ACTIVATED PROTEIN-C REDUCES THE SEVERITY OF COMPRESSION-INDUCED SPINAL-CORD INJURY IN RATS BY INHIBITING ACTIVATION OF LEUKOCYTES

Activated protein C (APC), an important inhibitor of the coagulation s ystem, has recently been shown to prevent tissue injury by blocking th e activation of leukocytes. To determine whether APC can also prevent post-traumatic spinal cord injury (SCI), a condition in which leukocyt es play an important role, we tested the effects of APC on SCI induced in rats by compression trauma. Administration of APC, either before o r after the induction of SCI, markedly reduced the motor disturbances in these animals. In contrast, neither an inactive derivative of activ ated factor X (DEG R-Xa), a selective inhibitor of thrombin generation , nor active site-blocked APC (DIP-APC) reduced the motor disturbances . Histological examination revealed that intramedullary hemorrhages, o bserved 24 hr after trauma, were significantly reduced in the animals administered APC. The increase in the tissue level of tumor necrosis f actor-alpha (TNF-alpha) and the accumulation of neutrophils in the dam aged segment of the spinal cord were significantly inhibited in the an imals that had received APC, but these were not inhibited in those adm inistered DIP-APC or DEGR-Xa. The induction of leukocytopenia had the same effect as APC, in that it significantly reduced motor disturbance s, tissue levels of TNF-alpha, and neutrophil accumulation in the anim als 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.