Activated protein C analog with reduced anticoagulant activity improves functional recovery and reduces bleeding risk following controlled cortical impact.
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.
Walker
Corey T
CT
Center for Neurodegenerative and Vascular Brain Disorders, University of Rochester Medical Center, Arthur Kornberg Medical Research Building, 601 Elmwood Ave, Box 670, Rochester, New York 14642, USA.
Marky
Andrew H
AH
Petraglia
Anthony L
AL
Ali
Tracy
T
Chow
Nienwen
N
Zlokovic
Berislav V
BV
D000818:Animals; D000925:Anticoagulants / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use*; D001522:Behavior, Animal; D001930:Brain Injuries / Q000150:complications; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004195:Disease Models, Animal; D006470:Hemorrhage / Q000188:drug therapy* / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D011597:Psychomotor Performance / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D020127:Recovery of Function / Q000187:drug effects*; D013997:Time Factors
D000925:Anticoagulants; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D011493:Protein Kinase C