Senkyunolide I protects rat brain against focal cerebral ischemia-reperfusion injury by up-regulating p-Erk1/2, Nrf2/HO-1 and inhibiting caspase 3
Senkyunolide I protects rat brain against focal cerebral ischemia-reperfusion injury by up-regulating p-Erk1/2, Nrf2/HO-1 and inhibiting caspase 3
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DOI：
10.1016/j.brainres.2015.02.015
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发表时间：
2015-04-24
期刊：
影响因子：
2.9
通讯作者：
Feng, Yi
中科院分区：
文献类型：
--
作者：
Hu, Yangye;Duan, Muyin;Feng, Yi
氧化损伤和细胞凋亡是导致中风期间神经元死亡的关键因素。本研究旨在评价番泻内酯I(SEI)对大鼠局灶性脑缺血再灌注(I/R)损伤的神经保护作用，并探讨其作用机制。雄性SD大鼠大脑中动脉闭塞(TMCAO)2 h后再灌注24 h，随机分为假手术组(Sham)、假手术组(tMCAO+生理盐水)、SEI-L组(tMCAO+SEI 36 mg/kg)和SEI-H组(tMCAO+SEI 72 mg/kg)。结扎后15min静脉注射SEI。再灌流24 h后检测神经功能评分、脑水肿和脑梗塞体积。苏木精-伊红染色观察大脑皮层和海马区的组织结构。比色法测定大脑皮层生化指标。利用荧光素酶报告基因分析SEI对Nrf2-ARE相互作用的影响。Western blotting分析细胞抗氧化和细胞凋亡相关蛋白的表达。SEI能明显改善神经功能障碍，缩小脑梗塞体积和脑水肿，逆转脑形态损害，降低丙二醛水平，提高超氧化物歧化酶活性。此外，大剂量SEI可通过上调ERK1/2的磷酸化水平，诱导Nrf2核转位，增强HO-1和NQO1的表达，从而显著激活Nrf2/ARE通路。此外，SEI还能显著提高Bcl2/Bax比值，抑制caspase3和caspase9的表达，提示SEI的神经保护机制与其抗氧化和抗细胞凋亡作用有关。(C)2015爱思唯尔B.V.保留所有权利。
Oxidative damage and apoptosis are critical factors contributing to neuronal death during a stroke. The aim of the present study was to evaluate the neuroprotective effects of senkyunolide I (SEI) on focal cerebral ischemia-reperfusion (I/R) injury in rats, and investigate the underlying mechanisms. Male Sprague-Dawley rats were subjected to transient middle cerebral artery occlusion (tMCAO) for 2 h, followed by 24 h reperfusion, and then randomly assigned into four groups: Sham (sham-operated), Vehicle (tMCAO +normal saline), SEI-L (tMCAO +SEI 36 mg/kg) and SEI-H (tMCAO +SEI 72 mg/kg) groups. SEI was administered intravenously, 15 min after occlusion. Neurological deficit, brain edema and infarct volume were detected after 24 h of reperfusion. Histological structures of cortices and hippocampus were observed by hematoxylin and eosin staining. Biochemical indexes in the cortex were assayed by colorimetry. The impact of SEI on the Nrf2-ARE-interaction was assayed using a luciferase reporter gene. Western blotting was performed to analysis the expressions of proteins related to anti-oxidation and apoptosis. SEI administration significantly ameliorated the neurological deficit, reduced the infarct volume and brain edema, reversed the cerebral morphologic damage, decreased the levels of MDA and increased the activities of superoxide dismutase. Furthermore, the high dose SEI could significantly activate the Nrf2/ARE pathway by up-regulating the phosphoryladon of Erk1/2 and inducing Nrf2 nuclear translocation with enhanced HO-1 and NQO1 expressions. Additionally, treatment with SEI remarkably promoted the ratio of Bcl-2/Bax and inhibited the expressions of cleaved caspase 3 and caspase 9. These results suggest that the neuroprotective mechanisms of SEI are associated with its anti-oxidation and anti-apoptosis properties. (C) 2015 Elsevier B.V. All rights reserved.