Abstract: OBJECTIVE To investigate the molecular mechanism of anti-depression and protective effects of medicated sera of Sinisan containing Bupleuri Radix and Paeoniae Radix Alba before and after vinegar-processing on CORT-induced PC12 cell injury. METHEODS Firstly， the MTT and morphological observation methods were used to evaluate whether the model was established successfully. Secondly， the cultured cells were divided into four groups (blank control group， CORT group， SNS serum group， VPSNS serum group). ELISA method was used to determine the contents of the monoamine neurotransmitters (DA and 5-HT) and the inflammatory cytokines (TNF-α and IL-1β) in cell supernatant. Then， the content of the injury index (LDH) and the activity of the protective index (SOD) in cell supernatant were measured using the microplate method， and the cell apoptosis rates were measured by flow cytometric analysis. Finally， the protein and gene expression of BDNF， ERK， and CREB were detected by Western blot and qPCR. RESULTS Compared to the model group， both 20%SNS serum group and 20%VPSNS serum group increased the contents of DA， 5-HT， the activity of SOD， and the protein and gene expression of BDNF， ERK， and CREB (P<0.05). And both of them reduced the contents of TNF-α， IL-1β， LDH， and the cell apoptosis rates (P<0.05). The protective effect of 20%VPSNS serum group on CORT-induced PC12 cell injury was better than that of 20%SNS serum group (P<0.05). CONCLUSION The BDNF-ERK-CREB pathway is probably involved in the protective effects of SNS and VPSNS on CORT-induced PC12 cell injury， and the protective effect of VPSNS is better than that of SNS.