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Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C

Academic Article
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Overview

authors

  • Liu, D.
  • Cheng, T.
  • Guo, H.
  • Fernandez, J. A.
  • Griffin, John
  • Song, X. M.
  • Zlokovic, B. V.

publication date

  • December 2004

journal

  • Nature Medicine  Journal

abstract

  • Although thrombolytic effects of tissue plasminogen activator (tPA) are beneficial, its neurotoxicity is problematic. Here, we report that tPA potentiates apoptosis in ischemic human brain endothelium and in mouse cortical neurons treated with N-methyl-D-aspartate (NMDA) by shifting the apoptotic pathways from caspase-9 to caspase-8, which directly activates caspase-3 without amplification through the Bid-mediated mitochondrial pathway. In vivo, tPA-induced cerebral ischemic injury in mice was reduced by intracerebroventricular administration of caspase-8 inhibitor, but not by caspase-9 inhibitor, in contrast to controls in which caspase-9 inhibitor, but not caspase-8 inhibitor, was protective. Activated protein C (APC), a serine protease with anticoagulant, anti-inflammatory and antiapoptotic activities, which is neuroprotective during transient ischemia and promotes activation of antiapoptotic mechanisms in brain cells by acting directly on endothelium and neurons, blocked tPA vascular and neuronal toxicities in vitro and in vivo. APC inhibited tPA-induced caspase-8 activation of caspase-3 in endothelium and caspase-3-dependent nuclear translocation of apoptosis-inducing factor in NMDA-treated neurons and reduced tPA-mediated cerebral ischemic injury in mice. Data suggest that tPA shifts the apoptotic signal in stressed brain cells from the intrinsic to the extrinsic pathway which requires caspase-8. APC blocks tPA's neurovascular toxicity and may add substantially to the effectiveness of tPA therapy for stroke.

subject areas

  • Animals
  • Apoptosis
  • Brain
  • Brain Ischemia
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspase Inhibitors
  • Caspases
  • Cells, Cultured
  • Endothelial Cells
  • Humans
  • Immunoblotting
  • In Situ Nick-End Labeling
  • Mice
  • Mice, Inbred C57BL
  • N-Methylaspartate
  • Neurons
  • Protein C
  • Time Factors
  • Tissue Plasminogen Activator
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Identity

International Standard Serial Number (ISSN)

  • 1078-8956

Digital Object Identifier (DOI)

  • 10.1038/nm1122

PubMed ID

  • 15516929
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Additional Document Info

start page

  • 1379

end page

  • 1383

volume

  • 10

issue

  • 12

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