组织型纤溶酶原激活剂给药时间对短暂性脑缺血性中风大鼠血脑屏障通透性及出血性转化的影响

Effects of tissue plasminogen activator timing on blood-brain barrier permeability and hemorrhagic transformation in rats with transient ischemic stroke.

作者信息

Zhang Yanrong, Wang Yi, Zuo Zhiyi, Wang Zhongxing, Roy Jack, Hou Qinghua, Tong Elizabeth, Hoffmann Angelika, Sperberg Emily, Bredno Joerg, Berr Stuart S, Xie Mingxing, Lee Kevin, Wintermark Max

机构信息

Department of Ultrasound, Union hospital, Tongji Medical College, HuazhongUniversity of Science and Technology, Wuhan, Hubei, China; University of Virginia, Department of Radiology, Neuroradiology Division, Charlottesville, VA, United States.

Department of Neuroscience, University of Virginia, Charlottesville, VA, United States.

出版信息

J Neurol Sci. 2014 Dec 15;347(1-2):148-54. doi: 10.1016/j.jns.2014.09.036. Epub 2014 Sep 28.

DOI:10.1016/j.jns.2014.09.036

PMID:25292413

Abstract

The goal of our study was to determine if the timing of the tissue plasminogen activator (tPA) administration influenced its effect on blood-brain barrier (BBB) permeability and the subsequent risk of hemorrhagic transformation. Thirty spontaneously hypertensive male rats were subjected to a 90-minute unilateral middle cerebral artery occlusion. Six rats did not receive tPA treatment (vehicle control: Group 0), intravenous tPA was administered immediately after reperfusion (Group 1) or 4h after reperfusion (Group 2). Dynamic contrast enhancement (DCE) and gradient-echo (GRE) MR sequences were used to assess the dynamic evolution of BBB permeability and hemorrhagic transformation changes at the following time points: during occlusion, and 3h, 6h, and 24h post reperfusion. In all groups, BBB permeability values in the ischemic tissue were low during occlusion. In Group 0, BBB permeability values increased at 3h after reperfusion (p=0.007, compared with the values during occlusion), and further at 6h after reperfusion (p=0.004, compared with those at 3h post reperfusion). At 24h post reperfusion, the values decreased to a level relative to but still higher than those during occlusion (p=0.025, compared with the values during occlusion). At 3h after reperfusion, BBB permeability values in the ischemic tissue increased, but to a greater extent in Group 1 than in Group 0 (p=0.034) and Group 2 (p=0.010). At 6h after reperfusion, BBB permeability values in the ischemic tissue increased further in Group 2 than in Group 0 (p=0.006) and Group 1 (p=0.001), while Group 1 exhibited BBB permeability that were still abnormal but less than those observed at 3h (p=0.001). Group 2 tended to have a higher hemorrhage incidence (36.4%, 4/11) than Group 1 (10.0%, 1/10, p=0.311) and Group 0 (0%), and hemorrhages occurred around 6h after reperfusion when BBB permeability values were the highest. Mortality was higher in Group 2 (63.6%, 7/11) than in Group 0 (0%) and Group 1 (10.0%, 1/10, p=0.024). The findings suggest that the timing of tPA administration is of importance for its impact on BBB permeability and subsequent risk of hemorrhagic transformation.

摘要

我们研究的目的是确定组织纤溶酶原激活剂（tPA）给药时间是否会影响其对血脑屏障（BBB）通透性的作用以及随后发生出血性转化的风险。30只自发性高血压雄性大鼠接受了90分钟的单侧大脑中动脉闭塞。6只大鼠未接受tPA治疗（溶剂对照组：第0组），静脉注射tPA分别在再灌注后立即进行（第1组）或再灌注后4小时进行（第2组）。使用动态对比增强（DCE）和梯度回波（GRE）磁共振序列在以下时间点评估BBB通透性和出血性转化变化的动态演变：闭塞期间、再灌注后3小时、6小时和24小时。在所有组中，缺血组织中的BBB通透性值在闭塞期间较低。在第0组中，BBB通透性值在再灌注后3小时增加（p = 0.007，与闭塞期间的值相比），并在再灌注后6小时进一步增加（p = 0.004，与再灌注后3小时的值相比）。在再灌注后24小时，这些值降至相对于闭塞期间但仍高于闭塞期间的值的水平（p = 0.025，与闭塞期间的值相比）。在再灌注后3小时，缺血组织中的BBB通透性值增加，但第1组增加的程度大于第0组（p = 0.034）和第2组（p = 0.010）。在再灌注后6小时，第2组缺血组织中的BBB通透性值比第0组（p = 0.006）和第1组（p = 0.001）增加得更多，而第1组的BBB通透性仍异常，但低于3小时时观察到的值（p = 0.001）。第2组的出血发生率（36.4%，4/11）倾向于高于第1组（10.0%，1/10，p = 0.311）和第0组（0%），出血发生在再灌注后约6小时，此时BBB通透性值最高。第2组的死亡率（63.6%，7/11）高于第0组（0%）和第1组（10.0%，1/10，p = 0.024）。研究结果表明，tPA给药时间对其对BBB通透性的影响以及随后发生出血性转化的风险具有重要意义。