Neuroprotective effects of gypenosides on LPS-induced anxiety and depression-like behaviors.

Aim: Depression, a prevalent mental disorder, significantly impairs the quality of life and social functioning. Targeting neuroinflammation is a promising therapeutic approach, highlighting the need for natural neuroprotective agents. Gypenosides (Gyp) from Gynostemma pentaphyllum exhibit anxiolytic and antidepressant effects, yet the underlying mechanisms remain unclear. We investigated whether Gyp, isolated and purified by our laboratory, can exert neuroprotective effects by modulating neuroinflammation in the hippocampus and prefrontal cortex (PFC) of mice with LPS-induced anxiety and depression, thereby ameliorating behavioral phenotypes.

Methods: LPS (1 mg/kg, i.p.) was used to induce anxiety and depression-like behaviors. Gyp was administered at 50, 100, or 200 mg/kg in pretreatment, with fluoxetine hydrochloride (Flu) as a positive control, for 10 consecutive days.

Results: Gyp, especially at 100 mg/kg, significantly ameliorated LPS-induced anxiety and depression in mice, normalizing cytokine expression in the hippocampus and PFC, with IL-1β showing the most pronounced regulation (Hippocampus: Ratio_Gyp-100/LPS = 30.73 %, PFC: Ratio_Gyp-100/LPS = 55.89 %). Gyp also reversed LPS-induced neuronal loss and necrosis, reduced glial cell activation, and prevented the transition of microglia to the M1 phenotype. Mechanistically, Gyp suppressed the activation of the NLRP3 inflammasome in the PFC, and modulated hippocampal synaptic protein loss, thereby mediating neuroinflammation.

Conclusions: Gyp improved anxiety and depression in LPS-induced mice, which may be achieved by balancing systemic inflammatory levels, regulating glial cell activation and phenotypic polarization, regulating hippocampal synaptic plasticity, and suppressing the NLRP3/Caspase-1/ASC signaling pathway in the PFC.