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SaPLIγ is a natural phospholipase A2 (PLA2) inhibitor, isolated from Sinonatrix annularis, that has been demonstrated to protect against envenomation by other venomous snakes. As snake venom PLA2s and mammalian secretory PLA2s are similar, saPLIγ is thought to have potential to alleviate inflammatory reactions in which PLA2s act as a key enzyme for arachidonic acid release. The aim of this study was to investigate the anti-inflammatory effects and mechanisms of action of saPLIγ in an animal model of carrageenan-induced acute inflammation. The results indicated that saPLIγ inhibited PLA2 subtypes extensively, especially IIA-PLA2, in a dose-dependent manner. Paw swelling in mice was reduced markedly by intraperitoneal saPLIγ 2.5 mg/kg, and the effect was significantly better than observed with dexamethasone at the same dose. Lower neutrophil infiltration and tissue edema was observed in the paws of saPLIγ-treated mice. Additionally, carrageenan-induced cyclooxygenase-2 (COX-2) and pro-inflammatory cytokines (TNFα and IL-1β) were also significantly down-regulated by saPLIγ in a dose-dependent manner. These results suggested that saPLIγ had effective anti-inflammatory effects in vivo, and these were produced by blocking mammalian IB, IIA, V and X sPLA2 subtypes.SaPLIγ, a PLA2 inhibitor isolated from S. annularis, showed good inhibitory effect on mammalian inflammation.SaPLIγ was extensive inhibitive to PLA2 subtypes, especially to IIA-PLA2 in dose-effect manner.SaPLIγ showed a better effect than dexamethasone in preventing paw swelling and neutrophil infiltration.Cyclooxygenase-2 (COX-2) and pro-inflammatory cytokines (TNFα, IL-1β) expression were significantly down-regulated by saPLIγ.