Abstract
Antidepressants increase hippocampal neurogenesis by activating the glucocorticoid receptor (GR), but excessive GR activation impairs hippocampal neurogenesis, suggesting that normal GR function is crucial for hippocampal neurogenesis. Baicalin was reported to regulate the expression of GR and facilitate hippocampal neurogenesis, but the underlying molecular mechanisms are still unknown. In this study, we used the chronic corticosterone (CORT)-induced mouse model of anxiety/depression to assess antidepressant-like effects of baicalin and illuminate possible molecular mechanisms by which baicalin affects GR-mediated hippocampal neurogenesis. We found that oral administration of baicalin (40, 80 or 160 mg/kg) for 4 weeks alleviated several chronic CORT-induced anxiety/depression-like behaviors. Baicalin also increased Ki-67- and DCX-positive cells to restore chronic CORT-induced suppression of hippocampal neurogenesis. Moreover, baicalin normalized the chronic CORT-induced decrease in GR protein levels, the increase in GR nuclear translocation and the increase in GR phosphorylation at Ser203 and Ser211. Finally, chronic CORT exposure increased the level of FK506-binding protein 51 (FKBP5) and of phosphorylated serum- and glucocorticoid-inducible kinase 1 (SGK1) at Ser422 and Thr256, whereas baicalin normalized these changes. Together, our findings suggest that baicalin improves anxiety/depression-like behaviors and promotes hippocampal neurogenesis. We propose that baicalin may normalize GR function through SGK1- and FKBP5-mediated GR phosphorylation.
Highlights
Stress is the most powerful risk factor for the development of depression
The results showed that chronic CORT exposure significantly slowed the gain in body weight compared to the vehicle-treated group (Fig. 1B, F(5, 84) = 14.561, P < 0.001)
These results demonstrated that baicalin can improve chronic CORT-induced anxiety-like behaviors
Summary
Stress is the most powerful risk factor for the development of depression. Excessive and prolonged chronic stress results in hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis and hypersecretion of corticosteroids, which are the most consistent biological findings in major depression disorders[1,2]. More and more evidence has consistently demonstrated that stress or high concentrations of glucocorticoids induce GR activation, which impairs hippocampal neurogenesis[4,5,6,7]. Baicalin was reported to regulate the expression of GR15 These studies revealed the effects of baicalin on hippocampal neurogenesis and GR protein levels. To further illuminate the potential molecular mechanisms by which baicalin affects GR-mediated hippocampal neurogenesis, we firstly assessed the antidepressant-like effects of baicalin on behaviors and hippocampal neurogenesis in the mouse model of chronic CORT-induced anxiety/depression. We characterized the effect of chronic CORT exposure and baicalin on GR level, GR nuclear translocation and GR phosphorylation in the hippocampus. To investigate the molecular mechanisms underlying the normalization of GR function by baicalin, we analyzed SGK1 and FKBP5, two proteins that are known to modulate GR function
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