Tissue-type plasminogen activator crosses the intact blood-brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis
Tissue-type plasminogen activator crosses the intact blood-brain barrier by low-density lipoprotein receptor-related protein-mediated transcytosis
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DOI：
10.1161/01.cir.0000163542.48611.a2
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发表时间：
2005-05-03
期刊：
影响因子：
37.8
通讯作者：
Vivien, D
中科院分区：
文献类型：
--
作者：
Benchenane, K;Berezowski, V;Vivien, D
背景 - 越来越多的证据表明组织型纤溶酶原激活物（tPA）在病理和生理脑状况中具有关键作用。因此，确定血管中的tPA是否以及如何穿过血脑屏障（BBB）进入大脑是很重要的，不仅在中风期间，在生理状况下也是如此。
方法和结果 - 在本研究中，我们在体内提供的证据表明，在没有血脑屏障渗漏的情况下，静脉注射tPA会增加N - 甲基 - D - 天冬氨酸（NMDA）诱导的纹状体损伤。相应地，我们表明在兴奋性毒性损伤后以及在对照条件下tPA都能穿过血脑屏障。实际上，血管内注射的tPA可以在脑实质内以及脑脊液中被检测到。通过使用血脑屏障的体外模型，我们已经证实tPA能够穿过完整的血脑屏障。它的通过在4℃时被阻断，是可饱和的，并且与其蛋白水解活性无关。我们已经表明tPA通过转胞吞作用穿过血脑屏障，这一过程由低密度脂蛋白受体相关蛋白家族的一个成员介导。
结论 - 我们证明了血液来源的tPA能够在不破坏血脑屏障的情况下到达脑实质。此处所描述的tPA从血液到大脑的通过的分子机制可能是改善中风溶栓治疗的一个有意义的靶点。
Background-Accumulating evidence demonstrates a critical involvement of tissue-type plasminogen activator (tPA) in pathological and physiological brain conditions. Determining whether and how vascular tPA can cross the blood-brain barrier (BBB) to enter the brain is thus important, not only during stroke but also in physiological conditions.Methods and Results-In the present work, we provide evidence in vivo that intravenous injection of tPA increases NMDA-induced striatal lesion in the absence of BBB leakage. Accordingly, we show that tPA crosses the BBB both after excitotoxic lesion and in control conditions. Indeed, vascular injected tPA can be detected within the brain parenchyma and in the cerebrospinal fluid. By using an in vitro model of BBB, we have confirmed that tPA can cross the intact BBB. Its passage was blocked at 4 degrees C, was saturable, and was independent of its proteolytic activity. We have shown that tPA crosses the BBB by transcytosis, mediated by a member of the LDL receptor-related protein family.Conclusions-We demonstrate that blood-derived tPA can reach the brain parenchyma without alteration of the BBB. The molecular mechanism of the passage of tPA from blood to brain described here could represent an interesting target to improve thrombolysis in stroke.