JAK-STAT通路抑制剂和自由基清除剂联合应用对大鼠局灶性脑缺血/再灌注损伤的保护作用研究

目的 研究联用Janus激酶信号转导及转录激活因子(JAK-STAT)信号通路抑制剂AG490和自由基清除剂二甲基硫脲(DMTU)对大鼠局灶忭脑缺血/再灌注(I/R)损伤的保护作用及其剂蹙-效应关系.方法 制备大鼠大脑中动脉阻塞(MCAO)模型.选择雄性SD大鼠.按照随机数字表法分组,每组10只.实验1 设I/R模型组、二甲亚砜(DMSO)对照组、生理盐水(NS)对照组、AG490组、DMTU组以及AG490联合DMTU(A+D)组;实验2分为模型组及高、中、低剂量联合组.于I/R 24、48和72 h对各组人鼠进行神经行为学评分(NBS);72 h后处死动物,测量其脑梗死体积.结果 I/R 24、48和72 h A+D组、AG490组和DMTU组NBS明显高于I/R模型组,脑梗死体积明显小于I/R模型组,其中A+D组脑梗死体积较AG490组和DMTU组明显减小(P均＜0.05).高、中剂链联合组NBS明显高于低剂量联合组和模型组.脑梗死体积明显小于后两组,其中高剂量联合组脑梗死体积较中剂量联合组明显减小(P均＜0.05).而低剂量联合组与模型组之间差异无统计学意义.结论 AG490和DMTU有明显的协同脑保护作用,并呈现剂量依赖性.

Neuroprotective effects of combined application of JAK-STAT signal pathway inhibitor and free radical scavenger on focal cerebral ischemia/reperfusion injury in rats

Objective To investigate the neuroprotective effects and dose-response relation by combining JAK-STAT signal pathway inhibitor(AG490)with free radical scavenger dimethylthiourea (DMTU)in rats subjected to focal cerebral ischemia/reperfusion(I/R)injury.Methods In all rats,the middle cerebral artery occlusion(MCAO)was produced by occlusion of right internal carotid artery with a nylon monofilament.One hundred male Sprague-Dawley(SD)rats were divided into ten groups according to random digits table,10 rats were in each group.The first experiment involved I/R modeI controI,dimethyl sulfoxide(DMSO)control,normaI saline(NS)control,AG490,DMTU and combination of AG490 and DMTU(A+D)groups.The second experiment involved model group and three experimental groups in which various doses of DMTU and AG490 were administered.The neurological behavior scores(NBS)were assessed at 24,48 and 72 hours after reperfusion respectively in both experiments,and all the animals were then decapi rated to determine the brain infarct volume after 72 hours.Results The values of NBS in A+D group,AG490 group and DMTU group were higher than those in model group at 24,48 and 72 hours after I/R,and their brain infarct volumes were obviously smaller than model group as well(all P＜0.05).The brain infarct volume in A+D group was obviously smaller compared with AG490 and DMTU alone(all P＜0.05).The values of NBS were higher and the brain infarct volumes were smaller in both high dose and medium dose combination groups than those in low dose combination and model groups respectively(all P＜0.05).In addition,brain infarct volumes in high dose group were smaller than medium dose group(P＜ 0.05),but there was no statistically significant difference between low dose and model groups.Conclusion The combined application of AG490 and DMTU produces a dose-dependent synergistic neuroprotective effect.