基于药物动力学及多靶标的新疆雪菊抗抑郁作用机制及药效物质基础研究

Coreopsis tinctoria Nutt. (C. tinctoria)，planted in Xinjiang and locally used for cardiovascular diseases, is an abundant plant resource, and it is necessary to search the new application of C. tinctoria. We found the extract of C. tinctoria (CCT) has antidepressant effect in pre-experiment, however, the mechanism, pharmacokinetics and pharmacodynamic material basis have not yet been elucidated. When confirm the active fraction of antidepressant effect (CCTE), inflammatory factor, 5-HT, HPA axis function, neurotrophic factors and oxidative stress injury, induced by CUMS, will be investigated to illuminate the antidepressant mechanism of CCTE with LC-MS/MS, Western-blot, ELISA, electron microscope and HE staining in this study. The inhibition of MAO-A and uptake1/2 transporters will be studied for the mechanism on the declining 5-HT in brain. The methods of gastrointestinal metabolism, pharmacokinetics, brain tissue distribution, component effect will be combined to investigated the antidepressant pharmacodynamic material basis of CCTE with the LC-MS/MS and pharmacological experiment. The result of this study will facilitate the development of C. tinctoria and the economy of Xinjiang medicine.

雪菊主产于新疆，民间用于防治心血管疾病，作为一种资源丰富的药食两用植物，仍需不断挖掘其新用途。项目组预实验发现雪菊提取物（CCT）具有抗抑郁作用，而其作用机制、体内过程及药效物质基础尚未阐明。本课题从整体、酶及细胞水平利用LC-MS/MS、Western-blot、ELISA、电镜和HE染色等技术，在明确CCT抗抑郁活性部位（CCTE）的基础上，着重考察CCTE对CUMS引起的炎症因子、5-HT、HPA轴功能、神经营养因子、氧化应激损伤等的调节作用及其对MAO-A及uptake1/2转运体的抑制，阐明其多靶标抗抑郁作用机制；结合前期已分离鉴定出的化学成分，本课题拟借助LC-MS/MS技术及药效实验，将“胃肠道代谢-药代动力学-脑组织分布-组分效应”等方法有机结合，阐明与CCTE抗抑郁作用相关的效应物质；本课题的完成，对基于新疆雪菊开发抗抑郁类药及保健食品、带动新疆地方经济均具有重要意义。

雪菊主产于新疆，民间用于防治心血管疾病，作为一种资源丰富的药食两用植物，仍需不断挖掘其新用途。本项目筛选出雪菊抗抑郁的有效部位，并进一步确定了其抗抑郁作用不仅与增加脑内5-HT等单胺类神经递质有关，还通过抑制应激状态下HPA轴功能的亢进、调节炎症因子和神经营养因子及抗氧化应激损伤发挥抗抑郁作用。大鼠灌胃雪菊抗抑郁有效部位，其中11个多酚能快速吸收，黄酮苷的平均血药浓度和体内暴露量明显低于黄酮苷元，其原因可能为黄酮苷可被胃肠道粘膜水解酶代谢为相应苷元。苷元被吸收后，在血浆中主要以二相结合物存在。有机阴离子转运蛋白OAT1可能介导了奥卡宁、异奥卡宁在脑部的跨膜转运。采用行为绝望模型实验证实奥卡宁、异奥卡宁是雪菊抗抑郁作用的效应物质。奥卡宁、异奥卡宁抑制单胺氧化酶及uptake2转运蛋白（hOCT2/3）介导的5-HT摄取可能是其抗抑郁作用的作用机制之一。本课题的完成，对基于新疆雪菊开发抗抑郁类药及保健食品、带动新疆地方经济均具有重要意义。