title: 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.affiliation: Equipe de recherche "Pharmacologie de la Circulation Cérébrale" EA4475, Université Paris Descartes, Sorbonne Paris Cité, Faculté des Sciences Pharmaceutiques et Biologiques, Paris, France.
authors.forename: Fei
authors.initials: F
authors.lastname: Teng
authors.forename: Virginie
authors.initials: V
authors.lastname: Beray-Berthat
authors.forename: Bérard
authors.initials: B
authors.lastname: Coqueran
authors.forename: Clémentine
authors.initials: C
authors.lastname: Lesbats
authors.forename: Mélanie
authors.initials: M
authors.lastname: Kuntz
authors.forename: Bruno
authors.initials: B
authors.lastname: Palmier
authors.forename: Marie
authors.initials: M
authors.lastname: Garraud
authors.forename: Cyrielle
authors.initials: C
authors.lastname: Bedfert
authors.forename: Niamh
authors.initials: N
authors.lastname: Slane
authors.forename: Vincent
authors.initials: V
authors.lastname: Bérézowski
authors.forename: Frédéric
authors.initials: F
authors.lastname: Szeremeta
authors.forename: Johan
authors.initials: J
authors.lastname: Hachani
authors.forename: Daniel
authors.initials: D
authors.lastname: Scherman
authors.forename: Michel
authors.initials: M
authors.lastname: Plotkine
authors.forename: Bich-Thuy
authors.initials: BT
authors.lastname: Doan
authors.forename: Catherine
authors.initials: C
authors.lastname: Marchand-Leroux
authors.forename: Isabelle
authors.initials: I
authors.lastname: Margaill
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D051379:Mice; D010616:Phenanthrenes / Q000494:pharmacology / Q000627:therapeutic use*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000009:adverse effects* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D010959:Tissue Plasminogen Activator
keywords: 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