高迁移率族蛋白B1抑制剂对白蛋白结合型紫杉醇致神经病理性疼痛的抑制作用及其机制  

Role and mechanism of high mobility group box 1 inhibitor in alleviating neuropathic pain induced by nab-paclitaxel in rats

作　　者：王力[1] 马莉[1] 贾丽君[1] 周雅卿 赵永林 WANG Li;MA Li;JIA Lijun;ZHOU Yaqing;ZHAO Yonglin(Department of Oncology,Second Affiliated Hospital of Xi’an Jiaotong University,Xi’an 710004,China)

机构地区：[1]西安交通大学第二附属医院肿瘤科,西安710004

出　　处：《山西医科大学学报》2022年第9期1120-1126,共7页Journal of Shanxi Medical University

基　　金：国家自然科学基金资助项目(82001327)。

摘　　要：目的探讨高迁移率族蛋白B1(HMGB1)抑制剂Glycyrrhizin(Gly)对白蛋白结合型紫杉醇导致的神经病理性疼痛的抑制作用及其机制。方法雄性SD大鼠共54只,分为对照组、紫杉醇组、紫杉醇+Gly组,每组18只。紫杉醇组大鼠实验第1,3,5,7天腹腔注射白蛋白结合型紫杉醇(2.47 mg/kg)建立神经病理性疼痛模型,紫杉醇+Gly组在注射白蛋白结合型紫杉醇(2.47 mg/kg)后,第1~7天每日腹腔注射Glycyrrhizin(50 mg/kg),两种药物间隔30 min。对照组给予等剂量生理盐水。实验第4,8天检测大鼠的机械刺激缩足反射阈值(MWT)和热刺激缩足反射潜伏期(TWL)。所有大鼠实验第8天处死,取L_(4-6)脊髓,免疫组化染色检测HMGB1、细胞骨架蛋白[神经微丝蛋白轻链(NF-L)、神经微丝蛋白中链(NF-M)]、胶质纤维酸性蛋白(GFAP)及离子钙接头蛋白抗体(Iba-1)的表达变化,Western blot检测Toll样受体4(TLR4)及核因子κB(NF-κB)的表达变化,ELISA检测TNF-α、IL-1β和IL-6的水平。结果与对照组相比,紫杉醇组MWT、TWL均降低,提示神经病理性疼痛模型构建成功;与紫杉醇组相比,紫杉醇+Gly组MWT、TWL均升高(P<0.05)。紫杉醇组大鼠L_(4-6)脊髓组织中HMGB1、NF-L、NF-M、GFAP、Iba-1、TLR4、NF-κB、TNF-α、IL-1β和IL-6的表达水平均高于对照组(均P<0.05),而紫杉醇+Gly组以上指标的表达均低于紫杉醇组(均P<0.05)。结论HMGB1抑制剂Glycyrrhizin可通过抑制TLR4/NF-κB通路,减少炎性因子TNF-α、IL-1β和IL-6的释放,减轻细胞骨架结构紊乱,进而缓解白蛋白结合型紫杉醇导致的神经病理性疼痛。Objective To investigate the effect of glycyrrhizin,a high mobility group protein B1(HMGB1)inhibitor,on neuropathic pain induced by nab-paclitaxel and its mechanism.Methods Totally 54 SD male rats were randomly divided into control group(n=18),paclitaxel group(n=18)and paclitaxel+Glycyrrhizin(Gly)group(n=18).A neuropathic pain model was established by intraperitoneal injection of nab-paclitaxel(2.47 mg/kg)at day 1,3,5,7 with a final cumulative dose of 9.9 mg/kg.Rats were intraperitoneally injected with nab-paclitaxel(2.47 mg/kg at day 1,3,5,7)and given Glycyrrhizin(50 mg/kg,7 consecutive days)after nab-paclitaxel in half an hour in paclitaxel+Gly group,and rats in control group were given an equal dose of normal saline.Mechanical withdrawal threshold(MWT)and thermal withdrawal latency(TWL)of rats in each group were detected at day 4 and day 8.All rats were sacrificed at day 8 and L_(4-6) spinal cord was taken.Immunohistochemical staining was used to detect the expression of HMGB1,cytoskeletal proteins including neurofilament light chain(NF-L)and neurofilament medium chain(NF-M),glial fibrillary acidic protein(GFAP)and ionized calcium binding adaptor molecule-1(Iba-1).Western blot was used to detect the expression of toll-like receptor 4(TLR4)and nuclear factor kappa-B(NF-κB).The levels of tumor necrosis factor alpha(TNF-α),interleukin-1β(IL-1β)and interleukin-6(IL-6)were detected by ELISA.Results Compared with control group,MWT and TWL in paclitaxel group were decreased,which indicated the neuropathic pain model was successfully established.Compared with paclitaxel group,MWT and TWL in paclitaxel+Gly group were increased(P<0.05).The expression of HMGB1,NF-L,NF-M,GFAP,Iba-1,TLR4,NF-κB,TNF-α,IL-1βand IL-6 in the L_(4-6) spinal cord tissue in paclitaxel group was higher than that in control group(all P<0.05),and these above indicators were lower in paclitaxel+Gly group than in paclitaxel group(all P<0.05).Conclusion Glycyrrhizin,the inhibitor of HMGB1,could improve the neuropathic pain induced by nab-paclitax

关 键 词：HMGB1 神经病理性疼痛 白蛋白结合型紫杉醇 GLYCYRRHIZIN TLR4/NF-κB 神经微丝蛋白 

分 类 号：R741[医药卫生—神经病学与精神病学]