Activated
protein C (APC), an important inhibitor of the coagulation system, has recently been shown to prevent tissue injury by blocking the activation of leukocytes. To determine whether APC can also prevent post-traumatic
spinal cord injury (SCI), a condition in which leukocytes play an important role, we tested the effects of APC on SCI induced in rats by compression
trauma. Administration of APC, either before or after the induction of SCI, markedly reduced the motor disturbances in these animals. In contrast, neither an inactive derivative of
activated factor X (
DEGR-Xa), a selective inhibitor of
thrombin generation, nor active site-blocked APC (DIP-APC) reduced the motor disturbances. Histological examination revealed that intramedullary
hemorrhages, observed 24 hr after
trauma, were significantly reduced in the animals administered APC. The increase in the tissue level of
tumor necrosis factor-alpha (
TNF-alpha) and the accumulation of neutrophils in the damaged segment of the spinal cord were significantly inhibited in the animals that had received APC, but these were not inhibited in those administered DIP-APC or
DEGR-Xa. The induction of
leukocytopenia had the same effect as APC, in that it significantly reduced motor disturbances, tissue levels of
TNF-alpha, and neutrophil accumulation in the animals subjected to compressive SCI. These findings suggest that in SCI, APC reduces motor disturbances primarily by reducing the amount of
TNF-alpha at the site of injury, thus inhibiting neutrophil accumulation and the resultant damage to the endothelial cells.