Journal
CARDIOVASCULAR RESEARCH
Volume 113, Issue 10, Pages 1219-1229Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvx069
Keywords
Thrombolytic therapy; Neuronal protection; Stroke; Matrix metalloproteinases; tPA
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Funding
- Foundation for Applied Medical Research, University of Navarra (Pamplona, Spain)
- Ministerio de Economia y Competitividad (MINECO)
- Federal Ministry of Education and Research (FEDER) funds [FIS PI15/01807]
- MINECO [ERANET-Neuron] [PRI-PIMNEU-2011-1334]
- Spanish Society of Thrombosis and Hemostasis [SETH]
- Navarra Government [02/2015]
- [RD12/0042/0009]
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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 mu g/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.
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