The glucagon-like peptide-1 receptor agonist reduces inflammation and blood-brain barrier breakdown in an astrocyte-dependent manner in experimental stroke
The glucagon-like peptide-1 receptor agonist reduces inflammation and blood-brain barrier breakdown in an astrocyte-dependent manner in experimental stroke
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胰高血糖素样肽 1 受体激动剂以星形胶质细胞依赖性方式减少实验性中风中的炎症和血脑屏障破坏
DOI：
10.1186/s12974-019-1638-6
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发表时间：
2019-11-28
影响因子：
9.3
通讯作者：
Lu, Zhengqi
中科院分区：
文献类型：
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作者：
Shan, Yilong;Tan, Sha;Lu, Zhengqi
研究背景保护血脑屏障（BBB）的完整性有利于避免急性缺血性脑卒中（AIS）后进一步的脑损伤。星形胶质细胞是血脑屏障的重要组成部分，通过分泌炎性因子促进AIS受试者的血脑屏障破坏。胰高血糖素样肽-1受体（GLP-1 R）激动剂毒蜥外泌肽-4（Ex-4）可保护BBB并减少脑缺血引起的脑炎症，GLP-1 R在星形胶质细胞上表达。然而，Ex-4对星形胶质细胞的影响在受试者与AIS.MethodsIn本研究中，我们调查了Ex-4对星形胶质细胞培养下的氧-葡萄糖剥夺（OGD）加复氧条件的影响，并确定是否影响bEnd。3细胞。我们使用了各种方法，包括渗透性测定，蛋白质印迹，免疫荧光染色，明胶酶谱，在体外和vivo.ResultsEx-4减少OGD诱导的星形胶质细胞衍生的血管内皮生长因子（VEGF-A），基质金属蛋白酶-9（MMP-9），趋化因子单核细胞趋化蛋白-1（MCP-1），和趋化因子C-X-C基序配体1（CXCL-1）。星形胶质细胞源性VEGF-A和MMP-9的减少与bEnd.3细胞中紧密连接蛋白（TJPs）的表达增加有关。Ex-4改善了大脑中动脉闭塞大鼠缺血性脑组织中的神经功能缺损评分，减少了梗死面积，改善了BBB破坏，并降低了星形胶质细胞衍生的VEGF-A、MMP-9、CXCL-1和MCP-1水平。Ex-4降低了OGD后星形胶质细胞中JAK 2/STAT 3信号通路的激活。结论基于这些发现，Ex-4可以通过星形胶质细胞依赖的方式改善缺血诱导的炎症和BBB破坏。
BackgroundPreserving the integrity of the blood-brain barrier (BBB) is beneficial to avoid further brain damage after acute ischemic stroke (AIS). Astrocytes, an important component of the BBB, promote BBB breakdown in subjects with AIS by secreting inflammatory factors. The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) protects the BBB and reduces brain inflammation from cerebral ischemia, and GLP-1R is expressed on astrocytes. However, the effect of Ex-4 on astrocytes in subjects with AIS remains unclear.MethodsIn the present study, we investigated the effect of Ex-4 on astrocytes cultured under oxygen-glucose deprivation (OGD) plus reoxygenation conditions and determined whether the effect influences bEnd.3 cells. We used various methods, including permeability assays, western blotting, immunofluorescence staining, and gelatin zymography, in vitro and in vivo.ResultsEx-4 reduced OGD-induced astrocyte-derived vascular endothelial growth factor (VEGF-A), matrix metalloproteinase-9 (MMP-9), chemokine monocyte chemoattractant protein-1 (MCP-1), and chemokine C-X-C motif ligand 1 (CXCL-1). The reduction in astrocyte-derived VEGF-A and MMP-9 was related to the increased expression of tight junction proteins (TJPs) in bEnd.3 cells. Ex-4 improved neurologic deficit scores, reduced the infarct area, and ameliorated BBB breakdown as well as decreased astrocyte-derived VEGF-A, MMP-9, CXCL-1, and MCP-1 levels in ischemic brain tissues from rats subjected to middle cerebral artery occlusion. Ex-4 reduced the activation of the JAK2/STAT3 signaling pathway in astrocytes following OGD.ConclusionBased on these findings, ischemia-induced inflammation and BBB breakdown can be improved by Ex-4 through an astrocyte-dependent manner.