Sex differences and drug dose influence the role of the alpha 7 nicotinic acetylcholine receptor in the mouse dextran sodium sulfate-induced colitis model

Abstract

Introduction: alpha 7 nicotinic acetylcholine receptors (nAChRs) play an important role in vagus nerve-based cholinergic anti-inflammatory effects. This study was designed to assess the role of alpha 7 nAChRs in dextran sodium sulfate (DSS)-induced colitis in male and female mouse. We first compared disease activity and pathogenesis of colitis in alpha 7 knockout and wild-type mice. We then evaluated the effect of several alpha 7 direct and indirect agonists on the severity of disease in the DSS-induced colitis. Methods: Male and female adult mice were administered 2.5% DSS solution freely in the drinking water for 7 consecutive days and the colitis severity (disease activity index) was evaluated as well as colon length, colon histology, and levels of tumor necrosis factor-alpha colonic levels. Results: Male, but not female, alpha 7 knockout mice displayed a significantly increased colitis severity and higher tumor necrosis factor-alpha levels as compared with their littermate wild-type mice. Moreover, pretreatment with selective alpha 7 ligands PHA-543613, choline, and PNU-120596 decreased colitis severity in male but not female mice. The anti-colitis effects of these alpha 7 compounds dissipated when administered at higher doses. Conclusions: Our results suggest the presence of a alpha 7-dependent anti-colitis endogenous tone in male mice. Finally, our results show for the first time that female mice are less sensitive to the anticolitis activity of alpha 7 agonists. Ovarian hormones may play a key role in the sex difference effect of alpha 7 nAChRs modulation of colitis in the mouse. Implications: Our collective results suggest that targeting alpha 7 nAChRs could represent a viable therapeutic approach for intestinal inflammation diseases such as ulcerative colitis with the consideration of sex differences.