Background

Parkinson's disease (PD) is the second most common neurodegenerative disease featured to mitochondrial dysfunction in neuronal cells. Dynamin-related protein 1 (Drp1) is an important regulator of mitochondrial fission and subsequent mitophagy. Mangiferin (MGF) is a glucosyl xanthone mainly derived from Mangifera indica L., possessing multifaceted properties, e.g., antioxidant, anti-inflammatory, and enhancement of cognitive ability. Besides, it can cross the blood-brain barrier, thereby exerting a neuroprotective effect. However, so far, MGF's effect in balancing mitochondrial homeostasis via regulation of Drp1 level and mitophagic pathway in PD remains rarely reported.

Purpose

We aimed to investigate the neuroprotective effect of MGF against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD and examine the possible mechanisms.

Methods

We utilized C57BL/6 mice exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); Behavioral parameters, containing the open field test, balance beam, pole test, and rotarod test, assessed the locomotor activity; immunohistochemistry assessed the number of TH-positive neurons; transmission electron microscopy detected ultrastructural mitochondrial morphology in the dopaminergic neuron; complex I enzymatic activity microplate assay kit measured the mitochondrial complex I activity; ATP determination kit measured ATP levels in mitochondria isolated from cells or striatal tissues; western blot measured the levels of Drp1 and mitophagic proteins.

Results

We observed that MGF could mitigate motor deficiency and improve the expression of tyrosine hydroxylase in the substantia nigra of MPTP-induced PD mice. Furthermore, MGF not only ameliorated mitochondrial ultrastructure, but also improved mitochondrial ATP content. Within mitochondria, MGF could reduce Drp1 expression and reverse the expressions of mitophagic proteins, including PINK1, Parkin, NIX, BNIP3, FUNDC1, and p62.

Conclusion

Present study indicates that MGF benefits mitochondrial networks by recovering mitochondrial ultrastructure and ATP contents, reducing mitochondrial Drp1, and modulating mitophagic proteins in the MPTP-induced PD mice model, which revealed a novel acting mechanism of MGF in PD's treatment.

中文翻译：

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Mangiferin 是一种天然葡糖蒽酮，可抑制帕金森病小鼠模型中线粒体动力相关蛋白 1 并减轻异常线粒体自噬蛋白

背景

帕金森病 (PD) 是第二常见的神经退行性疾病，其特征在于神经元细胞中的线粒体功能障碍。Dynamin 相关蛋白 1 (Drp1) 是线粒体裂变和随后的线粒体自噬的重要调节因子。Mangiferin (MGF)是一种主要来源于Mangifera indica L.的葡糖基黄酮，具有抗氧化、抗炎和增强认知能力等多方面的特性。此外，它可以穿过血脑屏障，从而发挥神经保护作用。然而，到目前为止，MGF 通过调节 PD 中的 Drp1 水平和线粒体自噬通路来平衡线粒体稳态的作用仍然很少报道。

目的

我们旨在研究 MGF 对 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) PD 小鼠模型的神经保护作用，并研究可能的机制。

方法

我们利用暴露于 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 的 C57BL/6 小鼠；行为参数，包括旷场测试、平衡木、杆测试和旋转杆测试，评估了运动活动；免疫组织化学评估了 TH 阳性神经元的数量；透射电子显微镜检测到多巴胺能神经元中的超微结构线粒体形态；复合物I酶活性微孔板测定试剂盒测定线粒体复合物I活性；ATP测定试剂盒测量从细胞或纹状体组织中分离的线粒体中的ATP水平；蛋白质印迹测量了 Drp1 和 mitophagic 蛋白的水平。

结果

我们观察到 MGF 可以减轻运动缺陷并改善 MPTP 诱导的 PD 小鼠黑质中酪氨酸羟化酶的表达。此外，MGF不仅改善了线粒体超微结构，还提高了线粒体ATP含量。在线粒体内，MGF 可以降低 Drp1 的表达并逆转线粒体蛋白的表达，包括 PINK1、Parkin、NIX、BNIP3、FUNDC1 和 p62。

结论

目前的研究表明，MGF 通过恢复线粒体超微结构和 ATP 含量、减少线粒体 Drp1 和调节 MPTP 诱导的 PD 小鼠模型中的线粒体自噬蛋白而有益于线粒体网络，这揭示了 MGF 在 PD 治疗中的新作用机制。