title: New thrombolytic strategy providing neuroprotection in experimental ischemic stroke: MMP10 alone or in combination with tissue-type plasminogen activator.
abstract: OBJECTIVE
  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.
  
  
  RESULTS
  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 < 0.05). In vitro, MMP10 reduced the tPA-promoted endothelial ionic permeability, preserved the expression of claudin-5 and decreased ERK1/2 activation. Moreover, combination of tPA/MMP10 prevented tPA-mediated neuronal excitotoxicity and calcium influx. These effects were reversed by blocking MMP10 activity with a monoclonal antibody.
  
  
  CONCLUSIONS
  These results show that MMP10, either alone or in combination with tPA, might represent a new strategy for thrombolysis in ischemic stroke, providing higher protection against cerebrovascular damage.
authors.affiliation: Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, IdiSNA, CIMA Building, Av. Pio XII, 55, 31008 Pamplona, Navarra, Spain.|CIBERCV, Ministry of Economy and Competitiveness, ISCIII, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Roncal
authors.affiliation: INSERM, UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit (SP2U), Caen, France.
authors.forename: Sara
authors.initials: S
authors.lastname: Martinez de Lizarrondo
authors.affiliation: Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, IdiSNA, CIMA Building, Av. Pio XII, 55, 31008 Pamplona, Navarra, Spain.
authors.forename: Agustina
authors.initials: A
authors.lastname: Salicio
authors.affiliation: INSERM, UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit (SP2U), Caen, France.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Chevilley
authors.affiliation: Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, IdiSNA, CIMA Building, Av. Pio XII, 55, 31008 Pamplona, Navarra, Spain.|CIBERCV, Ministry of Economy and Competitiveness, ISCIII, Spain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Rodriguez
authors.affiliation: Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Rosell
authors.affiliation: Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Couraud
authors.affiliation: Weill Cornell Medical College, Medicine Division of Hematology/Oncology, New York, NY, USA.
authors.forename: Babette
authors.initials: B
authors.lastname: Weksler
authors.affiliation: Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
authors.affiliation: INSERM, UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit (SP2U), Caen, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
authors.affiliation: Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, IdiSNA, CIMA Building, Av. Pio XII, 55, 31008 Pamplona, Navarra, Spain.|CIBERCV, Ministry of Economy and Competitiveness, ISCIII, Spain.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Páramo
authors.affiliation: Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, IdiSNA, CIMA Building, Av. Pio XII, 55, 31008 Pamplona, Navarra, Spain.|CIBERCV, Ministry of Economy and Competitiveness, ISCIII, Spain.
authors.forename: Josune
authors.initials: J
authors.lastname: Orbe
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020013:Calcium Signaling / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D062507:Claudin-5 / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000633:toxicity; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D053506:Matrix Metalloproteinase 10 / Q000008:administration & dosage*; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D015912:Thrombolytic Therapy / Q000009:adverse effects / Q000379:methods*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000633:toxicity
chemical_list: D062507:Claudin-5; C491511:Cldn5 protein, mouse; D005343:Fibrinolytic Agents; D018696:Neuroprotective Agents; C535148:Mapk1 protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010959:Tissue Plasminogen Activator; C511770:MMP10 protein, human; D053506:Matrix Metalloproteinase 10
keywords: Matrix metalloproteinases; Neuronal protection; Stroke; Thrombolytic therapy; tPA