Carmen Roncal1,2, Sara Martinez de Lizarrondo3, Agustina Salicio1, Arnaud Chevilley3, Jose A Rodriguez1,2, Anna Rosell4, Pierre-Olivier Couraud5, Babette Weksler6, Joan Montaner4, Denis Vivien3, Jose A Páramo1,2, Josune Orbe1,2. 1. Laboratory of Atherothrombosis, Program of Cardiovascular Diseases, CIMA-University of Navarra, IdiSNA, CIMA Building, Av. Pio XII, 55, 31008 Pamplona, Navarra, Spain. 2. CIBERCV, Ministry of Economy and Competitiveness, ISCIII, Spain. 3. INSERM, UMR-S 919, Serine Proteases and Pathophysiology of the Neurovascular Unit (SP2U), Caen, France. 4. Neurovascular Research Laboratory, Vall d'Hebron Research Institute, Universitat Autònoma de Barcelona, Barcelona, Spain. 5. Institut Cochin, INSERM U1016, CNRS UMR 8104, Université Paris Descartes, Sorbonne Paris Cité, Paris, France. 6. Weill Cornell Medical College, Medicine Division of Hematology/Oncology, New York, NY, USA.
Abstract
AIMS: 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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. METHODS AND 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Manuel Navarro-Oviedo; Carmen Roncal; Agustina Salicio; Miriam Belzunce; Obdulia Rabal; Estefanía Toledo; Beatriz Zandio; Jose A Rodríguez; Jose A Páramo; Roberto Muñoz; Josune Orbe Journal: Transl Stroke Res Date: 2018-07-27 Impact factor: 6.829
Authors: Monica Diez-Fairen; Gabrielle Houle; Sara Ortega-Cubero; Sara Bandres-Ciga; Ignacio Alvarez; Maria Carcel; Laura Ibañez; Maria Victoria Fernandez; John P Budde; Jean-Rémi Trotta; Raúl Tonda; Jessica X Chong; Michael J Bamshad; Deborah A Nickerson; Miquel Aguilar; Juan P Tartari; Alexandre Gironell; Elena García-Martín; Jose Ag Agundez; Hortensia Alonso-Navarro; Felix Javier Jimenez-Jimenez; Manel Fernandez; Francesc Valldeoriola; Maria Jose Marti; Eduard Tolosa; Francisco Coria; Maria A Pastor; Carles Vilariño-Güell; Alex Rajput; Patrick A Dion; Carlos Cruchaga; Guy A Rouleau; Pau Pastor Journal: Parkinsonism Relat Disord Date: 2020-11-24 Impact factor: 4.891
Authors: Koteswara Rao Nalamolu; Bharath Chelluboina; Ian B Magruder; Diane N Fru; Adithya Mohandass; Ishwarya Venkatesh; Jeffrey D Klopfenstein; David M Pinson; Krishna M Boini; Krishna Kumar Veeravalli Journal: Stroke Vasc Neurol Date: 2018-03-09
Authors: Manuel Navarro-Oviedo; Juan Marta-Enguita; Carmen Roncal; Jose A Rodríguez; Beatriz Zandio; Ramón Lecumberri; Jose Hermida; Julen Oyarzabal; Antonio Pineda-Lucena; Jose A Páramo; Roberto Muñoz; Josune Orbe Journal: Thromb Haemost Date: 2022-02-03 Impact factor: 6.681