New thrombolytic strategy providing neuroprotection in experimental ischemic stroke: MMP10 alone or in combination with tissue-type plasminogen activator

• Published in: Cardiovascular research 2017-08, Vol.113 (10), p.1219-1229
• Main Authors: Roncal, Carmen, Martinez de Lizarrondo, Sara, Salicio, Agustina, Chevilley, Arnaud, Rodriguez, Jose A, Rosell, Anna, Couraud, Pierre-Olivier, Weksler, Babette, Montaner, Joan, Vivien, Denis, Páramo, Jose A, Orbe, Josune
• Format: Article
• Language: English
• Subjects: Animals; Behavior, Animal - drug effects; Brain - drug effects; Brain - metabolism; Brain - pathology; Brain - physiopathology; Calcium Signaling - drug effects; Capillary Permeability - drug effects; Cell Survival - drug effects; Cells, Cultured; Claudin-5 - metabolism; Disease Models, Animal; Drug Therapy, Combination; Electric Impedance; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelial Cells - pathology; Fibrinolytic Agents - administration & dosage; Fibrinolytic Agents - toxicity; Humans; Infarction, Middle Cerebral Artery - metabolism; Infarction, Middle Cerebral Artery - pathology; Infarction, Middle Cerebral Artery - physiopathology; Infarction, Middle Cerebral Artery - prevention & control; Male; Matrix Metalloproteinase 10 - administration & dosage; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - metabolism; Motor Activity - drug effects; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotective Agents - administration & dosage; Thrombolytic Therapy - adverse effects; Thrombolytic Therapy - methods; Time Factors; Tissue Plasminogen Activator - administration & dosage; Tissue Plasminogen Activator - toxicity
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1093/cvr/cvx069

Early reperfusion with tissue-type plasminogen activator (tPA) is an effective therapeutic strategy to treat acute ischemic stroke, but only 1/3 of tPA-treated patients recover and are free from disability. tPA has also shown neurotoxicity in experimental models of cerebral ischemia. Considering that MMP-10 improves stroke injury, we have examined the therapeutic and protective effect of MMP10 and tPA/MMP10 as clot-dissolving and neuroprotective agent in an experimental model of ischemic stroke and studied in vitro the molecular pathways involved in MMP10-mediated effects. Cerebral ischemia was induced by the local injection of thrombin into the middle cerebral artery followed by reperfusion with MMP10 (6.5 µg/kg) and tPA (10 mg/kg) alone or in combination with MMP10. Cell cultures were also performed to determine the effect of MMP10 and tPA/MMP10 on brain endothelial cells and neurons. tPA/MMP10 significantly reduced the infarct size in the ischemic stroke model compared with tPA alone (P