Gypenosides ameliorate depression by modulating microglial state transition via the NLRP3/Caspase-1/ASC signaling...

Depression remains a major global health challenge. Microglial polarization imbalance and subsequent neuroinflammation are core pathological mechanisms. Given current treatment limitations, developing natural products with fewer side effects is a critical research priority.

Gypenosides (Gyp) have demonstrated anxiolytic and antidepressant activity in acute depression models, whereas the antidepressant potential and mechanisms of its key constituent, gypenoside LVI (Gyp-LVI), remain unclear. This study aims to elucidate the antidepressant properties and molecular pathways of Gyp-LVI, and to further explore the efficacy and mechanisms of Gyp in more extensive models.

This study utilized lipopolysaccharide (LPS)-induced BV-2 microglial cells and a chronic unpredictable mild stress (CUMS) mouse model to evaluate the antidepressant potential of Gyp/Gyp-LVI. Behavioral and molecular biological approaches were employed to investigate the underlying mechanisms of action.

In cellular experiments, Gyp/Gyp-LVI pretreatment inhibited BV-2 microglial proliferation induced by LPS, reduced the levels of inflammatory factors (TNF-α, IL-1β, IL-6), downregulated M1 markers (iNOS, CD86), and upregulated the M2 marker (Arg-1), while suppressing NLRP3 inflammasome activation. In mice, the 5-week CUMS model induced depression-like behaviors, elevated peripheral and central inflammation and oxidative stress, increased glial cell numbers in the hippocampus and PFC, shifted microglial polarization toward the M1 phenotype, and activated the NLRP3 pathway in the PFC. Gyp/Gyp-LVI intervention ameliorated these abnormalities and reversed the behaviors. Notably, Gyp and Gyp-LVI may differentially regulated microglial polarization: Gyp mainly inhibited M1 polarization, whereas Gyp-LVI both suppressed M1 and promoted a shift toward M2.

The antidepressant effects of Gyp/Gyp-LVI are associated with restoring inflammatory homeostasis, modulating oxidative stress, regulating glial cell polarization, and inhibiting the NLRP3/Caspase-1/ASC signaling pathway in the PFC.