Salidroside Alleviates Bone Cancer Pain Via The Nrf2/NF-κB Signaling Pathway

Objective: Bone cancer pain(BCP)often reduces the patient’s quality of life,and the effects of current treatments for BCP are limited.Therefore,novel therapeutic approaches are urgent for BCP management.Salidroside is the main component of Rhodiola which is a traditional medicine in China.Previous studies demonstrated that salidroside can alleviate neuropathic pain.However,whether salidroside has an analgesic effect on BCP is still unknown.Nuclear factor erythroid 2-related factor 2(Nrf2)activation relieves BCP in rats by upregulating the expression of heme oxygenase-1(HO-1).Besides,salidroside acts as a Nrf2 activator in many diseases.In the bone cancer model,decreasing the expression of nuclear factor-kappa B(NF-κB)can relieve BCP;meanwhile,inhibiting the activation of NF-κB also can reduce the generation of tumor necrosis factor-alpha(TNF-α),interleukin-6(IL-6)and interleukin-1 beta(IL-1β).Nrf2 activation alleviates BCP by downregulating the expression of NF-κB,TNF-α,IL-6 and IL-1β.In this study,a mouse model of BCP was used,we observed the effect of salidroside on BCP and investigated whether this effect was associated with the Nrf2/NF-κB signaling pathway.Methods: Male C57BL/6 mice were used in this experiment.Mouse lewis lung carcinoma(LLC)cells were used to establish the BCP model.Salidroside was intrathecally or intraperitoneally injected into mice,trigonelline(a selective Nrf2antagonist)was intrathecally injected into mice.The pain behavior of mice were assessed by paw withdrawal mechanical threshold(PWMT)and paw withdrawal thermal latency(PWTL).Bone histology of mice were observed by hematoxylin-eosin(HE)staining.The expression of Nrf2,HO-1 and NF-κB in the spinal cord of mice were measured by Western Blot.The concentration of Nrf2,HO-1,NF-κB,TNF-α,IL-6 and IL-1β in the spinal cord and blood of mice were determined by enzyme linked immunosorbent assay(ELISA).The localization and expression of Nrf2,HO-1 and NF-κB in the spinal cord of BCP mice were detected by immunofluorescence staining.Results: PWMT and PWTL of BCP group were obviously lower on 7-21 days after LLC cells inoculation compared with sham group.The bone trabecular structure of femur of BCP mice was destroyed and infiltrated by tumor cells on 21 day after LLC cells inoculation.The expression of Nrf2,HO-1,NF-κB,TNF-α,IL-6 and IL-1β in the spinal cord and blood of BCP group were increased compared with sham group.Nrf2,HO-1 and NF-κB are mainly localized in the spinal neurons of BCP mice.Intrathecal administration of salidroside dose-dependently increased the PWMT and PWTL of BCP mice,trigonelline decreased the PWMT and PWTL of salidroside group.Intraperitoneal administration of salidroside(2 mg)also increased the PWMT and PWTL of BCP mice.Additionally,intrathecal administration of salidroside upregulated the expression of Nrf2 and HO-1 in the spinal cord and blood of BCP mice,and the level of NF-κB,TNF-α,IL-6 and IL-1β in the spinal cord and blood of BCP mice were decreased after salidroside administration;trigonelline downregulated the expression of Nrf2 and HO-1in the spinal cord and blood of salidroside group,and the level of NF-κB,TNF-α,IL-6and IL-1β in the spinal cord and blood of salidroside group were increased after trigonelline administration.Conclusions: Salidroside alleviates BCP through Nrf2-dependent inhibition of the activation of NF-κB and inflammatory cytokines.