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. • SMG alleviates LPS-induced depressive behaviors by modulating neuroinflammation-pyroptosis axis in mice. • SMG restores neuroimmune balance via TNF-α suppression and IL-10 upregulation in hippocampus/brain tissue. • SMG inhibits microglial pyroptosis by reducing IL-1β and CD68/CD86 markers. • First evidence of SMG as a dual-target functional food for depression treatment.
Yang et al. (Thu,) studied this question.