Inhibition of NF-κB Signaling Pathway by Resveratrol Improves Spinal Cord Injury

Abstract

Spinal cord injury (SCI) can have a significant impact on an individual's life. Herein, we discuss how resveratrol improves SCI by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway. Evidences show resveratrol suppresses NF-κB signaling pathway to exert its beneficial effects on various diseases. NF-κB signaling pathway plays a significant role in the pathophysiological mechanisms of SCI including increase in inflammation, augmentation of damage caused by free radicals and lipid peroxidation as well as facilitation of apoptosis and axonal demyelination. We also discuss mechanisms between resveratrol and NF-κB signaling pathway in the wake of SCI, which can be potential targets for resveratrol to treat SCI.

Keywords: NF-κB signaling pathway; apoptosis; inflammation; resveratrol; spinal cord injury.

FIGURE 1

Negative effects of resveratrol on NF-κB via several pathways in SCI. In TNFR1 apoptotic pathway, Ub chains conjugated with RIPK1 function as scaffolds in the recruitment and activation of TAK1-binding protein 2/3–TAK1 complex and inhibition of IKK complex (NEMO-IKKa-IKKb), subsequently triggering off the classical NF-κB signaling pathways that collectively promote transcription of genes, which prevents cell death and sustains inflammation. In MyD88-dependent pathway, TLR recruits toll-interleukin 1 receptor domain containing adaptor protein at the cell membrane, subsequently facilitating recruitment of MyD88, which in turn triggers early-phase activation of NF-κB. Recruitment of TRAM and TRIF leads to late-phase activation of NF-κB. IKK phosphorylates IκBα and IκBβ leading to poly ubiquitination of IκBs. Degradation of IκBs results in activation of NF-κB. Besides, degenerated myelin activates FAK/PI3K/Akt/NF-κB pathway in macrophages and promotes expression of inflammatory mediators. Stimulation of TWEAK-Fn14 pathway also promotes NF-κB expression. On the contrary, SIRT1 inhibits NF-κB activation. Eventually, NF-κB enters the nucleus to activate target gene expression. Resveratrol potentially enhances SIRT1 and AMPK expressions. AMPK activation increases NAD+/NADH ratio and triggers its downstream whereas SIRT1 acts as an anti-inflammatory NAD+-dependent deacetylating enzyme via direct deacetylation of subunit of NF-κB such as p65, SIRT1 directly interacts with RelA/p65. Also, resveratrol suppresses IKK activity.