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Scientific article
English

Recombinant tissue plasminogen activator induces blood-brain barrier breakdown by a matrix metalloproteinase-9-independent pathway after transient focal cerebral ischemia in mouse

Published inEuropean journal of neuroscience, vol. 34, no. 7, p. 1085-1092
Publication date2011
Abstract

The role of the inducible matrix metalloproteinase (MMP)-9 in blood-brain barrier (BBB) disruption after ischemic stroke is well accepted. Recombinant tissue plasminogen activator (r-tPA) is the only approved thrombolytic treatment of ischemic stroke but r-tPA is potentially neurotoxic. Vasogenic edema after r-tPA treatment has been linked with an increase in cerebral MMP-9. However, because cerebral ischemia clearly increases the levels of endogenous tPA, the consequence of additional r-tPA may be questionable. In this study, wild type and MMP-9 knockout mice were subjected to 90 min transient middle cerebral artery occlusion and treated with 10 mg/kg r-tPA. At 24 h after occlusion, BBB permeability, hemispheric enlargement, collagen and laminin degradation as well as cerebral infarction were increased in both wild type and MMP-9 knockout treated animals as compared with non-treated animals. Mortality was increased in wild type but reduced in knockout treated mice. Cerebral MMP-9 concentration was not modified by r-tPA. However, pre-treatment with p-aminobenzoyl-gly-pro-D-leu-D-ala-hydroxamate, a broad-spectrum MMP inhibitor, counteracted the effects of r-tPA on the neurovascular unit and decreased mortality in both wild type and knockout mice. MMP inhibition did not modify cerebral infarction in r-tPA-treated animals. Our results suggest that r-tPA toxicity is mainly independent of MMP-9 after transient middle cerebral artery occlusion but could involve some other MMPs. Additionally, our results support the hypothesis of a dissociation between r-tPA-dependent mechanisms of BBB breakdown and cerebral infarction. Due to the importance of r-tPA in thrombolytic treatment of ischemic stroke patients, the MMPs that could participate in r-tPA-induced BBB disruption should be further characterized.

Keywords
  • Animals
  • Blood-Brain Barrier/drug effects/metabolism/pathology
  • Brain Ischemia/metabolism/pathology
  • Collagen Type IV/metabolism
  • Fibrinolytic Agents/pharmacology
  • Laminin/metabolism
  • Male
  • Matrix Metalloproteinase 9/genetics/metabolism
  • Mice
  • Mice, Knockout
  • Stroke/metabolism/pathology
  • Tissue Plasminogen Activator/pharmacology
Citation (ISO format)
COPIN, Jean-Christophe et al. Recombinant tissue plasminogen activator induces blood-brain barrier breakdown by a matrix metalloproteinase-9-independent pathway after transient focal cerebral ischemia in mouse. In: European journal of neuroscience, 2011, vol. 34, n° 7, p. 1085–1092. doi: 10.1111/j.1460-9568.2011.07843.x
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Article (Published version)
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ISSN of the journal0953-816X
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