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

Autor: Frédéric Szeremeta, Niamh Slane, Marie Garraud, Isabelle Margaill, Bérard Coqueran, Catherine Marchand-Leroux, Michel Plotkine, Mélanie Kuntz, Clémentine Lesbats, Vincent Berezowski, Virginie Beray-Berthat, Daniel Scherman, Fei Teng, Cyrielle Bedfert, Bich-Thuy Doan, Bruno Palmier, Johan Hachani
Přispěvatelé: Pharmacologie de la circulation cérébrale (EA 4475), Université Paris Descartes - Paris 5 (UPD5), Université Sorbonne Paris Cité (USPC), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Unité de pharmacologie chimique et génétique et d'imagerie (UPCGI - UMR 8151 / UMR_S 1022 ), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL (ENSCP), Laboratoire de Physiopathologie de la Barrière Hémato-Encéphalique (LBHE), Université d'Artois (UA), Centre de biophysique moléculaire (CBM), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut de Chimie du CNRS (INC), Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL), Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Poly ADP ribose polymerase
[SDV]Life Sciences [q-bio]
Ischemia
Pharmacology
Poly(ADP-ribose) Polymerase Inhibitors
Blood–brain barrier
Poly (ADP-Ribose) Polymerase Inhibitor
Brain Ischemia
Functional deficits
PARP
03 medical and health sciences
Mice
0302 clinical medicine
Developmental Neuroscience
N-dimethylamino)acetamide hydrochloride
PJ34
medicine
Animals
rt-PA
Stroke
030304 developmental biology
Poly(ADP-ribose)polymerase (PARP)
6-dihydrophenanthridin-2-yl)-(N
0303 health sciences
business.industry
Hemorrhagic transformation
Brain
N-(6-Oxo-5
Poly(ADP-ribose)polymerase
Phenanthrenes
Cerebral ischemia
medicine.disease
Molecular biology
In vitro
3. Good health
Disease Models
Animal
medicine.anatomical_structure
Neurology
Blood-Brain Barrier
Tissue Plasminogen Activator
Recombinant tissue plasminogen activator (rt-PA)
Toxicity
PARP inhibitor
recombinant tissue plasminogen activator
business
030217 neurology & neurosurgery
Zdroj: Experimental Neurology
Experimental Neurology, Elsevier, 2013, 248, pp.416-428. ⟨10.1016/j.expneurol.2013.07.007⟩
ISSN: 0014-4886
1090-2430
DOI: 10.1016/j.expneurol.2013.07.007⟩
Popis: International audience; 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.
Databáze: OpenAIRE
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