基于质谱成像技术的远志干预阿尔茨海默病的组织特异性分布—脑代谢调控研究

Radix Polygalae (RP) a well-known traditional Chinese medicine has been used as a tonic, tranquillizer and antipsychotic agent. A few modern pharmacological trials suggest that RP and its active components can significantly alleviate Alzheimer syndrome. The pathological changes of Alzheimer's disease (AD) occur in different brain regions during disease progression. Therefore, it’s important to investigate the tissue-specific distribution of bioactive components derived from RP and their effects on brain metabolism in order to unravel the exact composition of effective components and their roles in the prevention of AD. First of all, we will focus on the screening of the bioactive components using cell and animal models of AD. Secondly, MALDI MSI (matrix-assisted laser desorption/ionization mass spectrometry imaging) state of the art technology will be applied to visualize the tissue-specific distribution of RP components and/or their metabolites, as well as the spatial distribution of potential biomarkers associated with AD. MSI data will be analyzed by statistical analysis for the selection of biomarkers showing the significant change in AD mouse models treated with RP. Finally, the chemical and spatial information obtained in this work will be used to correlate the tissue-specific distribution of bioactive components and regulation of brain metabolism for understanding the effects of RP in the treatment of AD. The research strategy proposed here will provide a new tool and new thought for unraveling the effective components in anti-Alzheimer’s herbal medicines.

远志是一味常用益智安神良药，现代药理学研究表明远志具有干预阿尔茨海默病（Alzheimer’s Disease, AD）的作用。AD的发病过程具有时空特异性，随病程发展逐渐由海马区等边缘系统累及至新皮层。因此，明确远志药效成分和AD生物标记物的组织空间分布及含量变化，将为阐明远志干预AD的药效物质基础及其作用机制提供重要的科学依据。本项目将从远志干预AD的活性成分筛选及药效评价着手；在此基础上，运用基质辅助激光解吸电离质谱成像技术（MALDI MSI）识别和定位远志有效成分、远志体内代谢/转化产物和AD生物标记物在模型小鼠脑组织中的分布，并采用多元统计方法遴选出给予远志后发生显著变化的生物标记物，探索性的从药效成分“组织特异性分布—脑代谢调控”的角度研究远志益智安神的药效物质基础和作用机制。该项目的成功实施，将为快速发现抗AD中药的药效物质并可视化研究其组织分布提供新的技术手段和思路。

远志（Polygalae Radix）具有安神益智、交通心肾等功效，主要成分是皂苷类、糖酯类、Xanthone类等物质。本项目针对远志如何调控阿尔茨海默病（Alzheimer’s Disease，AD）模型小鼠脑功能区特异性代谢紊乱的科学问题，尝试从中枢-外周代谢紊乱调控的角度阐释远志改善AD的作用模式。项目完成了远志活性部位制备、化学成分表征及其药效学评价。在此基础上，建立了基质辅助激光解吸电离质谱成像新方法，原位分析AD模型小鼠不同脑功能区的代谢紊乱特征，以及远志调控AD小鼠脑代谢紊乱的作用模式。同时，采用液质联用技术表征远志干预前后AD小鼠血清、尿液、粪便的代谢物轮廓及特征代谢物的筛选。最后，通过整合分析脑功能区与血清、尿液、粪便中代谢物变化的相关性，全面探究远志对AD代谢紊乱的纠偏作用。研究结果表明，远志可通过纠偏AD小鼠中枢与外周的甘油磷脂代谢、牛磺酸和亚牛磺酸代谢、花生四烯酸代谢和亚油酸代谢等通路的紊乱，回调中枢与外周的牛磺酸、花生四烯酸和甘油磷脂类等水平异常的差异代谢物，多途径整体改善AD小鼠学习和记忆障碍的治疗作用。