title: Danzhi Xiaoyao San ameliorates depressive-like behavior by shifting toward serotonin via the downregulation of hippocampal indoleamine 2,3-dioxygenase.
abstract: BACKGROUND
  Danzhi Xiaoyao San (DXS) is a canonical Chinese medicine formula from Principles of Internal Medicine, which was written during the Ming dynasty. This formula is approved and commercialized for use in the prevention and treatment of affective disorders. This study is aimed to investigate the hypothesis that DXS treats depressive-like behavior by shifting the balance of the kynurenine (Kyn)/serotonin (5-HT) pathway toward the 5-HT pathway through the downregulation of hippocampal indoleamine 2,3-dioxygenase (IDO).
  
  
  METHODS
  Chemical fingerprints of gardenoside, paeoniflorin, ferulic acid, paeonol, and ligustilide in standard extraction were used as the material bases of DXS. Rats with depressive-like behavior induced by chronic unpredictable mild stress (CUMS) were randomly divided into four groups, namely the control, model, DXS, and fluoxetine groups. Cytokines, IDO, and tryptophan (Trp) catabolites were analyzed by enzyme-linked immunosorbent assay, western blot, and liquid chromatography-electrospray ionization tandem mass spectrometry, respectively.
  
  
  RESULTS
  DXS significantly increased crossing grid numbers, sucrose consumption, and body weight. This treatment significantly decreased the serum levels of tumor necrosis factor-α and interleukin 6 (IL-6). However, DXS elicited no significant effects on IL-1β, IL-2, and interferon γ. DXS downregulated the activity of IDO and subsequent production of Kyn in the hippocampus. This treatment upregulated the hippocampal contents of Trp and 5-HT but did not influence 5-HT turnover.
  
  
  CONCLUSIONS
  DXS exhibited antidepressant-like effects on rats exposed to CUMS. DXS reduced IDO activity to shift the balance of the Kyn/5-HT pathway toward the 5-HT pathway.
authors.affiliation: Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Traditional Chinese Medicine Integrated Hospital, Southern Medical University, Guangdong, Guangzhou 510305, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Jing
authors.affiliation: Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
authors.forename: Chun
authors.initials: C
authors.lastname: Chen
authors.affiliation: The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Shao
authors.affiliation: The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Fan
authors.affiliation: The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Diao
authors.affiliation: The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
authors.forename: Yuanliang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China. Electronic address: lzp_smu@126.com.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Lv
authors.affiliation: Department of Traditional Chinese Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; The Key Laboratory of Molecular Biology, State Administration of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China. Electronic address: sxg_smu@126.com.
authors.forename: Xuegang
authors.initials: X
authors.lastname: Sun
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D016207:Cytokines / Q000097:blood; D015536:Down-Regulation / Q000187:drug effects*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005473:Fluoxetine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D007737:Kynurenine / Q000096:biosynthesis; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D012701:Serotonin / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000928:Antidepressive Agents; D016207:Cytokines; D004365:Drugs, Chinese Herbal; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C531141:danzhi xiaoyao; D005473:Fluoxetine; D012701:Serotonin; D007737:Kynurenine; D014364:Tryptophan
keywords: 5-Hydroxyindole-3-acetic acid (PubChem CID: 9061); Cytokine; Danzhi Xiaoyao San; Depressive-like behavior; Ferulic acid (PubChem CID: 445858); Gardenoside (PubChem CID: 53297356); Hippocampus; Indoleamine-2,3-dioxygenase; Kynurenine (PubChem CID: 161166); Ligustilide (PbuChem CID: 5319022); Paeoniflorin (PubChem CID: 11092); Paeonol (PubChem CID: 11092); Serotonin (PubChem CID: 5202); Tryptophan (PubChem CID: 6305); Tryptophan catabolite