METHYLPREDNISOLONE INHIBITION OF TNF-ALPHA EXPRESSION AND NF-KAPPA-B ACTIVATION AFTER SPINAL-CORD INJURY IN RATS

Post-traumatic inflammatory reaction has been implicated in the second ary 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 leas t partially, through the activation of a pro-inflammatory transcriptio n factor, NF-kB, which in turn upregulates such genes as iNOS, cytokin es, adhesive molecules, and others. Consistent with a post-traumatic i nflammatory reaction after SCI, we noted an increase in TNF-alpha expr ession 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 activ ity in nuclear proteins isolated from the injured cord (3.9-fold incre ase, P < 0.01). MP is the only drug proven effective in improving neur ological function in patients with acute SCI. The mechanism of action of MP is not fully understood, but is thought to be related to its ant ioxidant effects. MP is also a potent anti-inflammatory agent, which h as 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 p ost-traumatic inflammatory activity that is mediated by the TNF-alpha- NF-kB cascade can be suppressed by MP. (C) 1998 Elsevier Science B.V. All rights reserved.