Inhibition of integrin alphavbeta3 ameliorates focal cerebral ischemic damage in the rat middle cerebral artery occlusion model.

Abstract

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 alphavbeta3 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 alphavbeta3, 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 alphavbeta3 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.

• Authors: Norihito Shimamura, Gerald Matchett, Hiroshi Yatsushige, John W Calvert, Hiroki Ohkuma, John Zhang
• Journal: Stroke (Stroke) Vol. 37 Issue 7 Pg. 1902-9 (Jul 2006) ISSN: 1524-4628 [Electronic] United States
• PMID: 16741177 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Integrin alphaVbeta3
• Nerve Tissue Proteins
• Neuroprotective Agents
• Peptides, Cyclic
• Vascular Endothelial Growth Factor A
• cyclo(arginyl-glycyl-aspartyl-phenylalanyl-valyl)
• vascular endothelial growth factor A, rat
• Evans Blue
• Fibrinogen
• Vascular Endothelial Growth Factor Receptor-2
• Focal Adhesion Kinase 1
• Ptk2 protein, rat

Topics

• Animals
• Blood-Brain Barrier (drug effects)
• Brain Edema (etiology, pathology, prevention & control)
• Cerebral Infarction (etiology, pathology, prevention & control)
• Drug Evaluation, Preclinical
• Evans Blue (pharmacokinetics)
• Extravasation of Diagnostic and Therapeutic Materials (prevention & control)
• Fibrinogen (analysis)
• Focal Adhesion Kinase 1 (metabolism)
• Infarction, Middle Cerebral Artery (complications, drug therapy, pathology, physiopathology)
• Integrin alphaVbeta3 (antagonists & inhibitors)
• Male
• Models, Animal
• Nerve Tissue Proteins (antagonists & inhibitors)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Peptides, Cyclic (pharmacology, therapeutic use)
• Phosphorylation
• Protein Processing, Post-Translational (drug effects)
• Random Allocation
• Rats
• Rats, Sprague-Dawley
• Vascular Endothelial Growth Factor A (metabolism)
• Vascular Endothelial Growth Factor Receptor-2 (metabolism)