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Sex differences and drug dose influence the role of the alpha 7 nicotinic acetylcholine receptor in the mouse dextran sodium sulfate-induced colitis model
Alsharari, S. D., Bagdas, D., Akbarali, H. I., Lichtman, P. A., Raborn, E. S., Cabral, G. A., Carroll, F. I., Mcgee, E. 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
INTRODUCTION: α7 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 α7 nAChRs in dextran sodium sulfate (DSS)-induced colitis in male and female mouse. We first compared disease activity and pathogenesis of colitis in α7 knockout and wild-type mice. We then evaluated the effect of several α7 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, α7 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 α7 ligands PHA-543613, choline, and PNU-120596 decreased colitis severity in male but not female mice. The anti-colitis effects of these α7 compounds dissipated when administered at higher doses.
CONCLUSIONS: Our results suggest the presence of a α7-dependent anti-colitis endogenous tone in male mice. Finally, our results show for the first time that female mice are less sensitive to the anti-colitis activity of α7 agonists. Ovarian hormones may play a key role in the sex difference effect of α7 nAChRs modulation of colitis in the mouse.
IMPLICATIONS: Our collective results suggest that targeting α7 nAChRs could represent a viable therapeutic approach for intestinal inflammation diseases such as ulcerative colitis with the consideration of sex differences.