title: 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: 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.
authors: Yaoming
authors: Y
authors: Wang
authors: Zhen
authors: Z
authors: Zhao
authors: Nienwen
authors: N
authors: Chow
authors: Tracy
authors: T
authors: Ali
authors: John H
authors: JH
authors: Griffin
authors: Berislav V
authors: BV
authors: Zlokovic
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000503:physiopathology; D020244:Infarction, Middle Cerebral Artery / Q000503:physiopathology; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055495:Neurogenesis / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D011486:Protein C / Q000008:administration & dosage / Q000627:therapeutic use*; D044463:Receptor, PAR-1 / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D020127:Recovery of Function; D020521:Stroke / Q000188:drug therapy* / Q000503:physiopathology
chemical_list: C000591161:3K3A-APC protein; D018696:Neuroprotective Agents; D011486:Protein C; D044463:Receptor, PAR-1; D011994:Recombinant Proteins