Improved Reperfusion and Vasculoprotection by the Poly(ADP-Ribose)Polymerase Inhibitor PJ34 After Stroke and Thrombolysis in Mice

Mol Neurobiol. 2018 Dec;55(12):9156-9168. doi: 10.1007/s12035-018-1063-3. Epub 2018 Apr 12.


Benefits from thrombolysis with recombinant tissue plasminogen activator (rt-PA) after ischemic stroke remain limited due to a narrow therapeutic window, low reperfusion rates, and increased risk of hemorrhagic transformations (HT). Experimental data showed that rt-PA enhances the post-ischemic activation of poly(ADP-ribose)polymerase (PARP) which in turn contributes to blood-brain barrier injury. The aim of the present study was to evaluate whether PJ34, a potent PARP inhibitor, improves poor reperfusion induced by delayed rt-PA administration, exerts vasculoprotective effects, and finally increases the therapeutic window of rt-PA. Stroke was induced by thrombin injection (0.75 UI in 1 μl) in the left middle cerebral artery (MCA) of male Swiss mice. Administration of rt-PA (0.9 mg kg-1) or saline was delayed for 4 h after ischemia onset. Saline or PJ34 (3 mg kg-1) was given intraperitoneally twice, just after thrombin injection and 3 h later, or once, 3 h after ischemia onset. Reperfusion was evaluated by laser Doppler, vascular inflammation by immunohistochemistry of vascular cell adhesion molecule-1 (VCAM-1) expression, and vasospasm by morphometric measurement of the MCA. Edema, cortical lesion, and sensorimotor deficit were evaluated. Treatment with PJ34 improved rt-PA-induced reperfusion and promoted vascular protection including reduction in vascular inflammation (decrease in VCAM-1 expression), HT, and MCA vasospasm. Additionally, the combined treatment significantly reduced brain edema, cortical lesion, and sensorimotor deficit. In conclusion, the combination of the PARP inhibitor PJ34 with rt-PA after cerebral ischemia may be of particular interest in order to improve thrombolysis with an extended therapeutic window.

Keywords: Recombinant tissue plasminogen activator; Reperfusion; Stroke; Vasculoprotection.

MeSH terms

  • Animals
  • Edema / complications
  • Edema / drug therapy
  • Edema / pathology
  • Endothelial Cells / drug effects
  • Endothelial Cells / metabolism
  • Hemorrhage / complications
  • Hemorrhage / drug therapy
  • Hemorrhage / pathology
  • Infarction, Middle Cerebral Artery / drug therapy
  • Infarction, Middle Cerebral Artery / pathology
  • Inflammation / pathology
  • Male
  • Mice
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Phenanthrenes / pharmacology
  • Phenanthrenes / therapeutic use*
  • Poly(ADP-ribose) Polymerase Inhibitors / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use*
  • Proteolysis / drug effects
  • Recombinant Proteins / administration & dosage
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use
  • Reperfusion*
  • Stroke / complications
  • Stroke / drug therapy*
  • Stroke / pathology
  • Thrombosis / complications
  • Thrombosis / drug therapy*
  • Thrombosis / pathology
  • Tissue Plasminogen Activator / administration & dosage
  • Tissue Plasminogen Activator / pharmacology
  • Tissue Plasminogen Activator / therapeutic use
  • Treatment Outcome
  • Vasospasm, Intracranial / complications
  • Vasospasm, Intracranial / drug therapy
  • Vasospasm, Intracranial / pathology


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