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 multiclose APC, compared with vehicle, showed significantly improved motor function on all tests. In the single-dose and multiclose 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. CONCLUSION: 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.