Key Laboratory of Basic Pharmacology of Ministry of Education and Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi, Guizhou, China.
Department of Pharmacology, Key Laboratory of Basic Pharmacology of Guizhou Province and School of Pharmacy, Zunyi Medical University, Zunyi, Guizhou, China.
Oxid Med Cell Longev. 2020 Nov 19;2020:2963540. doi: 10.1155/2020/2963540. eCollection 2020.
Neuroinflammation plays a crucial role in the pathological process of Parkinson's disease (PD). Nod-like receptor protein 3 (NLRP3) inflammasome was highly located in microglia and involved in the process of neuroinflammation. Activation of the NLRP3 inflammasome has been confirmed to contribute to the progression of PD. Thus, inhibition of NLRP3 inflammasome activation could be an important breakthrough point on PD therapy. Ellagic acid (EA) is a natural polyphenol that has been widely found in soft fruits, nuts, and other plant tissues with anti-inflammatory, antioxidant, and neuroprotective properties. However, the mechanisms underlying EA-mediated anti-inflammation and neuroprotection have not been fully elucidated. In this study, a lipopolysaccharide- (LPS-) induced rat dopamine (DA) neuronal damage model was performed to determine the effects of EA on the protection of DA neurons. In addition, the DA neuronal MN9D cell line and microglial BV-2 cell line were employed to explore whether EA-mediated neuroprotection was through an NLRP3-dependent mechanism. Results indicated that EA ameliorated LPS-induced DA neuronal loss in the rat substantia nigra. Further, inhibition of microglial NLRP3 inflammasome signaling activation was involved in EA-generated neuroprotection, as evidenced by the following observations. First, EA reduced NLRP3 inflammasome signaling activation in microglia and subsequent proinflammatory cytokines' excretion. Second, EA-mediated antineuroinflammation and further DA neuroprotection from LPS-induced neurotoxicity were not shown upon microglial NLRP3 siRNA treatment. In conclusion, this study demonstrated that EA has a profound effect on protecting DA neurons against LPS-induced neurotoxicity via the suppression of microglial NLRP3 inflammasome activation.
神经炎症在帕金森病（PD）的病理过程中起着关键作用。核苷酸结合寡聚化结构域样受体蛋白 3（NLRP3）炎性小体高度定位于小胶质细胞中，并参与神经炎症过程。NLRP3 炎性小体的激活已被证实有助于 PD 的进展。因此，抑制 NLRP3 炎性小体的激活可能是 PD 治疗的一个重要突破点。鞣花酸（EA）是一种天然多酚，广泛存在于软果、坚果和其他植物组织中，具有抗炎、抗氧化和神经保护作用。然而，EA 介导的抗炎和神经保护的机制尚未完全阐明。在这项研究中，进行了脂多糖（LPS）诱导的大鼠多巴胺（DA）神经元损伤模型，以确定 EA 对 DA 神经元保护的作用。此外，还使用 DA 神经元 MN9D 细胞系和小胶质细胞 BV-2 细胞系来探讨 EA 介导的神经保护是否通过 NLRP3 依赖的机制。结果表明，EA 改善了 LPS 诱导的大鼠黑质 DA 神经元丢失。此外，抑制小胶质细胞 NLRP3 炎性小体信号激活参与了 EA 产生的神经保护作用，这表现在以下观察结果中。首先，EA 减少了小胶质细胞中 NLRP3 炎性小体信号的激活以及随后促炎细胞因子的释放。其次，在用小胶质细胞 NLRP3 siRNA 处理后，EA 介导的抗神经炎症以及进一步防止 LPS 诱导的神经毒性对 DA 神经元的保护作用并未显示出来。总之，这项研究表明，EA 通过抑制小胶质细胞 NLRP3 炎性小体的激活，对保护 DA 神经元免受 LPS 诱导的神经毒性具有深远的影响。
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