Dl-3-n-Butylphthalide Rescues Dopaminergic Neurons in Parkinson's Disease Models by Inhibiting the NLRP3 Inflammasome and Ameliorating Mitochondrial Impairment.
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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Dl-3-n-丁基苯酞通过抑制 NLRP3 炎性体和改善线粒体损伤来拯救帕金森病模型中的多巴胺能神经元
DOI：
10.3389/fimmu.2021.794770
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发表时间：
2021
影响因子：
7.3
通讯作者：
Wang Q
中科院分区：
文献类型：
--
作者：
Que R;Zheng J;Chang Z;Zhang W;Li H;Xie Z;Huang Z;Wang HT;Xu J;Jin D;Yang W;Tan EK;Wang Q
神经炎症和线粒体损伤在帕金森病（PD）的神经发病机制中起重要作用。NLRP 3炎性体的激活和α-突触核蛋白（α-Syn）的积聚与神经炎症密切相关。因此，调节NLRP 3炎性体活化和α-Syn聚集可能具有治疗潜力。研究表明，DL-3-正丁基苯酞（NBP）对某些神经系统疾病如缺血性中风具有神经保护作用。本研究旨在探讨NBP是否能抑制NLRP 3炎性小体的激活并减少α-Syn的聚集，从而保护多巴胺能神经元免受神经炎症的影响。本研究建立了MPTP诱导的小鼠模型和6-OHDA诱导的SH-SY 5 Y细胞模型，以研究NBP的神经保护作用。然后，我们进行了行为测试，以检查NBP治疗后MPTP暴露小鼠的运动功能障碍。采用Western blotting、免疫荧光染色、流式细胞术和RT-qPCR检测NLRP 3炎性小体、神经炎性细胞因子、PARP 1、p-α-Syn以及小胶质细胞增生和星形胶质细胞增生标志物的表达。结果表明，NBP对实验性PD模型具有神经保护作用。在体内，NBP改善MPTP诱导的小鼠的行为障碍和减少多巴胺能神经元的损失。在体外，6-OHDA（100 μ M，24 h）处理SH-SY 5 Y细胞后，细胞活力明显降低，细胞内活性氧产生增加，细胞凋亡明显增加; 5 μ M NBP预处理可在一定程度上减轻6-OHDA诱导的细胞毒性、活性氧产生和细胞凋亡。重要的是，无论在体内还是体外，NBP都抑制了NLRP 3炎性体的激活和α-Syn的聚集，从而抑制了神经炎症，改善了线粒体损伤。总之，NBP通过减少NLRP 3炎性体活化、改善线粒体损伤和增加p-α-Syn水平来拯救多巴胺能神经元。这项研究可能提供新的神经保护机制NBP作为一个潜在的治疗剂。
Neuroinflammation 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. In 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. The 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. In 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.
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影响因子：
4.8
作者：
Du T;Wang L;Liu W;Zhu G;Chen Y;Zhang J
通讯作者：
Zhang J
影响因子：
4.8
作者：
Chen, Ningyuan;Zhou, Zhibing;Zhang, Jianfeng
通讯作者：
Zhang, Jianfeng
DOI：
10.1126/science.aat8407
发表时间：
2018-11-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kam TI;Mao X;Park H;Chou SC;Karuppagounder SS;Umanah GE;Yun SP;Brahmachari S;Panicker N;Chen R;Andrabi SA;Qi C;Poirier GG;Pletnikova O;Troncoso JC;Bekris LM;Leverenz JB;Pantelyat A;Ko HS;Rosenthal LS;Dawson TM;Dawson VL
通讯作者：
Dawson VL
影响因子：
168.9
作者：
Kalia, Lorraine V.;Lang, Anthony E.
通讯作者：
Lang, Anthony E.
影响因子：
9.9
作者：
Gao, Xiang;Chen, Honglei;Ascherio, Alberto
通讯作者：
Ascherio, Alberto