Encenicline, an  7 Nicotinic Acetylcholine Receptor Partial Agonist, Reduces Immune Cell Infiltration in the Colon and Improves Experimental Colitis in Mice

Abstract

The a7 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 a7 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 1 and interleukin (IL)-17A 1 T cells in the mouse colon. Encenicline attenuated TNBS-and DSS-induced colitis in mice via a7 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

Cholinergic modulation of the immune system presents new approaches for treating inflammation

“…Studies investigating the cellular and molecular mechanisms of spleen involvement in the cholinergic anti-inflammatory responses in experimental colitis have focused on dendritic cells and their ability to prime T cells (Munyaka et al, 2014) and on the presence of specific subtypes of T cells in the submucosa of the colon (Salaga et al, 2016). This work demonstrated that in vivo stimulation of α7nAChRs on dendritic cells via central vagal stimulation decreased release of Th1/Th17 pro-inflammatory cytokines from these cells in vitro and impaired their ability to prime T cells.…”

“…It remains unclear how anti-inflammatory signals are transferred to the gut, but it most likely involves trafficking of cells from the spleen. Recent work has in fact demonstrated that treatment with encenicline, a partial agonist at the α7nAChR, reduced the infiltration of macrophages, neutrophils and B cells into the mucosa and submucosa of the colon in TNBS induced colitis in mice (Salaga et al, 2016). Furthermore, while the total number of T cells infiltrating the colon was unaffected by encenicline, the drug did reduce the abundance of FoxP3 + IL-17A + T cells, which have a pro-inflammatory role in IBD.…”

Review article: the role of the autonomic nervous system in the pathogenesis and therapy of IBD

“…To combat this—several selective α7nAChR agonists have been developed and tested on animal models of DSS‐induced colitis as well as models of experimental endotoxemia in healthy human volunteers. These early pre‐clinical studies have yielded conflicting results to date, with results likely hampered by the pharmacodynamic and pharmacokinetic properties of these compounds, as optimum administration routes, dosages and translatability from animal to human models are still being investigated . Effects on disease activity in patients with IBD using vagal tone modulation by other means such as controlled slow deep breathing, chanting meditation and prescribed exercise programs are yet to be reported.…”

Hazards associated with municipal waste storage. Vol. I

“…6x) by evaporation of dichloromethane at ca. 37°C [36][37][38][39][40]. After concentration the samples were subjected to GC-MS analysis on a Shimadzu QP2010 apparatus [41][42][43][44][45][46].…”