Activated protein C analog with reduced anticoagulant activity improves functional recovery and reduces bleeding risk following controlled cortical impact

Brain Res. 2010 Aug 6;1347:125-31. doi: 10.1016/j.brainres.2010.05.075. Epub 2010 Jun 1.

Abstract

The anticoagulant activated protein C (APC) protects neurons and vascular cells from injury through its direct cytoprotective effects that are independent of its anticoagulant action. Wild-type recombinant murine APC (wt-APC) exerts significant neuroprotection in mice if administered early after traumatic brain injury (TBI). Here, we compared efficacy and safety of a late therapy for TBI with wt-APC and 3K3A-APC, an APC analog with approximately 80% reduced anticoagulant activity but normal cytoprotective activity, using a controlled cortical impact model of TBI. Mice received 0.8 mg/kg intraperitoneally of recombinant murine 3K3A-APC, wt-APC or saline at 6, 12, 24 and 48 h after injury. 3K3A-APC (n=15) relative to wt-APC (n=15) improved motor and sensorimotor recovery within the first three days post-trauma as demonstrated by rotarod (p<0.05) and beam balance test (p<0.05), respectively. Both, wt-APC and 3K3A-APC reduced the lesion volume seven days after injury by 36% (n=8; p<0.01) and 56% (n=8; p<0.01), respectively, compared to saline (n=8). Three days post-TBI, the hemoglobin levels in the injured brain were increased by approximately 3-fold after wt-APC treatment compared to saline indicating an increased risk for intracerebral bleeding. In contrast, comparable levels of brain hemoglobin in 3K3A-APC-treated and saline-treated mice suggested that 3K3A-APC treatment did not increase risk for bleeding after TBI. Thus, compared to wt-APC, 3K3A-APC is more efficacious and safer therapy for TBI with no risk for intracerebral hemorrhage.

Publication types

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

MeSH terms

  • Animals
  • Anticoagulants / metabolism
  • Anticoagulants / pharmacology*
  • Anticoagulants / therapeutic use*
  • Behavior, Animal
  • Brain Injuries / complications
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Disease Models, Animal
  • Hemorrhage / drug therapy*
  • Hemorrhage / etiology
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Motor Activity / physiology
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use*
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Psychomotor Performance / drug effects
  • Recombinant Proteins / pharmacology
  • Recombinant Proteins / therapeutic use
  • Recovery of Function / drug effects*
  • Time Factors

Substances

  • Anticoagulants
  • Neuroprotective Agents
  • Recombinant Proteins
  • Protein Kinase C