Gentiopicroside alleviates depression-like symptoms in animal models through regulating COX-2-mediated autophagy and inflammation.

Depression is a serious mental illness affecting millions of people worldwide. This study investigates the effects of gentiopicroside, a compound found in traditional Chinese medicine, on depression-like animal models and its potential mechanism of action. The study utilized rat models with corticosterone-induced depression and treated them with various concentrations of gentiopicroside. The effects on hippocampal cells, serum 5-HT levels, inflammation, autophagy, and oxidative stress markers were observed. The role of Cyclooxygenase-2 (COX-2) expression and mitophagy was also examined using in vitro neuron cell models. Gentiopicroside demonstrated dose-dependent effects on alleviating hippocampal cell damage, restoring serum 5-HT levels, and inhibiting inflammation and oxidative stress markers. It also promoted autophagy and modulated COX-2 expression in the rat models. The in vitro study revealed that gentiopicroside could regulate COX-2 expression, reduce mitochondrial membrane potential loss and cell apoptosis, and inhibit NLRP3 (NOD-like receptor family, pyrin domain-containing 3) inflammatory complex-related proteins and cytokines. Overexpression of COX-2 significantly reversed the positive effects of gentiopicroside, while PINK1 (PTEN-induced kinase 1) overexpression promoted mitophagy, inhibited NLRP3 inflammatory complex activation, and reduced oxidative stress. Gentiopicroside ameliorates depression-like symptoms in animal models by suppressing COX-2 expression. This suppression is necessary for the subsequent enhancement of PINK1-mediated mitophagy, which helps to re-establish mitochondrial homeostasis and attenuate neuroinflammation and oxidative stress. This novel mechanism may potentially lead to the development of new therapies for depression treatment.