TY - JOUR
T1 - Inhibition of integrin αvβ3 ameliorates focal cerebral ischemic damage in the rat middle cerebral artery occlusion model
AU - Shimamura, Norihito
AU - Matchett, Gerald
AU - Yatsushige, Hiroshi
AU - Calvert, John W.
AU - Ohkuma, Hiroki
AU - Zhang, John
PY - 2006/7
Y1 - 2006/7
N2 - 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 αvβ3 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 αvβ3, 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 αvβ3 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.
AB - 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 αvβ3 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 αvβ3, 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 αvβ3 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.
KW - Cerebral ischemia
KW - Fibrinogen
KW - Integrin αvβ3
KW - VEGF
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U2 - 10.1161/01.STR.0000226991.27540.f2
DO - 10.1161/01.STR.0000226991.27540.f2
M3 - Article
C2 - 16741177
AN - SCOPUS:33745934127
SN - 0039-2499
VL - 37
SP - 1902
EP - 1909
JO - Stroke
JF - Stroke
IS - 7
ER -