高海拔缺氧条件下血脑屏障通透性受紧密连接蛋白表达变化的影响--这可能对脑药物转运产生影响

IF 5 3区 医学 Q1 PHARMACOLOGY & PHARMACY
Guiqin Liu, Qian Wang, Lu Tian, Mengyue Wang, Delong Duo, Yabin Duan, Yue Lin, Junjun Han, Qiangqiang Jia, Junbo Zhu, Xiangyang Li
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引用次数: 0

摘要

血脑屏障结构和功能的变化可能会影响药物向大脑的输送。在高海拔缺氧环境下,血脑屏障的结构和功能如何发生变化,以及这种变化如何影响药物的运输,值得进一步研究。DIA高通量测序技术表明,大鼠血脑屏障共鉴定出7252个蛋白,8个紧密连接蛋白,其中Claudin-7是高海拔缺氧环境下的高原特异性紧密连接蛋白,根据相互作用网络研究,发现2421个蛋白之间存在相互作用,ZO-1是主要的作用靶点。预测基因功能分析的结果表明,紧连结蛋白的变化与炎症介质对TRP通道的控制、wnt信号通路、ABC转运系统以及药物代谢-CYP450酶调控有关。此外,电子显微镜、伊文思蓝联合激光共聚焦扫描显微镜、Western Blot和RT-qPCR等研究发现,高海拔缺氧环境诱导血脑屏障紧密连接开放,血脑屏障通透性增加,ZO-1、Occludin、Claudin-5蛋白和mRNA表达减少。我们的研究表明,高海拔缺氧诱导的血脑屏障结构和功能改变可能会影响药物在中枢神经系统内的转运,而药物转运体和药物代谢酶可能是这一过程中的关键角色。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Blood-Brain Barrier Permeability is Affected by Changes in Tight Junction Protein Expression at High-Altitude Hypoxic Conditions-this may have Implications for Brain Drug Transport.

Blood-Brain Barrier Permeability is Affected by Changes in Tight Junction Protein Expression at High-Altitude Hypoxic Conditions-this may have Implications for Brain Drug Transport.

Changes to blood-brain barrier structure and function may affect the delivery of drugs into the brain. It is worthwhile to exploring more study on how the blood-brain barrier changes in structure and function and how that affects drug transport in high-altitude hypoxic environment. The DIA high-throughput sequencing technique indicate that the rats blood-brain barrier has been identified to have 7252 proteins overall and 8 tight junction proteins, among which Claudin-7 was a plateau-specific tight junction protein under high-altitude hypoxia, and based on the interaction network study, 2421 proteins are found to interact with one another, with ZO-1 being the primary target. The results of the projected gene function analysis demonstrated that changes in tight junction proteins are related to the control of TRP channels by inflammatory mediators, the wnt signaling pathway, the ABC transporter system, and drug metabolism-CYP450 enzyme regulation. Additionally, the electron microscopy, the Evans blue combination with confocal laser scanning microscopy, and the Western Blot and RT-qPCR revealed that high-altitude hypoxic environment induces blood-brain barrier tight junctions to open, blood-brain barrier permeability increases, ZO-1, Occludin, Claudin-5 protein and mRNA expression decreased. Our research implies that structural and functional alterations in the blood-brain barrier induced by high altitude hypoxia may impact drug transport inside the central nervous system, and that drug transporters and drug-metabolizing enzymes may be key players in this process.

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来源期刊
AAPS Journal
AAPS Journal 医学-药学
CiteScore
7.80
自引率
4.40%
发文量
109
审稿时长
1 months
期刊介绍: The AAPS Journal, an official journal of the American Association of Pharmaceutical Scientists (AAPS), publishes novel and significant findings in the various areas of pharmaceutical sciences impacting human and veterinary therapeutics, including: · Drug Design and Discovery · Pharmaceutical Biotechnology · Biopharmaceutics, Formulation, and Drug Delivery · Metabolism and Transport · Pharmacokinetics, Pharmacodynamics, and Pharmacometrics · Translational Research · Clinical Evaluations and Therapeutic Outcomes · Regulatory Science We invite submissions under the following article types: · Original Research Articles · Reviews and Mini-reviews · White Papers, Commentaries, and Editorials · Meeting Reports · Brief/Technical Reports and Rapid Communications · Regulatory Notes · Tutorials · Protocols in the Pharmaceutical Sciences In addition, The AAPS Journal publishes themes, organized by guest editors, which are focused on particular areas of current interest to our field.
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