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

ABSTRACT

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.