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

Apr 6, 2017Cardiovascular research

New blood clot treatment that may protect the brain in experimental stroke using MMP10 alone or with tissue-type plasminogen activator

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Abstract

tPA/MMP10 significantly reduced infarct size in an ischemic stroke model compared with tPA alone (P < 0.05).

MMP10 may improve stroke injury by enhancing neuroprotection in ischemic conditions.
In vitro studies indicated that MMP10 reduced tPA-promoted permeability in brain endothelial cells.
MMP10 preserved the expression of claudin-5 and decreased activation of ERK1/2.
The combination of tPA and MMP10 prevented neuronal excitotoxicity and calcium influx associated with tPA.
Blocking MMP10 activity with a monoclonal antibody reversed its protective effects.

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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 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.

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