Suppression of peripheral NGF attenuates neuropathic pain induced by chronic constriction injury through the TAK1-MAPK/NF-κB signaling pathways.

Dai WL ，Yan B ，Bao YN ，Fan JF ，Liu JH ... -  《Cell Communication and Signaling》

Levo-corydalmine attenuates microglia activation and neuropathic pain by suppressing ASK1-p38 MAPK/NF-κB signaling pathways in rat spinal cord.

Neuropathic pain is partially refractory to currently available treatments. Although some studies have reported that apoptosis signal-regulating kinase 1 (ASK1) may inhibit chronic pain, the mechanisms underlying this process have not been fully elucidated. Chronic constriction injury (CCI) of the rat sciatic nerve was used to establish a neuropathic pain model. Nociception was assessed using von Frey hair and Hargreaves' methods. Western blot and immunofluorescence were used to detect the cell signaling pathway. BV2 cell line was cultured for in vitro evaluation. Our results indicated that spinal ASK1 was co-expressed with the microglia marker ionized calcium binding adaptor 1. Additionally, intrathecal administration of ASK1 inhibitor suppressed the activation of spinal microglia and attenuated CCI-induced neuropathic pain. The ASK1 inhibitor also decreased the levels of phosphorylated ASK1 (p-ASK1), p65, p38 mitogen-activated protein kinase (MAPK) and tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) messenger RNA in lipopolysaccharide-stimulated BV2 microglia cells. Intragastric administration of levo-corydalmine (l-CDL) significantly attenuated CCI-induced neuropathic pain and inhibited the expression of p-ASK1 in the spinal cord. l-CDL conspicuously suppressed the activation of spinal microglia in vitro and in vivo. Translocation of nuclearfactor-kappa B (NF-κB) and upregulation of p-p65, TNF-α, IL-1β were inhibited by l-CDL. Further, the analgesic effects of l-CDL were associated with reduced levels of phosphorylated protein kinase C (PKC γ), c-JunNH2-terminal kinase, and extracellular signal-regulated kinase. This study showed that the expression of ASK1 in spinal microglia and ASK1 inhibitor suppressed microglia activation via suppression of p38 MAPK/NF-κB, which ultimately attenuated CCI-induced neuropathic pain. l-CDL also inhibited the ASK1-P38 MAPK/NF-κB axis to attenuate CCI-induced neuropathic pain.

Dai WL ，Bao YN ，Fan JF ，Li SS ，Zhao WL ，Yu BY ，Liu JH ... -  《-》

Montelukast attenuates neuropathic pain through inhibiting p38 mitogen-activated protein kinase and nuclear factor-kappa B in a rat model of chronic constriction injury.

Zhou C ，Shi X ，Huang H ，Zhu Y ，Wu Y ... -  《-》

Loganin prevents chronic constriction injury-provoked neuropathic pain by reducing TNF-α/IL-1β-mediated NF-κB activation and Schwann cell demyelination.

Peripheral nerve injury can produce chronic and ultimately neuropathic pain. The chronic constriction injury (CCI) model has provided a deeper understanding of nociception and chronic pain. Loganin is a well-known herbal medicine with glucose-lowering action and neuroprotective activity. This study investigated the molecular mechanisms by which loganin reduced CCI-induced neuropathic pain. Sprague-Dawley rats were randomly divided into four groups: sham, sham+loganin, CCI and CCI+loganin. Loganin (1 or 5 mg/kg/day) was injected intraperitoneally once daily for 14 days, starting the day after CCI. For behavioral testing, mechanical and thermal responses were assessed before surgery and on d1, d3, d7 and d14 after surgery. Sciatic nerves (SNs) were collected to measure proinflammatory cytokines. Proximal and distal SNs were collected separately for Western blotting and immunofluorescence studies. Thermal hyperalgesia and mechanical allodynia were reduced in the loganin-treated group as compared to the CCI group. Loganin (5 mg/kg/day) prevented CCI from inducing proinflammatory cytokines (TNF-α, IL-1β), inflammatory proteins (TNF-α, IL-1β, pNFκB, pIκB/IκB, iNOS) and receptor (TNFR1, IL-1R), adaptor protein (TRAF2) of TNF-α, and Schwann cell demyelination and axonal damage. Loganin also blocked IκB phosphorylation (p-IκB). Double immunofluorescent staining further demonstrated that pNFκB/pIκB protein was reduced by loganin in Schwann cells on d7 after CCI. In the distal stumps of injured SN, Schwann cell demyelination was correlated with pain behaviors in CCI rats. Our findings indicate that loganin improves CCI-induced neuroinflammation and pain behavior by downregulating TNF-α/IL-1β-dependent NF-κB activation.

Chu LW ，Cheng KI ，Chen JY ，Cheng YC ，Chang YC ，Yeh JL ，Hsu JH ，Dai ZK ，Wu BN ... -  《-》

Analgesic effects of TLR4/NF-κB signaling pathway inhibition on chronic neuropathic pain in rats following chronic constriction injury of the sciatic nerve.

Chronic neuropathic pain (CNP) is attributed to a lesion or disease of the somatosensory system, may be derived from the peripheral and central system. Recent study revealed that spinal cord stimulation attenuated CNP by inhibiting TLR4/NF-κB signaling pathway. The present study focuses on the potential analgesic effects of TLR4/NF-κB signaling pathway on CNP in a rat model of chronic constriction injury (CCI). We successfully established the rat model of CCI by Bennett method, and then inhibited the TLR4/NF-κB signaling pathway in rat models. Next, we measured the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) 0D, 2D, 6D, 8D and 12D after operation respectively. MTS510 100 mg/kg, an inhibitor of TLR4, was intrathecal injected into rats after 6D, 8D and 12D after operation. The experiment lasted for 12 days, and then the rats were sacrificed to collect the spinal cord tissues. Protein and mRNA expression levels of toll-like receptor 4 (TLR4), nuclear factor-kappaB (NF-κB), glial cell line-derived neurotrophic factor (GDNF), glial fibrillary acidic protein (GFAP) and nerve growth factor (NGF) were detected by western blot analysis and RT-qPCR, respectively. Immunohistochemistry was performed to detect GDNF, GFAP and NGF expression. With the prolongation of MTS510 treatment time, MWT and TWL were increased and finally, the MWT and TWL were close to the baseline level. The levels of TLR4, NF-κB, GDNF, and GFAP as well as NGF increased in rats treated with CCI + Immunoglobulin G1 (IgG1) or CCI + MTS510, suggesting the model establishment was successful. Besides, with the prolongation of MTS510 treatment time, the protein level and mRNA expression of NF-kB, GDNF, GFAP and NGF decreased in rats treated with CCI + IgG1 or CCI + MTS510. Moreover, the GDNF, GFAP and NGF expression in spinal cord tissue in rats treated with CCI + IgG1 or CCI + MTS510 increased obviously, while the GDNF, GFAP and NGF expression decreased in spinal cord tissue in rats treated with CCI + IgG1 or CCI + MTS510 after MTS510 treatment. Collectively, this study defines the role of TLR4 and NF-κB, and inhibition of TLR4/NF-κB signaling pathway might contribute to the alleviation of CNP and improvement of MWT and TWL in a rat model of CCI. Additionally, the results obtained from the study provided a promising basis that could aid as an experimental basis for the potential treatment of TLR4/NF-κB signaling pathway.

Xu L ，Liu Y ，Sun Y ，Li H ，Mi W ，Jiang Y ... -  《-》