PMID- 29217494 OWN - NLM STAT- MEDLINE DCOM- 20180813 LR - 20231213 IS - 1872-7573 (Electronic) IS - 0378-8741 (Linking) VI - 214 DP - 2018 Mar 25 TI - Regulation of the kynurenine metabolism pathway by Xiaoyao San and the underlying effect in the hippocampus of the depressed rat. PG - 13-21 LID - S0378-8741(16)31627-0 [pii] LID - 10.1016/j.jep.2017.11.037 [doi] AB - ETHNOPHARMACOLOGICAL RELEVANCE: Xiaoyao San (XYS) is a classic Chinese herbal formula for treatment of depression. The present study aimed to investigate the antidepressant effects of XYS in a rat model of chronic unpredictable mild stress (CUMS) and the underlying mechanisms. MATERIALS AND METHODS: A CUMS rat model of depression was established via 4 weeks of unpredictable stimulation. Then the rats were orally administered paroxetine and XYS for 2 weeks with continued stress. Behavioral assessments, including an open field test (OFT), sucrose preference test (SPT) and forced swim test (FST), were conducted to evaluate the antidepressant effects of XYS. The concentrations in rat plasma of tryptophan (Trp) and its metabolic products, including kynurenine (Kyn) and quinolinic acid (QUIN), were determined using high performance liquid chromatography tandem mass spectrometry with electrochemical detection (HPLC-MS/MS). The mRNA and protein levels in rat hippocampus of depression-related brain derived neurotrophic factor (BDNF), cyclic AMP response element binding protein (CREB) and nerve cell adhesion molecule (NCAM) were determined by real-time qPCR and Western blot, respectively. Enzyme Linked Immunosorbent Assay (ELISA) was used to detect the activities of indoleamine 2,3-dioxygenase (IDO) and kynurenine-3-monooxygenase (KMO) in rat plasma. RESULTS: The results showed that a successful CUMS rat model was established through 4 weeks of continuous unpredictable stimulation, as indicated by the significant decrease in locomotor activity and increase in immobility time in the OFT, reduction in body weight and food intake etc. Compared with the normal group, the concentrations of Kyn and QUIN had significantly (p < 0.05) decreased at day 28 in the control group, but then improved after drug treatment with paroxetine and XYS. There were no obvious changes in the activities of IDO and KMO. Compared with the normal group, the mRNA of NCAM, CREB and BDNF were significantly down-regulated (p < 0.001) in the control group, BDNF gene was up-regulated by paroxetine or XYS treatment, NCAM and CREB gene did not change in XYS group, protein expressions of BDNF and CREB were significantly increased, and NCAM was significantly reduced (p < 0.05). CONCLUSIONS: XYS reversed the abnormalities of the tryptophan-kynurenine metabolic pathways in depressed rats and achieved an excellent antidepressant effect. Its direct impact may be observed as changes in biological indicators in rat hippocampus tissue. CI - Copyright (c) 2017 Elsevier B.V. All rights reserved. FAU - Wang, Jiajia AU - Wang J AD - The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), 36 Mingxin Road, Guangzhou 510370, PR China; Guangzhou University of Traditional Chinese Medicine, 16 Airport Road, Guangzhou 510405, PR China. FAU - Li, Xiaofang AU - Li X AD - The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), 36 Mingxin Road, Guangzhou 510370, PR China. FAU - He, Shugui AU - He S AD - Guangzhou University of Traditional Chinese Medicine, 16 Airport Road, Guangzhou 510405, PR China. FAU - Hu, Lijun AU - Hu L AD - The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), 36 Mingxin Road, Guangzhou 510370, PR China. FAU - Guo, Jiewen AU - Guo J AD - Guangzhou Hospital of Traditional Chinese Medicine, 16 Zhuji Road, Guangzhou 510130, PR China. FAU - Huang, Xiangning AU - Huang X AD - Guangzhou Xinhai Hospital, Guangzhou, 167 Xingang West Road, Guangzhou 510300, PR China. FAU - Hu, Jinqing AU - Hu J AD - The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), 36 Mingxin Road, Guangzhou 510370, PR China. FAU - Qi, Yaoqun AU - Qi Y AD - Guangzhou University of Traditional Chinese Medicine, 16 Airport Road, Guangzhou 510405, PR China. FAU - Chen, Bin AU - Chen B AD - Guangzhou University of Traditional Chinese Medicine, 16 Airport Road, Guangzhou 510405, PR China. FAU - Shang, Dewei AU - Shang D AD - The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), 36 Mingxin Road, Guangzhou 510370, PR China. Electronic address: shang_dewei@163.com. FAU - Wen, Yuguan AU - Wen Y AD - The Affiliated Brain Hospital of Guangzhou Medical University (Guangzhou Huiai Hospital), 36 Mingxin Road, Guangzhou 510370, PR China. Electronic address: wenyuguande@163.com. LA - eng PT - Journal Article DEP - 20171205 PL - Ireland TA - J Ethnopharmacol JT - Journal of ethnopharmacology JID - 7903310 RN - 0 (Antidepressive Agents) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Creb1 protein, rat) RN - 0 (Cyclic AMP Response Element-Binding Protein) RN - 0 (Drugs, Chinese Herbal) RN - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase) RN - 0 (Neural Cell Adhesion Molecules) RN - 0 (xiaoyaosan) RN - 343-65-7 (Kynurenine) RN - 8DUH1N11BX (Tryptophan) RN - EC 1.14.13.9 (Kynurenine 3-Monooxygenase) RN - F6F0HK1URN (Quinolinic Acid) SB - IM MH - Animals MH - Antidepressive Agents/*pharmacology MH - Behavior, Animal/*drug effects MH - Brain-Derived Neurotrophic Factor/genetics/metabolism MH - Cyclic AMP Response Element-Binding Protein/genetics/metabolism MH - Depression/*drug therapy/metabolism/physiopathology/psychology MH - Disease Models, Animal MH - Dose-Response Relationship, Drug MH - Drugs, Chinese Herbal/*pharmacology MH - Hippocampus/*drug effects/metabolism/physiopathology MH - Indoleamine-Pyrrole 2,3,-Dioxygenase/genetics/metabolism MH - Kynurenine/blood/*metabolism MH - Kynurenine 3-Monooxygenase/genetics/metabolism MH - Locomotion/drug effects MH - Male MH - Neural Cell Adhesion Molecules/genetics/metabolism MH - Quinolinic Acid/metabolism MH - Rats, Sprague-Dawley MH - Signal Transduction/drug effects MH - Tryptophan/metabolism OTO - NOTNLM OT - Depression OT - HPLC-MS/MS OT - Kynurenine metabolism pathway OT - Xiaoyao san EDAT- 2017/12/09 06:00 MHDA- 2018/08/14 06:00 CRDT- 2017/12/09 06:00 PHST- 2016/10/29 00:00 [received] PHST- 2017/10/31 00:00 [revised] PHST- 2017/11/30 00:00 [accepted] PHST- 2017/12/09 06:00 [pubmed] PHST- 2018/08/14 06:00 [medline] PHST- 2017/12/09 06:00 [entrez] AID - S0378-8741(16)31627-0 [pii] AID - 10.1016/j.jep.2017.11.037 [doi] PST - ppublish SO - J Ethnopharmacol. 2018 Mar 25;214:13-21. doi: 10.1016/j.jep.2017.11.037. Epub 2017 Dec 5.