Antidepressant Mechanism of Traditional Chinese Medicine Formula Xiaoyaosan in CUMS-Induced Depressed Mouse Model via RIPK1-RIPK3-MLKL Mediated Necroptosis Based on Network Pharmacology Analysis

Background: Depression is a stress-related disorder that seriously threatens people’s physical and mental health. Xiaoyaosan is a classical traditional Chinese medicine formula, which has been used to treat mental depression since ancient times. More and more notice has been given to the relationshi...

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Autores principales:	Zhi-Yi Yan, Hai-Yan Jiao, Jian-Bei Chen, Kai-Wen Zhang, Xi-Hong Wang, You-Ming Jiang, Yue-Yun Liu, Zhe Xue, Qing-Yu Ma, Xiao-Juan Li, Jia-Xu Chen
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	xiaoyaosan chronic unpredictable mild stress depression necroptosis neuroinflammation microglial activation Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/75aa1e158c4e4cb29ed3548e6cb012ca
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spelling	oai:doaj.org-article:75aa1e158c4e4cb29ed3548e6cb012ca2021-11-19T05:26:03ZAntidepressant Mechanism of Traditional Chinese Medicine Formula Xiaoyaosan in CUMS-Induced Depressed Mouse Model via RIPK1-RIPK3-MLKL Mediated Necroptosis Based on Network Pharmacology Analysis1663-981210.3389/fphar.2021.773562https://doaj.org/article/75aa1e158c4e4cb29ed3548e6cb012ca2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fphar.2021.773562/fullhttps://doaj.org/toc/1663-9812Background: Depression is a stress-related disorder that seriously threatens people’s physical and mental health. Xiaoyaosan is a classical traditional Chinese medicine formula, which has been used to treat mental depression since ancient times. More and more notice has been given to the relationship between the occurrence of necroptosis and the pathogenesis of mental disorders.Objective: The purpose of present study is to explore the potential mechanism of Xiaoyaosan for the treatment of depression using network pharmacology and experimental research, and identify the potential targets of necroptosis underlying the antidepressant mechanism of Xiaoyaosan.Methods: The mice model of depression was induced by chronic unpredictable mild stress (CUMS) for 6 weeks. Adult C57BL/6 mice were randomly divided into five groups, including control group, chronic unpredictable mild stress group, Xiaoyaosan treatment group, necrostatin-1 (Nec-1) group and solvent group. Drug intervention performed from 4th to 6th week of modeling. The mice in Xiaoyaosan treatment group received Xiaoyaosan by intragastric administration (0.254 g/kg/d), and mice in CUMS group received 0.5 ml physiological saline. Meanwhile, the mice in Nec-1 group were injected intraperitoneally (i.p.) with Nec-1 (10 mg/kg/d), and the equivalent volume of DMSO/PBS (8.3%) was injected into solvent group mice. The behavior tests such as sucrose preference test, forced swimming test and novelty-suppressed feeding test were measured to evaluate depressive-like behaviors of model mice. Then, the active ingredients in Xiaoyaosan and the related targets of depression and necroptosis were compiled through appropriate databases, while the “botanical drugs-active ingredients-target genes” network was constructed by network pharmacology analysis. The expressions of RIPK1, RIPK3, MLKL, p-MLKL were detected as critical target genes of necroptosis and the potential therapeutic target compounds of Xiaoyaosan. Furthermore, the levels of neuroinflammation and microglial activation of hippocampus were measured by detecting the expressions of IL-1β, Lipocalin-2 and IBA1, and the hematoxylin and eosin (H&E) stained was used to observe the morphology in hippocampus sections.Results: After 6-weeks of modeling, the behavioral data showed that mice in CUMS group and solvent group had obvious depressive-like behaviors, and the medication of Xiaoyaosan or Nec-1 could improve these behavioral changes. A total of 96 active ingredients in Xiaoyaosan which could regulate the 23 key target genes were selected from databases. Xiaoyaosan could alleviate the core target genes in necroptosis and improve the hippocampal function and neuroinflammation in depressed mice.Conclusion: The activation of necroptosis existed in the hippocampus of CUMS-induced mice, which was closely related to the pathogenesis of depression. The antidepressant mechanism of Xiaoyaosan included the regulation of multiple targets in necroptosis. It also suggested that necroptosis could be a new potential target for the treatment of depression.Zhi-Yi YanZhi-Yi YanHai-Yan JiaoJian-Bei ChenKai-Wen ZhangXi-Hong WangYou-Ming JiangYue-Yun LiuZhe XueQing-Yu MaXiao-Juan LiJia-Xu ChenJia-Xu ChenFrontiers Media S.A.articlexiaoyaosanchronic unpredictable mild stressdepressionnecroptosisneuroinflammationmicroglial activationTherapeutics. PharmacologyRM1-950ENFrontiers in Pharmacology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	xiaoyaosan chronic unpredictable mild stress depression necroptosis neuroinflammation microglial activation Therapeutics. Pharmacology RM1-950
spellingShingle	xiaoyaosan chronic unpredictable mild stress depression necroptosis neuroinflammation microglial activation Therapeutics. Pharmacology RM1-950 Zhi-Yi Yan Zhi-Yi Yan Hai-Yan Jiao Jian-Bei Chen Kai-Wen Zhang Xi-Hong Wang You-Ming Jiang Yue-Yun Liu Zhe Xue Qing-Yu Ma Xiao-Juan Li Jia-Xu Chen Jia-Xu Chen Antidepressant Mechanism of Traditional Chinese Medicine Formula Xiaoyaosan in CUMS-Induced Depressed Mouse Model via RIPK1-RIPK3-MLKL Mediated Necroptosis Based on Network Pharmacology Analysis
description	Background: Depression is a stress-related disorder that seriously threatens people’s physical and mental health. Xiaoyaosan is a classical traditional Chinese medicine formula, which has been used to treat mental depression since ancient times. More and more notice has been given to the relationship between the occurrence of necroptosis and the pathogenesis of mental disorders.Objective: The purpose of present study is to explore the potential mechanism of Xiaoyaosan for the treatment of depression using network pharmacology and experimental research, and identify the potential targets of necroptosis underlying the antidepressant mechanism of Xiaoyaosan.Methods: The mice model of depression was induced by chronic unpredictable mild stress (CUMS) for 6 weeks. Adult C57BL/6 mice were randomly divided into five groups, including control group, chronic unpredictable mild stress group, Xiaoyaosan treatment group, necrostatin-1 (Nec-1) group and solvent group. Drug intervention performed from 4th to 6th week of modeling. The mice in Xiaoyaosan treatment group received Xiaoyaosan by intragastric administration (0.254 g/kg/d), and mice in CUMS group received 0.5 ml physiological saline. Meanwhile, the mice in Nec-1 group were injected intraperitoneally (i.p.) with Nec-1 (10 mg/kg/d), and the equivalent volume of DMSO/PBS (8.3%) was injected into solvent group mice. The behavior tests such as sucrose preference test, forced swimming test and novelty-suppressed feeding test were measured to evaluate depressive-like behaviors of model mice. Then, the active ingredients in Xiaoyaosan and the related targets of depression and necroptosis were compiled through appropriate databases, while the “botanical drugs-active ingredients-target genes” network was constructed by network pharmacology analysis. The expressions of RIPK1, RIPK3, MLKL, p-MLKL were detected as critical target genes of necroptosis and the potential therapeutic target compounds of Xiaoyaosan. Furthermore, the levels of neuroinflammation and microglial activation of hippocampus were measured by detecting the expressions of IL-1β, Lipocalin-2 and IBA1, and the hematoxylin and eosin (H&E) stained was used to observe the morphology in hippocampus sections.Results: After 6-weeks of modeling, the behavioral data showed that mice in CUMS group and solvent group had obvious depressive-like behaviors, and the medication of Xiaoyaosan or Nec-1 could improve these behavioral changes. A total of 96 active ingredients in Xiaoyaosan which could regulate the 23 key target genes were selected from databases. Xiaoyaosan could alleviate the core target genes in necroptosis and improve the hippocampal function and neuroinflammation in depressed mice.Conclusion: The activation of necroptosis existed in the hippocampus of CUMS-induced mice, which was closely related to the pathogenesis of depression. The antidepressant mechanism of Xiaoyaosan included the regulation of multiple targets in necroptosis. It also suggested that necroptosis could be a new potential target for the treatment of depression.
format	article
author	Zhi-Yi Yan Zhi-Yi Yan Hai-Yan Jiao Jian-Bei Chen Kai-Wen Zhang Xi-Hong Wang You-Ming Jiang Yue-Yun Liu Zhe Xue Qing-Yu Ma Xiao-Juan Li Jia-Xu Chen Jia-Xu Chen
author_facet	Zhi-Yi Yan Zhi-Yi Yan Hai-Yan Jiao Jian-Bei Chen Kai-Wen Zhang Xi-Hong Wang You-Ming Jiang Yue-Yun Liu Zhe Xue Qing-Yu Ma Xiao-Juan Li Jia-Xu Chen Jia-Xu Chen
author_sort	Zhi-Yi Yan
title	Antidepressant Mechanism of Traditional Chinese Medicine Formula Xiaoyaosan in CUMS-Induced Depressed Mouse Model via RIPK1-RIPK3-MLKL Mediated Necroptosis Based on Network Pharmacology Analysis
title_short	Antidepressant Mechanism of Traditional Chinese Medicine Formula Xiaoyaosan in CUMS-Induced Depressed Mouse Model via RIPK1-RIPK3-MLKL Mediated Necroptosis Based on Network Pharmacology Analysis
title_full	Antidepressant Mechanism of Traditional Chinese Medicine Formula Xiaoyaosan in CUMS-Induced Depressed Mouse Model via RIPK1-RIPK3-MLKL Mediated Necroptosis Based on Network Pharmacology Analysis
title_fullStr	Antidepressant Mechanism of Traditional Chinese Medicine Formula Xiaoyaosan in CUMS-Induced Depressed Mouse Model via RIPK1-RIPK3-MLKL Mediated Necroptosis Based on Network Pharmacology Analysis
title_full_unstemmed	Antidepressant Mechanism of Traditional Chinese Medicine Formula Xiaoyaosan in CUMS-Induced Depressed Mouse Model via RIPK1-RIPK3-MLKL Mediated Necroptosis Based on Network Pharmacology Analysis
title_sort	antidepressant mechanism of traditional chinese medicine formula xiaoyaosan in cums-induced depressed mouse model via ripk1-ripk3-mlkl mediated necroptosis based on network pharmacology analysis
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/75aa1e158c4e4cb29ed3548e6cb012ca
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Antidepressant Mechanism of Traditional Chinese Medicine Formula Xiaoyaosan in CUMS-Induced Depressed Mouse Model via RIPK1-RIPK3-MLKL Mediated Necroptosis Based on Network Pharmacology Analysis

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