Traditional Chinese Formula Xiaoyaosan Alleviates Depressive-Like Behavior in CUMS Mice by Regulating PEBP1-GPX4-Mediated Ferroptosis in the Hippocampus

Haiyan Jiao,1 Hongjun Yang,1 Zhiyi Yan,1 Jianbei Chen,1 Mengbai Xu,1 Youming Jiang,1 Yueyun Liu,1 Zhe Xue,1 Qingyu Ma,2 Xiaojuan Li,2 Jiaxu Chen1,2 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2Formula-Pattern...

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Autores principales: Jiao H, Yang H, Yan Z, Chen J, Xu M, Jiang Y, Liu Y, Xue Z, Ma Q, Li X
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Publicado: Dove Medical Press 2021
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spelling oai:doaj.org-article:35c6d1cc2cc34da586b52ce830d97dc32021-12-02T14:25:51ZTraditional Chinese Formula Xiaoyaosan Alleviates Depressive-Like Behavior in CUMS Mice by Regulating PEBP1-GPX4-Mediated Ferroptosis in the Hippocampus1178-2021https://doaj.org/article/35c6d1cc2cc34da586b52ce830d97dc32021-04-01T00:00:00Zhttps://www.dovepress.com/traditional-chinese-formula-xiaoyaosan-alleviates-depressive-like-beha-peer-reviewed-article-NDThttps://doaj.org/toc/1178-2021Haiyan Jiao,1 Hongjun Yang,1 Zhiyi Yan,1 Jianbei Chen,1 Mengbai Xu,1 Youming Jiang,1 Yueyun Liu,1 Zhe Xue,1 Qingyu Ma,2 Xiaojuan Li,2 Jiaxu Chen1,2 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2Formula-Pattern Research center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, Guangdong, People’s Republic of ChinaCorrespondence: Jiaxu Chen Tel +86 1064286656Email chenjiaxu@hotmail.comBackground: At present, the pathogenesis of depression is not fully understood, and nearly half of depression patients experience no obvious effects during treatment. This study aimed to establish a depression mouse model to explore the possible role of ferroptosis in the pathogenesis of depression, and observe the effects of Xiaoyaosan on PEBP1-GPX4-mediated ferroptosis in the hippocampus.Methods: Forty-eight male C57BL/6 mice were randomly divided into a control group, CUMS group, Xiaoyaosan group and fluoxetine group, and the model was established by chronic unpredictable mild stress (CUMS) for a successive 6 weeks. The medication procedure was performed from the 4th to the 6th week of modeling. The behavioral evaluations were measured to evaluate depressive-like behaviors. The expressions of GPX4, FTH1, ACSL4 and COX2 were detected as ferroptosis-related indicators. Then, the total iron and ferrous content in the hippocampus were measured. The levels of PEBP1 and ERK1/2 were observed, and the expressions of GFAP and IBA1 were also detected to measure the functions of astrocytes and microglia in the hippocampus.Results: Eight herbs of Xiaoyaosan had 133 active ingredients which could regulate the 43 ferroptosis-related genes in depression. After 6 weeks of modeling, the data showed that mice in the CUMS group had obvious depressive-like behaviors, and medication with Xiaoyaosan or fluoxetine could significantly improve the behavioral changes. The expressions of GPX4, FTH1, ACSL4, COX2, PEBP1, ERK1/2, GFAP and IBA1 changed in the CUMS group mice, while the total iron and ferrous content also changed. Xiaoyaosan and fluoxetine had obvious curative effects that could significantly alleviate the above changes in the hippocampus.Conclusion: Our results revealed that the activation of ferroptosis might exist in the hippocampi of CUMS-induced mice. The PEBP1-GPX4-mediated ferroptosis could be involved in the antidepressant mechanism of Xiaoyaosan. It also implied that ferroptosis could become a new target for research into the depression mechanism and antidepressant drugs.Keywords: chronic unpredictable mild stress, depression, Xiaoyaosan, ferroptosis, GPX4, PEBP1Jiao HYang HYan ZChen JXu MJiang YLiu YXue ZMa QLi XChen JDove Medical Pressarticlechronic unpredictable mild stressdepressionxiaoyaosanferroptosisgpx4pebp1Neurosciences. Biological psychiatry. NeuropsychiatryRC321-571Neurology. Diseases of the nervous systemRC346-429ENNeuropsychiatric Disease and Treatment, Vol Volume 17, Pp 1001-1019 (2021)
institution DOAJ
collection DOAJ
language EN
topic chronic unpredictable mild stress
depression
xiaoyaosan
ferroptosis
gpx4
pebp1
Neurosciences. Biological psychiatry. Neuropsychiatry
RC321-571
Neurology. Diseases of the nervous system
RC346-429
spellingShingle chronic unpredictable mild stress
depression
xiaoyaosan
ferroptosis
gpx4
pebp1
Neurosciences. Biological psychiatry. Neuropsychiatry
RC321-571
Neurology. Diseases of the nervous system
RC346-429
Jiao H
Yang H
Yan Z
Chen J
Xu M
Jiang Y
Liu Y
Xue Z
Ma Q
Li X
Chen J
Traditional Chinese Formula Xiaoyaosan Alleviates Depressive-Like Behavior in CUMS Mice by Regulating PEBP1-GPX4-Mediated Ferroptosis in the Hippocampus
description Haiyan Jiao,1 Hongjun Yang,1 Zhiyi Yan,1 Jianbei Chen,1 Mengbai Xu,1 Youming Jiang,1 Yueyun Liu,1 Zhe Xue,1 Qingyu Ma,2 Xiaojuan Li,2 Jiaxu Chen1,2 1School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2Formula-Pattern Research center, School of Traditional Chinese Medicine, Jinan University, Guangzhou, 510632, Guangdong, People’s Republic of ChinaCorrespondence: Jiaxu Chen Tel +86 1064286656Email chenjiaxu@hotmail.comBackground: At present, the pathogenesis of depression is not fully understood, and nearly half of depression patients experience no obvious effects during treatment. This study aimed to establish a depression mouse model to explore the possible role of ferroptosis in the pathogenesis of depression, and observe the effects of Xiaoyaosan on PEBP1-GPX4-mediated ferroptosis in the hippocampus.Methods: Forty-eight male C57BL/6 mice were randomly divided into a control group, CUMS group, Xiaoyaosan group and fluoxetine group, and the model was established by chronic unpredictable mild stress (CUMS) for a successive 6 weeks. The medication procedure was performed from the 4th to the 6th week of modeling. The behavioral evaluations were measured to evaluate depressive-like behaviors. The expressions of GPX4, FTH1, ACSL4 and COX2 were detected as ferroptosis-related indicators. Then, the total iron and ferrous content in the hippocampus were measured. The levels of PEBP1 and ERK1/2 were observed, and the expressions of GFAP and IBA1 were also detected to measure the functions of astrocytes and microglia in the hippocampus.Results: Eight herbs of Xiaoyaosan had 133 active ingredients which could regulate the 43 ferroptosis-related genes in depression. After 6 weeks of modeling, the data showed that mice in the CUMS group had obvious depressive-like behaviors, and medication with Xiaoyaosan or fluoxetine could significantly improve the behavioral changes. The expressions of GPX4, FTH1, ACSL4, COX2, PEBP1, ERK1/2, GFAP and IBA1 changed in the CUMS group mice, while the total iron and ferrous content also changed. Xiaoyaosan and fluoxetine had obvious curative effects that could significantly alleviate the above changes in the hippocampus.Conclusion: Our results revealed that the activation of ferroptosis might exist in the hippocampi of CUMS-induced mice. The PEBP1-GPX4-mediated ferroptosis could be involved in the antidepressant mechanism of Xiaoyaosan. It also implied that ferroptosis could become a new target for research into the depression mechanism and antidepressant drugs.Keywords: chronic unpredictable mild stress, depression, Xiaoyaosan, ferroptosis, GPX4, PEBP1
format article
author Jiao H
Yang H
Yan Z
Chen J
Xu M
Jiang Y
Liu Y
Xue Z
Ma Q
Li X
Chen J
author_facet Jiao H
Yang H
Yan Z
Chen J
Xu M
Jiang Y
Liu Y
Xue Z
Ma Q
Li X
Chen J
author_sort Jiao H
title Traditional Chinese Formula Xiaoyaosan Alleviates Depressive-Like Behavior in CUMS Mice by Regulating PEBP1-GPX4-Mediated Ferroptosis in the Hippocampus
title_short Traditional Chinese Formula Xiaoyaosan Alleviates Depressive-Like Behavior in CUMS Mice by Regulating PEBP1-GPX4-Mediated Ferroptosis in the Hippocampus
title_full Traditional Chinese Formula Xiaoyaosan Alleviates Depressive-Like Behavior in CUMS Mice by Regulating PEBP1-GPX4-Mediated Ferroptosis in the Hippocampus
title_fullStr Traditional Chinese Formula Xiaoyaosan Alleviates Depressive-Like Behavior in CUMS Mice by Regulating PEBP1-GPX4-Mediated Ferroptosis in the Hippocampus
title_full_unstemmed Traditional Chinese Formula Xiaoyaosan Alleviates Depressive-Like Behavior in CUMS Mice by Regulating PEBP1-GPX4-Mediated Ferroptosis in the Hippocampus
title_sort traditional chinese formula xiaoyaosan alleviates depressive-like behavior in cums mice by regulating pebp1-gpx4-mediated ferroptosis in the hippocampus
publisher Dove Medical Press
publishDate 2021
url https://doaj.org/article/35c6d1cc2cc34da586b52ce830d97dc3
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