Blood-brain barrier permeability and tPA-mediated neurotoxicity.
Blood-brain barrier permeability and tPA-mediated neurotoxicity.
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DOI：
10.1016/j.neuropharm.2009.12.017
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发表时间：
2010-06
影响因子：
4.7
通讯作者：
Higazi, Abd Al-Roof
中科院分区：
文献类型：
--
作者：
Abu Fanne, Rami;Nassar, Taher;Yarovoi, Sergei;Rayan, Anwar;Lamensdorf, Itschak;Karakoveski, Michael;Vadim, Polianski;Jammal, Mahmud;Cines, Douglas B.;Higazi, Abd Al-Roof
组织型纤溶酶原激活剂（tPA）诱导神经元凋亡，破坏血脑屏障（BBB），促进脑血管扩张。tPA的这些和其他有害作用的时间、顺序和贡献，以及它们对中风后缺血性脑损伤的贡献，尚未完全阐明。为了分离tPA对血脑屏障通透性、脑血管舒张和蛋白酶依赖途径的影响，我们开发了几个tPA突变体和PAI-1衍生肽，这些肽是通过tPA的计算机同源建模构建的。我们的数据显示，大鼠静脉注射人tPA通过非催化过程增加血脑屏障的通透性，这与可逆的神经毒性、脑损伤、水肿和死亡率有关，并对其短暂的治疗窗口期有重要贡献。此外，我们的数据表明，在不影响其催化活性的情况下，抑制tPA对血脑屏障功能的影响，可以改善结果，并显著延长其在机械和血栓栓塞中风模型中的治疗窗口期。
Tissue type plasminogen activator (tPA) induces neuronal apoptosis, disrupt the blood-brain-barrier (BBB), and promotes dilation of the cerebral vasculature. The timing, sequence and contributions of these and other deleterious effects of tPA and their contribution to post-ischemic brain damage after stroke, have not been fully elucidated. To dissociate the effects of tPA on BBB permeability, cerebral vasodilation and protease-dependent pathways, we developed several tPA mutants and PAI-1 derived peptides constructed by computerized homology modeling of tPA. Our data show that intravenous administration of human tPA to rats increases BBB permeability through a non-catalytic process, which is associated with reversible neurotoxicity, brain damage, edema, mortality and contributes significantly to its brief therapeutic window. Furthermore, our data show that inhibiting the effect of tPA on BBB function without affecting its catalytic activity, improves outcome and significantly extends its therapeutic window in mechanical as well as thromboembolic models of stroke.
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影响因子：
20.3
作者：
Nassar, T;Akkawi, S;Higazi, AA
通讯作者：
Higazi, AA
影响因子：
82.9
作者：
Su, Enming J.;Fredriksson, Linda;Lawrence, Daniel A.
通讯作者：
Lawrence, Daniel A.
DOI：
10.1073/pnas.87.9.3530
发表时间：
1990-05-01
影响因子：
11.1
作者：
MADISON, EL;GOLDSMITH, EJ;BASSELDUBY, RS
通讯作者：
BASSELDUBY, RS
影响因子：
4.8
作者：
HIGAZI, AAR;BARGHOUTI, II;ABUMUCH, R
通讯作者：
ABUMUCH, R
影响因子：
37.8
作者：
Nagai, N;De Mol, M;Collen, D
通讯作者：
Collen, D