Revealing Antidepressant Mechanisms of Baicalin in Hypothalamus Through Systems Approaches in Corticosterone- Induced Depressed Mice

Abstract

Baicalin, the main active flavonoid constituent of Scutellaria baicalensis Georgi, has been reported to exert antidepressant effects. Hypothalamic-pituitary-adrenal (HPA) axis plays important roles in depression. However, antidepressant effect and mechanism of baicalin on HPA axis in hypothalamus are still unknown. In present study, we find baicalin significantly attenuates the increase of immobility time in tail suspension and forced swimming, improves the decrease of spending time in open arms, and restores the aberrant negative feedback of HPA axis in chronic corticosterone (CORT)-induced depressed mice. Moreover, proteomics finds 370 differentially expressed proteins after baicalin treatment, including 114 up-regulation and 256 down-regulation in hypothalamus. Systems biology analysis indicates the functions of differentially expressed proteins focus on phosphoserine binding and phosphorylation, especially participate in GR signaling pathway. Finally, our findings demonstrate that baicalin normalizes hypothalamic GR nuclear translocation via reducing GR phosphorylation to remodel negative feedback of HPA axis in CORT-induced mice.

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

“…In fact, baicalin selectively targets CORT-induced alterations in the nuclear/cytoplasmic GR distribution in the hippocampus. In detail, baicalin selectively reverses the CORT-induced decrease of GR levels in cytoplasm and the concomitant increase of GR levels in nucleus [133]. On the other hand, the CORT-induced enhancement of GR in nucleus, as well as the increased GR phosphorylation status at its crucial serine residues are similarly decreased by both baicalin and fluoxetine [133].…”

“…In detail, baicalin selectively reverses the CORT-induced decrease of GR levels in cytoplasm and the concomitant increase of GR levels in nucleus [133]. On the other hand, the CORT-induced enhancement of GR in nucleus, as well as the increased GR phosphorylation status at its crucial serine residues are similarly decreased by both baicalin and fluoxetine [133]. Baicalin, similar to fluoxetine, restores normal GR function by normalizing the levels of two GR-phosphorylating proteins, namely FK506-binding protein 51 (FKBP5) and serum-and glucocorticoid-inducible kinase 1 (SGK1) [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]. By applying proteomics and systems biology, biological processes related to glucocorticoid receptor (GR) signaling were identified as potential molecular targets.…”

“…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].…”

“…A summary of both experimental and clinical studies on the antidepressant effects of S. baicalensis, H. erinaceus and R. rosea is provided in Table 1. Baicalin (40,80, and 160 mg/kg) [133,134] ↑cytoplasmic GR levels ↓nuclear GR levels ↓GR phosphorylation ↑negative feedback of HPA axis [133] ↑neurogenesis (Ki67-DCX-positive cells) in the dentate gyrus of the hippocampus [134].…”