Baicalin promotes hippocampal neurogenesis via SGK1- and FKBP5-mediated glucocorticoid receptor phosphorylation in a neuroendocrine mouse model of anxiety/depression

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.

Checks and balances: The glucocorticoid receptor and NFĸB in good times and bad

“…The interactions of GR and NFκB may be particularly salient. In addition to effects of glucocorticoids on neurogenesis, hippocampal structure, and cell viability (Behl, Lezoualc'h et al 1997, Zhang, Pan et al 2016), synthetic glucocorticoid treatment impairs NFκB DNA binding activity in hippocampal cells and subsequently impairs NFκB mediated transcription. This additional impairment may facilitate a second and compounding pathway of alterations given that impaired NFκB transcriptional activity increases susceptibility to oxidative stress induced cell death (Braun, Liebetrau et al 2000).…”

Long‐term stability and characteristics of behavioral, biochemical, and molecular markers of three different rodent models for depression

“…High levels of serum cortisol, related to elevated hypothalamo‐pituitary‐adrenal (HPA) axis activity, can be associated with depression. The CORT model tests the pharmacologically evoked anxio‐depressive state in animals by application of corticosterone, the rodent functional analogue of cortisol (Krugers, Lucassen, Karst, & Joels, ; Rosa et al, ) where corticosterone are subcutaneously applied on daily basis for two, three, five, or eight weeks (Gupta, Radhakrishnan, & Kurhe, ; Kv et al, ; Schloesser et al, ; Zhang et al, ). The OB models chronic agitated hypo‐serotonergic depression in mice (Lumia, Teicher, Salchli, Ayers, & Possidente, ).…”

Potential Antidepressant Effects of Scutellaria baicalensis, Hericium erinaceus and Rhodiola rosea

“…In mice models of chronic corticosterone (CORT)-induced depression, baicalin (40,80, and 160 mg/kg) administered either orally or intragastrically produces anxyolitic-and antidepressant-like effects which are reproduced by the conventional antidepressant fluoxetine [133,134]. In fact, baicalin rescues the behavioral alterations induced by chronic CORT, namely the decreased time spent in the center and non-periphery zone in the open-field test, the increased immobility time in tail suspension test and forced swimming test, as well as the decreased time spent in open arms in the elevated plus maze test [133,134]. In chronic CORT-treated mice, baicalin restores the aberrant negative feedback of HPA axis, as assessed by dexamethasone suppression test [133].…”