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(Stroke. 2006;37:1902.)
© 2006 American Heart Association, Inc.

Original Contributions

Inhibition of Integrin vß3 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 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.

Correspondence to John H. Zhang, MD, PhD, Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Risley Hall, Loma Linda, CA 92350. 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 vß3 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 vß3, 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 vß3 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 vß3 • VEGF

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