Treatment with DNA “decoy” that targets COX-2 gene promoter improves mechanical and thermal allodynia after spinal cord injury in rats

Spinal cord injury (SCI) results in a number of deficits and triggers primary and secondary injury signaling cascades characterized by an early and prolonged inflammatory response. Early after SCI, IL-1B increases, an inflammatory agent, that triggers increased activation of the transcription factor Nuclear Factor-kB (NF-kB). NF-kB mediates secondary injuries via regulation of synthesis of proteins that are detrimental to the recovery process and can maintain inflammation in the injured spinal cord. There are different NF-kB subunits and subunit-specific inhibition can be accomplished with synthetic double stranded “decoy” deoxyoligonucleotides containing selective NF-kB protein dimer binding consensus sequences. In this project, DNA ”decoys” target the COX-2 gene promoter NF-kB binding site, attenuate the SCI-induced increases in the levels of COX-2 and iNOS protein levels and significantly decrease cell death and increases in inflammatory signaling. Spinal cord contusion injury and outcomes were measured as described in Experimental Design below. The results demonstrate a significant improvement in locomotor scores, mechanical allodynia (for both cutaneous and pressure), thermal hyperalgesia and improved clinical measures (weight and bladder) in the group treated with COX-2 decoys compared to the vehicle group. Decoy treatment also resulted in significant reductions in COX-2 and iNOS expression following SCI and neuronal rescue. These experiments demonstrate the efficacy of novel interventions in the inflammatory cascade triggered by SCI as a strategy for treatment of SCI-induced physiological functional impairments. The approach is innovative in that it assesses the use of a new technology (DNA promoter decoys) to selectively block injury response mechanisms that can result in neuropathy. Supported by Mission Connect/ TIRR Foundation, The M.D. Anderson Foundation, The Liddell and The Dunn Foundations and NS11255.