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.
Thiyagarajan
Meenakshisundaram
M
Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester Medical Center, Rochester, New York 14642, USA.
Fernández
José A
JA
Lane
Steven M
SM
Griffin
John H
JH
Zlokovic
Berislav V
BV
D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D020520:Brain Infarction / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002536:Cerebral Arteries / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D009416:Nerve Regeneration / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects* / Q000502:physiology; D011486:Protein C / Q000378:metabolism / Q000494:pharmacology*; D044463:Receptor, PAR-1 / Q000235:genetics*; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D015427:Reperfusion Injury / Q000201:enzymology / Q000503:physiopathology; D010959:Tissue Plasminogen Activator / Q000633:toxicity; D016896:Treatment Outcome
D011486:Protein C; D044463:Receptor, PAR-1; D010959:Tissue Plasminogen Activator