Saikosaponin-d attenuates postpartum estrogen withdrawal-induced depressive symptoms by modulating glucocorticoid metabolism and inhibiting hippocampal NLRP3 inflammatory vesicle activation.

Postpartum depression (PPD) is a prevalent mental disorder affecting women worldwide. Radix Bupleuri, a traditional Chinese herb frequently used in PPD treatment formulations, contains saikosaponin-d (SSd) as one of its major bioactive constituents. Dysregulation of glucocorticoid metabolism and activation of the NLRP3 inflammasome have been implicated in the pathophysiology of depression. However, whether SSd alleviates PPD through modulation of these pathways remains unclear. In this study, we investigated the therapeutic effects and underlying mechanisms of SSd in a hormone-simulated PPD rat model. Following model establishment, anhedonia-like behavior was assessed using the sucrose preference test, while locomotor activity and anxiety-like behavior were evaluated using the open field test. Serum inflammatory cytokines levels were measured by ELISA, and hippocampal NLRP3 inflammasome-related proteins were examined by Western blot. SSd treatment significantly ameliorated PPD-induced behavioral deficits, as evidenced by increased sucrose preference and locomotor activity. Both SSd and fluoxetine (FLU) markedly suppressed the expression of NLRP3 inflammasome components (NLRP3, caspase-1) and reduced serum levels of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α). Notably, SSd—but not FLU—significantly decreased plasma corticosterone (CORT) and 11-dehydrocorticosterone (11-DHCORT) levels and was associated with altered 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity, suggesting differential modulation of glucocorticoid metabolism. Additionally, SSd treatment coincided with increased estrogen receptor (ERα/ERβ) expression in key brain regions. Comprehensive analysis of these data suggests that SSd is associated with reduced neuroinflammation, restoration of glucocorticoid metabolic balance, and increased estrogen receptor expression, which may collectively contribute to the amelioration of PPD-like behaviors.