Nuclear factor-kappaB decoy amelioration of spinal cord injury-induced inflammation and behavior outcomes.
Spinal cord injury (SCI) results in a pathophysiology characterized by multiple locomotor and sensory deficits, resulting in altered nociception and hyperalgesia. SCI triggers an early and prolonged inflammatory response, with increased interleukin-1beta levels. Transient changes are observed in subunit populations of the transcription factor nuclear factor-kappaB (NF-kappaB). There were decreases in neuronal c-Rel levels and inverse increases in p65 and p50 levels. There were no changes in neuronal p52 or RelB subunits after SCI at any time point tested. Similarly, SCI had no effect on oligodendroglial levels of any NF-kappaB subunit. There were significant early increases in COX-2 and inducible nitric oxide synthase mRNA and protein levels after SCI. We used synthetic double-stranded "decoy" deoxyoligonucleotides containing selective NF-kappaB protein dimer binding consensus sequences. Decoys targeting the p65/p50 binding site on the COX-2 promoter decreased SCI-induced cell losses, NF-kappaB p65/p50 DNA-binding activity, and COX-2 and iNOS protein levels. NF-kappaB p65/p50 targeted decoys improved early locomotor recovery after moderate but not severe SCI, yet ameliorated SCI-induced hypersensitization after both moderate and severe SCI. To determine whether changes in GABA activity played a role in decreased hypersensitivity after SCI and p65/p50 targeted decoy, we counted gamma-aminobutyric acid (GABA)-containing neurons in laminae 1-3. There were significantly more GABAergic neurons in the p65/p50 targeted decoy-treated group at the level of injury.
Rafati
Danny Salah
DS
Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, Texas, USA.
Geissler
Katja
K
Johnson
Kathia
K
Unabia
Geda
G
Hulsebosch
Claire
C
Nesic-Taylor
Olivera
O
Perez-Polo
J Regino
JR
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001665:Binding Sites / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013119:Spinal Cord Injuries / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D051996:Transcription Factor RelA / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D004791:Enzyme Inhibitors; D052002:NF-kappa B p50 Subunit; C468119:NF-kappaB decoy; D009838:Oligodeoxyribonucleotides; D020569:Proto-Oncogene Proteins c-rel; D051996:Transcription Factor RelA; D005680:gamma-Aminobutyric Acid; D004247:DNA; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2