Jk. Relton et al., Inhibition of alpha 4 integrin protects against transient focal cerebral ischemia in normotensive and hypertensive rats, STROKE, 32(1), 2001, pp. 199-205
Background and Purpose-The present study was performed to determine the rol
e of alpha4 (CD49d), a member of the integrin family of adhesion molecules,
in ischemic brain pathology.
Methods-Male spontaneously hypertensive rats (SHR) or Sprague-Dawley rats u
nderwent 60-minute middle cerebral artery occlusion (MCAO) followed by 23-h
our reperfusion. Animals were injected intravenously with 2.5 mg/kg anti-ra
t alpha4 antibody (TA-2) or isotype control antibody (anti-human LFA-3 IgG(
1), 1E6) 24 hours before MCAO. Infarct volume was quantified by staining of
fresh tissue with tetrazolium chloride and myeloperoxidase activity measur
ed in SHR tissue homogenates 24 hours after MCAO. In SHR, mean arterial blo
od pressure was recorded before and after MCAO in animals treated with TA-2
and 1E6. Fluorescence-activated cell sorting analysis was performed on per
ipheral 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 mm(3), n=17; TA-2, 35.7+/-5.9 mm(3),
n=16) and 35.5% in hypertensive rats (1E6, 146.6+/-15.5 mm(3), n=15; TA-2,
94.4+/-25.8 mm(3), n=11). In both strains, TA-2 treatment significantly re
duced body weight loss and attenuated the hyperthermic response to MCAO. In
SHR, treatment with TA-2 significantly reduced brain myeloperoxidase activ
ity. Resting mean arterial blood pressure was unaffected by treatment. Leuk
ocyte counts were elevated in TA-2-treated rats. Fluorescence-activated cel
l 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 alpha4 integrin can p
rotect the brain against ischemic brain injury and implicate endogenous alp
ha4 integrin in the pathogenesis of acute brain injury. The mechanism by wh
ich a4 integrin inhibition offers cerebroprotection is independent of blood
pressure modulation and is likely due to inhibition of leukocyte function.