槲皮素通过 Nrf2 信号通路对 MPP+诱导的多巴胺能神经元损伤的保护作用。
Protective Effects of Querectin against MPP-Induced Dopaminergic Neurons Injury via the Nrf2 Signaling Pathway.
机构信息
Department of Neurology, Shanghai East Hospital, Tongji University School of Medicine, 200120 Shanghai, China.
Department of Neurology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 200080 Shanghai, China.
出版信息
Front Biosci (Landmark Ed). 2023 Mar 2;28(3):42. doi: 10.31083/j.fbl2803042.
BACKGROUND
Parkinson's disease (PD) is a common selective and progressive neurodegenerative disorder of nigrostriatal dopaminergic (DA) neurons. Quercetin is a bioflavonoid with antioxidant, anti-inflammatory, anti-aging and anti-cancer properties. However, the exact mechanism by which quercetin exerts its protective effect on DAergic neurons remains unclear.
PURPOSE
To investigate the underlying molecular mechanism of quercetin's protective effect on DA neurons using 1-methyl-4-phenylpyridinium (MPP+)-induced PD ferroptosis model .
METHODS
MPP+ was used to induce cytotoxicity in SH-SY5Y/primary neurons. Cell viability and apoptosis were assessed by CCK-8 assay and flow cytometry. The expression levels of ferroptosis-related proteins (NCOA4, SLC7A11, Nrf2, and GPX4) were determined by Western blotting. Malondialdehyde (MDA), iron, and GPX4 levels were assesed using corresponding assay kits. Lipid peroxidation was assessed by C11-BODIPY staining.
RESULTS
In the MPP+-induced ferroptosis model of SH-SY5Y cells, the expressions of SLC7A11 and GPX4 were inhibited, and the expression of NCOA4 protein was increased, causing the overproduction of MDA and lipid peroxidation. Quercetin can reduce the above changes caused by MPP+, that is, reduce the protein expression of NCOA4 in SH-SY5Y cells, increase SLC7A11 and GPX4 partially inhibited by MPP+, and reduce MDA overproduction and lipid peroxidation to protect DA neurons. Nrf2 inhibitor ML385 could inhibit quercetin-induced increase of GPX4 and SLC7A11 protein expression, indicating that the protective effect of quercetin was mediated through Nrf2.
CONCLUSIONS
The results of this study suggest that quercetin regulates ferroptosis through Nrf2-dependent signaling pathways, thereby inhibiting MPP+-induced neurotoxicity in SH-SY5Y/primary neurons.
背景
帕金森病（PD）是一种常见的选择性和进行性黑质纹状体多巴胺能（DA）神经元神经退行性疾病。槲皮素是一种具有抗氧化、抗炎、抗衰老和抗癌特性的生物类黄酮。然而，槲皮素对 DA 能神经元发挥保护作用的确切机制尚不清楚。
目的
使用 1-甲基-4-苯基吡啶（MPP+）诱导的 PD 铁死亡模型，研究槲皮素对 DA 神经元保护作用的潜在分子机制。
方法
用 MPP+诱导 SH-SY5Y/原代神经元细胞产生细胞毒性。通过 CCK-8 法和流式细胞术评估细胞活力和细胞凋亡。通过 Western blot 测定铁死亡相关蛋白（NCOA4、SLC7A11、Nrf2 和 GPX4）的表达水平。使用相应的测定试剂盒测定丙二醛（MDA）、铁和 GPX4 水平。通过 C11-BODIPY 染色评估脂质过氧化。
结果
在 MPP+诱导的 SH-SY5Y 细胞铁死亡模型中，SLC7A11 和 GPX4 的表达受到抑制，NCOA4 蛋白表达增加，导致 MDA 过度产生和脂质过氧化。槲皮素可以减少 MPP+引起的上述变化，即减少 SH-SY5Y 细胞中 NCOA4 的蛋白表达，部分增加被 MPP+抑制的 SLC7A11 和 GPX4，并减少 MDA 过度产生和脂质过氧化，从而保护 DA 神经元。Nrf2 抑制剂 ML385 可抑制槲皮素诱导的 GPX4 和 SLC7A11 蛋白表达增加，表明槲皮素的保护作用是通过 Nrf2 介导的。
结论
本研究结果表明，槲皮素通过 Nrf2 依赖性信号通路调节铁死亡，从而抑制 MPP+诱导的 SH-SY5Y/原代神经元神经毒性。
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