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<i>Daphne odora</i>, a blooming shrub, has been traditionally used for various medicinal purposes. However, information on its anti-melanogenic activity and dermal application is limited. In this study, the <i>Daphne odora</i> extract (DOE), with constituents including daphnetin, was used to investigate depigmenting activity and the underlying mechanism of <i>Daphne odora</i>. DOE inhibited in vitro and cellular tyrosinase activity in a dose-dependent manner, and reduced the α-MSH-induced melanin biosynthesis to a control level. The protein expressions of melanin synthesis-related enzymes were also significantly reduced by DOE. Moreover, DOE decreased the phosphorylation of cAMP-response element binding proteins (CREBs) induced by α-MSH in B16F10 cells, while it activated phosphorylated extra-cellular signal-regulated kinases (ERKs) and protein kinase B (AKT) expression. These results suggest that DOE might inhibit the melanogenesis signaling pathways by activating ERK- and AKT-signaling pathways to regulate the expression of CREB and MITF and its downstream pathways. Therefore, DOE could potentially be developed as a depigmenting agent.