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Brain Res. 2013 Apr 24;1507:97-104. doi: 10.1016/j.brainres.2013.02.023. Epub 2013 Feb 21.

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

Author information

1
Center for Neurodegeneration and Regeneration, Zilkha Neurogenetic Institute, Department of Physiology and Biophysics, University of Southern California, Keck School of Medicine, Los Angeles, CA 90089, USA.

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.

PMID:
23438513
PMCID:
PMC3739836
DOI:
10.1016/j.brainres.2013.02.023
[Indexed for MEDLINE]
Free PMC Article

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