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

Abstract

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.

• Authors: 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, Isabelle Margaill
• Journal: Experimental neurology (Exp Neurol) Vol. 248 Pg. 416-28 (Oct 2013) ISSN: 1090-2430 [Electronic] United States
• PMID: 23876515 (Publication Type: Journal Article)
• Copyright: © 2013.

Chemical References

• N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
• Phenanthrenes
• Poly(ADP-ribose) Polymerase Inhibitors
• Tissue Plasminogen Activator

Topics

• Animals
• Blood-Brain Barrier (drug effects, pathology)
• Brain (blood supply, drug effects, pathology)
• Brain Ischemia (drug therapy, pathology)
• Disease Models, Animal
• Mice
• Phenanthrenes (pharmacology, therapeutic use)
• Poly(ADP-ribose) Polymerase Inhibitors
• Stroke (drug therapy, pathology)
• Tissue Plasminogen Activator (adverse effects, pharmacology, therapeutic use)