Methylprednisolone inhibition of TNF-alpha expression and NF-kB activation after spinal cord injury in rats.
Post-traumatic inflammatory reaction has been implicated in the secondary injury after SCI. TNF-alpha is a key inflammatory mediator, which plays a pathogenetic role in cell death in inflammatory disorders and traumatic brain injury. TNF-alpha exerts its effector actions, at least partially, through the activation of a pro-inflammatory transcription factor, NF-kB, which in turn upregulates such genes as iNOS, cytokines, adhesive molecules, and others. Consistent with a post-traumatic inflammatory reaction after SCI, we noted an increase in TNF-alpha expression by Western blotting (4.5-fold increase at 1 day after SCI, P<0.01) and immunohistochemistry in a rat SCI model. Post-traumatic TNF-alpha expression was accompanied by an increase in NF-kB binding activity in nuclear proteins isolated from the injured cord (3.9-fold increase, P<0.01). MP is the only drug proven effective in improving neurological function in patients with acute SCI. The mechanism of action of MP is not fully understood, but is thought to be related to its antioxidant effects. MP is also a potent anti-inflammatory agent, which has been recently shown to inhibit NF-kB binding activity. MP (30 mg/kg, i.v.) given immediately after SCI reduced TNF-alpha expression by 55% (P<0.01) and NF-kB binding activity. These findings suggest that post-traumatic inflammatory activity that is mediated by the TNF-alpha-NF-kB cascade can be suppressed by MP.
Xu
J
J
Department of Neurology, Box 8111, Washington University, School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
Fan
G
G
Chen
S
S
Wu
Y
Y
Xu
X M
XM
Hsu
C Y
CY
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001369:Axons / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D008775:Methylprednisolone / Q000494:pharmacology*; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D020318:Rats, Long-Evans; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D014158:Transcription, Genetic / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D000893:Anti-Inflammatory Agents; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D008775:Methylprednisolone