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1,2,4-三唑衍生物通过抑制炎症和保护急性缺血性脑卒中血脑屏障完整性的神经保护作用。

The Neuroprotection of 1,2,4-Triazole Derivative by Inhibiting Inflammation and Protecting BBB Integrity in Acute Ischemic Stroke.

机构信息

Department of Medicinal Chemistry, School of Pharmaceutical Science, Sun Yat-Sen University, Guangzhou, China.

出版信息

CNS Neurosci Ther. 2024 Nov;30(11):e70113. doi: 10.1111/cns.70113.

DOI:10.1111/cns.70113
PMID:39500736
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11537802/
Abstract

BACKGROUND

The oxidative stress and neuroinflammation are important factors in acute ischemic stroke (AIS). Our former study showed the 1,2,4- triazole derivative (SYS18) had obviously neuroprotection by anti- oxidative stress on rat middle cerebral artery occlusion (MCAO) model.

AIM

In this study, we continue to investigate its neuroprotection by anti-inflammatory effects and protecting BBB integrity in AIS.

METHODS AND RESULTS

First, its effect on acute inflammation was evaluated by the mice model of increased peritoneal capillary permeability. Then, the MCAO cerebral edema models were built to evaluate its neuroprotection by reducing the neurological score, cerebral edema, improving the biochemical indicators, and pathological damage of brain tissue. At the same time, its protection on blood-brain barrier (BBB) integrity was proved by decreasing the BBB permeability and inhibiting glycocalyx degradation and regulating the BBB tight junction proteins expression of matrix metalloproteinase- 9 (MMP- 9) and claudin- 5 in brain tissue. Meanwhile, pharmacokinetic experiments showed that the compound had good BBB penetration. It has some advantages in the intensity of efficacy compared with the marketed drug edaravone.

CONCLUSION

Based on these findings, SYS18 has a strong potential to become a neuroprotectant in the future.

摘要

背景

氧化应激和神经炎症是急性缺血性脑卒中（AIS）的重要因素。我们之前的研究表明，1,2,4-三唑衍生物（SYS18）通过对大鼠大脑中动脉闭塞（MCAO）模型的抗氧化应激作用具有明显的神经保护作用。

目的

本研究继续通过抗炎作用和保护血脑屏障（BBB）完整性来研究其在 AIS 中的神经保护作用。

方法和结果

首先，通过增加腹膜毛细血管通透性的小鼠模型评估其对急性炎症的影响。然后，建立 MCAO 脑水肿模型，通过降低神经功能评分、脑水肿、改善生化指标以及脑组织病理损伤来评估其神经保护作用。同时，通过降低 BBB 通透性、抑制糖萼降解以及调节基质金属蛋白酶-9（MMP-9）和脑组织中紧密连接蛋白 Claudin-5 的表达来证明其对 BBB 完整性的保护作用。同时，药代动力学实验表明，该化合物具有良好的 BBB 穿透性。与市售药物依达拉奉相比，该化合物在疗效强度上具有一定优势。

结论

基于这些发现，SYS18 具有成为未来神经保护剂的强大潜力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a75/11537802/431a9e024b36/CNS-30-e70113-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a75/11537802/9d36ef55b010/CNS-30-e70113-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a75/11537802/688f66eabb50/CNS-30-e70113-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5a75/11537802/431a9e024b36/CNS-30-e70113-g005.jpg

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