α7 nicotinic acetylcholine receptor agonist GTS-21 attenuates DSS-induced intestinal colitis by improving intestinal mucosal barrier function

Background and aims: Cholinergic output, which could modulate innate immune responses through stimulation of alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR), might be a target to minimize tissue damage in autoimmune disease. GTS-21, a selective alpha 7nAChR agonist, has previously demonstrated to inhibit synovium inflammation in rheumatoid arthritis. In this study, we investigated the effect of GTS-21 on dextran sulfate sodium (DSS)-induced colitis model and its potential mechanism. Methods: Male BABL/c mice (n=32) were randomly divided into four groups: normal control group, DSS-induced colitis group, GTS-21 treatment with or without alpha 7nAChR antagonist alpha-BGT treatment group. Disease activity index (DAI), histological activity index (HAI) and colonic macroscopic damage were evaluated. Fluorescein isothiocyanate (FITC)-dextran assay was applied to measure intestinal permeability. The expressions of tight junction (TJ) proteins and NF-kappa B associated proteins were detected by Western blot. Results: GTS-21 could decrease DAI scores, HAI scores, intestinal permeability and reduce the intestinal bacterial translocation in DSS-induced colitis group, whereas alpha 7nAChR antagonist alpha-BGT could impair this protective influence. The expressions ofTJ proteins were increased with administration of GTS-21 both in vivo and in vitro. Furthermore, GTS-21 also inhibited the NF-kappa B activation in intestinal epithelial cells and colitis model, while alpha-BGT reversed the inhibitory effect. Conclusion: The alpha 7nAChR agonist GTS-21 attenuated DSS-induced colitis through increasing expressions of TJ proteins in colon tissues and improved intestinal barrier function, which might be due to modulating NF-kappa B activation in intestinal epithelial cells.