Bay11-7082 attenuates neuropathic pain via inhibition of nuclear factor-kappa B and nucleotide-binding domain-like receptor protein 3 inflammasome activation in dorsal root ganglions in a rat model of lumbar disc herniation

Abstract

Lumbar disc herniation (LDH) is an important cause of radiculopathy, but the underlying mechanisms are incompletely understood. Many studies suggested that local inflammation, rather than mechanical compression, results in radiculopathy induced by LDH. On the molecular and cellular level, nuclear factor-kappa B (NF-κB) and nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome have been implicated in the regulation of neuroinflammation formation and progression. In this study, the autologous nucleus pulposus (NP) was implanted in the left L5 dorsal root ganglion (DRG) to mimic LDH in rats. We investigated the expression of NF-κB and the components of NLRP3 inflammasome in the DRG neurons in rats. Western blotting and immunofluorescence for the related molecules, including NLRP3, apoptosis-associated speck-like protein containing caspase-1 activator domain (ASC), caspase-1, interleukin (IL)-1β, IL-18, IκBα, p-IκBα, p65, p-p65, and calcitonin gene-related peptide (CGRP) were examined. In the NP-treated group, the activations of NLRP3, ASC, caspase-1, IL-1β, IL-18, p-IκBα, and p-p65 in DRG neurons in rats were elevated at 1 day after surgery, and the peak occurred at 7 days. Treatment with Bay11-7082, an inhibitor of the actions of IKK-β, was able to inhibit expression and activation of the molecules (NLRP3, ASC, caspase-1, IL-1β, IL-18, p-IκBα, and p-p65) and relieve the pain in rats. Our study shows that NF-κB and NLRP3 inflammasome are involved in the maintenance of NP-induced pain, and that Bay11-7082 could alleviate mechanical allodynia and thermal hyperalgesia by inhibiting NF-κB and NLRP3 inflammasome activation.

Nuclear factor kappa B regulated monocyte chemoattractant protein-1/chemokine CC motif receptor-2 expressing in spinal cord contributes to the maintenance of cancer-induced bone pain in rats

“… 43 , 46 For example, using potential inhibitor BAY11–7082 or transgenic inhibition to reduce NF-кB activation in the DRG level or spinal level reduces pain behavior and inflammation after peripheral nerve injury and attenuates neuropathic pain. 47 , 48 Our study showed that intrathecal injection of NF-кB inhibitor at ninth day after modeling attenuated tumor induced hypersensitivity and decreased MCP-1 and CCR2 level in spinal cord, supporting the involvement of NF-кB in the development and maintenance of CIBP via MCP-1 and CCR2 produce in the spinal cord. Furthermore, our results showed NF-кB to be predominantly expressed in neurons of the spinal cord after modeling.…”

NFkB Inhibition Mitigates Serum Amyloid A-Induced Pro-Atherogenic Responses in Endothelial Cells and Leukocyte Adhesion and Adverse Changes to Endothelium Function in Isolated Aorta

“…At 10 μM (BAY11-7082), secretory VEGF was reduced by ~40% compared to SAA alone and this concentration of the NFB inhibitor (BAY11-7082) was selected for all further studies on gene and protein analysis. This selected (active) dose of BAY11-7082 (10 μM) is lower than that used by others [28,29] and provides an advantage of minimising potential non-specific inhibitory activity in cultured HCtAEC.…”

NFκB Inhibition Mitigates Serum Amyloid A-Induced Pro-Atherogenic Responses in Endothelial Cells and Leukocyte Adhesion and Adverse Changes to Endothelium Function in Isolated Aorta

“…At 10 μM (BAY11-7082), secretory VEGF was reduced by ~40% compared to SAA alone and this concentration of the NFκB inhibitor (BAY11-7082) was selected for all further studies on gene and protein analysis. This selected (active) dose of BAY11-7082 (10 μM) is lower than that used by others [28,29] and provides an advantage of minimising potential non-specific inhibitory activity in cultured HCtAEC.…”