Activated protein C analog promotes neurogenesis and improves neurological outcome after focal ischemic stroke in mice via protease activated receptor 1.

Abstract

3K3A-APC is a recombinant analog of activated protein C (APC) which is an endogenous protease with multiple functions in the body. Compared to APC, 3K3A-APC has reduced anticoagulant activity but preserved cell signaling activities. In the brain, 3K3A-APC exerts neuroprotective effects after an acute or chronic injury. 3K3A-APC is currently under clinical assessment as a neuroprotective agent following acute ischemic stroke. Whether 3K3A-APC can influence post-ischemic neurogenesis and improve neurological outcome by promoting brain repair remains unknown. Here we show that murine 3K3A-APC 0.8mg/kg intraperitoneally given at 12h, 1, 3, 5 and 7 days after permanent distal middle cerebral artery occlusion (dMCAO) in mice compared to vehicle improves significantly sensorimotor and locomotor activity 7 and 14 days after stroke, reduces infarct and edema volumes 7 days after stroke by 43% (P<0.05) and 50% (P<0.05), respectively, increases the number of newly formed neuroblasts in the subventricular zone, corpus callosum and the peri-infarct area 7 days after stroke by 2.2-fold, 2.3-fold and 2.2-fold (P<0.05), respectively, and increases the cortical width index 14 days after stroke by 28% (P<0.05). Functional outcome in 3K3A-APC-treated group, but not in vehicle-treated group, correlated inversely with the reductions in the infarct volume, and positively with the number of neuroblasts migrating in the peri-infarct area and the cortical width index. The effects of 3K3A-APC on neuroprotection, neurogenesis and brain repair were lost in protease activated receptor 1 (PAR1) deficient mice. Thus, late therapy with 3K3A-APC is neuroprotective and promotes stroke-induced neurogenesis and repair through PAR1 in mice.

• Authors: Yaoming Wang, Zhen Zhao, Nienwen Chow, Tracy Ali, John H Griffin, Berislav V Zlokovic
• Journal: Brain research (Brain Res) Vol. 1507 Pg. 97-104 (Apr 24 2013) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 23438513 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• 3K3A-APC protein
• Neuroprotective Agents
• Protein C
• Receptor, PAR-1
• Recombinant Proteins

Topics

• Animals
• Brain Ischemia (drug therapy, physiopathology)
• Infarction, Middle Cerebral Artery (physiopathology)
• Locomotion (drug effects)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Neurogenesis (drug effects)
• Neuroprotective Agents (administration & dosage, therapeutic use)
• Protein C (administration & dosage, therapeutic use)
• Receptor, PAR-1 (genetics, physiology)
• Recombinant Proteins (administration & dosage, therapeutic use)
• Recovery of Function
• Stroke (drug therapy, physiopathology)