Inhibition of α4 Integrin Protects Against Transient Focal Cerebral Ischemia in Normotensive and Hypertensive Rats

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Abstract
Background and Purpose—The present study was performed to determine the role of α4 (CD49d), a member of the integrin family of adhesion molecules, in ischemic brain pathology. Methods—Male spontaneously hypertensive rats (SHR) or Sprague-Dawley rats underwent 60-minute middle cerebral artery occlusion (MCAO) followed by 23-hour reperfusion. Animals were injected intravenously with 2.5 mg/kg anti-rat α4 antibody (TA-2) or isotype control antibody (anti-human LFA-3 IgG1, 1E6) 24 hours before MCAO. Infarct volume was quantified by staining of fresh tissue with tetrazolium chloride and myeloperoxidase activity measured in SHR tissue homogenates 24 hours after MCAO. In SHR, mean arterial blood pressure was recorded before and after MCAO in animals treated with TA-2 and 1E6. Fluorescence-activated cell sorting analysis was performed on peripheral blood leukocytes before and after MCAO. Results—TA-2 treatment significantly reduced total infarct volume by 57.7% in normotensive rats (1E6, 84.2±11.5 mm3, n=17; TA-2, 35.7±5.9 mm3, n=16) and 35.5% in hypertensive rats (1E6, 146.6±15.5 mm3, n=15; TA-2, 94.4±25.8 mm3, n=11). In both strains, TA-2 treatment significantly reduced body weight loss and attenuated the hyperthermic response to MCAO. In SHR, treatment with TA-2 significantly reduced brain myeloperoxidase activity. Resting mean arterial blood pressure was unaffected by treatment. Leukocyte counts were elevated in TA-2–treated rats. Fluorescence-activated cell sorting analysis demonstrated the ability of TA-2 to bind to CD3+, CD4+, CD8+, and CD11b+ cells in both naive animals and after MCAO. Conclusions—These data demonstrate that inhibition of α4 integrin can protect the brain against ischemic brain injury and implicate endogenous α4 integrin in the pathogenesis of acute brain injury. The mechanism by which α4 integrin inhibition offers cerebroprotection is independent of blood pressure modulation and is likely due to inhibition of leukocyte function.