| 烟碱抑制单胺氧化酶B活性及其对抗帕金森病作用研究 |
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| 引用本文： | 徐家佳,李菁菁,李延岩,李文政,管明婧,金宇,李林,张承武,王孝峰,张晓宇,周顺,曹芸.烟碱抑制单胺氧化酶B活性及其对抗帕金森病作用研究[J].中国烟草学报,2021,27(3):88-96. |
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| 作者姓名： | 徐家佳 李菁菁 李延岩 李文政 管明婧 金宇 李林 张承武 王孝峰 张晓宇 周顺 曹芸 |
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| 作者单位： | 1.安徽中烟工业责任有限公司，安徽省合肥市高新区天达路9号 230088 |
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| 基金项目： | 烟草化学安徽省重点实验室开放课题201811402019年江苏省研究生科研与实践创新计划KYCX19_0858 |
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| 摘 要： | 背景和目的 流行病学调查结果表明，吸烟与帕金森发病率呈负相关，但吸烟对抗帕金森病的机制仍不清楚。本文拟探讨烟碱对单胺氧化酶B（MAO-B）的抑制作用，明确对抗帕金森病的机制。 方法 通过小分子与蛋白对接模型模拟技术，分析烟碱和MAO-B相互作用及蛋白活性抑制率；对细胞及果蝇的帕金森病模型给予烟碱药物干预，利用分子生物学和动物行为学，验证烟碱通过抑制MAO-B进而对抗帕金森病的作用。 结果 （1）Docking分析表明，烟碱可以与MAO-B活性位点特异性结合，最短距离为3.8 ?，优于现有MAO-B抑制剂Pargyline（5.1 ?）；（2）在体外蛋白活性抑制实验中，0.01 μM烟碱可实现MAO-B 72%的抑制率，当浓度逐渐增大至1 μM以上时，烟碱的抑制率增加至80%，即达到饱和；（3）在细胞实验中，烟碱可在0.5 h内到达线粒体并在6 h内在线粒体中浓度维持在2.5 ng/mL左右；烟碱可对抗神经毒素（MPTP）引起的多巴胺能神经细胞损伤，保护效果在MAO-B过表达的细胞中更加显著，细胞活力从75%提升至90%，细胞早期凋亡比例由84.7%下调至77.5%；（4）在动物实验中，烟碱可显著改善帕金森病果蝇的运动功能，增加果蝇大脑中多巴胺含量。 结论 本研究结果表明，烟碱具有抑制MAO-B纯蛋白活性的作用，且对MAO-B过表达的神经细胞和parkin null果蝇具有保护作用。该研究为阐明烟碱对抗帕金森病的补充机制奠定了研究基础，为烟草的综合利用提供了新的思路。
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| 关 键 词： | 烟碱 帕金森病 单胺氧化酶B(MAO-B) 线粒体 |
| 收稿时间： | 2020-11-18 |
Inhibitory effect of nicotine on the activity of monoamine oxidase B and its application in treatment of Parkinson's disease |
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| Affiliation: | 1.Anhui China Tobacco Industry Co. Ltd, 9 Tianda Road, Hefei High Tech Zong, Anhui Province, China2.Institute of Advanced Materials (IAM), Nanjing Tech University (NanjingTech), 30 South Puzhu Road, Nanjing 211816, China |
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| Abstract: | Background Epidemiological investigation shows that smoking is negatively correlated with the incidence of Parkinson's disease (PD), but its mechanism has not been fully elucidated yet. The aim of this study is to investigate the inhibitory effect of nicotine on monoamine oxidase B (MAO B) and its therapeutic mechanism against Parkinson's disease. Methods We firstly used docking model simulation technology to analyze the interaction between nicotine and MAO-B. Then the in vitro assay was carried out to confirm the inhibition effect of nicotine on MAO-B. In the cellular and drosophila PD models, the neuroprotective role of nicotine was investigated. Results 1) In docking simulation, the shortest distance between nicotine and active sites of MAO-B protein was 3.8 ?, which was shorter than that of pargyline (5.1 ?). 2) In vitro protein activity inhibition assay, 0.01 μM nicotine inhibited 72% activity of MAO-B. When the concentration of nicotine was 1 μM, the inhibition rate reached 80%. 3) In cellular experiments, it was found that nicotine reached mitochondria in 0.5 h and maintained at 2.5 ng/mL in the mitochondria in 6 h. Nicotine could protect against MPTP-induced dopaminergic nerve cell damage, and the protective effect was more significant in the cells with MAO-B overexpression. The cell viability increased from 75% to 90%, and the proportion of early apoptosis decreased from 84.7% to 77.5%. 4) Nicotine significantly improved the motor function and dopamine level of Drosophila PD model. Conclusion Based on the above results, it suggests that nicotine could inhibit the activity of MAO-B. Nicotine can protect against PD in vitro and in vivo. This study lays a research foundation for clarifying the mechanism of nicotine protecting against Parkinson's disease and provides a new idea for comprehensive utilization of tobacco. |
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