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The antidepressant-like effect of chiisanoside from the leaves of Acanthopanax sessiliflorus was evaluated by using mice models of depression, forced swim test (FST) and tail suspension test (TST). The results showed that treatment with chiisanoside at dose of 5.0 mg/kg significantly decreased immobility time in the FST and TST. Pretreatment with haloperidol (a non-selective D2 receptor antagonist), bicuculline (a competitive GABA antagonist) and N-methyl-D-aspartic acid (NMDA, an agonist at the glutamate site) effectively reversed the antidepressant-like effect of chiisanoside (5.0 mg/kg). Moreover, chiisanoside treatment did not change the locomotor activity. And chiisanoside (5.0 mg/kg) also effectively increased the dopamine (DA) and γ-aminobutyric acid (GABA) levels in mice brains exposed to the FST and TST in the co-treatment groups. Then we designed lipopolysaccharide (LPS)-induced antidepressant behavioral experiment, the results showed that LPS significantly increased immobility duration in the TST and FST. Chiisanoside administration could effectively reduce serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels; at the same time, the changes of related indexes of oxidative stress are improved, such as superoxide dismutase (SOD) and malondialdehyde (MDA). Moreover, chiisanoside effectively down-regulated brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB) and nuclear factor-κB (NF-κB) in hippocampal. In conclusion, chiisanoside displayed significant antidepressant-like effect, which was probably related to the DAergic, GABAergic and glutamatergic systems. And the mechanism of anti-depressant effect of chiisanoside might be via the alterations of animal behaviors, hippocampus inflammation, oxidative stress and neurotrophy, which might be attributed by the BDNF/TrkB/NF-κB pathway.Chiisanoside, a triterpenoid saponin extracted from Acanthopanax sessiliflorus, may have antidepressant activity.The antidepressant effect of chiisanoside may be associated with GABAergic, dopaminergic and glutamatergic systems.The mechanism of the action of chiisanoside may be attributed to the BDNF/TrkB/NF-κB signaling pathways.