Siraitia grosvenorii extract (Sweet Mogrosides) alleviates LPS-induced depressive-like behaviors through modulating neuroinflammation-pyroptosis axis

This study investigates the antidepressant effects of Sweet Mogrosides (SMG) derived from Siraitia grosvenorii (SG), focusing on the outcomes of its oral administration and its novel dual-axis modulation of the neuroinflammation-pyroptosis pathway in an LPS-induced depression model. Behaviorally, oral SMG treatment significantly alleviated depressive-like behaviors in mice. Mechanistically, our results demonstrate that orally administered SMG not only rebalanced hippocampal pro- and anti-inflammatory cytokines (suppressing TNF-α while upregulating IL-10) but also significantly inhibited the NLRP3 inflammasome-mediated pyroptotic pathway, as evidenced by reduced IL-1β expression and decreased expression of GSDMD and microglial activation markers (CD68/CD86). Immunofluorescence analysis confirmed that oral SMG suppressed IBA1+ microglial activation and attenuated pro-inflammatory phenotypic shifts. By systematically elucidating that oral SMG can concurrently target both neuroinflammatory and pyroptosis cascades, this study highlights a novel mechanism of action and provides strong evidence for developing SMG as a dietary-based or orally active neuroprotective agent for inflammation-related depression.