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Tenuigenin (TGN), a major active component of polygala tenuifolia root, has been reported to have anti-inflammatory effect. In this study, we investigated the anti-neuroinflammatory effects of TGN on LPS-induced inflammation both in vitro and in vivo. The levels of tumor necrosis factor -α (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6), and prostaglandin E2 (PGE2) were measured by ELISA. The expression of Nuclear factor E2–related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) were detected by western blot analysis. The results showed that TGN strongly inhibited LPS-induced TNF-α, IL-1β, IL-6, and PGE2 production. The expression of Nrf2 and HO-1 were up-regulated by TGN in a dose-dependent manner. Furthermore, the anti-inflammatory effects of TGN were significantly inhibited by transfection with Nrf2 siRNA or protoporphyrin (SnPP), an HO-1 activity inhibitor. In vivo, TGN attenuated LPS-induced memory deficit in the Morris water maze and passive avoidance tasks. Also, TGN inhibited LPS-induced TNF-α and IL-1β expression in brain tissues.In conclusion, the results of this study indicated that TGN inhibited LPS-induced inflammatory responses in microglia via activating the Nrf2-mediated HO-1 signaling pathway.