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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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