Nobiletin, an active component of Wenyang Yiqi Formula, alleviates constipation associated depression through targeting MAPT to inhibit the MAPK signaling pathway

Slow transit constipation (STC) is a common gastrointestinal disorder that is often accompanied by depression. Nobiletin is a natural compound that has been shown to have anti-inflammatory and anti-depressant effects.To study the effects of nobiletin extracted from Wenyang Yiqi Formula 19 (WYF) on STC accompanied by depression and the related mechanism in STC mouse models.In this study, the effects of nobiletin on STC accompanied by depression were investigated in both an STC animal model and an in vitro study. The animal model was induced by loperamide, and the in vitro study used Interstitial cells of Cajal (ICCs) isolated from STC mice. The efficacy of nobiletin was assessed by comparing various parameters, including stool particle counts, moisture content, intestinal propulsive rate, colon histopathology, microtubule-associated protein-tau (MAPT) expression in colon tissue, serum levels of TNF-α, IL-1β, IL-6, IFN-γ, and the levels of MAPK pathway-related proteins among three experimental groups.Nobiletin treatment significantly improved stool particle counts, moisture content, intestinal propulsive rate, and colon histopathology in the STC animal model. Nobiletin also decreased MAPT expression in colon tissue and serum levels of TNF-α, IL-1β, IL-6, IFN-γ, and the levels of MAPK pathway-related proteins. In the in vitro study, nobiletin treatment reversed the increased cell proliferation and cell apoptosis observed in ICC isolated from the STC model.The findings of this study indicate that nobiletin exhibits promising therapeutic potential in addressing STC accompanied by depression. This potential may be attributed to its ability to regulate the function of ICC by targeting MAPT.