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The Journal of Neuroscience, November 26, 2008, 28(48):12788-12797; doi:10.1523/JNEUROSCI.3485-08.2008

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Neurobiology of Disease
Activated Protein C Promotes Neovascularization and Neurogenesis in Postischemic Brain via Protease-Activated Receptor 1

Meenakshisundaram Thiyagarajan,¹ José A. Fernández,² Steven M. Lane,¹ John H. Griffin,² and Berislav V. Zlokovic¹

¹Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester Medical Center, Rochester, New York 14642, and ²Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037

Correspondence should be addressed to Dr. Berislav V. Zlokovic, Center for Neurodegenerative and Vascular Brain Disorders, 601 Elmwood Avenue, Box 670, Rochester, NY 14642. Email: berislav_zlokovic{at}urmc.rochester.edu

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 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.

Key words: activated protein C; serine protease; transient cerebral ischemia; neuroprotection; neurogenesis; angiogenesis

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Received July 24, 2008; revised Sept. 18, 2008; accepted Oct. 13, 2008.

Correspondence should be addressed to Dr. Berislav V. Zlokovic, Center for Neurodegenerative and Vascular Brain Disorders, 601 Elmwood Avenue, Box 670, Rochester, NY 14642. Email: berislav_zlokovic{at}urmc.rochester.edu

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