Intravenous administration of thioredoxin decreases brain damage following transient focal cerebral ischemia in mice
Intravenous administration of thioredoxin decreases brain damage following transient focal cerebral ischemia in mice
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DOI：
10.1089/152308604771978372
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发表时间：
2004-02-01
影响因子：
6.6
通讯作者：
Yodoi, J
中科院分区：
文献类型：
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作者：
Hattori, I;Takagi, Y;Yodoi, J
硫氧还蛋白（TRX）是由多种氧化刺激诱导的，对氧化应激具有细胞保护作用。为了阐明临床应用的可能性，我们在这项研究中检查了静脉注射TRX在短暂局灶性脑缺血模型中的作用。成熟雄性C57 BL/6 j小鼠在短暂性大脑中动脉闭塞（MCAO）90分钟后，连续静脉输注1-10 mg/kg范围内的重组人TRX（rhTRX）、牛血清白蛋白或单独溶媒2 h。短暂MCAO后24小时，对动物进行神经学评价，并评估梗死体积。与对照组动物相比，rhTRX治疗组小鼠的脑体积、神经功能缺损和蛋白质羰基含量（蛋白质氧化的标志物）在3和10 mg/kg剂量下显著改善。此外，p38丝裂原活化蛋白激酶的激活，其途径是参与缺血性神经元死亡，在rhTRX治疗的小鼠被抑制。此外，通过蛋白质印迹分析在缺血半球中检测到rhTRX，表明rhTRX能够渗透缺血半球中的血脑屏障。这些数据表明，外源性TRX通过其氧化还原调节活性对小鼠脑缺血/再灌注损伤具有明显的细胞保护作用。
Thioredoxin (TRX) is induced by a variety of oxidative stimuli and shows cytoprotective roles against oxidative stress. To clarify the possibility of clinical application, we examined the effects of intravenously administered TRX in a model of transient focal cerebral ischemia in this study. Mature male C57BL/6j mice received either continuous intravenous infusion of recombinant human TRX (rhTRX) over a range of 1-10 mg/kg, bovine serum albumin, or vehicle alone for 2 h after 90-min transient middle cerebral artery occlusion (MCAO). Twenty-four hours after the transient MCAO, the animals were evaluated neurologically and the infarct volumes were assessed. Infarct volume, neurological deficit, and protein carbonyl contents, a marker of protein oxidation, in the brain were significantly ameliorated in rhTRX-treated mice at the dose of 3 and 10 mg/kg versus these parameters in control animals. Moreover, activation of p38 mitogen-activated protein kinase, whose pathway is involved in ischemic neuronal death, was suppressed in the rhTRX-treated mice. Further, rhTRX was detected in the ischemic hemisphere by western blot analysis, suggesting that rhTRX was able to permeate the blood-brain barrier in the ischemic hemisphere. These data indicate that exogenous TRX exerts distinct cytoprotective effects on cerebral ischemia/reperfusion injury in mice by means of its redox-regulating activity.