Abstract
To explore the effect of the integrin αvβ3 inhibitor Cilengitide on the blood brain barrier (BBB) permeability, brain edema, neuronal cell apoptosis and the relation with the vascular endothelial growth factor (VEGF)expression in acute cerebral ischemia rats. A rat focal cerebral ischemia/reperfusion model was established by middle cerebral artery occlusion. Rats with middle cerebral artery occlusion, in accordance with the random number table, were divided into four groups: (1) the rats in Cilengitide group A (n=30) were treated with Cilengitide at a dose of 100 μg/kg; (2) the rats in Cilengitide group B (n=28) were treated with Cilengitide at a dose of 200 μg/kg; (3) the rats in sham group (n=31), without inserting thread into middle cerebral artery, were treated with normal saline; (4) the rats in control group (n=27) were treated with normal saline.All rats were treated with Cilengitide or saline 1 hour after infarction, given reperfusion 2 hours after infarction and were sacrificed 22 hours after reperfusion.The brain-water content was measured by dry/wet weight method. The permeability of BBB was measured by quantifying Evans Blue. The infarction volume was measured by 2, 3, 5-tripheyl tetrazolium Chloride (TTC) staining. Expression level of VEGF, P-Flk, Cleaved-Caspase-3 was measured by immunohistochemistry and Western blot, respectively.The neuronal cell apoptosis was evaluated by terminal deoxynucleotidyl transferased UTP nick end labeling (TUNEL). Compared with Control group, treatment groups with cilengitide at the dose of 100 μg/kg and 200 μg/kg reduced brain-water content [(80.8±1.1)% vs (84.8±1.4)%, (81.0±1.4)% vs (84.8±1.4)%, P<0.05], reduced exudation of Evans blue[(9.2±1.1) μg/g vs (12.2±0.8) μg/g, (8.6±0.6) μg/g vs (12.2±0.8) g/g, P<0.05], reduced infarction volume[(31.9±4.9) mm(3) vs(43.0±2.2) mm(3), (29.2±3.5) mm(3) vs(43.0±2.2) mm(3), P<0.05] , reduced neuronal cell apoptosis [(36±4)vs(69±6)、(35±3)vs (69±6), P<0.05]. Compared with sham group, Cilengitide group A and Cilengitide group B had lower brain-water content, permeability of BBB, infarction volume, expression level of VEGF, P-Flk, Cleaved-Caspase-3 and neuronal cell apoptosis (P<0.05). When Cilengitide group A was compared with Cilengitide group B, there were no significant differences in brain-water content, permeability of BBB, infarction volume, expression level of VEGF, P-Flk, Cleaved-Caspase-3 and neuronal cell apoptosis (P>0.05). The integrin αvβ3 inhibitor Cilengitide improves outcomes in the MCAO model by preserving the blood-brain barrier, attenuating brain edema and inhibiting neuronal cell apoptosis, which may occur in a VEGF-and VEGF-receptor-dependent manner, with the same efficacy between Cilengitide 100 μg/kg and 200 μg/kg after 23 hours treatment.
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