of a7 nAChRs as a target for anticolitic drugs. Introduction The a7 nAChRs are located in both central and the peripheral nervous systems (de Jonge and Ulloa, 2007; Snoek et al., Inflammatory bowel diseases (IBD), comprising ulcerative 2010). In the periphery, a7 nAChRs participate in cholinergic ’ colitis (UC), and Crohn s disease (CD), is a group of chronic and transmission and are involved in control of the heart rate, relapsing gastrointestinal (GI) disorders manifested mainly hormone secretion, GI motility, and immunomodulation (de by imbalanced immunologic response leading to an inflamma- Jonge and Ulloa, 2007). tory state in the gut, disrupted motility, and abdominal pain The main neurotransmitter of the vagal nerve is acetylcho- ł (Sa aga et al., 2013; Sobczak et al., 2014). Although several line, which is thought to control the functions of immune cells pharmacological strategies have been employed to treat IBD, via nAChRs. Borovikova et al. (2000a) reported that acetyl- none of them has entirely succeeded. Recent studies point choline significantly attenuated the release of proinflamma- toward the role of a7 homopentamer nicotinic acetylocholine tory, such as tumor necrosis factor-a (TNF-a), but not the receptors (nAChRs) in the cholinergic modulation of immune anti-inflammatory cytokines, such as interleukin-10 (IL-10), cell activity (de Jonge and Ulloa, 2007; Snoek et al., 2010). in human macrophages in vitro. From a pharmacological point of view, nAChR agonists are more efficient than acetylcholine in inhibition of inflammatory signaling and production of 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 proinflammatory cytokines. For example, it has been demon- Medical University of Lodz [502-03/1-156-02/502-14-140 to MS and #503/1-156- strated that activation of nAChRs by nicotine reduces, in a 04/503-01 to J.F.] and National Science Centre [No. UMO-2013/11/N/NZ7/ dose-dependent way, the release of TNF-a and IL-6 from 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 isolated mouse peritoneal macrophages stimulated with lipo- Research Council for Strategic Research [COGNITO] and the Novo Nordisk polysaccharide (de Jonge et al., 2005). This observation is Foundation. Study sponsored by a Polpharma Scientific Foundation scholar- ship to M.S. further supported by studies in animal models of GI tract dx.doi.org/10.1124/jpet.115.228205. disorders indicating that activation of vagal a7 nAChRs may ABBREVIATIONS: CD, Crohn’s disease; DSS, dextran sulfate sodium; GI, gastrointestinal tract; HEX, hexamethonium; IBD, inflammatory bowel diseases; IHC, immunohistochemistry; IL, interleukin; MLA, methyllycaconitine; MPO, myeloperoxidase; nAChR, nicotinic acetylcholine receptor; PBS, phosphate-buffered saline; TNBS, 2,4,6-trinitrobenzene sulfonic acid; TNF-a, tumor necrosis factor-a; UC, ulcerative colitis. 157 158 Salaga et al. effectively attenuate colitis by reductionincytokinesecre- (3 mg/kg, i.p. twice daily) was administered from day 0 to day 2 tion from immune cells (de Jonge and Ulloa, 2007; Ji et al., with the first treatment 30 minutes before the induction of colitis. 2014), as well as by clinical reports indicating that smoking Animals were sacrificed on day 3 and the evaluation of colonic and administration of nicotine (i.e., via patches) may pro- tissue damage was performed (Fig. 1A). The a7 nAChRs antagonist vide beneficial effect on colonic inflammation in UC pa- MLA (3 mg/kg i.p.) was administered 60 minutes before encenicline (n 5 8). tients (Pullan et al., 1994). The ganglionic blocker HEX was administered at the dose of To explore the therapeutic potential of a7 nAChRs in the 10 mg/kg i.p., 30 minutes prior to encenicline. In the semichronic treatment of IBD, we tested the anti-inflammatory properties TNBS model a curative treatment mode was applied: Inflammation and mechanisms of action of a novel partial a7 nAChR agonist, was induced on day 0 and animals received encenicline treatment encenicline, which exhibits high efficacy at a7 nAChRs with (3 mg/kg, i.p. twice daily) between days 3 and 6 (Fig. 1B). On day 125 aKi value of 4.33 nM versus [ I]a-bungarotoxin in rat 7miceweresacrificedandtheevaluationofcolonicdamagewas brain homogenate (Prickaerts et al., 2012) and is currently in performed. the phase 3 clinical trial (ClinicalTrials.gov Identifier: In DSS-model animals were treated with encenicline (3 mg/kg, i.p. NCT01969136). To assess the anti-inflammatory activity of twice daily) either from day 0 to day 6 (Fig. 1C) with the first encenicline, we used trinitrobenezenesulfonic acid (TNBS)- treatment 30 minutes before the addition of DSS to the drinking water, or from day 3 to day 6 (Fig. 1D). On day 7 mice were sacrificed and dextran sulfate sodium (DSS)-induced models of colitis. and the evaluation of colonic damage was performed. In all To investigate the mechanism of action of encenicline, we used experiments control animals received vehicle (intraperitoneally) the a7 nAChRs antagonist methyllycaconitine (MLA). More- alone. Downloaded from over, we applied the ganglionic blocker hexamethonium For the in vitro assay, a stock solution of encenicline in dimethyl (HEX) to investigate whether the blockade of peripherally- sulfoxide (1022 M) was prepared and diluted accordingly. located nAChRs may abolish the potential ant-inflammatory action of encenicline. Using quantitative immunohistochem- Evaluation of Colonic Damage istry (IHC) and flow cytometry, we examined whether treat- TNBS Model. Animals were sacrificed by cervical dislocation. The ment with encenicline affects the number of immunocytes colon was removed, opened longitudinally, rinsed with phosphate jpet.aspetjournals.org (macrophages, neutrophils, T cells, and B cells) and changes buffered saline (PBS), and immediately examined. Macroscopic co- the ratio of pro- and anti-inflammatory T-cell subtypes in the lonic damage was assessed by an established semiquantitative scor- colonic tissue. ing system by adding individual scores for ulcer, colonic shortening, wall thickness, and presence of hemorrhage, fecal blood, and diarrhea, as described before (Fichna et al., 2012). For scoring ulcer and colonic Materials and Methods shortening the following scale was used: ulcer, 0.5 points for each . Animals 0.5 cm; shortening of the colon, 1 point for 15%, 2 points for 25% (with the basis being a mean length of the colon in untreated mice at ASPET Journals on October 1, 2021 Male BALB/c mice obtained from Animal Facility of the University of 8.01 6 0.15 cm; n 5 6). The wall thickness was measured in of Lodz, Poland, weighing 22–26 g, were used for all experiments. Mice millimeters, a thickness of n mm corresponding to n scoring points. were housed at a constant temperature (22–24°C) and maintained in sawdust-lined plastic cages under a 12-hour light/dark cycle with free access to laboratory chow and tap water ad libitum. The study was carried out in accordance with the European Communities Council Directive of November 24, 1986 (86/609/EEC) and with the institu- tional recommendations. The experimental protocol was approved by the Local Ethical Committee for Animal Experiments in Lodz (No. 589/2011).
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