Estrogen Replacement Therapy in Ovariectomized Rats: Complementary Roles of ER and GPR30 in Alleviating Depressive-like Behavior.

Women are twice as likely to suffer from major depressive disorder (MDD). The underlying mechanism between estrogen and depression is still unknown. We used ovariectomized rats to simulate menopausal status and established a depression model of chronic and acute stress. The therapeutic effects of estrogen were systematically studied through behavioral testing, Western blotting, ELISA, LC-MS, and cell experiments. In chronic stress, OVX rats showed depressive-like behaviors, and elevated hippocampal ER, BDNF, IL-1β/IL-18, and body weight. ERT reduced depression-like behavior by 64% to 76% in the behavioral test. ERT also reversed the molecules without affecting GPR30. In acute stress, ERT reduced depression-like behavior by 20% to 58% in the behavioral test. OVX decreased ER, BDNF, P2X7, IL-1β/IL-18, spine density, and microglia and increased the expression of GPR30. ERT reversed all the above. ERT normalized metabolic abnormalities caused by CUMS. Our study demonstrates that estrogen deficiency contributes to the onset and progression of depression in a rat model of menopause-like estrogen deficiency. Estrogen replacement therapy appears to alleviate depressive-like behaviors by reducing brain inflammation and supporting the brain's adaptive capacities through ER. Furthermore, the dual function positions GPR30 as a promising potential target for future treatments of menopausal depression, and GPR30 regulates neuroinflammation and neuroplasticity through the NLRP3/P2X7/IL-1β pathway.