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Inhibition of α 5 β 1 integrin with the clinically validated small peptide, ATN‐161 stabilizes cerebral vasculature, reduces inflammation, and decreases blood‐brain barrier permeability after experimental ischemic stroke
Author(s) -
Edwards Danielle,
Salmeron Katie,
Lukins Douglas,
Trout Amanda,
Fraser Justin,
Bix Gregory
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.680.4
Subject(s) - blood–brain barrier , medicine , stroke (engine) , ischemia , tight junction , edema , evans blue , inflammation , reperfusion injury , endothelium , pathology , cardiology , anesthesia , chemistry , central nervous system , mechanical engineering , engineering , biochemistry
Stroke is the second leading cause of death and the leading cause of long‐term disability worldwide. Blood‐brain barrier (BBB) dysfunction exacerbates reperfusion‐induced injury after recanalization in ischemic stroke. Endothelial cell integrin receptors, specifically the β 1 subtype, play a direct role in this BBB dysfunction through regulation of barrier‐forming tight junction (TJ) proteins. We hypothesize that inhibition of a specific β 1 integrin subtype, α 5 β 1 , will stabilize the BBB, and thereby reduce infarct volumes and improve functional recovery after experimental stroke. Method Male C57BLJ6 mice underwent transient middle cerebral artery occlusion for 1 hour. Upon reperfusion, vehicle or the clinically validated α 5 β 1 inhibitor, ATN‐161 (1mg/kg), was injected intraperitoneally and repeated 24 and 48 hours later. Infarct volume (TTC and MRI – DTI sequence) and edema volume (T2‐weighted MRI) was determined on PSD3. Functional recovery was determined by an 11‐point Neuroscore on PSD1‐PSD7. Physiological measurements, including pulse distention, heart rate and body temperature, were obtained before, during and after the initial dose of ATN‐161. Immunohistochemical analysis of α 5 β 1 , claudin‐5, CD45 (pan‐leukocyte), and IgG, expression was performed on PSD3. qPCR analysis on claudin‐5, collagen IV, MMP‐9, IL‐1β, and CXCL12 were performed on PSD3. Results ATN‐161 administration reduced infarct volume, edema volume, and functional deficit. ATN‐161 also resulted in cerebral vascular stabilization by a decrease in MMP‐9 and increases in claudin‐5, and collagen IV. Furthermore, IL‐1β and CD45 was reducedupon ATN‐161 administration, suggesting a decrease in the post‐stroke inflammatory response. Together, the cerebrovascular stabilization and decrease in inflammation resulted in less IgG extraversion, suggesting a more intact BBB. Collectively, administration of ATN‐161 post‐stroke produced significant benefits, and thus could represent a novel stroke therapy worthy of further investigation. Support or Funding Information This work was supported by NIH R01NS065842. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .