Lactulose and Melibiose Attenuate MPTP-Induced Parkinson's Disease in Mice by Inhibition of Oxidative Stress, Reduction of Neuroinflammation and Up-Regulation of Autophagy
Lactulose and Melibiose Attenuate MPTP-Induced Parkinson's Disease in Mice by Inhibition of Oxidative Stress, Reduction of Neuroinflammation and Up-Regulation of Autophagy
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DOI：
10.3389/fnagi.2020.00226
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发表时间：
2020-07-24
影响因子：
4.8
通讯作者：
Lee-Chen, Guey-Jen
中科院分区：
文献类型：
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作者：
Lin, Chih-Hsin;Wei, Pei-Cih;Lee-Chen, Guey-Jen
帕金森病（PD）是一种常见的神经退行性疾病，其特征是腹侧脑中多巴胺能（DA能）神经元的进行性丢失。二糖海藻糖已证明有潜力减轻PD疾病模型中DA能损失。然而，海藻糖在肠道中被海藻糖酶迅速水解成葡萄糖，限制了其临床应用的潜力。在这里，我们研究了两种海藻糖酶难消化类似物乳果糖和蜜二糖在亚慢性1-甲基-4-苯基-1，2，3，6-四氢吡啶（MPTP）诱导的PD小鼠模型中的神经保护潜力。MPTP治疗产生了显着的运动缺陷，抑制多巴胺水平，并下调多巴胺转运蛋白（DAT）在纹状体。参与抗氧化应激途径的基因的表达水平，包括超氧化物歧化酶2（SOD 2），核因子红细胞2相关因子2（NRF 2）和NAD（P）H脱氢酶（NQO 1）也下调。同时，氧化应激标志物4-羟基壬烯醛（4-HNE）的表达上调沿着MPTP处理后腹侧中脑中小胶质细胞和星形胶质细胞反应性的增加。MPTP还降低了自噬的活性，通过自噬体标记物微管相关蛋白1轻链3（LC 3）-II进行评估。乳果糖和蜜二糖显著挽救了运动缺陷，增加了纹状体中的多巴胺，降低了小胶质细胞和星形胶质细胞的反应性，并降低了4-HNE的水平。此外，乳果糖和蜜二糖上调SOD 2，NRF 2和NQO 1水平，以及增强腹侧中脑的LC 3-II/LC 3-I比率与MPTP治疗。我们的研究结果表明乳果糖和蜜二糖具有保护PD DA能神经元的潜力。
Parkinson's disease (PD) is a common neurodegenerative disease characterized by the progressive loss of dopaminergic (DAergic) neurons in the ventral brain. A disaccharide trehalose has demonstrated the potential to mitigate the DAergic loss in disease models for PD. However, trehalose is rapidly hydrolyzed into glucose by trehalase in the intestine, limiting its potential for clinical practice. Here, we investigated the neuroprotective potential of two trehalase-indigestible analogs, lactulose and melibiose, in sub-chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Treatment with MPTP generated significant motor deficits, inhibited dopamine levels, and down-regulated dopamine transporter (DAT) in the striatum. Expression levels of genes involved in anti-oxidative stress pathways, including superoxide dismutase 2 (SOD2), nuclear factor erythroid 2-related factor 2 (NRF2), and NAD(P)H dehydrogenase (NQO1) were also down-regulated. Meanwhile, expression of the oxidative stress marker 4-hydroxynonenal (4-HNE) was up-regulated along with increased microglia and astrocyte reactivity in the ventral midbrain following MPTP treatment. MPTP also reduced the activity of autophagy, evaluated by the autophagosomal marker microtubule-associated protein 1 light chain 3 (LC3)-II. Lactulose and melibiose significantly rescued motor deficits, increased dopamine in the striatum, reduced microglia and astrocyte reactivity as well as decreased levels of 4-HNE. Furthermore, lactulose and melibiose up-regulated SOD2, NRF2, and NQO1 levels, as well as enhanced the LC3-II/LC3-I ratio in the ventral midbrain with MPTP treatment. Our findings indicate the potential of lactulose and melibiose to protect DAergic neurons in PD.