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.
To investigate a possible role of supreoxide dismutase (SOD) in the pathogenesis of spinal cord injury (SCI), the change in the circulatory status in an experimental SCI model of rats was examined. The blood pressure (BP) of the SCI group decreased markedly by compression or head-up-tilt (60°). The extent of the BP decrease was diminished by the administration of a long acting SOD (SM-SOD) prior to injury. Compression, tilting and the administration of SM-SOD increased the sensitivity of resistant arteries to acetylcho line. SM-SOD treated rats had a significantly lower mortality than was found in untreated rats. These findings indicate that superoxide radicals may contribute to the pathogenesis of spinal cord injury and orthostatic hypotension caused by SCI.
The compression trauma-induced spinal cord injury demonstrated by this model was mainly mediated by leukocytes. Gabexate mesilate prevented spinal cord injury not by inhibiting coagulation, but by inhibiting the activation of leukocytes.
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