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Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease-activated receptor 1

Academic Article
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Overview

authors

  • Thiyagarajan, M.
  • Fernandez, J. A.
  • Lane, S. M.
  • Griffin, John
  • Zlokovic, B. V.

publication date

  • November 2008

journal

  • Journal of Neuroscience  Journal

abstract

  • Activated protein C (APC) is a serine protease with anticoagulant and direct cytoprotective activities. Early postischemic APC application activates the cellular protein C pathway in brain endothelium and neurons, which is neuroprotective. Whether late APC administration after a transient ischemic attack is neuroprotective and whether APC influences brain repair is not known. Here, we determined safety and efficacy of late APC and tissue-plasminogen activator (tPA) administrations in a mouse model of transient brain ischemia. tPA given at 6 h after onset of ischemia killed all mice within 2 d, whereas APC given at 6 or 24 h after ischemia onset improved significantly functional outcome and reduced spread of the ischemic lesion. At 7 d postischemia, APC multiple dosing (0.8 mg/kg, i.p.) at 6-72 or 72-144 h enhanced comparably cerebral perfusion in the ischemic border by approximately 40% as shown by in vivo lectin-FITC angiography, blocked blood-brain barrier leakage of serum proteins, and increased the number of endothelial replicating cells by 4.5- to 4.7-fold. APC multidosing at 6-72 h or 72-144 h increased proliferation of neuronal progenitor cells in the subventricular zone (SVZ) by 40-50% and migration of newly formed neuroblasts from the SVZ toward the ischemic border by approximately twofold. The effects of APC on neovascularization and neurogenesis were mediated by protease-activated receptor 1 and were independent of the reduction by APC of infarction volume. Our data show that delayed APC administration is neuroprotective and mediates brain repair (i.e., neovascularization and neurogenesis), suggesting a significant extension of the therapeutic window for APC intervention in postischemic brain.

subject areas

  • Animals
  • Blood-Brain Barrier
  • Brain
  • Brain Infarction
  • Brain Ischemia
  • Cell Movement
  • Cell Proliferation
  • Cerebral Arteries
  • Disease Models, Animal
  • Enzyme Activation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Physiologic
  • Nerve Regeneration
  • Neurogenesis
  • Protein C
  • Receptor, PAR-1
  • Recovery of Function
  • Reperfusion Injury
  • Tissue Plasminogen Activator
  • Treatment Outcome
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Research

keywords

  • activated protein C
  • angiogenesis
  • neurogenesis
  • neuroprotection
  • serine protease
  • transient cerebral ischemia
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Identity

PubMed Central ID

  • PMC2742231

International Standard Serial Number (ISSN)

  • 0270-6474

Digital Object Identifier (DOI)

  • 10.1523/jneurosci.3485-08.2008

PubMed ID

  • 19036971
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Additional Document Info

start page

  • 12788

end page

  • 12797

volume

  • 28

issue

  • 48

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