Inhibition of Thrombin-Activatable Fibrinolysis Inhibitor and Plasminogen Activator Inhibitor-1 Reduces Ischemic Brain Damage in Mice
Inhibition of Thrombin-Activatable Fibrinolysis Inhibitor and Plasminogen Activator Inhibitor-1 Reduces Ischemic Brain Damage in Mice
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DOI：
10.1161/strokeaha.116.014091
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发表时间：
2016-09-01
期刊：
影响因子：
8.3
通讯作者：
De Meyer, Simon F.
中科院分区：
文献类型：
--
作者：
Denorme, Frederik;Wyseure, Tine;De Meyer, Simon F.
背景与目的脑缺血再灌注与脑微血管内凝血级联激活和纤维蛋白沉积有关。凝血酶活化纤维蛋白溶解抑制剂（TAFI）和纤溶酶原激活剂抑制剂-1 （PAI-1）都能减弱纤维蛋白溶解，因此是缺血性卒中治疗的有吸引力的靶点。方法用单克隆抗体对小鼠短暂性大脑中动脉闭塞模型的TAFI和PAI-1进行抑制。脑卒中24小时后，对小鼠进行神经学评分，评估脑血栓负荷，计算脑梗死面积。结果抑制TAFI或PAI-1可使脑梗死面积减少50%。脑损伤的减少与缺血脑中纤维蛋白（原）沉积的显著减少有关。同时，动物的功能恢复得到改善。有趣的是，联合靶向TAFI和PAI-1使用低剂量的抗体，它们本身是无活性的，改善了脑血流量，减少了50%的脑纤维蛋白（原）沉积和梗死面积。双药治疗延迟至再灌注开始后1小时，仍可减轻脑损伤；然而，这在统计学上并不显著。结论以PAI-1和TAFI为靶点，通过减少纤维蛋白（原）沉积，改善再灌注，对缺血性脑卒中模型具有保护作用。联合抑制具有协同作用，可能在缺血性中风治疗中变得有用。
Background and Purpose Cerebral ischemia and reperfusion is associated with activation of the coagulation cascade and fibrin deposition in cerebral microvessels. Both thrombin-activatable fibrinolysis inhibitor (TAFI) and plasminogen activator inhibitor-1 (PAI-1) attenuate fibrinolysis and are therefore attractive targets for the treatment of ischemic stroke.Methods TAFI and PAI-1 were inhibited by monoclonal antibodies in a mouse model of transient middle cerebral artery occlusion. Twenty-four hours after stroke, mice were neurologically scored, cerebral thrombotic burden was assessed, and brain infarct sizes were calculated.Results Inhibition of TAFI or PAI-1 significantly decreased cerebral infarct sizes by 50% 24 hours after stroke. This reduction in cerebral damage was associated with a significant decrease in fibrin(ogen) deposition in the ischemic brain. Concurrently, functional recovery of the animals was improved. Interestingly, combined targeting of TAFI and PAI-1 using low, and by themselves inactive, doses of antibodies improved cerebral blood flow and reduced cerebral fibrin(ogen) deposition and infarct sizes by 50%. When dual treatment was delayed to 1 hour after the start of reperfusion, it still reduced brain injury; however, this was not statistically significant.Conclusions Targeting of PAI-1 and TAFI is protective in an ischemic stroke model by attenuating fibrin(ogen) deposition, thereby improving reperfusion. Combined inhibition has a co-operative effect that could become useful in ischemic stroke therapy.