Exendin-4 Preserves Blood-Brain Barrier Integrity via Glucagon-Like Peptide 1 Receptor/Activated Protein Kinase-Dependent Nuclear Factor-Kappa B/Matrix Metalloproteinase-9 Inhibition After Subarachnoid Hemorrhage in Rat.
Exendin-4 Preserves Blood-Brain Barrier Integrity via Glucagon-Like Peptide 1 Receptor/Activated Protein Kinase-Dependent Nuclear Factor-Kappa B/Matrix Metalloproteinase-9 Inhibition After Subarachnoid Hemorrhage in Rat.
复制标题
大鼠蛛网膜下腔出血后，Exendin-4 通过胰高血糖素样肽 1 受体/活化蛋白激酶依赖性核因子-Kappa B/基质金属蛋白酶-9 抑制保持血脑屏障完整性。
DOI：
10.3389/fnmol.2021.750726
复制
发表时间：
2021
影响因子：
4.8
通讯作者：
Zhang JH
中科院分区：
文献类型：
--
作者：
Xie Z;Enkhjargal B;Nathanael M;Wu L;Zhu Q;Zhang T;Tang J;Zhang JH
在这项研究中，我们研究了Exendin-4（Ex-4），一种胰高血糖素样肽1受体（GLP-1 R）激动剂，在大鼠蛛网膜下腔出血（SAH）后血脑屏障（BBB）破坏中的作用。在Sprague-Dawley大鼠中进行SAH的血管内穿孔模型。在SAH诱导后1小时腹膜内注射Ex-4。为了阐明潜在的分子机制，GLP-1 R的小干扰核糖核酸（siRNA）和Dorsomorphin，一种特异性的腺苷一磷酸激活的蛋白激酶（AMPK）的抑制剂，分别在诱导SAH前48 h脑室内注射。免疫荧光结果支持SAH后脑微血管内皮细胞表达GLP-1 R。给予Ex-4显著降低了两个半球的脑含水量和Evans蓝外渗，从而改善了SAH后24 h的神经评分。在机制研究中，Ex-4处理显著增加GLP-1 R、p-AMPK、IκB-α、Occludin和Claudin-5的表达，而p-核因子-κ B（NF-κB）p65、基质金属蛋白酶-9（MMP-9）和白蛋白的表达显著降低。Ex-4的作用分别通过GLP-1 R siRNA或Dorsomorphin的干预逆转。结论：Ex-4可通过GLP-1 R/AMPK依赖的NF-κB/MMP-9抑制作用保护SAH后BBB的完整性，可作为SAH的潜在治疗靶点进一步研究。
In this study, we investigated the role of Exendin-4 (Ex-4), a glucagon-like peptide 1 receptor (GLP-1R) agonist, in blood-brain barrier (BBB) disruption after subarachnoid hemorrhage (SAH) in rats. The endovascular perforation model of SAH was performed in Sprague-Dawley rats. Ex-4 was intraperitoneally injected 1 h after SAH induction. To elucidate the underlying molecular mechanism, small interfering ribonucleic acid (siRNA) for GLP-1R and Dorsomorphin, a specific inhibitor of adenosine monophosphate-activated protein kinase (AMPK), were intracerebroventricularly injected 48 h before induction of SAH correspondingly. Immunofluorescence results supported GLP-1R expressed on the endothelial cells of microvessels in the brain after SAH. Administration of Ex-4 significantly reduced brain water content and Evans blue extravasation in both hemispheres, which improved neurological scores at 24 h after SAH. In the mechanism study, Ex-4 treatment significantly increased the expression of GLP-1R, p-AMPK, IκB-α, Occludin, and Claudin-5, while the expression of p-nuclear factor-kappa B (NF-κB) p65, matrix metalloproteinase-9 (MMP-9), and albumin was significantly decreased. The effects of Ex-4 were reversed by the intervention of GLP-1R siRNA or Dorsomorphin, respectively. In conclusion, Ex-4 could preserve the BBB integrity through GLP-1R/AMPK-dependent NF-κB/MMP-9 inhibition after SAH, which should be further investigated as a potential therapeutic target in SAH.
登录
查看更多内容
胰高血糖素样肽-1（GLP-1）类似物liraglutide通过钙和AMPK依赖机制抑制内皮细胞炎症。
影响因子：
3.7
作者：
Krasner NM;Ido Y;Ruderman NB;Cacicedo JM
通讯作者：
Cacicedo JM
二甲双胍联合利拉鲁肽通过GLP-1受体和PKA信号通路对抗内皮功能障碍的协同作用
影响因子：
4.6
作者：
Ke J;Liu Y;Yang J;Lu R;Tian Q;Hou W;Wang G;Wei R;Hong T
通讯作者：
Hong T
影响因子：
8.3
作者：
GARCIA, JH;WAGNER, S;HU, XJ
通讯作者：
HU, XJ
影响因子：
82.9
作者：
Kawasaki, Yasuhiko;Xu, Zhen-Zhong;Ji, Ru-Rong
通讯作者：
Ji, Ru-Rong
影响因子：
10.8
作者：
Bond, M;Chase, AJ;Newby, AC
通讯作者：
Newby, AC