木犀草素通过抑制 Toll 样受体 4 缓解多巴胺能神经元退化并抑制微胶质细胞 M1 极化

IF 2.5 4区 医学 Q3 NEUROSCIENCES
Yangzhi Xie, Hao Zhang, Jiacheng Chen, Sicong Xu, Yan Luo
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引用次数: 0

摘要

背景:木犀草素是一种天然类黄酮,其神经保护和抗炎作用已被证实可减轻神经变性。尽管有这些发现,但导致这些作用的潜在机制仍不清楚。Toll 样受体 4(TLR4)广泛分布于小胶质细胞中,在神经炎症和神经退行性变中发挥着关键作用。本文概述的研究旨在利用帕金森病(PD)啮齿动物模型确定木犀草素抗炎和神经保护作用的机制,并特别关注 TLR4 在这一过程中的作用:本实验中使用的帕金森病小鼠模型是通过单次注射脂多糖(LPS)建立的。随后将小鼠随机分配到木犀草素或药物治疗组,然后评估小鼠的运动表现和多巴胺能神经元损伤情况。在 LPS 挑战之前,用木犀草素或生理盐水处理 BV2 小神经胶质细胞。通过实时聚合酶链式反应(RT-PCR)和酶联免疫吸附试验(ELISA)分别定量检测了间脑组织和 BV2 中小胶质细胞特异性标记物离子化钙结合适配体分子 1(IBA-1)和 M1/M2 极化标记物的 MRNA 表达,以及相关促炎细胞因子的丰度。检测了与 BV2 共同培养的神经元样 PC12 细胞系的细胞活力和凋亡情况。检测间脑组织和 BV2 细胞中的 TLR4 RNA 转录本和蛋白质丰度。免疫印迹法评估了核因子卡巴基因结合(NF-κB)p65亚基在体外和体内的磷酸化情况:结果:木犀草素治疗可改善帕金森病模型的功能,缓解多巴胺能神经元的丧失。木犀草素可抑制 PC12 细胞凋亡并促进细胞存活。在体外和体内,叶黄素都能使小胶质细胞的M1/M2极化转向抗炎的M2表型。最后,研究发现木犀草素能显著下调 TLR4 mRNA 和蛋白的表达,并抑制 NF-κB p65 亚基的磷酸化:结论:木犀草素通过阻断TLR4介导的神经炎症,抑制了体外和体内的多巴胺能退化。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Luteolin Mitigates Dopaminergic Neuron Degeneration and Restrains Microglial M1 Polarization by Inhibiting Toll Like Receptor 4.

Background: Luteolin is a natural flavonoid and its neuroprotective and anti-inflammatory effects have been confirmed to mitigate neurodegeneration. Despite these findings, the underlying mechanisms responsible for these effects remain unclear. Toll-like receptor 4 (TLR4) is widely distributed in microglia and plays a pivotal role in neuroinflammation and neurodegeneration. Here studies are outlined that aimed at determining the mechanisms responsible for the anti-inflammatory and neuroprotective actions of luteolin using a rodent model of Parkinson's disease (PD) and specifically focusing on the role of TLR4 in this process.

Methods: The mouse model of PD used in this experiment was established through a single injection of lipopolysaccharide (LPS). Mice were then subsequently randomly allocated to either the luteolin or vehicle-treated group, then motor performance and dopaminergic neuronal injury were evaluated. BV2 microglial cells were treated with luteolin or vehicle saline prior to LPS challenge. MRNA expression of microglial specific marker ionized calcium-binding adapter molecule 1 (IBA-1) and M1/M2 polarization markers, as well as the abundance of indicated pro-inflammatory cytokines in the mesencephalic tissue and BV2 were quantified by real time-polymerase chain reaction (RT-PCR) and Enzyme-linked Immunosorbent Assay (ELISA), respectively. Cell viability and apoptosis of neuron-like PC12 cell line co-cultured with BV2 were detected. TLR4 RNA transcript and protein abundance in mesencephalic tissue and BV2 cells were detected. Nuclear factor kappa-gene binding (NF-κB) p65 subunit phosphorylation both in vitro and in vivo was evaluated by immunoblotting.

Results: Luteolin treatment induced functional improvements and alleviated dopaminergic neuronal loss in the PD model. Luteolin inhibited apoptosis and promoted cell survival in PC12 cells. Luteolin treatment shifted microglial M1/M2 polarization towards an anti-inflammatory M2 phenotype both in vitro and in vivo. Finally, it was found that luteolin treatment significantly downregulated both TLR4 mRNA and protein expression as well as restraining NF-κB p65 subunit phosphorylation.

Conclusions: Luteolin restrained dopaminergic degeneration in vitro and in vivo by blocking TLR4-mediated neuroinflammation.

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来源期刊
CiteScore
2.80
自引率
5.60%
发文量
173
审稿时长
2 months
期刊介绍: JIN is an international peer-reviewed, open access journal. JIN publishes leading-edge research at the interface of theoretical and experimental neuroscience, focusing across hierarchical levels of brain organization to better understand how diverse functions are integrated. We encourage submissions from scientists of all specialties that relate to brain functioning.
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