MEK1/2 inhibition attenuates vascular ETA and ETB receptor alterations after cerebral ischaemia
MEK1/2 inhibition attenuates vascular ETA and ETB receptor alterations after cerebral ischaemia
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DOI：
10.1007/s00221-006-0753-7
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发表时间：
2007-04-01
影响因子：
2
通讯作者：
Edvinsson, Lars
中科院分区：
文献类型：
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作者：
Henriksson, Marie;Stenman, Emelie;Edvinsson, Lars
脑缺血与同侧大脑中动脉(MCA)内皮素B(ETB)受体水平升高有关。ET受体的这种上调是通过丝裂原活化蛋白激酶(MAPK)的从头转录实现的。本研究的目的是研究抑制MAP/ERK激酶(MEK)1/2对实验性脑缺血时ET受体改变、脑损伤和神经学的影响。采用线栓法建立雄性Wistar大鼠大脑中动脉一过性闭塞模型。动物在结扎的同时，腹腔注射MEK1/2抑制剂U0126或赋形剂100 mg/kg。24小时后断头取脑。分离大脑中动脉，进行肌电图或免疫组织化学检查。比较了大脑的缺血区。大脑中动脉阻塞后，同侧大脑中动脉ETA和ETB受体的收缩反应增强。U0126可减少ET受体反应的这种改变。此外，U0126治疗显著减轻了脑损伤并改善了神经功能评分。免疫组织化学结果显示，U0126处理组大鼠肺组织中磷酸化的细胞外信号调节蛋白(ERK)1/2和磷酸化转录因子Elk-1的蛋白水平均低于对照组。结果表明，MEK1/2抑制剂U0126治疗缺血性卒中可减轻脑损伤、神经症状和ET受体改变。U0126的血管效应为MAPK抑制脑缺血的可能作用机制提供了新的视角。
Cerebral ischaemia is associated with elevated levels of endothelin B (ETB) receptors in the ipsilateral middle cerebral artery (MCA). This up-regulation of ET receptors occurs via de novo transcription involving mitogen-activated protein kinases (MAPK). The aim of this study was to examine the effect of inhibition of the MAP kinase/ERK kinase (MEK)1/2 on ET receptor alteration, brain damage, and neurology in experimental cerebral ischaemia. Transient middle cerebral artery occlusion (MCAO) was induced in male Wistar rats by the intraluminal filament technique. The animals received 100 mg/kg intraperitoneally of the MEK1/2 inhibitor U0126 or vehicle in conjunction with the occlusion. After 24 h, the rats were decapitated and the brains removed. The middle cerebral arteries were dissected out and examined with myographs or immunohistochemistry. The ischaemic areas of the brains were compared. After the MCAO, the contractile responses of the ETA and ETB receptors were augmented in the ipsilateral MCA. U0126 decreased this alteration in ET receptor response. Furthermore, treatment with U0126 significantly decreased the brain damage and improved neurological scores. Immunohistochemistry showed that there were lower protein levels of phosphorylated extracellular signal-regulated kinases (ERK)1/2 and phosphorylated transcription factor Elk-1 in the U0126-treated rats compared to control. The results show that treatment with the MEK1/2 inhibitor U0126 in ischaemic stroke decreases brain damage, neurological symptoms, and ET receptor alteration. The vascular effects of U0126 provide new perspective on possible mechanisms of actions of MAPK inhibition in cerebral ischaemia.