Activated protein C is neuroprotective and mediates new blood vessel formation and neurogenesis after controlled cortical impact.
OBJECTIVE
Activated protein C (APC) is neuroprotective in stroke models and promotes postischemic neovascularization and neurogenesis. We used a controlled cortical impact (CCI) in mice to determine the effects of APC on neuroprotection and angiogenesis and neurogenesis after traumatic brain injury (TBI).


METHODS
Mice were given (1) single-dose APC (0.8 mg/kg intraperitoneally) 15 minutes after injury, (2) multidose APC (0.8 mg/kg intraperitoneally) 15 minutes and 6 to 48 hours after injury, or (3) vehicle. We then assessed the effects of APC on posttraumatic motor function with the rotarod and wire grip and beam balance tasks, and we determined the lesion volumes and studied the formation of new blood vessels and markers of neurogenesis.


RESULTS
Mice treated with single-dose or multidose APC, compared with vehicle, showed significantly improved motor function on all tests. In the single-dose and multidose APC treatment groups, at 7 days after treatment, lesion volume was significantly decreased by 30% and 50%, respectively. Multidose APC, but not single-dose APC, increased new blood vessel formation as shown by CD105(+)/Ki-67(+) double immunostaining by nearly 2-fold at 7 days. Multidose APC also promoted posttraumatic proliferation of neuroblasts in the subventricular zone (SVZ) and their migration from the SVZ to the perilesional area.


CONCLUSIONS
Activated protein C improves functional outcome and is neuroprotective after TBI. It also promotes angiogenesis and survival and migration of neuroblasts from the SVZ to the perilesional area, but the exact role of these brain repair mechanisms remains to be determined. The present findings suggest that APC therapy may hold a significant therapeutic potential for TBI.
Petraglia
Anthony L
AL
Department of Neurosurgery, University of Rochester Medical Center, Rochester, New York, USA.
Marky
Andrew H
AH
Walker
Corey
C
Thiyagarajan
Meenakshisundaram
M
Zlokovic
Berislav V
BV
D000704:Analysis of Variance; D000818:Animals; D001930:Brain Injuries / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology*; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D018737:Hand Strength / Q000502:physiology; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D009479:Neuropeptides / Q000378:metabolism; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011486:Protein C / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011597:Psychomotor Performance / Q000187:drug effects; D045442:Rotarod Performance Test; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000089622:Doublecortin Domain Proteins; D019394:Ki-67 Antigen; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D018696:Neuroprotective Agents; D011486:Protein C; D019010:Vascular Cell Adhesion Molecule-1; D001973:Bromodeoxyuridine