title: Encenicline, an α7 Nicotinic Acetylcholine Receptor Partial Agonist, Reduces Immune Cell Infiltration in the Colon and Improves Experimental Colitis in Mice.
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.
authors.affiliation: 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.).
authors.forename: M
authors.initials: M
authors.lastname: Salaga
authors.affiliation: 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.).
authors.forename: L V
authors.initials: LV
authors.lastname: Blomster
authors.affiliation: 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.).
authors.forename: A
authors.initials: A
authors.lastname: Piechota-Polańczyk
authors.affiliation: 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.).
authors.forename: M
authors.initials: M
authors.lastname: Zielińska
authors.affiliation: 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.).
authors.forename: D
authors.initials: D
authors.lastname: Jacenik
authors.affiliation: 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.).
authors.forename: A I
authors.initials: AI
authors.lastname: Cygankiewicz
authors.affiliation: 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.).
authors.forename: W M
authors.initials: WM
authors.lastname: Krajewska
authors.affiliation: 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.).
authors.forename: J D
authors.initials: JD
authors.lastname: Mikkelsen
authors.affiliation: 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.) jakub.fichna@umed.lodz.pl.
authors.forename: Jakub
authors.initials: J
authors.lastname: Fichna
mesh_terms: D000818:Animals; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D003106:Colon / Q000473:pathology*; D016264:Dextran Sulfate; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D018738:Hexamethonium / Q000494:pharmacology; D020381:Interleukin-17 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018722:Nicotinic Agonists / Q000627:therapeutic use*; D018733:Nicotinic Antagonists / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D011812:Quinuclidines / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D013876:Thiophenes / Q000627:therapeutic use*; D014302:Trinitrobenzenesulfonic Acid; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000819:agonists*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D020381:Interleukin-17; C000605814:N-(7-chloro-N-quinuclidin-3-yl)benzo(b)thiophene-2-carboxamide; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011812:Quinuclidines; D013876:Thiophenes; D064569:alpha7 Nicotinic Acetylcholine Receptor; D018738:Hexamethonium; D014302:Trinitrobenzenesulfonic Acid; D016264:Dextran Sulfate; D009195:Peroxidase