Quercetin alleviates chronic unpredictable mild stress-induced depression-like behavior by inhibiting NMDAR1 with α2δ-1 in rats

Depression is a serious mental disorder and the most prevalent cause of disability and suicide worldwide. Chronic unpredictable mild stress (CUMS) can lead to a significant acceleration of depression development. Quercetin (Que) is a flavonoid compound with a wide range of pharmacological effects. Recent studies have shown that quercetin can improve CUMS-induced depression-like behavior, but the mechanism of its improvement is still unclear. α2δ-1 is a regulatory subunit of voltage-gated calcium channel, which can interact with N-methyl-D-aspartate receptor (NMDAR) to form a complex.

Que has a good antidepressant effect and can significantly improve the depression-like behavior caused by CUMS. It exerts antidepressant effects by inhibiting the expression level of α2δ-1, interfering with the interaction between α2δ-1 and NMDAR, and then reducing the excitability of the HPA axis.

Rats were randomly exposed to two stressors every day for 4 weeks to establish a CUMS rat model, then sucrose preference test (SPT), forced swimming test (FST), tail suspension test (TST), and open field test (OFT) were performed to detect the behavior of CUMS rats, so as to evaluate whether the CUMS rat model was successfully established and the improvement effect of Que on CUMS-induced depression-like behavior in rats. Experimental techniques such as serum enzyme-linked immunosorbent assay (ELISA), immunofluorescence, Western blot, and co-immunoprecipitation, as well as in vitro experiments, were used to investigate the mechanisms by which Que exerts its antidepressant effects.

In this study, we found that Que could inhibit the increase of α2δ-1 and NMDAR expression in rat hypothalamus induced by CUMS. In pain, chronic hypertension and other studies have shown that α2δ-1 interacts with the NMDAR to form a complex, which subsequently affects the expression level of NMDAR. Consequently, the present study aimed to investigate the antidepressant effect of Que in vivo and in vitro and to explore its mechanism of action in terms of the interaction between α2δ-1 and NMDAR.

Behavioral and ELISA test results showed that Que could produce a reduction in the excitability of the hypothalamic-pituitary-adrenal (HPA) axis in CUMS rats and lead to significant improvements in their depressive behavior. Western blot, immunofluorescence, and co-immunoprecipitation experiments showed that Que produced a decrease in NMDAR1 and α2δ-1 expression levels and interfered with α2δ-1 and NMDAR1 binding. In addition, the neural regulation mechanism of Que on antidepressant effect in PC12 cells knocked out α2δ-1 gene was further verified. Cellular experiments demonstrated that Que led to a reversal of up-regulation of NMDAR1 and α2δ-1 expression levels in corticosterone-injured PC12 cells, while Que had no effects on NMDAR1 expression in PC12 cells with the α2δ-1 gene knockout. Conclusions: Que has a good antidepressant effect and can significantly improve the depression-like behavior caused by CUMS. It exerts antidepressant effects by inhibiting the expression level of α2δ-1, interfering with the interaction between α2δ-1 and NMDAR, and then reducing the excitability of the HPA axis.