OBJECTIVE To investigate the antidepressant effect of triptolide in chronically unpredictable stressed mice and its possible protective effect on brain derived neurotrophic factor(BDNF). METHODS One method was selected from 8 different stress methods each day,and the mice were treated with triptolide(20,40,80 and 160μg·kg-1)10 min before the stress method. A chroni?cally unpredictable stressed model was established and after 14 d stress experiment, the total distance in the locomotor activity and the immobility time in the force swimming test and tail test were observed respectively. Triptolide(20,40,80 and 160μg·kg-1)was given 10 min before the test. In addition, Western blot was used to analyze the expression of phosphorylated cAMP response element binding protein(p-CREB) and BDNF in the hippocampus and frontal cortex. RESULTS There was no effect on the locomotor activity in any group. Compared with the normal control group,the chronically unpre?dictable stressed group showed obvious depressive-like behavior,while the immobility time in the force swimming test decreased from(161 ± 18)s in chronically stressed group to(102 ± 14)s(P<0.05) and(83±14)s(P<0.01)when mice were ip given triptolide 80 and 160μg·kg-1, respectively,and(77± 11)s(P<0.01)in imipramine(IMI)hydrochloride group(10 mg?kg-1),and(96±9)s(P<0.01)in fluox?etine(FLU)group(10 mg?kg-1). The immobility time in the tail suspension test decreased from(128± 8)s in chronically stressed group to(93±9)s(P<0.05),(85±8)s(P<0.01)and(77±11)s(P<0.01)when mice were ip given triptolide 40,80 and 160μg · kg-1 respectively,and(64 ± 9)s(P<0.01)in IMI hydro?chloride 10 mg?kg-1 group,and(72±6)s(P<0.01)in FLU group(10 mg?kg-1). Moreover,the expression of p-CREB in the hippocampus and frontal cortex significantly increased in triptolide 80 and 160μg·kg-1 groups(P<0.05),so did the expression of BDNF in the hippocampus and frontal cortex in triptolide 80 and 160μg·kg-1 groups(P<0.05). CONCLUSION Triptolide can ameliorate the depressive-like behavior in chronically unpredictable stressed mice,which may be related to the cAMP-CREB-BDNF signal transduction cascades.