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Icariin, a flavonoid and a major constituent of Herba Epimedii, has been previously demonstrated to possess potential antidepressant-like effects. In the present study, we established a rat model of depression induced by unpredictable chronic mild stress (CMS) in order to examine the effects of icariin treatment. The rats were allocated into the control group or one of the treatment groups [exposure to CMS plus oral administration of saline, icariin (20 or 40 mg/kg) or fluoxetine (10mg/kg)]. We examined the therapeutic effects of icariin administration on depression‑like behaviors (with a sucrose preference test), on the mRNA and protein expression of glucocorticoid receptor (GR), FK506 binding protein 5 (FKBP5) and serum- and glucocorticoid-inducible kinase 1 (SGK1), as well as on the distribution of GR (in the cytoplasm and nucleus) in both the hippocampus and the prefrontal cortex following exposure to CMS. Our results revealed that the oral administration of icariin (20 and 40 mg/kg) for 35 consecutive days attenuated the development of depression-like behaviors induced by exposure to CMS. The increased mRNA expression of GR and SGK1 in the prefrontal cortex was reversed by icariin treatment. Moreover, the CMS-induced increases in the levels of cytosolic GR and SGK1 were partially restored by icariin administration in both the hippocampus and the prefrontal cortex, particularly in the hippocampus. Icariin also partially reversed the upregulated epxression of nuclear GR in the prefrontal cortex and that of FKBP5 in the hippocampus. On the whole, our findings indicate that icariin may have therapeutic applications as a potential antidepressant with multiple targets in both the hippocampus and prefrontal cortex. It exerts antidepressant-like effects by restoring the negative feedback regulation of the hypothalamic-pituitary-adrenal axis, which is at least partially attributed to normalization of the distribution of GR, and decreases in the expression levels of FKBP5 and SGK1.

Icariin alters the expression of glucocorticoid receptor, FKBP5 and SGK1 in rat brains following exposure to chronic mild stress