• Fei Teng, Virginie Beray-Berthat, Bérard Coqueran, Clémentine Lesbats, Mélanie Kuntz, Bruno Palmier, Marie Garraud, Cyrielle Bedfert, Niamh Slane, Vincent Bérézowski, Frédéric Szeremeta, Johan Hachani, Daniel Scherman, Michel Plotkine, Bich-Thuy Doan, Catherine Marchand-Leroux, and Isabelle Margaill.
• Equipe de recherche "Pharmacologie de la Circulation Cérébrale" EA4475, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
• Exp. Neurol. 2013 Oct 1; 248: 416-28.

AbstractRecombinant 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.) 6h 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 vitro studies 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.© 2013.

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