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

Fei Teng (1, 2, 3, 4) , Virginie Beray-Berthat (1, 2, 3, 4) , Bérard Coqueran (1, 2, 3, 4) , Clémentine Lesbats (1, 2, 3, 4, 5, 6) , Mélanie Kuntz , Bruno Palmier (1, 2, 3, 4) , Marie Garraud (1, 2, 3, 4) , Cyrielle Bedfert (1, 2, 3, 4) , Niamh Slane (1, 2, 3, 4) , Vincent Berezowski (7) , Frédéric Szeremeta (8) , Johan J. Hachani (7) , Daniel Scherman (5, 2, 3) , Michel Plotkine (1, 2, 3, 4) , Bich-Thuy Doan (5, 2, 4) , Catherine Marchand-Leroux (1, 2, 3, 4) , Isabelle Margaill (1, 2, 3, 4)

1 EA 4475 - Pharmacologie de la circulation cérébrale
2 UPD5 - Université Paris Descartes - Paris 5
3 USPC - Université Sorbonne Paris Cité
4 UPD5 Pharmacie - Faculté de Pharmacie de Paris - Université Paris Descartes
5 UPCGI - UMR 8151 / UMR_S 1022 - Unité de pharmacologie chimique et génétique et d'imagerie
6 ENSCP - Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL
7 LBHE - Laboratoire de Physiopathologie de la Barrière Hémato-Encéphalique
8 CBM - Centre de biophysique moléculaire

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.) 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.

Mots clés: Blood–brain barrier; Cerebral ischemia; Functional deficits; Hemorrhagic transformation; N-(6-Oxo-5; 6-dihydrophenanthridin-2-yl)-(N; N-dimethylamino)acetamide hydrochloride; PARP; PJ34; Poly(ADP-ribose)polymerase; Poly(ADP-ribose)polymerase (PARP); Recombinant tissue plasminogen activator (rt-PA); recombinant tissue plasminogen activator; rt-PA

Domaines: Sciences du Vivant [q-bio]

Fei Teng, Virginie Beray-Berthat, Bérard Coqueran, Clémentine Lesbats, Mélanie Kuntz, et al.. Prevention of rt-PA induced blood–brain barrier component degradation by the poly(ADP-ribose)polymerase inhibitor PJ34 after ischemic stroke in mice. Experimental Neurology, 2013, 248, pp.416-428. ⟨10.1016/j.expneurol.2013.07.007⟩. ⟨hal-02070926⟩