Inhibition of integrin alphavbeta3 reduces blood-brain barrier breakdown in focal ischemia in rats.
Ischemic stroke is a major cause of morbidity and mortality in industrialized nations. We tested the effect of postischemic treatment of cyclo-RGDfV (cRGDfV), a selective inhibitor of integrin alphavbeta3, in the middle cerebral artery occlusion (MCAO) model of ischemic stroke in rats. Rats were randomly divided into three groups: sham operation (n = 13), MCAO with no treatment (n = 18), and MCAO with cRGDfV treatment (n = 28). Focal ischemia was induced with the suture occlusion method for 2 hr, and treatment was given 1 hr after reperfusion (3 hr after ischemia). All animals were sacrificed 24 hr after reperfusion. Assessment included neurological scores, infarction volumes, brain water content, Evans blue exudation, IgG exudation, histology, immunohistochemistry, and Western blotting. Treatment with cRGDfV ameliorated neurological deficits, reduced brain edema, and reduced exudation of Evans blue dye and IgG, but failed to reduce infarction volumes. Western blotting showed a reduction in phosphorylation of one subset of vascular endothelial growth factor (VEGF) receptors in the cRGDfV treatment group. Western blotting also demonstrated a significant reduction of fibrinogen in the cRGDfV treatment group. We conclude that poststroke treatment with cRGDfV reduces blood-brain barrier breakdown in focal ischemia, possibly through inhibition of VEGF-mediated vascular breakdown.
Shimamura
Norihito
N
Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Matchett
Gerald
G
Solaroglu
Ihsan
I
Tsubokawa
Tamiji
T
Ohkuma
Hiroki
H
Zhang
John
J
D000704:Analysis of Variance; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000503:physiopathology*; D015153:Blotting, Western / Q000379:methods; D001929:Brain Edema / Q000188:drug therapy; D004195:Disease Models, Animal; D005070:Evans Blue; D005340:Fibrinogen / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D007377:Interleukin-3 / Q000378:metabolism; D008297:Male; D009460:Neurologic Examination / Q000379:methods; D010456:Peptides, Cyclic / Q000627:therapeutic use; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D011994:Recombinant Proteins; D060149:Tetraspanin 30; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D005070:Evans Blue; D005340:Fibrinogen; D016179:Granulocyte Colony-Stimulating Factor; D039302:Integrin alphaVbeta3; D007377:Interleukin-3; D010456:Peptides, Cyclic; D010980:Platelet Membrane Glycoproteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D060149:Tetraspanin 30; D042461:Vascular Endothelial Growth Factor A; C554586:CD63 protein, human; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C404145:myelopoietin