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

Exp Neurol. 2013 Oct;248:416-28. doi: 10.1016/j.expneurol.2013.07.007. Epub 2013 Jul 20.

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.

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.

MeSH terms

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

Substances

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