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.

• Authors: Meenakshisundaram Thiyagarajan, José A Fernández, Steven M Lane, John H Griffin, Berislav V Zlokovic
• Journal: The 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
• PMID: 19036971 (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