期刊
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM
卷 40, 期 8, 页码 1695-1708出版社
SAGE PUBLICATIONS INC
DOI: 10.1177/0271678X19880161
关键词
Blood-brain barrier permeability; inflammation; integrin alpha 5 beta 1; stroke; tight junctions
资金
- NIH [R01NS065842, TL1TR001997]
Stroke remains a leading cause of death and disability with limited therapeutic options. Endothelial cell beta(1) integrin receptors play a direct role in blood-brain barrier (BBB) dysfunction through regulation of tight junction proteins and infiltrating leukocytes, potentially mediated by beta 1 integrins. Following tandem transient common carotid artery/middle cerebral artery occlusion on wild-type mice, we administered the integrin a5b1 inhibitor, ATN-161, intraperitoneal (IP) injection at 1 mg/kg acutely after reperfusion, on post-stroke day (PSD)1 and PSD2. Systemic changes (heart rate, pulse distension, and body temperature) were determined. Additionally, infarct volume and edema were determined by 2,3-triphenyltetrazolium chloride and magnetic resonance imaging, while neurological changes were evaluated using an 11-point Neuroscore. Brain immunohistochemistry was performed for claudin-5, alpha 5 beta 1, IgG, and CD45 + cells, and quantitative polymerase chain reaction (qPCR) was performed for matrix metalloproteinase-9 (MMP-9), interleukin (IL)-1 beta, collagen IV, and CXCL12. ATN-161 significantly reduced integrin alpha 5 beta 1 expression in the surrounding peri-infarct region with no systemic changes. Infarct volume, edema, and functional deficit were significantly reduced in ATN-161-treated mice. Furthermore, ATN-161 treatment reduced IgG extravasation into the parenchyma through conserved claudin-5, collagen IV, CXCL12 while reducing MMP-9 transcription. Additionally, IL-1 beta and CD45 + cells were reduced in the ipsilateral cortex following ATN-161 administration. Collectively, ATN-161 may be a promising novel stroke therapy by reducing post-stroke inflammation and BBB permeability.
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