Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson’s Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment

BackgroundNeuroinflammation and mitochondrial impairment play important roles in the neuropathogenesis of Parkinson’s disease (PD). The activation of NLRP3 inflammasome and the accumulation of α-synuclein (α-Syn) are strictly correlated to neuroinflammation. Therefore, the regulation of NLRP3 inflam...

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Autores principales:	Rongfang Que, Jialing Zheng, Zihan Chang, Wenjie Zhang, Hualing Li, Zhenchao Xie, Zifeng Huang, Hai-Tao Wang, Jiangping Xu, Dana Jin, Wanlin Yang, Eng-King Tan, Qing Wang
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Parkinson’s disease dl-3-n-Butylphthalide NLRP3 inflammasome neuroinflammation α-Synuclein PARP1 Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/b7d5643e59ba4472b6f50778febfc8f8
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spelling	oai:doaj.org-article:b7d5643e59ba4472b6f50778febfc8f82021-12-01T23:39:03ZDl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson’s Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment1664-322410.3389/fimmu.2021.794770https://doaj.org/article/b7d5643e59ba4472b6f50778febfc8f82021-12-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.794770/fullhttps://doaj.org/toc/1664-3224BackgroundNeuroinflammation and mitochondrial impairment play important roles in the neuropathogenesis of Parkinson’s disease (PD). The activation of NLRP3 inflammasome and the accumulation of α-synuclein (α-Syn) are strictly correlated to neuroinflammation. Therefore, the regulation of NLRP3 inflammasome activation and α-Syn aggregation might have therapeutic potential. It has been indicated that Dl-3-n-butylphthalide (NBP) produces neuroprotection against some neurological diseases such as ischemic stroke. We here intended to explore whether NBP suppressed NLRP3 inflammasome activation and reduced α-Syn aggregation, thus protecting dopaminergic neurons against neuroinflammation.MethodsIn our study, we established a MPTP-induced mouse model and 6-OHDA-induced SH-SY5Y cell model to examine the neuroprotective actions of NBP. We then performed behavioral tests to examine motor dysfunction in MPTP-exposed mice after NBP treatment. Western blotting, immunofluorescence staining, flow cytometry and RT-qPCR were conducted to investigate the expression of NLRP3 inflammasomes, neuroinflammatory cytokines, PARP1, p-α-Syn, and markers of microgliosis and astrogliosis.ResultsThe results showed that NBP exerts a neuroprotective effect on experimental PD models. In vivo, NBP ameliorated behavioral impairments and reduced dopaminergic neuron loss in MPTP-induced mice. In vitro, treatment of SH-SY5Y cells with 6-OHDA (100uM,24 h) significantly decreased cell viability, increased intracellular ROS production, and induced apoptosis, while pretreatment with 5uM NBP could alleviated 6-OHDA-induced cytotoxicity, ROS production and cell apoptosis to some extent. Importantly, both in vivo and in vitro, NBP suppressed the activation of the NLRP3 inflammasome and the aggregation of α-Syn, thus inhibited neuroinflammation ameliorated mitochondrial impairments.ConclusionsIn summary, NBP rescued dopaminergic neurons by reducing NLRP3 inflammasome activation and ameliorating mitochondrial impairments and increases in p-α-Syn levels. This current study may provide novel neuroprotective mechanisms of NBP as a potential therapeutic agent.Rongfang QueJialing ZhengZihan ChangWenjie ZhangHualing LiZhenchao XieZifeng HuangHai-Tao WangJiangping XuDana JinWanlin YangEng-King TanEng-King TanQing WangQing WangFrontiers Media S.A.articleParkinson’s diseasedl-3-n-ButylphthalideNLRP3 inflammasomeneuroinflammationα-SynucleinPARP1Immunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Parkinson’s disease dl-3-n-Butylphthalide NLRP3 inflammasome neuroinflammation α-Synuclein PARP1 Immunologic diseases. Allergy RC581-607
spellingShingle	Parkinson’s disease dl-3-n-Butylphthalide NLRP3 inflammasome neuroinflammation α-Synuclein PARP1 Immunologic diseases. Allergy RC581-607 Rongfang Que Jialing Zheng Zihan Chang Wenjie Zhang Hualing Li Zhenchao Xie Zifeng Huang Hai-Tao Wang Jiangping Xu Dana Jin Wanlin Yang Eng-King Tan Eng-King Tan Qing Wang Qing Wang Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson’s Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment
description	BackgroundNeuroinflammation and mitochondrial impairment play important roles in the neuropathogenesis of Parkinson’s disease (PD). The activation of NLRP3 inflammasome and the accumulation of α-synuclein (α-Syn) are strictly correlated to neuroinflammation. Therefore, the regulation of NLRP3 inflammasome activation and α-Syn aggregation might have therapeutic potential. It has been indicated that Dl-3-n-butylphthalide (NBP) produces neuroprotection against some neurological diseases such as ischemic stroke. We here intended to explore whether NBP suppressed NLRP3 inflammasome activation and reduced α-Syn aggregation, thus protecting dopaminergic neurons against neuroinflammation.MethodsIn our study, we established a MPTP-induced mouse model and 6-OHDA-induced SH-SY5Y cell model to examine the neuroprotective actions of NBP. We then performed behavioral tests to examine motor dysfunction in MPTP-exposed mice after NBP treatment. Western blotting, immunofluorescence staining, flow cytometry and RT-qPCR were conducted to investigate the expression of NLRP3 inflammasomes, neuroinflammatory cytokines, PARP1, p-α-Syn, and markers of microgliosis and astrogliosis.ResultsThe results showed that NBP exerts a neuroprotective effect on experimental PD models. In vivo, NBP ameliorated behavioral impairments and reduced dopaminergic neuron loss in MPTP-induced mice. In vitro, treatment of SH-SY5Y cells with 6-OHDA (100uM,24 h) significantly decreased cell viability, increased intracellular ROS production, and induced apoptosis, while pretreatment with 5uM NBP could alleviated 6-OHDA-induced cytotoxicity, ROS production and cell apoptosis to some extent. Importantly, both in vivo and in vitro, NBP suppressed the activation of the NLRP3 inflammasome and the aggregation of α-Syn, thus inhibited neuroinflammation ameliorated mitochondrial impairments.ConclusionsIn summary, NBP rescued dopaminergic neurons by reducing NLRP3 inflammasome activation and ameliorating mitochondrial impairments and increases in p-α-Syn levels. This current study may provide novel neuroprotective mechanisms of NBP as a potential therapeutic agent.
format	article
author	Rongfang Que Jialing Zheng Zihan Chang Wenjie Zhang Hualing Li Zhenchao Xie Zifeng Huang Hai-Tao Wang Jiangping Xu Dana Jin Wanlin Yang Eng-King Tan Eng-King Tan Qing Wang Qing Wang
author_facet	Rongfang Que Jialing Zheng Zihan Chang Wenjie Zhang Hualing Li Zhenchao Xie Zifeng Huang Hai-Tao Wang Jiangping Xu Dana Jin Wanlin Yang Eng-King Tan Eng-King Tan Qing Wang Qing Wang
author_sort	Rongfang Que
title	Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson’s Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment
title_short	Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson’s Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment
title_full	Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson’s Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment
title_fullStr	Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson’s Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment
title_full_unstemmed	Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson’s Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment
title_sort	dl-3-n-butylphthalide rescues dopaminergic neurons in parkinson’s disease models by inhibiting the nlrp3 inflammasome and ameliorating mitochondrial impairment
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/b7d5643e59ba4472b6f50778febfc8f8
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Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson’s Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment

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