Tong Huichun, Zhang Xiuping, Meng Xingjun, Lu Lingli, Mai Dongmei, Qu Shaogang
Clinical Medicine Research Center, Shunde Hospital, Southern Medical University, Foshan, China.
Teaching Center of Experimental Medicine, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Front Mol Neurosci. 2018 May 22;11:165. doi: 10.3389/fnmol.2018.00165. eCollection 2018.
Evidence suggests that oxidative stress is involved in the pathogenesis of Parkinson disease (PD). Simvastatin has been suggested to protect against oxidative stress in several diseases. However, the molecular mechanisms by which simvastatin protects against neuropathology and oxidative damage in PD are poorly elucidated. In this study, we aimed to investigate the potential neuroprotective effects of simvastatin owing to its anti-oxidative properties in 6-hydroxydopamine (6-OHDA)-treated SH-SY5Y cells and mice. The results of 2',7'-dichlorodihydrofluorescein diacetate (DCFH-DA) fluorescence and CCK-8 assay demonstrated that simvastatin reduced intracellular reactive oxygen species (ROS) levels and reversed apoptosis in 6-OHDA-treated SH-SY5Y cells. Mechanistic studies revealed that 6-OHDA-induced activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase/p38 mitogen-activated protein kinase (MAPK) pathway was inhibited and nuclear factor-κB (NF-κB) nuclear transcription decreased in SH-SY5Y cells after simvastatin treatment. Enhanced expression levels of superoxide dismutase (SOD), heme oxygenase-1 (HO-1), peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and glutamate-cysteine ligase modifier subunit (GCLM) were observed after simvastatin treatment in 6-OHDA-treated SH-SY5Y cells. studies revealed that administration of simvastatin by gavage decreased limb-use asymmetry and apomorphine-induced rotations in 6-OHDA-lesioned mice. Simvastatin increased dopaminergic neurons and reduced protein tyrosine nitration and gliosis in the midbrain of PD mice. An inhibitory effect on activation of the NADPH oxidase/p38 MAPK was observed, and increased antioxidant protein expression in the midbrain were seen in the simvastatin plus 6-OHDA group compared with the 6-OHDA-lesioned group. Taken together, these results demonstrate that simvastatin might inhibit the activation of NADPH oxidase/p38 MAPK pathway, enhance antioxidant protein expression and protect against oxidative stress, thereby providing a novel antioxidant mechanism that has therapeutic validity.
有证据表明氧化应激参与帕金森病（PD）的发病机制。辛伐他汀已被证明在多种疾病中可抵御氧化应激。然而，辛伐他汀预防PD神经病理学和氧化损伤的分子机制尚不清楚。在本研究中，我们旨在研究辛伐他汀因其抗氧化特性对6-羟基多巴胺（6-OHDA）处理的SH-SY5Y细胞和小鼠的潜在神经保护作用。2',7'-二氯二氢荧光素二乙酸酯（DCFH-DA）荧光和CCK-8检测结果表明，辛伐他汀降低了6-OHDA处理的SH-SY5Y细胞内活性氧（ROS）水平并逆转了细胞凋亡。机制研究表明，辛伐他汀处理后，SH-SY5Y细胞中6-OHDA诱导的烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶/p38丝裂原活化蛋白激酶（MAPK）途径的激活受到抑制，核因子-κB（NF-κB）核转录减少。在6-OHDA处理的SH-SY5Y细胞中，辛伐他汀处理后观察到超氧化物歧化酶（SOD）、血红素加氧酶-1（HO-1）、过氧化物酶体增殖物激活受体-γ共激活因子-1α（PGC-1α）和谷氨酸-半胱氨酸连接酶修饰亚基（GCLM）的表达水平升高。研究表明，通过灌胃给予辛伐他汀可减少6-OHDA损伤小鼠的肢体使用不对称和阿扑吗啡诱导的旋转。辛伐他汀增加了PD小鼠中脑的多巴胺能神经元数量，减少了蛋白质酪氨酸硝化和胶质增生。与6-OHDA损伤组相比，辛伐他汀加6-OHDA组对NADPH氧化酶/p38 MAPK激活有抑制作用，且中脑抗氧化蛋白表达增加。综上所述，这些结果表明辛伐他汀可能抑制NADPH氧化酶/p38 MAPK途径的激活，增强抗氧化蛋白表达并抵御氧化应激，从而提供一种具有治疗有效性的新型抗氧化机制。
