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Mechanistic Studies of Gypenosides in Microglial State Transition and its Implications in Depression-Like Behaviors: Role of TLR4/MyD88/NF-κB Signaling

Depression is a prevalent psychiatric disorder. Microglial state transition has been found in many neurological disorders including depression. Gypenosides (Gypenosides I-LXXVIII, Gps) are saponin extracts isolated from the traditional Chinese herb Gynostemma pentaphyllum (Thunb.) Makino that exert...

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Autores principales: Cao, Li-Hua, Zhao, Yuan-Yuan, Bai, Ming, Geliebter, David, Geliebter, Jan, Tiwari, Raj, He, Hong-Juan, Wang, Zhen-zhen, Jia, Xing-Yuan, Li, Jin, Li, Xiu-Min, Miao, Ming-San
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8973912/
https://www.ncbi.nlm.nih.gov/pubmed/35370734
http://dx.doi.org/10.3389/fphar.2022.838261
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author Cao, Li-Hua
Zhao, Yuan-Yuan
Bai, Ming
Geliebter, David
Geliebter, Jan
Tiwari, Raj
He, Hong-Juan
Wang, Zhen-zhen
Jia, Xing-Yuan
Li, Jin
Li, Xiu-Min
Miao, Ming-San
author_facet Cao, Li-Hua
Zhao, Yuan-Yuan
Bai, Ming
Geliebter, David
Geliebter, Jan
Tiwari, Raj
He, Hong-Juan
Wang, Zhen-zhen
Jia, Xing-Yuan
Li, Jin
Li, Xiu-Min
Miao, Ming-San
author_sort Cao, Li-Hua
collection PubMed
description Depression is a prevalent psychiatric disorder. Microglial state transition has been found in many neurological disorders including depression. Gypenosides (Gypenosides I-LXXVIII, Gps) are saponin extracts isolated from the traditional Chinese herb Gynostemma pentaphyllum (Thunb.) Makino that exert anti-inflammatory and neuroprotective activities and regulate depression-like behaviors. However, its effect on microglial state transition in depression remains unknown. We aimed to evaluate the potential relationship between Gps and TLR4/MyD88/NF-κB signaling in microglial state transition in vitro and in vivo. First, BV-2 cells (microglial cell line) were exposed to lipopolysaccharides (LPS) and treated with 10 or 5 μg/ml Gps. Second, the chronic unpredictable mild stress (CUMS)-induced depression mouse model was used to investigate the antidepressant-like behaviors effects of Gps (100 or 50 mg/kg). We determined depression-like behaviors using the open-field test (OFT), forced swim test (FST), and sucrose preference test (SPT). Proteins and inflammatory factors in the TLR4/MyD88/NF-κB signaling pathway and the different microglial reaction states markers were subsequently conducted using enzyme-linked immunosorbent assay, immunocytochemistry, immunofluorescence, qPCR, or Western blotting analyses to evaluate the anti-inflammatory and antidepressant properties of Gps and the underlying molecular mechanisms. We found that Gps regulated the microglial cell line state transition in LPS-exposed BV-2 cells, as evidenced by the significantly decreased expression of inflammatory parameters iNOS, IL-1β, IL-6, and TNF-α and significantly promoted anti-inflammatory microglial phenotypes markers CD206 (Mrc1) and IL-10. More importantly, Gps protected against the loss of monoamine neurotransmitters and depression-like behavior in a mouse model of depression, which was accompanied by a regulation of the microglial state transition. Mechanistically, Gps inhibited TLR4/MyD88/NF-κB signaling, which reduced the release of downstream inflammatory cytokines (IL-1β, IL-6, and TNF-α) and promoted microglial phenotype transition, which all together contributed to the antidepressant effect. Our results suggest that Gps prevents depression-like behaviors by regulating the microglial state transition and inhibiting the TLR4/MyD88/NF-κB signaling pathway. Thus, Gps could be a promising therapeutic strategy to prevent and treat depression-like behaviors and other psychiatric disorders.
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spelling pubmed-89739122022-04-02 Mechanistic Studies of Gypenosides in Microglial State Transition and its Implications in Depression-Like Behaviors: Role of TLR4/MyD88/NF-κB Signaling Cao, Li-Hua Zhao, Yuan-Yuan Bai, Ming Geliebter, David Geliebter, Jan Tiwari, Raj He, Hong-Juan Wang, Zhen-zhen Jia, Xing-Yuan Li, Jin Li, Xiu-Min Miao, Ming-San Front Pharmacol Pharmacology Depression is a prevalent psychiatric disorder. Microglial state transition has been found in many neurological disorders including depression. Gypenosides (Gypenosides I-LXXVIII, Gps) are saponin extracts isolated from the traditional Chinese herb Gynostemma pentaphyllum (Thunb.) Makino that exert anti-inflammatory and neuroprotective activities and regulate depression-like behaviors. However, its effect on microglial state transition in depression remains unknown. We aimed to evaluate the potential relationship between Gps and TLR4/MyD88/NF-κB signaling in microglial state transition in vitro and in vivo. First, BV-2 cells (microglial cell line) were exposed to lipopolysaccharides (LPS) and treated with 10 or 5 μg/ml Gps. Second, the chronic unpredictable mild stress (CUMS)-induced depression mouse model was used to investigate the antidepressant-like behaviors effects of Gps (100 or 50 mg/kg). We determined depression-like behaviors using the open-field test (OFT), forced swim test (FST), and sucrose preference test (SPT). Proteins and inflammatory factors in the TLR4/MyD88/NF-κB signaling pathway and the different microglial reaction states markers were subsequently conducted using enzyme-linked immunosorbent assay, immunocytochemistry, immunofluorescence, qPCR, or Western blotting analyses to evaluate the anti-inflammatory and antidepressant properties of Gps and the underlying molecular mechanisms. We found that Gps regulated the microglial cell line state transition in LPS-exposed BV-2 cells, as evidenced by the significantly decreased expression of inflammatory parameters iNOS, IL-1β, IL-6, and TNF-α and significantly promoted anti-inflammatory microglial phenotypes markers CD206 (Mrc1) and IL-10. More importantly, Gps protected against the loss of monoamine neurotransmitters and depression-like behavior in a mouse model of depression, which was accompanied by a regulation of the microglial state transition. Mechanistically, Gps inhibited TLR4/MyD88/NF-κB signaling, which reduced the release of downstream inflammatory cytokines (IL-1β, IL-6, and TNF-α) and promoted microglial phenotype transition, which all together contributed to the antidepressant effect. Our results suggest that Gps prevents depression-like behaviors by regulating the microglial state transition and inhibiting the TLR4/MyD88/NF-κB signaling pathway. Thus, Gps could be a promising therapeutic strategy to prevent and treat depression-like behaviors and other psychiatric disorders. Frontiers Media S.A. 2022-03-15 /pmc/articles/PMC8973912/ /pubmed/35370734 http://dx.doi.org/10.3389/fphar.2022.838261 Text en Copyright © 2022 Cao, Zhao, Bai, Geliebter, Geliebter, Tiwari, He, Wang, Jia, Li, Li and Miao. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Cao, Li-Hua
Zhao, Yuan-Yuan
Bai, Ming
Geliebter, David
Geliebter, Jan
Tiwari, Raj
He, Hong-Juan
Wang, Zhen-zhen
Jia, Xing-Yuan
Li, Jin
Li, Xiu-Min
Miao, Ming-San
Mechanistic Studies of Gypenosides in Microglial State Transition and its Implications in Depression-Like Behaviors: Role of TLR4/MyD88/NF-κB Signaling
title Mechanistic Studies of Gypenosides in Microglial State Transition and its Implications in Depression-Like Behaviors: Role of TLR4/MyD88/NF-κB Signaling
title_full Mechanistic Studies of Gypenosides in Microglial State Transition and its Implications in Depression-Like Behaviors: Role of TLR4/MyD88/NF-κB Signaling
title_fullStr Mechanistic Studies of Gypenosides in Microglial State Transition and its Implications in Depression-Like Behaviors: Role of TLR4/MyD88/NF-κB Signaling
title_full_unstemmed Mechanistic Studies of Gypenosides in Microglial State Transition and its Implications in Depression-Like Behaviors: Role of TLR4/MyD88/NF-κB Signaling
title_short Mechanistic Studies of Gypenosides in Microglial State Transition and its Implications in Depression-Like Behaviors: Role of TLR4/MyD88/NF-κB Signaling
title_sort mechanistic studies of gypenosides in microglial state transition and its implications in depression-like behaviors: role of tlr4/myd88/nf-κb signaling
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8973912/
https://www.ncbi.nlm.nih.gov/pubmed/35370734
http://dx.doi.org/10.3389/fphar.2022.838261
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