Effect of anesthetic post-treatment on blood-brain barrier integrity and cerebral edema after transient cerebral ischemia in rats

Abstract

Although anesthetics, such as propofol and isoflurane, have been reported to offer neuroprotection against cerebral ischemia injury, their impact on cerebral edema following ischemia is not clear. The objective of this investigation is to evaluate the effects of anesthetic post-treatment on blood-brain barrier (BBB) integrity and cerebral edema after transient cerebral ischemia and its mechanism of action, focusing on modulation of aquaporins (AQPs), matrix metalloproteinases (MMPs), vascular endothelial growth factor (VEGF) and hypoxia inducible factor (HIF)-1α.Cerebral ischemia was induced in male Sprague-Dawley rats (n=103) by occlusion of the right middle cerebral artery for 1 h. For post-treatment with propofol (n=37), 1 mg/kg/min of propofol was administered for 1 h from the start of reperfusion, and for post-treatment with isoflurane (n=25), 2.1 vol% of isoflurane was administered for 1 h from the start of reperfusion. Saline-treated controls received 0.9% normal saline at the rate of 0.1 ml/kg/min for 1 h from the start of reperfusion (n=41). Nineteen rats undergoing sham surgery were also included in the investigation. Edema and BBB integrity were assessed by quantification of cerebral water content and extravasation of Evans blue, respectively, following 24 h of reperfusion. In addition, the expression of AQP-1, AQP-4, MMP-2, MMP-9, and VEGF was determined 24 h after reperfusion and the expression of HIF-1α was determined 8 h after reperfusion.Propofol or isoflurane post-treatment significantly reduced cerebral edema (P<0.05) and BBB disruption (P<0.05) compared with the saline-treated control. Furthermore, post-treatment with propofol or isoflurane reduced the expression of AQP-4 and MMP-2, compared to the saline-treated control (P<0.05). However, there were no differences in cerebral edema, BBB disruption, and expression of AQP-4 and MMP-2 between propofol and isoflurane post-treatment. In further evaluation of the factors related to the formation of cerebral edema, the expression of AQP-1, AQP-4, MMP-2, MMP-9, and VEGF at 24 h and of HIF-1α at 8 h following ischemia/reperfusion was significantly suppressed in the propofol post-treatment group (P<0.05).In conclusion, propofol post-treatment attenuated cerebral edema and BBB disruption after transient cerebral ischemia and the effects of propofol post-treatment on cerebral edema and BBB integrity were not different from those of isoflurane post-treatment. Additionally, alleviation of cerebral edema by propofol post-treatment was shown to be associated with reduced expression of AQP-1, AQP-4, MMP-2, MMP-9, VEGF and HIF-1α.