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Polydatin Prevents Lipopolysaccharide (LPS)-Induced Parkinson's Disease via Regulation of the AKT/GSK3β-Nrf2/NF-κB Signaling Axis

Parkinson's disease (PD) is a common neurodegenerative disease characterized by selective loss of dopaminergic neurons in the substantia nigra (SN). Neuroinflammation induced by over-activation of microglia leads to the death of dopaminergic neurons in the pathogenesis of PD. Therefore, downreg...

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Autores principales: Huang, Bingxu, Liu, Juxiong, Meng, Tianyu, Li, Yuhang, He, Dewei, Ran, Xin, Chen, Guangxin, Guo, Wenjin, Kan, Xingchi, Fu, Shoupeng, Wang, Wei, Liu, Dianfeng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230593/
https://www.ncbi.nlm.nih.gov/pubmed/30455692
http://dx.doi.org/10.3389/fimmu.2018.02527
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author Huang, Bingxu
Liu, Juxiong
Meng, Tianyu
Li, Yuhang
He, Dewei
Ran, Xin
Chen, Guangxin
Guo, Wenjin
Kan, Xingchi
Fu, Shoupeng
Wang, Wei
Liu, Dianfeng
author_facet Huang, Bingxu
Liu, Juxiong
Meng, Tianyu
Li, Yuhang
He, Dewei
Ran, Xin
Chen, Guangxin
Guo, Wenjin
Kan, Xingchi
Fu, Shoupeng
Wang, Wei
Liu, Dianfeng
author_sort Huang, Bingxu
collection PubMed
description Parkinson's disease (PD) is a common neurodegenerative disease characterized by selective loss of dopaminergic neurons in the substantia nigra (SN). Neuroinflammation induced by over-activation of microglia leads to the death of dopaminergic neurons in the pathogenesis of PD. Therefore, downregulation of microglial activation may aid in the treatment of PD. Polydatin (PLD) has been reported to pass through the blood-brain barrier and protect against motor degeneration in the SN. However, the molecular mechanisms underlying the effects of PLD in the treatment of PD remain unclear. The present study aimed to determine whether PLD protects against dopaminergic neurodegeneration by inhibiting the activation of microglia in a rat model of lipopolysaccharide (LPS)-induced PD. Our findings indicated that PLD treatment protected dopaminergic neurons and ameliorated motor dysfunction by inhibiting microglial activation and the release of pro-inflammatory mediators. Furthermore, PLD treatment significantly increased levels of p-AKT, p-GSK-3β(Ser9), and Nrf2, and suppressed the activation of NF-κB in the SN of rats with LPS-induced PD. To further explore the neuroprotective mechanism of PLD, we investigated the effect of PLD on activated microglial BV-2 cells. Our findings indicated that PLD inhibited the production of pro-inflammatory mediators and the activation of NF-κB pathways in LPS-induced BV-2 cells. Moreover, our results indicated that PLD enhanced levels of p-AKT, p-GSK-3β(Ser9), and Nrf2 in BV-2 cells. After BV-2 cells were pretreated with MK2206 (an inhibitor of AKT), NP-12 (an inhibitor of GSK-3β), or Brusatol (BT; an inhibitor of Nrf2), treatment with PLD suppressed the activation of NF-κB signaling pathways and the release of pro-inflammatory mediators in activated BV-2 cells via activation of the AKT/GSK3β-Nrf2 signaling axis. Taken together, our results are the first to demonstrate that PLD prevents dopaminergic neurodegeneration due to microglial activation via regulation of the AKT/GSK3β-Nrf2/NF-κB signaling axis.
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spelling pubmed-62305932018-11-19 Polydatin Prevents Lipopolysaccharide (LPS)-Induced Parkinson's Disease via Regulation of the AKT/GSK3β-Nrf2/NF-κB Signaling Axis Huang, Bingxu Liu, Juxiong Meng, Tianyu Li, Yuhang He, Dewei Ran, Xin Chen, Guangxin Guo, Wenjin Kan, Xingchi Fu, Shoupeng Wang, Wei Liu, Dianfeng Front Immunol Immunology Parkinson's disease (PD) is a common neurodegenerative disease characterized by selective loss of dopaminergic neurons in the substantia nigra (SN). Neuroinflammation induced by over-activation of microglia leads to the death of dopaminergic neurons in the pathogenesis of PD. Therefore, downregulation of microglial activation may aid in the treatment of PD. Polydatin (PLD) has been reported to pass through the blood-brain barrier and protect against motor degeneration in the SN. However, the molecular mechanisms underlying the effects of PLD in the treatment of PD remain unclear. The present study aimed to determine whether PLD protects against dopaminergic neurodegeneration by inhibiting the activation of microglia in a rat model of lipopolysaccharide (LPS)-induced PD. Our findings indicated that PLD treatment protected dopaminergic neurons and ameliorated motor dysfunction by inhibiting microglial activation and the release of pro-inflammatory mediators. Furthermore, PLD treatment significantly increased levels of p-AKT, p-GSK-3β(Ser9), and Nrf2, and suppressed the activation of NF-κB in the SN of rats with LPS-induced PD. To further explore the neuroprotective mechanism of PLD, we investigated the effect of PLD on activated microglial BV-2 cells. Our findings indicated that PLD inhibited the production of pro-inflammatory mediators and the activation of NF-κB pathways in LPS-induced BV-2 cells. Moreover, our results indicated that PLD enhanced levels of p-AKT, p-GSK-3β(Ser9), and Nrf2 in BV-2 cells. After BV-2 cells were pretreated with MK2206 (an inhibitor of AKT), NP-12 (an inhibitor of GSK-3β), or Brusatol (BT; an inhibitor of Nrf2), treatment with PLD suppressed the activation of NF-κB signaling pathways and the release of pro-inflammatory mediators in activated BV-2 cells via activation of the AKT/GSK3β-Nrf2 signaling axis. Taken together, our results are the first to demonstrate that PLD prevents dopaminergic neurodegeneration due to microglial activation via regulation of the AKT/GSK3β-Nrf2/NF-κB signaling axis. Frontiers Media S.A. 2018-11-05 /pmc/articles/PMC6230593/ /pubmed/30455692 http://dx.doi.org/10.3389/fimmu.2018.02527 Text en Copyright © 2018 Huang, Liu, Meng, Li, He, Ran, Chen, Guo, Kan, Fu, Wang and Liu. http://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 Immunology
Huang, Bingxu
Liu, Juxiong
Meng, Tianyu
Li, Yuhang
He, Dewei
Ran, Xin
Chen, Guangxin
Guo, Wenjin
Kan, Xingchi
Fu, Shoupeng
Wang, Wei
Liu, Dianfeng
Polydatin Prevents Lipopolysaccharide (LPS)-Induced Parkinson's Disease via Regulation of the AKT/GSK3β-Nrf2/NF-κB Signaling Axis
title Polydatin Prevents Lipopolysaccharide (LPS)-Induced Parkinson's Disease via Regulation of the AKT/GSK3β-Nrf2/NF-κB Signaling Axis
title_full Polydatin Prevents Lipopolysaccharide (LPS)-Induced Parkinson's Disease via Regulation of the AKT/GSK3β-Nrf2/NF-κB Signaling Axis
title_fullStr Polydatin Prevents Lipopolysaccharide (LPS)-Induced Parkinson's Disease via Regulation of the AKT/GSK3β-Nrf2/NF-κB Signaling Axis
title_full_unstemmed Polydatin Prevents Lipopolysaccharide (LPS)-Induced Parkinson's Disease via Regulation of the AKT/GSK3β-Nrf2/NF-κB Signaling Axis
title_short Polydatin Prevents Lipopolysaccharide (LPS)-Induced Parkinson's Disease via Regulation of the AKT/GSK3β-Nrf2/NF-κB Signaling Axis
title_sort polydatin prevents lipopolysaccharide (lps)-induced parkinson's disease via regulation of the akt/gsk3β-nrf2/nf-κb signaling axis
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230593/
https://www.ncbi.nlm.nih.gov/pubmed/30455692
http://dx.doi.org/10.3389/fimmu.2018.02527
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