SRT1720靶向激活SIRT1抑制NLRP3炎症小体活化缓解病理性疼痛

SIRT1 activation by SRT1720 alleviates chronic pain by inhibiting NLRP3 inflammasome sensitization

目的:明确SRT1720靶向激活SIRT1(NAD-dependent protein deacetylase sirtuin-1)抑制炎症诱导的疼痛的作用及机制。方法:(1)用雄性Sprague-Dawley(SD)大鼠分别构建急性痛和慢性炎症痛动物模型,鞘内注射肿瘤坏死因子α(TNF-α)以构建急性痛模型;足底注射完全弗氏佐剂(complete Freund's adjuvant,CFA)构建慢性炎症痛模型;(2)鞘内给药SIRT1选择性激活剂SRT1720;(3)记录给药后TNF-α-急性痛和CFA-慢性炎症痛动物痛觉行为的变化;(4)Western blot分析各组大鼠脊髓组织SIRT1、核因子κB(nuclear factor-κB,NF-κB)、小胶质细胞标记物离子钙接头蛋白1(ionized calcium binding adaptor molecule 1,Iba1)和NLRP3(NOD-,LRR-and pyrin domain-con-taining protein 3)的表达水平;(5)免疫荧光分析Iba1在脊髓组织的表达和定位。结果:鞘内给药SRT1720可显著缓解TNF-α-诱导的和CFA-诱导的机械痛敏;SRT1720给药处理显著下调TNF-α-急性痛和CFA-慢性炎症痛大鼠脊髓组织中Iba1与NLRP3的表达水平。结论:SRT1720靶向激活SIRT1可抑制脊髓小胶质细胞中炎症信号的激活并缓解炎症痛。

AIM:To clarify the roles of SRT1720 targeting and activating SIRT1(NAD-dependent protein deacetylase sirtuin-1) in inhibiting inflammation-induced pain.METHODS:(1) Male Sprague-Dawley(SD) rats were used to establish animal models of acute pain and chronic inflammatory pain.Intrathecal injection of tumor necrosis factor-α(TNF-α) was used to establish animal model of acute pain,and plantar injection of complete Freund’s adjuvant(CFA)was used to establish animal model of chronic inflammatory pain.(2)SIRT1 selective activator SRT1720 was intrathecally administered.(3) The changes of animal pain behavior in TNF-α-acute pain and CFA-chronic inflammatory pain after administration were record.(4) Western blot were used to analyze the protein levels in the spinal cord,including SIRT1,nuclear factor-κB(NF-κB),microglia marker ionized calcium binding adaptor molecule 1(Iba1) and NLRP3.(5) The expression and localization of Ibal in spinal cord were analyzed by immunofluorescence.RESULTS:Intrathecal administration of SRT1720 significantly alleviated TNF-α/CFA-induced mechanical hyperalgesia.SRT1720 treatment significantly down-regulated the expression level of Ibal and NLRP3 in the spinal cord of rats with TNF-α-acute pain and CFA-chronic inflammatory pain.CONCLUSION:SRT1720 targeted activation of SIRT1 inhibits the activation of inflammatory signals in spinal microglia and relieves inflammatory pain.