基于SIRT1/PGC-1α通路探讨氯吡格雷对紫杉醇诱发的周围神经病理性疼痛的干预作用  

To investigate intervening effect of clopidogrel on paclitaxel-induced peripheral neuropathic pain based on SIRT1/PGC-1αpathway

作　　者：郗扬 周海滨[1] 冯磊[1] 周雁[1] XI Yang;ZHOU Haibin;FENG Lei;ZHOU Yan(Beijing Jishuitan Hospital,Capital Medical University,Beijing 100035,China)

机构地区：[1]首都医科大学附属北京积水潭医院,北京100035

出　　处：《新疆医科大学学报》2025年第2期134-140,148,共8页Journal of Xinjiang Medical University

基　　金：北京市属医院科研培育计划项目(PX2018017)。

摘　　要：目的探讨氯吡格雷对紫杉醇诱发的周围神经病理性疼痛大鼠的干预作用及大鼠脊髓腰段背根部神经节(DRG)中沉默信息调节因子2相关酶1/过氧化物酶体增殖物激活受体γ共激活因子1α(SIRT1/PGC-1α)信号通路的影响。方法采用紫杉醇诱发化疗后周围神经病理性疼痛大鼠模型,将40只雄性SD大鼠随机分为正常组、模型组、6 mg/kg氯吡格雷组和12 mg/kg氯吡格雷组,每组10只。在实验前1天(T0)、实验第8天(T1)和实验第14天(T2)分别测定大鼠的50%机械缩足阈值(50%MWT)和热缩足潜伏期(TWL)。取大鼠DRG,原位末端转移酶标记实验(TUNEL)检测DRG中细胞凋亡。酶联免疫吸附试验(ELISA)测定DRG中炎症因子白介素-6(IL-6)、IL-1β以及肿瘤坏死因子-α(TNF-α)水平。采用丙二醛(MDA)和超氧化物歧化酶(SOD)试剂盒测定DRG中MDA和SOD水平。Western blot测定DRG组织中SIRT1和PGC-1α蛋白表达水平。结果与正常组相比,模型组在T1和T2时间点的50%MWT和TWL值均显著降低(P<0.01)。与模型组相比,6 mg/kg和12 mg/kg氯吡格雷组在T1和T2时间点的50%MWT和TWL值均显著升高(P<0.01~0.05)。与正常组相比,模型组DRG组织中细胞凋亡水平,IL-6、IL-1β、TNF-α以及MDA水平均升高,SOD水平降低,SIRT1和PGC-1α蛋白表达显著下调(P<0.01)。与模型组相比,6 mg/kg和12 mg/kg氯吡格雷组DRG组织中上述指标被逆转(P<0.01~0.05)。与6 mg/kg氯吡格雷组相比,12 mg/kg氯吡格雷组对周围神经病理性疼痛大鼠中上述指标的改善更显著。结论氯吡格雷能减轻紫杉醇诱发的周围神经病理学疼痛,抑制DRG中炎症反应,减少细胞凋亡及氧化应激水平,其机制可能与激活SIRT1/PGC-1α信号通路相关。Objective To investigate the interventional effect of clopidogrel on paclitaxel-induced peripheral neuropathic pain in rats and its impact on the silent information regulator 2-related enzyme 1/peroxisome proliferator-activated receptor gamma coactivator 1-alpha(SIRT1/PGC-1α)signaling pathway in the dorsal root ganglion(DRG)of the lumbar spinal cord in rats.Methods A rat model of peripheral neuropathic pain induced by paclitaxel chemotherapy was established.40 male SD rats were randomly divided into a normal group,a model group,a 6 mg/kg clopidogrel group and a 12 mg/kg clopidogrel group,with 10 rats in each group.The 50%mechanical withdrawal threshold(50%MWT)and thermal withdrawal latency(TWL)were measured on the day before the experiment(T0),the 8th day of the experiment(T1)and the 14th day of the experiment(T2).The DRG was extracted,and TdT-mediated dUTP nick end labeling(TUNEL)was used to detect cell apoptosis in the DRG.Enzyme-linked immunosorbent assay(ELISA)was performed to measure the levels of inflammatory cytokines interleukin-6(IL-6),IL-1β,and tumor necrosis factor-alpha(TNF-α)in the DRG.Malondialdehyde(MDA)and superoxide dismutase(SOD)kits were used to determine the levels of MDA and SOD in the DRG.Western blot was employed to measure the protein expression levels of SIRT1 and PGC-1αin DRG tissues.Results Compared with normal group,the model group showed significantly decreased 50%MWT and TWL values at T1 and T2 time points(P<0.01).Compared with model group,the 6 mg/kg clopidogrel and 12 mg/kg clopidogrel group exhibited significantly increased 50%MWT and TWL values at T1 and T2 time points(P<0.01~0.05).Compared with normal group,the model group demonstrated increased levels of cell apoptosis,IL-6,IL-1β,TNF-α,and MDA,decreased SOD levels,and reduced protein expression levels of SIRT1 and PGC-1αin DRG tissues(P<0.01).Compared with model group,these indicators in the DRG tissues were reversed in the 6 mg/kg clopidogrel and 12 mg/kg clopidogrel group(P<0.01~0.05).Compared with 6 mg/kg clopidogrel

关 键 词：SIRT1 PGC-1Α 氯吡格雷 紫杉醇 周围神经病理性疼痛 

分 类 号：R741[医药卫生—神经病学与精神病学]