PMID- 35610650 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231108 IS - 1749-8546 (Print) IS - 1749-8546 (Electronic) IS - 1749-8546 (Linking) VI - 17 IP - 1 DP - 2022 May 24 TI - Saikosaponin D exerts antidepressant effect by regulating Homer1-mGluR5 and mTOR signaling in a rat model of chronic unpredictable mild stress. PG - 60 LID - 10.1186/s13020-022-00621-8 [doi] LID - 60 AB - BACKGROUND: Many studies about depression have focused on the dysfunctional synaptic signaling in the hippocampus that drives the pathophysiology of depression. Radix Bupleuri has been used in China for over 2000 years to regulate liver-qi. Extracted from Radix Bupleuri, Saikosaponin D (SSD) is a pharmacologically active substance that has antidepressant effects. However, its underlying mechanism remains unknown. MATERIALS AND METHODS: A chronic unpredictable mild stress (CUMS) paradigm was used as a rat model of depression. SD rats were randomly assigned to a normal control (NC) group or one exposed to a CUMS paradigm. Of the latter group, rats were assigned to four subgroups: no treatment (CUMS), fluoxetine-treated (FLU), high-dose and low-dose SSD-treated (SSDH and SSDL). SSD was orally administrated of 1.50 mg/kg and 0.75 mg/kg/days for three weeks in the SSDH and SSDL groups, respectively. Fluoxetine was administrated at a dose of 2.0 mg/kg/days. SSD's antidepressant effects were assessed using the open field test, forced swim test, and sucrose preference test. Glutamate levels were quantified by ELISA. Western blot and immunochemical analyses were conducted to quantify proteins in the Homer protein homolog 1 (Homer1)-metabotropic glutamate receptor 5 (mGluR5) and mammalian target of rapamycin (mTOR) pathways in the hippocampal CA1 region. To measure related gene expression, RT-qPCR was employed. RESULTS: CUMS-exposed rats treated with SSD exhibited increases in food intake, body weight, and improvements in the time spent in the central are and total distance traveled in the OFT, and less pronounced pleasure-deprivation behaviors. SSD also decreased glutamate levels in CA1. In CA1 region of CUMS-exposed rats, SSD treatment increased mGluR5 expression while decreasing Homer1 expression. SSD also increased expressions of postsynaptic density protein 95 (PSD95) and synapsin I (SYP), and the ratios of p-mTOR/mTOR, p-p70S6k/p70S6k, and p-4E-BP1/4E-BP1 in the CA1 region in CUMS-exposed rats. CONCLUSIONS: SSD treatment reduces glutamate levels in the CA1 region and promotes the expression of the synaptic proteins PSD-95 and SYP via the regulation of the Homer1-mGluR5 and downstream mTOR signaling pathways. These findings suggest that SSD could act as a natural neuroprotective agent in the prevention of depression. CI - (c) 2022. The Author(s). FAU - Liu, Chen-Yue AU - Liu CY AD - School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. AD - Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, China. FAU - Chen, Jian-Bei AU - Chen JB AD - School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Liu, Yue-Yun AU - Liu YY AD - School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Zhou, Xue-Ming AU - Zhou XM AD - School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. AD - School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Haerbin, 150040, China. FAU - Zhang, Man AU - Zhang M AD - School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Jiang, You-Ming AU - Jiang YM AD - School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Ma, Qing-Yu AU - Ma QY AD - Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China. FAU - Xue, Zhe AU - Xue Z AD - School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Zhao, Zong-Yao AU - Zhao ZY AD - School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. FAU - Li, Xiao-Juan AU - Li XJ AD - Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China. lixiaojuan@jnu.edu.cn. FAU - Chen, Jia-Xu AU - Chen JX AUID- ORCID: 0000-0002-9980-0643 AD - School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, China. chenjiaxu@hotmail.com. AD - Formula-Pattern Research Center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, China. chenjiaxu@hotmail.com. LA - eng GR - 82174278/National Natural Science Foundation of China/ GR - 81803999/National Natural Science Foundation of China/ GR - 81803972/National Natural Science Foundation of China/ GR - 2020B1111100001/Key-Area Research and Development Program of Guangdong Province/ GR - 202102010014/Guangzhou Key Laboratory of Formula-Pattern of Traditional Chinese Medicine/ GR - 2021B1212040007/Guangdong Provincial Key Laboratory of Traditional Chinese Medicine Informatization/ PT - Journal Article DEP - 20220524 PL - England TA - Chin Med JT - Chinese medicine JID - 101265109 EIN - Chin Med. 2023 Nov 8;18(1):147. PMID: 37941004 PMC - PMC9128259 OTO - NOTNLM OT - Chronic unpredictable mild stress OT - Homer1-mGluR5 OT - Saikosaponin D OT - mTOR COIS- The authors declare that they have no known competing financial interest or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/05/25 06:00 MHDA- 2022/05/25 06:01 PMCR- 2022/05/24 CRDT- 2022/05/24 23:48 PHST- 2022/02/25 00:00 [received] PHST- 2022/05/08 00:00 [accepted] PHST- 2022/05/24 23:48 [entrez] PHST- 2022/05/25 06:00 [pubmed] PHST- 2022/05/25 06:01 [medline] PHST- 2022/05/24 00:00 [pmc-release] AID - 10.1186/s13020-022-00621-8 [pii] AID - 621 [pii] AID - 10.1186/s13020-022-00621-8 [doi] PST - epublish SO - Chin Med. 2022 May 24;17(1):60. doi: 10.1186/s13020-022-00621-8.