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

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.
AuthorsMeenakshisundaram Thiyagarajan, José A Fernández, Steven M Lane, John H Griffin, Berislav V Zlokovic
JournalThe Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 28 Issue 48 Pg. 12788-97 (Nov 26 2008) ISSN: 1529-2401 [Electronic] United States
PMID19036971 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Protein C
  • Receptor, PAR-1
  • Tissue Plasminogen Activator
Topics
  • Animals
  • Blood-Brain Barrier (drug effects, metabolism, physiopathology)
  • Brain (enzymology, metabolism, physiopathology)
  • Brain Infarction (drug therapy, enzymology, physiopathology)
  • Brain Ischemia (drug therapy, enzymology, physiopathology)
  • Cell Movement (drug effects, physiology)
  • Cell Proliferation (drug effects)
  • Cerebral Arteries (enzymology, metabolism, physiopathology)
  • Disease Models, Animal
  • Enzyme Activation (physiology)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neovascularization, Physiologic (drug effects, physiology)
  • Nerve Regeneration (physiology)
  • Neurogenesis (drug effects, physiology)
  • Protein C (metabolism, pharmacology)
  • Receptor, PAR-1 (genetics)
  • Recovery of Function (drug effects, physiology)
  • Reperfusion Injury (enzymology, physiopathology)
  • Tissue Plasminogen Activator (toxicity)
  • Treatment Outcome

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