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-alpha (TNF-alpha) plays a critical role in posttraumatic SCI in rats. Since MPS has been shown to inhibit TNF-alpha production in vitro, it is possible that MPS can reduce SCI by inhibiting TNF-alpha production. To examine this possibility, we investigated the effect of MPS on TNF-alpha production in injured segments of rat spinal cord. Leukocytopenia and high-dose intravenous administration of MPS markedly reduced the motor disturbances observed following spinal cord trauma. Both treatments also reduced the intramedullary hemorrhages observed histologically 24 hr posttrauma. Leukocytopenia significantly reduced tissue levels of both TNF-alpha mRNA and TNF-alpha, 1 and 4 hr posttrauma, respectively, and it also inhibited the accumulation of leukocytes in the injured segments 3 hr posttrauma, while MPS had no effects. Lipid peroxidation and vascular permeability at the site of spinal cord lesion were both significantly increased over time after the induction of SCI, peaking 3 hr posttrauma. These events were significantly reduced in animals with leukocytopenia and in those given anti-P-selectin monoclonal antibody compared to sham-operated animals. Administration of MPS significantly inhibited both the increase in lipid peroxidation and the vascular permeability. 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, but by inhibiting activated leukocyte induced lipid peroxidation of the endothelial cell membrane. This suggests that MPS may attenuate spinal cord ischemia by inhibiting the increase in endothelial permeability at the site of spinal cord injury.
Taoka
Y
Y
Department of Laboratory Medicine, Kumamoto University School of Medicine, Japan.
Okajima
K
K
Uchiba
M
M
Johno
M
M
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D002199:Capillary Permeability / Q000187:drug effects / Q000276:immunology; D007970:Leukopenia / Q000139:chemically induced / Q000503:physiopathology; D015227:Lipid Peroxidation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008775:Methylprednisolone / Q000627:therapeutic use*; D019957:Motor Skills Disorders / Q000188:drug therapy / Q000378:metabolism; D019007:P-Selectin / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000098:blood supply / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D013904:Thoracic Vertebrae; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D019007:P-Selectin; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D008775:Methylprednisolone