Combined therapy with PJ34, a poly(ADP-ribose)polymerase inhibitor, reduces tissue plasminogen activator-induced hemorrhagic transformations in cerebral ischemia in mice.

Abstract

Recombinant tissue-type plasminogen activator (rt-PA) is presently the only pharmacological treatment approved for thrombolysis in patients suffering from ischemic stroke. Although reperfusion of ischemic tissue is essential, the use of rt-PA is limited due to its narrow therapeutic window and risk of hemorrhagic transformations. Recent studies have shown that rt-PA amplifies the post-ischemic activation of the nuclear enzyme poly(ADP-ribose)polymerase (PARP). This enzyme has been shown to contribute to both the breakdown of the blood brain barrier and spontaneous hemorrhagic transformations after ischemia. We therefore examined the capacity of PJ34 (N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-2-(N,N-dimethylamino) acetamide hydrochloride), a potent inhibitor of PARP, to reduce the hemorrhagic transformations that occur after rt-PA in mice with permanent focal cerebral ischemia. Ischemia was produced by intraluminal occlusion of the left middle cerebral artery and treated with vehicle, rt-PA (10 mg/kg, i.v., 6 h after occlusion) or rt-PA plus PJ34 (3, 6 or 12 mg/kg, i.p., at ischemia onset and 4 h later). Hemorrhagic transformations, neurological examination, and infarct volumes were evaluated 48 h after the onset of ischemia. Delayed administration of rt-PA resulted in increased hemorrhagic transformations and aggravated the neurological deficit. Giving PJ34 (3 mg/kg) markedly reduced the hemorrhagic transformations, an effect not owing to a modification of matrix metalloprotease activity. Furthermore, PJ34 improved the neurological functions of rt-PA-treated ischemic mice. To conclude, the PARP inhibitor PJ34 makes rt-PA safer in experimental ischemic stroke.

• Authors: Marianne Haddad, Virginie Beray-Berthat, Bérard Coqueran, Michel Plotkine, Catherine Marchand-Leroux, Isabelle Margaill
• Journal: Fundamental & clinical pharmacology (Fundam Clin Pharmacol) Vol. 27 Issue 4 Pg. 393-401 (Aug 2013) ISSN: 1472-8206 [Electronic] England
• PMID: 22436003 (Publication Type: Journal Article)
• Copyright: © 2012 The Authors Fundamental and Clinical Pharmacology © 2012 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.

Chemical References

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

Topics

• Animals
• Brain Ischemia (drug therapy, metabolism)
• Enzyme Inhibitors (pharmacology)
• Hemorrhage (drug therapy, metabolism)
• Infarction, Middle Cerebral Artery (drug therapy, metabolism)
• Male
• Matrix Metalloproteinases (metabolism)
• Mice
• Middle Cerebral Artery (drug effects, metabolism)
• Phenanthrenes (pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors
• Recombinant Proteins (pharmacology)
• Tissue Plasminogen Activator (metabolism)