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Blocking Two-Pore Domain Potassium Channel TREK-1 Inhibits the Activation of A1-Like Reactive Astrocyte Through the NF-κB Signaling Pathway in a Rat Model of Major Depressive Disorder

Major depressive disorder (MDD) refers to a widespread psychiatric disorder. Astrocytes play a pivotal role in regulating inflammation which is a well-acknowledged key component in depression pathogenesis. However, the effects of the neuroinflammation-inducing A1-like astrocytes on MDD are still unk...

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Autores principales: Cong, Ting, Sun, Ye, Zhou, Yitong, Wu, Haikuo, Li, Liya, Chu, Zhenchen, Chen, Xue, Li, Jinying, Zhao, Danmei, Wang, Yanfang, Liu, Yingxin, Yin, Shengming, Xiao, Zhaoyang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10119044/
https://www.ncbi.nlm.nih.gov/pubmed/36670238
http://dx.doi.org/10.1007/s11064-023-03857-4
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author Cong, Ting
Sun, Ye
Zhou, Yitong
Wu, Haikuo
Li, Liya
Chu, Zhenchen
Chen, Xue
Li, Jinying
Zhao, Danmei
Wang, Yanfang
Liu, Yingxin
Yin, Shengming
Xiao, Zhaoyang
author_facet Cong, Ting
Sun, Ye
Zhou, Yitong
Wu, Haikuo
Li, Liya
Chu, Zhenchen
Chen, Xue
Li, Jinying
Zhao, Danmei
Wang, Yanfang
Liu, Yingxin
Yin, Shengming
Xiao, Zhaoyang
author_sort Cong, Ting
collection PubMed
description Major depressive disorder (MDD) refers to a widespread psychiatric disorder. Astrocytes play a pivotal role in regulating inflammation which is a well-acknowledged key component in depression pathogenesis. However, the effects of the neuroinflammation-inducing A1-like astrocytes on MDD are still unknown. TWIK-related K(+) channel 1 (TREK-1) has been demonstrated to regulate the action of antidepressants. Nevertheless, its mechanisms and effects on A1-like astrocyte stimulation in MDD are not clear. Therefore, we conducted in vivo and in vitro experiments using TREK-1 specific inhibitor spadin. In vivo, rats were subjected to a 6-week chronic unpredictable mild stress (CUMS) followed by spadin treatment. Behavioral tests were employed to surveil depressive-like behaviors. Hippocampal proteomic analysis was carried out with the purpose of identifying differentially expressed proteins after CUMS and spadin treatments. In vitro, astrocyte-conditioned medium and spadin were used to treat rat astrocyte cell line. The activated microglia, inflammatory factors, A1 astrocyte markers, and activated nuclear factor kappa B (NF-κB) pathway were later analyzed using immunofluorescence, western blot, and RT-qPCR. Our findings indicated that blockage of TREK-1 reduced CUMS-induced depressive-like behavior in rats, inhibited the microglial stimulation, reduced inflammatory factor levels, and suppressed the activation of A1-like reactive astrocytes in the hippocampus. We also verified that the suppression of A1-like astrocytes by spadin necessitated the NF-κB pathway. According to the findings, blocking TREK-1 inhibited the activation of A1-like reactive astrocytes via the NF-κB signaling pathway in MDD. Our study preliminarily identifies a novel antidepressant mechanism of TREK-1 action and provides a therapeutic path for MDD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11064-023-03857-4.
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spelling pubmed-101190442023-04-22 Blocking Two-Pore Domain Potassium Channel TREK-1 Inhibits the Activation of A1-Like Reactive Astrocyte Through the NF-κB Signaling Pathway in a Rat Model of Major Depressive Disorder Cong, Ting Sun, Ye Zhou, Yitong Wu, Haikuo Li, Liya Chu, Zhenchen Chen, Xue Li, Jinying Zhao, Danmei Wang, Yanfang Liu, Yingxin Yin, Shengming Xiao, Zhaoyang Neurochem Res Original Paper Major depressive disorder (MDD) refers to a widespread psychiatric disorder. Astrocytes play a pivotal role in regulating inflammation which is a well-acknowledged key component in depression pathogenesis. However, the effects of the neuroinflammation-inducing A1-like astrocytes on MDD are still unknown. TWIK-related K(+) channel 1 (TREK-1) has been demonstrated to regulate the action of antidepressants. Nevertheless, its mechanisms and effects on A1-like astrocyte stimulation in MDD are not clear. Therefore, we conducted in vivo and in vitro experiments using TREK-1 specific inhibitor spadin. In vivo, rats were subjected to a 6-week chronic unpredictable mild stress (CUMS) followed by spadin treatment. Behavioral tests were employed to surveil depressive-like behaviors. Hippocampal proteomic analysis was carried out with the purpose of identifying differentially expressed proteins after CUMS and spadin treatments. In vitro, astrocyte-conditioned medium and spadin were used to treat rat astrocyte cell line. The activated microglia, inflammatory factors, A1 astrocyte markers, and activated nuclear factor kappa B (NF-κB) pathway were later analyzed using immunofluorescence, western blot, and RT-qPCR. Our findings indicated that blockage of TREK-1 reduced CUMS-induced depressive-like behavior in rats, inhibited the microglial stimulation, reduced inflammatory factor levels, and suppressed the activation of A1-like reactive astrocytes in the hippocampus. We also verified that the suppression of A1-like astrocytes by spadin necessitated the NF-κB pathway. According to the findings, blocking TREK-1 inhibited the activation of A1-like reactive astrocytes via the NF-κB signaling pathway in MDD. Our study preliminarily identifies a novel antidepressant mechanism of TREK-1 action and provides a therapeutic path for MDD. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11064-023-03857-4. Springer US 2023-01-20 2023 /pmc/articles/PMC10119044/ /pubmed/36670238 http://dx.doi.org/10.1007/s11064-023-03857-4 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Paper
Cong, Ting
Sun, Ye
Zhou, Yitong
Wu, Haikuo
Li, Liya
Chu, Zhenchen
Chen, Xue
Li, Jinying
Zhao, Danmei
Wang, Yanfang
Liu, Yingxin
Yin, Shengming
Xiao, Zhaoyang
Blocking Two-Pore Domain Potassium Channel TREK-1 Inhibits the Activation of A1-Like Reactive Astrocyte Through the NF-κB Signaling Pathway in a Rat Model of Major Depressive Disorder
title Blocking Two-Pore Domain Potassium Channel TREK-1 Inhibits the Activation of A1-Like Reactive Astrocyte Through the NF-κB Signaling Pathway in a Rat Model of Major Depressive Disorder
title_full Blocking Two-Pore Domain Potassium Channel TREK-1 Inhibits the Activation of A1-Like Reactive Astrocyte Through the NF-κB Signaling Pathway in a Rat Model of Major Depressive Disorder
title_fullStr Blocking Two-Pore Domain Potassium Channel TREK-1 Inhibits the Activation of A1-Like Reactive Astrocyte Through the NF-κB Signaling Pathway in a Rat Model of Major Depressive Disorder
title_full_unstemmed Blocking Two-Pore Domain Potassium Channel TREK-1 Inhibits the Activation of A1-Like Reactive Astrocyte Through the NF-κB Signaling Pathway in a Rat Model of Major Depressive Disorder
title_short Blocking Two-Pore Domain Potassium Channel TREK-1 Inhibits the Activation of A1-Like Reactive Astrocyte Through the NF-κB Signaling Pathway in a Rat Model of Major Depressive Disorder
title_sort blocking two-pore domain potassium channel trek-1 inhibits the activation of a1-like reactive astrocyte through the nf-κb signaling pathway in a rat model of major depressive disorder
topic Original Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10119044/
https://www.ncbi.nlm.nih.gov/pubmed/36670238
http://dx.doi.org/10.1007/s11064-023-03857-4
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