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Objective:To study the antidepressant-like effect and action mechanism of geniposide and eleutheroside B combination treatment on the lipopolysaccharide (LPS)-induced depression mice model.Methods:Depression mice model was established by lipopolysaccharide (LPS) injection.Totally 48 mice were randomly divided into 6 groups (8 rats per group) according to a random number table,including normal,model,fluoxetine(20 mg/kg),geniposide (100 mg/kg) + eleutheroside B (100 mg/kg),geniposide + eleutheroside B + WAY 100635(0.03 mg/kg),geniposide + eleutheroside B+ N-methyl-D-aspartic acid receptor (NMDA,75 mg/kg) groups,respectively.After continuous administration for 10 days,autonomic activity tests after 30 min of administration were performed on the 10th day.On the 11th day,except for the normal group,the mice in the other groups were intraperitoneally injected with LPS (1 mg/kg),and the behavioral tests were performed 4 h later.Enzyme linked immunosorbent assay was used to detect tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β)levels in mice serum.The mRNA expression of indoleamine 2,3-dioxygenase (IDO) and nuclear transcription factor (NF-κB) were detected by real-time quantitative polymerase chain reaction.Western-blot analysis was used to detect IDO and NF-κB protein expressions in hippocampus tissue.Results:Compared with the normal group,a single administration of LPS increased the immobility time in the forced swimming test (FST) and tail suspension test (TST,P＜0.01),without affecting autonomous activity.Compared with the model group,fluoxetine and geniposide + eleutheroside B administration significantly improved the immobility time of depressed mice in the FST and TST,decreased serum IL-1β content,inhibited the expression levels of NF-κB gene and protein in hippocampus tissues (P＜0.05 or P＜0.01).Compared with the model group,geniposide + eleutheroside B treatment significantly reduced serum TNF-α content and inhibited IDO mRNA and protein expressions in hippocampus (P＜0.05 or P＜0.01).In addition,NMDA partly prevented the inhibition of IDO mRNA expression by geniposide + eleutheroside B;NMDA and WAY-100635 also partly prevented the reduction of IL-1β content induced by geniposide + eleutheroside B treatment (P＜0.05 or P＜0.01).Conclusions:The combination of geniposide and eleutheroside B showed a certain antidepression-like effect.Its main mechanism of action may be contributed to inhibiting the activation of NF-κB,decreasing the proinflammatory cytokines such as TNF-α,IL-1β,and inhibiting in the neuroinflammatory reaction.Additionally,it also affects tryptophan metabolism,reduces the expression of a key enzyme of tryptophan metabolism,IDO.And this antidepressant-like effect may be mediated by 5-hydroxytryptamine and glutamate systems.