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Translational Stroke Research

, Volume 10, Issue 4, pp 389–401 | Cite as

MMP10 Promotes Efficient Thrombolysis After Ischemic Stroke in Mice with Induced Diabetes

  • Manuel Navarro-Oviedo
  • Carmen Roncal
  • Agustina Salicio
  • Miriam Belzunce
  • Obdulia Rabal
  • Estefanía Toledo
  • Beatriz Zandio
  • Jose A. Rodríguez
  • Jose A. Páramo
  • Roberto Muñoz
  • Josune OrbeEmail author
Original Article

Abstract

Diabetes is an important risk factor for ischemic stroke (IS). Tissue-type plasminogen activator (tPA) has been associated with less successful revascularization and poor functional outcome in diabetes. We assessed whether a new thrombolytic strategy based on MMP10 was more effective than tPA in a murine IS model of streptozotocin (STZ)-induced diabetes. Wild-type mice were administered a single dose of streptozotocin (STZ) (180 mg/kg) to develop STZ-induced diabetes mellitus. Two weeks later, IS was induced by thrombin injection into the middle cerebral artery and the effect of recombinant MMP10 (6.5 μg/kg), tPA (10 mg/kg) or tPA/MMP10 on brain damage and functional outcome were analysed. Motor activity was assessed using the open field test. Additionally, we studied plasminogen activator inhibitor-1 (PAI-1) and thrombin-antithrombin complex levels (TAT) by ELISA and oxidative stress and blood-brain barrier (BBB) integrity by immunohistochemistry and western blot. MMP10 treatment was more effective at reducing infarct size and neurodegeneration than tPA 24 h and 3 days after IS in diabetic mice. Locomotor activity was impaired by hyperglycemia and ischemic injury, but not by the thrombolytic treatments. Additionally, TAT, oxidative stress and BBB permeability were reduced by MMP10 treatment, whereas brain bleeding or PAI-1 expression did not differ between treatments. Thrombolytic treatment with MMP10 was more effective than tPA at reducing stroke and neurodegeneration in a diabetic murine model of IS, without increasing haemorrhage. Thus, we propose MMP10 as a potential candidate for the clinical treatment of IS in diabetic patients.

Keywords

Fibrinolysis Thrombosis Stroke, diabetes mellitus Matrix metalloproteinases 

Notes

Acknowledgements

We thank Lara Montori for the help with the experimental work and Rosa Tordera and Mikel Aleixo from Pharmacology and Toxicology Department, University of Navarra for their technical assistance with behavioural tests.

Author’s Contribution

MNO participated in the design of the project, experimental work, statistical analysis, and wrote, reviewed, and edited the manuscript; CR participated in the design of the project and reviewed the manuscript. AS was in charge of the animal experiments; MB performed histological studies; OR participated in the design of the project and reviewed the manuscript; ET participated in the statistical analysis and reviewed the manuscript; BZ participated in the design of the project and reviewed the manuscript; JAR participated in the design of the project and reviewed the manuscript; JAP participated in the design of the project, supervised the work, and edited and reviewed the manuscript; RM participated in the design of the project and edited and reviewed the manuscript; JO was in charge of the whole project design, supervised the work, and wrote, edited, and reviewed this manuscript.

Funding

This work was supported by the Ministerio de Economía y Competitividad, Instituto de Salud Carlos III [FIS PI15/01807] and Federal Ministry of Education and Research (FEDER) funds; grants from the Spanish Society of Thrombosis and Haemostasis (SETH), Navarra Government (02/2015), Patrimonio Praga (Mexico) and Virto Group (Navarra, Spain); and PhD scholarship from the Asociación de Amigos de la Universidad de Navarra (ADA).

Compliance with Ethical Standards

Experiments were performed in accordance with European Communities Council Directive guidelines (2010/63/EU) for the care and use of laboratory animals and were approved by the University of Navarra Animal Research Review Committee.

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All animal experiments were performed in accordance with European Communities Council Directive guidelines (2010/63/EU) for the care and use of laboratory animals and were approved by the University of Navarra Animal Research Review Committee.

Supplementary material

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Manuel Navarro-Oviedo
    • 1
  • Carmen Roncal
    • 1
    • 2
    • 3
  • Agustina Salicio
    • 1
    • 2
  • Miriam Belzunce
    • 1
  • Obdulia Rabal
    • 4
  • Estefanía Toledo
    • 3
    • 5
    • 6
  • Beatriz Zandio
    • 7
  • Jose A. Rodríguez
    • 1
    • 2
    • 3
  • Jose A. Páramo
    • 2
    • 3
    • 8
  • Roberto Muñoz
    • 3
    • 7
  • Josune Orbe
    • 1
    • 2
    • 3
    Email author
  1. 1.Atherothrombosis Research Laboratory, Center for Applied Medical Research (CIMA)University of NavarraPamplonaSpain
  2. 2.CIBER Cardiovascular (CIBERCV), Ministry of Economy and CompetitivenessISCIIIMadridSpain
  3. 3.IdiSNA, Instituto de Investigación Sanitaria de NavarraPamplonaSpain
  4. 4.Small Molecule Discovery Platform, Molecular Therapeutics Program, Center for Applied Medical Research (CIMA)University of NavarraPamplonaSpain
  5. 5.Department of Preventive Medicine and Public Health, School of MedicineUniversity of NavarraPamplonaSpain
  6. 6.CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Ministry of Economy and CompetitivenessISCIIIPamplonaSpain
  7. 7.Neurology DepartmentComplejo Hospitalario de NavarraPamplonaSpain
  8. 8.Haematology Service, Clínica Universidad de NavarraUniversity of NavarraPamplonaSpain

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