Anti-inflammatory effect and potential mechanism of betulinic acid on λ-carrageenan-induced paw edema in mice

lambda-Carrageenan (Carr), a seaweed polysaccharide, is used as a proinflammatory agent in research. Betulinic acid (BA), a naturally occurring pentacyclic triterpenoid, exerts immunomodulatory, antioxidant, anti-inflammatory, anti-tumor, anti-malarial and anti-HIV effects. The aim of this study was to investigate whether BA exerts anti-inflammatory effect against Carr-induced paw edema in mice, and how BA could mediate the expression of inflammation-associated MAPK-COX-2-PGE(2) signal pathway. BA pretreatment significantly reduced the in-flammatory response to Carr-induced paw edema, especially at 4 h after injection. BA reduced the serum levels of pro-inflammatory cytokines, such as IL-1 alpha, IL-1 beta, IL-5, IL-6, GM-CSF, KC, MCP-1 and PGE(2) in Carr-treated mice, and increased those of anti-inflammatory cytokines, such as IL-12. It also increased SOD, CAT and GSH-Px activities, and GSH content, and reduced MDA content in the liver of Carr-treated mice. Besides, BA reduced neutrophil infiltration in the basal and subcutaneous layers of the paw of Carr-treated mice, decreased the expression of COX-2 protein, and reduced the phosphorylation of JNK, p38 and ERK1/2. These results indicated that the protective effect of BA on Carr-induced paw edema might be due to its alleviation of inflammatory response and inhibition of oxidative stress, possibly by inhibiting MAPK-COX-2-PGE(2) signaling pathway activation.