Methylprednisolone reduces spinal cord injury in rats without affecting tumor necrosis factor-alpha production

Methylprednisolone (MPS) is the only therapeutic agent currently available for traumatic spinal cord injury (SCI). However, little is known about its therapeutic mechanisms. We have demonstrated that tumor necrosis factor-alp ha (TNF-alpha) plays a critical role in posttraumatic SCI in rats. Since MP S has been shown to inhibit TNF-alpha production in vitro, it is possible t hat MPS can reduce SCI by inhibiting TNF-alpha production. To examine this possibility, we investigated the effect of MPS on TNF-alpha production in i njured segments of rat spinal cord. Leukocytopenia and high-dose intravenou s administration of MPS markedly reduced the motor disturbances observed fo llowing spinal cord trauma. Both treatments also reduced the intramedullary hemorrhages observed histologically 24 hr posttrauma. Leukocytopenia signi ficantly reduced tissue levels of both TNF-alpha mRNA and TNF-alpha, 1 and 4 hr posttrauma, respectively, and it also inhibited the accumulation of le ukocytes in the injured segments 3 hr posttrauma, while MPS had no effects. Lipid peroxidation and vascular permeability at the site of spinal cord le sion were both significantly increased over time after the induction of SCI , peaking 3 hr posttrauma. These events were significantly reduced in anima ls with leukocytopenia and in those given anti-P-selectin monoclonal antibo dy compared to sham-operated animals. Administration of MPS significantly i nhibited both the increase in lipid peroxidation and the vascular permeabil ity. These findings suggested that MPS reduces the severity of SCI, not by inhibiting the production of TNF-alpha at the site of spinal cord trauma, b ut by inhibiting activated leukocyte induced lipid peroxidation of the endo thelial cell membrane. This suggests that MPS may attenuate spinal cord isc hemia by inhibiting the increase in endothelial permeability at the site of spinal cord injury.