右美托咪定在改善缺血性脑损伤中表现出多种神经保护机制。在这项研究中,我们探讨了右美托咪定对脑缺血/再灌注损伤中血脑屏障(BBB)完整性和神经炎症的有益作用。SD大鼠大脑中动脉阻断(MCAO)1.5h,再灌注24h,建立大鼠脑缺血再灌注损伤模型。右美托咪定(9?g/kg)在MCAO后30分钟通过静脉注射给予大鼠,和SB203580(一种p38MAPK抑制剂,200?g/kg)在MCAO前30分钟腹膜内注射。通过氯化2,3,5-三苯基四唑染色评估脑损伤,苏木精-伊红染色,尼氏染色,和大脑含水量评估。通过伊文思蓝染色检查BBB通透性。claudin-5、小带闭塞蛋白1、闭塞蛋白的表达水平,和基质金属蛋白酶-9(MMP-9)以及M1/M2表型相关标志物使用免疫荧光进行评估,RT-qPCR,西方印迹,和明胶酶谱。酶联免疫吸附试验用于检测炎性细胞因子水平。我们发现右美托咪定或SB203580可以减轻梗死体积,脑水肿,BBB通透性,和神经炎症,并促进脑缺血再灌注损伤后的M2小胶质细胞极化。右美托咪定或SB203580抑制缺血/再灌注损伤引起的MMP-9活性增加。右美托咪定抑制ERK的激活,JNK,和p38MAPK途径。此外,激活JNK或p38MAPK可逆转右美托咪定对缺血性脑损伤的保护作用。总的来说,右美托咪定通过抑制JNK和p38MAPK通路的激活,减轻实验性脑缺血再灌注损伤模型的BBB通透性,促进M2极化,改善脑损伤。
Dexmedetomidine displays multiple mechanisms of neuroprotection in ameliorating ischemic brain injury. In this study, we explored the beneficial effects of dexmedetomidine on blood-brain barrier (BBB) integrity and neuroinflammation in cerebral ischemia/reperfusion injury. Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 1.5 h and reperfusion for 24 h to establish a rat model of cerebral ischemia/reperfusion injury. Dexmedetomidine (9 g/kg) was administered to rats 30 min after MCAO through intravenous injection, and SB203580 (a p38 MAPK inhibitor, 200 g/kg) was injected intraperitoneally 30 min before MCAO. Brain damages were evaluated by 2,3,5-triphenyltetrazolium chloride staining, hematoxylin-eosin staining, Nissl staining, and brain water content assessment. BBB permeability was examined by Evans blue staining. Expression levels of claudin-5, zonula occludens-1, occludin, and matrix metalloproteinase-9 (MMP-9) as well as M1/M2 phenotypes-associated markers were assessed using immunofluorescence, RT-qPCR, Western blotting, and gelatin zymography. Enzyme-linked immunosorbent assay was used to examine inflammatory cytokine levels. We found that dexmedetomidine or SB203580 attenuated infarct volume, brain edema, BBB permeability, and neuroinflammation, and promoted M2 microglial polarization after cerebral ischemia/reperfusion injury. Increased MMP-9 activity by ischemia/reperfusion injury was inhibited by dexmedetomidine or SB203580. Dexmedetomidine inhibited the activation of the ERK, JNK, and p38 MAPK pathways. Moreover, activation of JNK or p38 MAPK reversed the protective effects of dexmedetomidine against ischemic brain injury. Overall, dexmedetomidine ameliorated brain injury by alleviating BBB permeability and promoting M2 polarization in experimental cerebral ischemia/reperfusion injury model by inhibiting the activation of JNK and p38 MAPK pathways.