Nuclear factor‐κB decoy amelioration of spinal cord injury‐induced inflammation and behavior outcomes

Abstract

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.

<i>Dipsacus asperoides</i> (Xue Duan) inhibits spinal cord injury-induced inflammatory responses in rats

“…Secondary phase increases the pathology of SCI because of the activation of inflammatory responses [4][5][6]. The expression of NF-kB and other transcription factors like cRel, Rel B, Rel A/p65, p50 and p52 are increased as a result of the activation of inflammatory responses, however, preventing activation of NF-kB can attenuate secondary damage after SCI [7][8][9][10]. It has been shown in different reports that a direct inhibition of I-kB kinase (IKK) can result in regulation of inhibition of products of NF-kB genes [11,12].…”

Caffeic acid phenethyl ester reduces spinal cord injury-evoked locomotor dysfunction

“…Alternatively, CAPE may directly inhibit transcriptional activity of NF-κB irrespective of down-regulation of IL-1β gene expression, because it has been reported that CAPE prevents the binding of NF-κB to DNA (20). In fact, an NF-κB decoy ameliorates behavior outcomes in SCI animal models (25), supporting the involvement of NF-κB in the CAPE-dependent amelioration of locomotor function.…”

“…The nuclear factor (NF)-κB transcription factor is a key mediator in inflammatory responses and has been implicated in the progression of this secondary injury. NF-κB can be activated by a variety of stimuli, including inflammatory cytokines such as interleukin (IL)-1, which is released from spinal cord-resident cells and/or infiltrating monocytes (4,25). In response to SCI, NF-κB induces the transcriptional activation of proinflammatory genes including inducible nitric oxide (NO) synthase (iNOS), which produces NO, and cyclooxygenase-2 (COX-2) (23).…”

Effects of the root extract of <i>Dipsacus asperoides</i> (Caprifoliaceae) on locomotor function and inflammation following spinal cord injury in rats

“…Different genes are expressed that mediate inflammatory responses by transcribing a family of transcription factors include p52, p50, RelB, RelA/p65 and cRel [7,8]. Inhibition of the NF-kB pathway works as a treatment for SCI due to inhibition of various gene products that are mediated through the NF-kB pathway [9,10].…”