Targeting Caveolin-1 and Claudin-5 with AY9944, Improve Blood–Brain Barrier Permeability; Computational Simulation and Experimental Study,Cellular and Molecular Neurobiology

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Targeting Caveolin-1 and Claudin-5 with AY9944, Improve Blood–Brain Barrier Permeability; Computational Simulation and Experimental Study
Cellular and Molecular Neurobiology ( IF 3.6 ) Pub Date : 2020-11-21 , DOI: 10.1007/s10571-020-01004-z
Leila Gholami _{1,

2} , Safura Jokar ₃ , Yousef Fatahi _{4,

5,

6} , Hedayat Samandari ₁ , Javad Hamzehalipour Almaki _{5,

7} , Marjan Hosseini ₁ , Mohsen Parviz _{1,

2}

Affiliation

Abstract

The current study aimed to determine the protective effect of AY9944 related to Caveolin-1 and Claudin-5 role in lipid raft, which can rescue the blood–brain barrier from enhanced permeability. Therefore, in vivo analyses were performed following ischemia in normal, ischemic, and AY9944-treated animal groups. The results revealed that AY9944 reduced the infarct size, edema, and brain water content. The extravasation of Alb-Alexa 594 and biocytin-TMR was minimum in the AY9944-treated animals. The results showed a significant decrease in the expression level of Caveolin-1 over 8 h and 48 h and a remarkable increase in the level of Claudin-5 over 48 h following ischemia in AY9944-treated animals. Molecular docking simulation demonstrated that AY9944 exerts a possible protective role via attenuating the interaction of the Caveolin-1 and cholesterol in lipid raft. These findings point out that AY9944 plays a protective role in stroke by means of blood–brain barrier preservation.

Graphic Abstract

Proper neural function essentially needs a constant homeostatic brain environment which is provided by the blood-brain barrier. Rescuing blood-brain barrier from enhanced permeability via inducing the protective effect of AY9944 related to caveolin-1 and claudin-5 role in lipid raft was the aim of the current study.

中文翻译：

AY9944靶向Caveolin-1和Claudin-5，提高血脑屏障通透性；计算模拟与实验研究

摘要

目前的研究旨在确定 AY9944 与 Caveolin-1 和 Claudin-5 在脂筏中的作用相关的保护作用，这可以挽救血脑屏障的渗透性增强。因此，在正常、缺血和 AY9944 治疗的动物组缺血后进行体内分析。结果显示，AY9944 减少了梗死面积、水肿和脑含水量。在 AY9944 处理的动物中，Alb-Alexa 594 和 biocytin-TMR 的外渗最少。结果显示，在 AY9944 处理的动物缺血后，Caveolin-1 的表达水平在 8 小时和 48 小时内显着降低，而 Claudin-5 的水平在 48 小时内显着增加。分子对接模拟表明AY9944通过减弱Caveolin-1和脂筏中胆固醇的相互作用发挥了可能的保护作用。这些发现指出，AY9944 通过保存血脑屏障在中风中发挥保护作用。