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

• Published in: Molecular neurobiology Vol. 55; no. 12; pp. 9156 - 9168
• Main Authors: El Amki, Mohamad, Lerouet, Dominique, Garraud, Marie, Teng, Fei, Beray-Berthat, Virginie, Coqueran, Bérard, Barsacq, Benoît, Abbou, Charlotte, Palmier, Bruno, Marchand-Leroux, Catherine, Margaill, Isabelle
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-12-2018; Springer Nature B.V; Humana Press
• Subjects: Adenosine diphosphate; Animals; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Brain injury; Cell adhesion & migration; Cell adhesion molecules; Cell Biology; Combined treatment; Cortex; Edema; Edema - complications; Edema - drug therapy; Edema - pathology; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Hemorrhage; Hemorrhage - complications; Hemorrhage - drug therapy; Hemorrhage - pathology; Immunohistochemistry; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - pathology; Inflammation - pathology; Injection; Ischemia; Life Sciences; Male; Mice; Neurobiology; Neurology; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neurosciences; Phenanthrenes - pharmacology; Phenanthrenes - therapeutic use; Poly(ADP-ribose) polymerase; 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; Ribose; Sensorimotor system; Stroke; Stroke - complications; Stroke - drug therapy; Stroke - pathology; t-Plasminogen activator; Thrombin; Thrombolysis; Thrombosis - complications; Thrombosis - drug therapy; Thrombosis - pathology; Tissue Plasminogen Activator - administration & dosage; Tissue Plasminogen Activator - pharmacology; Tissue Plasminogen Activator - therapeutic use; Treatment Outcome; Vascular cell adhesion molecule 1; Vasoconstriction; Vasospasm, Intracranial - complications; Vasospasm, Intracranial - drug therapy; Vasospasm, Intracranial - pathology; Stroke; Recombinant tissue plasminogen activator; Reperfusion; Vasculoprotection
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-018-1063-3

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.