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

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.

Alsharari, S. D., Bagdas, D., Akbarali, H. I., Lichtman, P. A., Raborn, E. S., Cabral, G. A., ... Damaj, M. I. (2017). Sex differences and drug dose influence the role of the alpha 7 nicotinic acetylcholine receptor in the mouse dextran sodium sulfate-induced colitis model. Nicotine and Tobacco Research, 19(4), 460-468. https://doi.org/10.1093/ntr/ntw245