Published Online
on June 1, 2006

A more recent version of this article appeared on July 1, 2006

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Submitted on March 11, 2006
Accepted on April 11, 2006

Inhibition of Integrin v3 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 v3 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 v3, 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 v3 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 v3 • VEGF

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