Tsou Yi-Hsien, Shih Ching-Ting, Ching Cheng-Hsin, Huang Jui-Yen, Jen Chauying J, Yu Lung, Kuo Yu-Min, Wu Fong-Sen, Chuang Jih-Ing
Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
Institute of Behavioral Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.
Exp Neurol. 2015 Jan;263:50-62. doi: 10.1016/j.expneurol.2014.09.021. Epub 2014 Oct 5.
Exercise induces oxidative stress, which may activate adaptive antioxidant responses. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays an important role in the defense of oxidative stress by regulating the expression of antioxidant enzymes, gamma-glutamylcysteine ligase (γGCL) and heme oxygenase-1 (HO-1). We investigated whether treadmill exercise protects dopaminergic neurons by regulating the Nrf2 antioxidant system in a 1-methyl-4-phenylpyridine (MPP(+))-induced parkinsonian rat model. We found that MPP(+) induced early decreases in total glutathione level and Nrf2/γGCLC (catalytic subunit of γGCL) expression, but late upregulation of HO-1 expression in association with loss of nigral dopaminergic neurons and downregulation of tyrosine hydroxylase and dopamine transporter expression in the striatum. Treadmill exercise for 4weeks induced upregulation of Nrf2 and γGCLC expression, and also prevented the MPP(+)-induced downregulation of Nrf2/γGCLC/glutathione, HO-1 upregulation, and nigrostriatal dopaminergic neurodegeneration. Moreover, the protective effect of exercise was blocked by the knockdown of Nrf2 using a lentivirus-carried shNrf2 delivery system. These results demonstrate an essential role of Nrf2 in the exercise-mediated protective effect that exercise enhances the nigrostriatal Nrf2 antioxidant defense capacity to protect dopaminergic neurons against the MPP(+)-induced toxicity.
运动可诱导氧化应激，这可能会激活适应性抗氧化反应。核因子红细胞2相关因子2（Nrf2）通过调节抗氧化酶γ-谷氨酰半胱氨酸连接酶（γGCL）和血红素加氧酶-1（HO-1）的表达，在氧化应激防御中发挥重要作用。我们研究了在1-甲基-4-苯基吡啶（MPP(+)）诱导的帕金森病大鼠模型中，跑步机运动是否通过调节Nrf2抗氧化系统来保护多巴胺能神经元。我们发现，MPP(+)诱导总谷胱甘肽水平和Nrf2/γGCLC（γGCL的催化亚基）表达早期降低，但后期HO-1表达上调，同时伴有黑质多巴胺能神经元丢失以及纹状体中酪氨酸羟化酶和多巴胺转运体表达下调。跑步机运动4周可诱导Nrf2和γGCLC表达上调，还可防止MPP(+)诱导的Nrf2/γGCLC/谷胱甘肽下调、HO-1上调以及黑质纹状体多巴胺能神经变性。此外，使用携带慢病毒的shNrf2递送系统敲低Nrf2可阻断运动的保护作用。这些结果表明，Nrf2在运动介导的保护作用中起关键作用，即运动增强黑质纹状体Nrf2抗氧化防御能力，以保护多巴胺能神经元免受MPP(+)诱导的毒性作用。
