Research has unveiled an important role for neuroinflammation in the pathogenesis of Parkinsons disease (PD) and many neurodegenerative diseases.Neuroinflammation is characterized by the activation of glial cells.Activated microglia and astrocytes consequently release various pro-inflammatory cytokine and neurotoxic factors and then deleterious to surrounding neurons and eventually induce neurodegeneration.Inhibiting over-activated glial cells has been shown to be a unique and effective therapeutic strategy for neuroinflammation-mediated neurodegenerative diseases.FLZ is a synthetic cyclic derivative of squamosamide from Annona glabra.The present study is to investigate the pharmacological effect and underline mechanism of FLZ against cellular and rodent PD models.For in vivo studies, rodent PD model induced by a single injection of LPS to the SN region of Wistar rats was used.The results showed that FLZ treatment significantly improved the abnormal behavior of PD model rats.FLZ showed potent efficacy in protecting dopaminergic (DA) neurons and inhibiting glial activation as shown in immunohistochemical results.FLZ also increased the content of dopamine and its metabolites in striatum of PD model rats.Effect of FLZ on the mRNA expression of inflammatory cytokines was assayed by real-time RT-PCR.The results suggested that FLZ inhibited LPS induced mRNA expression of pro-inflammatory cytokines including TNF-α, iNOS, MCP-1, and increased mRNA expression of anti-inflammatory cytokine IL-10.For in vitro studies, microglial cell line BV2 was used to investigate the molecular mechanism of FLZ against LPS-induced neuroinflammation.The results revealed that the anti-inflammatory properties of FLZ were mediated through inhibition of Src/Pyk2-PI3K/Akt-NFκB pathway.Taken together, our results demonstrated that FLZ is a potential anti-PD drug candidate and its mechanism is at least partially through inhibiting neuroinflammation by modulating inflammatory signal transduction pathway.