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

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
  • 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

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research network!

Choose Username:
Verify Password: