1. Academic Validation
  2. 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

  • J Neuroinflammation. 2019 Nov 28;16(1):242. doi: 10.1186/s12974-019-1638-6.
Yilong Shan 1 Sha Tan 2 Yinyao Lin 2 Siyuan Liao 2 Bingjun Zhang 2 Xiaodong Chen 2 Jihui Wang 3 Zhezhi Deng 3 Qin Zeng 2 Lei Zhang 4 Yuge Wang 2 Xueqiang Hu 2 Wei Qiu 2 Lisheng Peng 2 Zhengqi Lu 5
Affiliations

Affiliations

  • 1 Department of Rehabilitation Medicine, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou City, China.
  • 2 Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou City, China.
  • 3 Department of Psychiatry, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou City, China.
  • 4 Department of Neurology, The Fifth Affiliated Hospital of Sun Yat-sen University, No. 52 Meihuadong Road, Zhuhai City, China.
  • 5 Department of Neurology, The Third Affiliated Hospital of Sun Yat-sen University, No. 600 Tianhe Road, Guangzhou City, China. lzq1828@163.com.
Abstract

Background: Preserving 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.

Methods: In 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.

Results: Ex-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.

Conclusion: Based on these findings, ischemia-induced inflammation and BBB breakdown can be improved by Ex-4 through an astrocyte-dependent manner.

Keywords

Astrocyte; Blood-brain barrier; Exendin-4; Ischemic stroke; Oxygen-glucose deprivation.

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