Prevention of rt-PA induced blood–brain barrier component degradation by the poly(ADP-ribose)polymerase inhibitor PJ34 after ischemic stroke in mice
Prevention of rt-PA induced blood–brain barrier component degradation by the poly(ADP-ribose)polymerase inhibitor PJ34 after ischemic stroke in mice
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DOI：
10.1016/j.expneurol.2013.07.007
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发表时间：
2013-10
影响因子：
5.3
通讯作者：
F. Teng;V. Beray-Berthat;B. Coqueran;Clémentine Lesbats;Mélanie Kuntz;B. Palmier;Marie Garraud;Cyrielle Bedfert;Niamh Slane;V. Bérézowski;F. Szeremeta;J. Hachani;D. Scherman;M. Plotkine;B. Doan;C. Marchand-Leroux;I. Margaill
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文献类型：
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作者：
F. Teng;V. Beray-Berthat;B. Coqueran;Clémentine Lesbats;Mélanie Kuntz;B. Palmier;Marie Garraud;Cyrielle Bedfert;Niamh Slane;V. Bérézowski;F. Szeremeta;J. Hachani;D. Scherman;M. Plotkine;B. Doan;C. Marchand-Leroux;I. Margaill
重组组织纤溶酶原激活剂（rt-PA）是唯一批准用于缺血性卒中患者溶栓的药物治疗，但其给药可降低出血性转化的风险。实验数据表明，rt-PA增加聚（ADP-核糖）聚合酶（PARP）的活性。本研究的目的是调查是否PJ 34，一个有效的（PARP）抑制剂，保护血脑屏障组件从rt-PA毒性。在我们的小鼠脑缺血模型中，给予rt-PA（10 mg/kg，i. v.）缺血6 h后ZO-1、claudin-5和VE-钙粘蛋白的降解加重，出血性转化增加（通过脑血红蛋白含量和磁共振成像评估）。此外，rt-PA还加重了缺血引起的功能障碍。PJ 34与rt-PA联合应用可保护ZO-1、claudin-5和VE-cadherin的表达，减少出血性转化，改善感觉运动功能，体外研究表明PJ 34可通过血脑屏障作用于内皮细胞和/或脑实质细胞，从而发挥其保护作用。因此，与PARP抑制剂的联合治疗似乎是减少卒中后rt-PA诱导的血管毒性的有前景的策略。
Recombinant tissue plasminogen activator (rt-PA) is the only pharmacological treatment approved for thrombolysis in patients suffering from ischemic stroke, but its administration aggravates the risk of hemorrhagic transformations. Experimental data demonstrated that rt-PA increases the activity of poly(ADP-ribose)polymerase (PARP). The aim of the present study was to investigate whether PJ34, a potent (PARP) inhibitor, protects the blood–brain barrier components from rt-PA toxicity. In our mouse model of cerebral ischemia, administration of rt-PA (10 mg/kg, i.v.) 6 h after ischemia aggravated the post-ischemic degradation of ZO-1, claudin-5 and VE-cadherin, increased the hemorrhagic transformations (assessed by brain hemoglobin content and magnetic resonance imaging). Furthermore, rt-PA also aggravated ischemia-induced functional deficits. Combining PJ34 with rt-PA preserved the expression of ZO-1, claudin-5 and VE-cadherin, reduced the hemorrhagic transformations and improved the sensorimotor performances.In vitrostudies also demonstrated that PJ34 crosses the blood–brain barrier and may thus exert its protective effect by acting on endothelial and/or parenchymal cells. Thus, co-treatment with a PARP inhibitor seems to be a promising strategy to reduce rt-PA-induced vascular toxicity after stroke.