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on June 1, 2006

Stroke. 2006
Published online before print June 1, 2006, doi: 10.1161/01.STR.0000226991.27540.f2
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Submitted on March 11, 2006
Accepted on April 11, 2006

Inhibition of Integrin {alpha}v{beta}3 Ameliorates Focal Cerebral Ischemic Damage in the Rat Middle Cerebral Artery Occlusion Model

Norihito Shimamura MD; Gerald Matchett MD; Hiroshi Yatsushige MD; John W. Calvert PhD; Hiroki Ohkuma MD; and John Zhang MD, PhD*

From the Department of Physiology & Pharmacology (N.S., H.Y., J.W.C., J.Z.), and the Departments of Neurosurgery and Anesthesiology (G.M., J.Z.), Loma Linda University School of Medicine, Loma Linda, Calif; and the Neurosurgery Hirosaki University (N.S., H.O.), Hirosaki, Japan.

* To whom correspondence should be addressed. E-mail: johnzhang3910{at}yahoo.com.

Background and Purpose--Recent studies have shown that selective inhibition of specific subsets of intercellular adhesion molecules protects the brain during ischemia. We studied selective inhibition of integrin {alpha}v{beta}3 with cyclo [Arg-Gly-Asp-D-Phe-Val] (cRGDfV) in the rat middle cerebral artery occlusion model (MCAO).

Methods--Rats were treated before and after MCAO with cRGDfV. Physiological parameters, expression of integrin {alpha}v{beta}3, infarction volume, brain water content, Evans Blue exudation, IgG exudation, histology, immunohistochemistry, and western blotting were studied in 4 groups of animals: sham operation (n=13), untreated (n=18), nonfunctioning peptide treatment (n=19), and cRGDfV treatment (n=27).

Results--Treatment with cRGDfV reduced infarction, reduced brain edema, reduced exudation of Evans blue and IgG, and prevented fibrinogen deposition. Western blotting showed reduction of phosphorylated Flk-1 (a vascular endothelial growth factor [VEGF] receptor), reduction of phosphorylated FAK (an intracellular kinase phosphorylated in the presence of VEGF), reduction of VEGF, and reduction of fibrinogen in the cRGDfV treatment group.

Conclusions--The selective integrin {alpha}v{beta}3 inhibitor cRGDfV improves outcomes in the MCAO model by preserving the blood-brain barrier, which mechanistically may occur in a VEGF- and VEGF-receptor-dependent manner.


Key words: cerebral ischemia • fibrinogen • integrin {alpha}v{beta}3 • VEGF




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