Chaihu-Shugan-San exerts rapid antidepressant effects via sex-specific suppression of hippocampal neuroinflammation: dissociation from peripheral anti-inflammatory and hormonal actions

Major depressive disorder is a major contributor to disability and a key component of the overall global burden of disease. Women consistently demonstrate a higher prevalence of depression in comparison to men; however, the underlying mechanisms driving this gender-based disparity remain unclear. Chaihu-Shugan-San (CSS) is a classic formula that has the function of soothing the liver and relieving depression. It is widely used in female patients clinically and has been previously determined to produce rapid antidepressant-like effects in female rather than male mice. The mechanism of its antidepressant gender advantage still needs to be further revealed. This study investigates the gender-specific effects of CSS on depression, focusing on the roles of hormones and neuroinflammation. We established a mouse depressive model by chronic restraint stress (CRS) for 14 days and used the tail suspension test, sucrose preference test, and forced swimming test to detect the rapid antidepressant effects of CSS. ELISA was used to detect inflammatory factors and hormone levels in serum. Immunofluorescence was used to detect the expression of astrocytes and microglia in the mouse hippocampus. Using a CRS model in C57BL/6J mice, we demonstrate that CSS significantly alleviates depressive behaviors in female mice but not in males 2 h after administration. CSS treatment reduces serum levels of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1 beta, interferon-gamma) in both genders, but its effect on estrogen levels is more pronounced in females, or not androgen levels in males. Furthermore, CSS inhibits the CRS-induced increase in glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 expression in the hippocampus of female mice, indicating a modulation of neuroinflammation and glial cell responses. Collectively, these findings suggest CSS holds therapeutic potential for female depression, likely via dual regulation of estrogen homeostasis and neuroinflammation, warranting further exploration of sex-specific mechanisms and neuropathology.