Prevention of rt-PA induced bloodabrain barrier component degradation by the poly(ADP-ribose)polymerase inhibitor PJ34 after ischemic stroke in mice

• Published in: Experimental neurology Vol. 248; pp. 416 - 428
• Main Authors: Teng, Fei, Beray-Berthat, Virginie, Coqueran, Berard, Lesbats, Clementine, Kuntz, Melanie, Palmier, Bruno, Garraud, Marie, Bedfert, Cyrielle, Slane, Niamh, Berezowski, Vincent, Szeremeta, Frederic, Hachani, Johan, Scherman, Daniel, Plotkine, Michel, Doan, Bich-Thuy, Marchand-Leroux, Catherine, Margaill, Isabelle
• Format: Journal Article
• Language: English
• Published: 01-10-2013
• ISSN: 0014-4886
• DOI: 10.1016/j.expneurol.2013.07.007

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 bloodabrain 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 vitro studies also demonstrated that PJ34 crosses the bloodabrain 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.