Depression and related mood disorders are among the world's greatest public health problems. Previous studies have demonstrated that astilbin (AST) has broad pharmacological functions which may modulate numerous pathways, such as antioxidant, scavenging free radicals, anti-inflammatory and so on, similarly to some of other flavonoids. In this study, the antidepressant-like effect of AST was investigated using chronic unpredictable mild stress ( Key words depression; astilbin; chronic unpredictable mild stress; serotonin; dopamine; brain-derived neurotrophic factor Depression is a serious medical illness that characterized by affective disorder. According to the World Health Organization (WHO), by the year 2030, depression will result in more years of life lost to disability than any other illness.1) At present, most antidepressants used clinically with low efficacy and many side effects can not meet the clinical needs. Therefore, with the increased prevalence of depression and social burden every year, the development of new antidepressants is becoming a top priority.Despite the fact that the molecular and cellular mechanisms remain unclear, a leading hypothesis of depression recently suggests that neurotrophic factors and adult neurogenesis play critical roles in mediating the behavioural responses to antidepressants.2) The brain-derived neurotrophic factor (BDNF) is closely related to neuronal survival and neurogenesis and plays an important role in animal models of depression. Various stress procedures including chronic unpredictable mild stress (CUMS) result in obviously decreases of BDNF expression in the brain, while chronic administration of almost all kinds of antidepressants including imipramine regulates BDNF levels. [3][4][5] The extracellular signal-regulated kinases (ERK) and AKT pathways are the two important downstream signaling pathways of BDNF. It has been reported that some of new antidepressants under development upregulate the expression of BDNF in different brain regions of stress mice via promoting the phosphorylation of ERK1/2 and AKT and thus activating the ERK, AKT pathways to produce antidepressant effects. [6][7][8] In recent studies, natural flavonoids especially resveratrol, tea polyphenols and curcumin show attractive prospect in the field of neural protection research.7,9,10) There is growing evidence indicated that flavonoids ameliorate the symptoms of depression via upregulating the levels of monoaminergic neurotransmitters 11) and promoting the expression of neurotrophic factors. 12,13)