摘要:OBJECTIVE Diosgenin(DG), a naturally occurring steroidal saponin, has been reported to offer a variety ofpharmacological activities including anti-diabetic and anti-tumor activity, anti-inflammatory and anti-AD. However, the clinical application of DG is limited by its extremely low solubility and poor pharmacokinetic profile. In the present report,a novel diosgenin derivative with improved water-solubility was synthesized and its effect on the LPS-impaired hippocampal neurogenesis, cognition function and underlying mechanism was investigated. METHODS The effects of DG derivative on the adult hippocampal neurogenesis and cognition decline were investigated in a central LPS-induced inflammatory mice model, along with the fundamental mechanisms in vivo and in vitro using LPS-stimulated microglial BV2 cells. RESULTS DG derivative attenuates LPS-impaired neurogenesis by ameliorating the proliferation and differentiation of neural stem cells(NSCs), and prolonging their survival. The impaired neurogenesis in the hippocampal DG triggered the cognitive function, and that treatment of Arg-DG led to the recovery of cognitive decline. Arg-DG also suppressed the production of LPS-induced pro-inflammatory cytokines in hippocampal DG by blocking microglial activation. In in vitro study, Arg-DG inhibited the production of nitric oxide(NO), nitric oxide synthase(i NOS), cyclooxygenase-2(COX-2) expression, and prostaglandin D2 production(PGD2), as well as the pro-inflammatory cytokines, such as interleukin(IL)-6, IL-1β, and tumor necrosis factor alpha(TNF-α). The anti-inflammatory effect of Arg-DG was regulated by NF-κB and MAPK JNK signaling both in vivo, and in LPS-stimulated microglial BV2 cells. CONCLUSION These results suggest that Arg-DG might have the potential to treat the neurodegenerative disorders resulting from microgliamediated neuroinflammation.
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