In this study, we investigated the antidepressant-like effect of piperine in mice exposed to chronic mild stress (CMS) procedure. Repeated administration of piperine for 14 days at the doses of 2.5, 5 and 10 mg/kg reversed the CMS-induced changes in sucrose consumption, plasma corticosterone level and open field activity. Furthermore, the decreased proliferation of hippocampal progenitor cells was ameliorated and the level of brain-derived neurotrophic factor (BDNF) in hippocampus of CMS stressed mice was up-regulated by piperine treatment in the same time course. In addition, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactic dehydrogenase (LDH) assays showed that piperine (6.25-25 microM) or fluoxetine (FLU, 1 microM) dose-dependently protected primary cultured hippocampal neurons from the lesion induced by 10 microM corticosterone (CORT). Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect the messenger ribonucleic acid (mRNA) level of BDNF in cultured neurons. Treatment with piperine (6.25-25 microM) for 72 h reversed the CORT-induced reduction of BDNF mRNA expression in cultured hippocampal neurons. In summary, up-regulation of the progenitor cell proliferation of hippocampus and cytoprotective activity might be mechanisms involved in the antidepressant-like effect of piperine, which may be closely related to the elevation of hippocampal BDNF level.