title: Antidepressant-like effects of Xiaochaihutang in a neuroendocrine mouse model of anxiety/depression.
abstract: BACKGROUND
  Hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis is often observed in the pathophysiology of depression. Antidepressant therapy can restore hippocampal neurogenesis to rescue the HPA axis regulation defects. Xiaochaihutang (XCHT), a famous Chinese herbal formula, has been used clinically in depressive disorders in China. Our previous studies have demonstrated XCHT improved depressive-like behaviors in chronic unpredictable mild stress rat, but the underlying mechanisms of XCHT on hippocampal neurogenesis and the HPA axis were still unclear.
  
  
  METHODS
  We used chronic corticosterone (CORT)-induced mouse model of anxiety/depression to investigate antidepressant-like effects of XCHT by several physical and behavioral testing, including body weight, coat state, open field test, elevated plus maze, tail suspension test and forced swimming test. The integrity of negative feedback function on HPA axis was assessed by the dexamethasone (DEX) suppression test. In addition, Ki-67 and doublecortin (DCX) were performed to assess hippocampal cell proliferation and neurogenesis by immunohistochemistry. Chemical profile of active constituents in brain after oral administration of XCHT was revealed by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS).
  
  
  RESULTS
  Our results showed that oral administration of XCHT (2.3, 7 and 21g/kg) for 30 days remarkably normalized chronic CORT-induced the slowness in weight gain, the deterioration in coat state, the escape behavior in open field test and elevated plus maze, and the increase of immobility time in tail suspension test and forced swimming test. Moreover, XCHT significantly reversed chronic CORT-induced the reduction of DEX-induced plasma corticosterone/c-Fos suppression and Ki-67/DCX positive cells. Finally, a total 13 potential active constituents in brain were identified by UPLC-MS/MS after oral administration of XCHT, including 10 prototype components and 3 metabolites.
  
  
  CONCLUSIONS
  Our findings showed that XCHT could remarkably alleviate chronic CORT-induced anxiety/depression-like behaviors, which were probably attribute to promoting hippocampal neurogenesis and remodeling the integrity of the negative feedback loop on HPA axis. The constituents identified in brain might contribute to understanding the therapeutic basis of XCHT on depression.
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors.forename: Kuo
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors.forename: Jingyu
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of School of Functional Food And Wine, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors.forename: Xing
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of pharmaceutical analysis, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of School of Functional Food And Wine, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors.forename: Guangyue
authors.initials: G
authors.lastname: Su
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors.forename: Yingxu
authors.initials: Y
authors.lastname: Dong
authors.affiliation: Department of pharmaceutical analysis, Shenyang Pharmaceutical University, 110016 Shenyang, PR China.
authors.forename: Zhili
authors.initials: Z
authors.lastname: Xiong
authors.affiliation: Department of Pharmacology, Shenyang Pharmaceutical University, 110016 Shenyang, PR China. Electronic address: wucf@syphu.edu.cn.
authors.forename: Chunfu
authors.initials: C
authors.lastname: Wu
mesh_terms: D000818:Animals; D001007:Anxiety / Q000188:drug therapy*; D001522:Behavior, Animal; D003863:Depression / Q000188:drug therapy*; D003907:Dexamethasone / Q000008:administration & dosage; D004195:Disease Models, Animal; D000089662:Doublecortin Protein; D004365:Drugs, Chinese Herbal; D008297:Male; D008516:Medicine, Chinese Traditional; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: C000714847:Dcx protein, mouse; C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; D004365:Drugs, Chinese Herbal; C461320:shosaiko-to; D003907:Dexamethasone
keywords: Antidepressant; Corticosterone; Hippocampal neurogenesis; Hypothalamic-pituitary-adrenal axis; Xiaochaihutang