Stroke Research Laboratory, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.
Stroke. 2013 Feb;44(2):505-11. doi: 10.1161/STROKEAHA.112.679043. Epub 2013 Jan 3.
The sphingosine 1-phosphate receptor agonist fingolimod reduces infarct size in rodent models of stroke and enhances blood-brain barrier integrity. Based on these observations, we hypothesized that combination of fingolimod with tissue plasminogen activator (tPA) would reduce the risk of hemorrhagic transformation associated with delayed administration of tPA.
We evaluated the effects of fingolimod in a mouse model of thromboembolic stroke, in which both the beneficial effect of reperfusion associated with early tPA treatment and hemorrhagic transformation associated with delayed administration mimic clinical observations in humans.
Our results demonstrate that fingolimod treatment attenuates the neurological deficit and reduces infarct volume after in situ thromboembolic occlusion of the middle cerebral artery. Combination of fingolimod and tPA improves the neurological outcome of the thrombolytic therapy and reduces the risk of hemorrhagic transformation associated with delayed administration of tPA.
This study confirms the protective efficacy of fingolimod as a treatment against ischemic stroke in another rodent model of stroke (thromboembolic occlusion), and suggests that fingolimod could potentially be used in combination with tPA to reduce the risk of brain hemorrhage.
鞘氨醇 1-磷酸受体激动剂 fingolimod 可减少中风啮齿动物模型中的梗死面积,并增强血脑屏障的完整性。基于这些观察结果,我们假设 fingolimod 与组织型纤溶酶原激活物(tPA)联合使用将降低与 tPA 延迟给药相关的出血性转化风险。
我们在血栓栓塞性中风的小鼠模型中评估了 fingolimod 的作用,其中与早期 tPA 治疗相关的再灌注的有益作用以及与延迟给药相关的出血性转化都模拟了人类的临床观察。
我们的结果表明,fingolimod 治疗可减轻大脑中动脉原位血栓栓塞闭塞后的神经功能缺损并减少梗死体积。fingolimod 和 tPA 的联合使用改善了溶栓治疗的神经学结局,并降低了与 tPA 延迟给药相关的出血性转化风险。
这项研究在另一种中风(血栓栓塞性闭塞)啮齿动物模型中证实了 fingolimod 作为缺血性中风治疗的保护作用,并表明 fingolimod 可能与 tPA 联合使用以降低脑出血风险。