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黄芪桂枝五物汤减少铂蓄积预防奥沙利铂慢性外周神经毒性机制研究
Experimental Study of Huangqi GuizhiWuwu Decoction to Prevent Oxaliplatin-Induced Chronic Peripheral Neuropathy by Reducing Platinum Accumulation
  
DOI:10.11842/wst.2019.07.027
中文关键词:  黄芪桂枝五物汤  奥沙利铂  慢性外周神经毒性  铂蓄积  OCT2  ATP7A
英文关键词:Huangqi Guizhi Wuwu Decoction, Oxaliplatin, Chronic peripheral neuropathy, Platinum accumulation, OCT2, ATP7A
基金项目:江苏省中医药局面上项目(NO.YB2015035):基于TRPs通道探讨当归四逆汤对奥沙利铂神经毒性作用的研究,负责人:霍介格;中央级公益性科研院所基本科研业务费专项资金资助课题(NO.ZZ08080014):黄芪桂枝五物配方颗粒缓解奥沙利铂相关周围神经毒性的临床评价,负责人:霍介格;江苏省卫生厅(No:BRA2015493):益气温经复方中药对OXIN作用的临床研究,负责人:霍介格。
作者单位
魏国利 南京中医药大学附属中西医结合医院 南京 210028 
顾展丞 江苏省海门中医院 海门 226100 
李灵常 南京中医药大学附属中西医结合医院 南京 210028 
马骏 江苏省淮安市中医院 淮安 223001 
陈晨 江苏省盐城市中医院 盐城 224002 
钱峻 南京中医药大学中医学院/中西医结合学院 南京 210023 
霍介格 南京中医药大学附属中西医结合医院 南京 210028 
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中文摘要:
      目的 观察黄芪桂枝五物汤对铂蓄积的影响,探讨黄芪桂枝五物汤预防奥沙利铂慢性外周神经毒性可能机制。方法 45只健康雄性Wistar大鼠随机分为3组,空白组、奥沙利铂模型组、黄芪桂枝五物汤组,各15只。空白组予以腹腔注射5%葡萄糖注射液2 mL?kg -1,其余4组按照4 mg?kg -1,2 mL?kg -1予以腹腔注射奥沙利铂造模,一周2次,共4周。黄芪桂枝五物汤组灌胃给药2.48 g?mL -1,每日1次,空白组、奥沙利铂模型组予等量0.9%NaCl溶液灌胃,每日1次。每周测量大鼠体重,Von Frey试验检测大鼠机械性缩足阈值。第28 d处死大鼠,解剖分离双侧坐骨神经、L4-5背根神经节,光镜、电镜观察理形态变化,测量背根神经节核仁大小变化。ICP-MS法检测背根神经节细胞内铂含量,qPCR检测细胞铂蓄积相关因子OCT2和ATP7A mRNA表达。结果 与空白组相比,模型组大鼠体重下降(P < 0.05),机械性缩足阈值下降(P < 0.05),随着剂量的累积越明显;坐骨神经神经纤维排列紊乱,背根神经节细胞核仁缩小,线粒体肿胀,背根神经节铂含量明显升高(P < 0.01),铂摄入关键蛋白OCT2mRNA表达量增加(P < 0.05),铂泵出关键蛋白ATP7A mRNA表达量无显著变化(P > 0.05);与模型组相比黄芪桂枝五物汤组大鼠体重无统计学差异(P > 0.05),未出现明显的机械性缩足阈值下降(P >0.05);坐骨神经、背根神经节细胞病理损伤轻,背根神经节铂含量明显降低(P < 0.05),OCT2mRNA表达量减少(P < 0.05),ATP7A mRNA表达量增加(P < 0.05)。结论 黄芪桂枝五物汤可能通过下调背根神经节细胞中OCT2的表达,减少铂摄入,上调ATP7A mRNA的表达,促进铂泵出,从而减少背根神经节铂蓄积,发挥预防奥沙利铂慢性外周神经毒性的作用。
英文摘要:
      Objective To observe the effect of Huangqi Guizhi Wuwu Decoction on platinum accumulation, and explore the possible mechanism of preventing oxaliplatin-induced chronic peripheral neuropathy. Methods A total of 45 healthy Decoction group. The blank group was intraperitoneally injected with 2 mL?kg-1 5% glucose injection, and the other 4 groups were intraperitoneally injected with oxaliplatin in accordance with 4 mg?kg-1 and 2 mL?kg-1, twice a week for 4 weeks (d 1, 2, 8, 9, 15, 16, 22, 23), Huangqi Guizhi Wuwu Decoction group was given 2.48 g?mL-1, 10 mL?kg-1 once a day, while the blank group and oxaliplatin model group were given 0.9% NaCl solution once a day. The weight of rats was measured and Von Frey test was performed to detect the mechanical allodynia of rats every week. On the 28th day, rats were sacrificed and dissected bilateral sciatic nerve and L4-5 dorsal root ganglion. Morphological changes were observed by light microscopy and electron microscopy, and the nucleolus size of dorsal root ganglion was measured. ICP-MS method was used to detect the content of platinum in the cells of dorsal root ganglion, and qPCR was used to detect the expression of platin-accumulating related factor OCT2 and ATP7A mRNA. Results Compared with the blank group, the body weight of the model group decreased (P < 0.05), and the mechanical allodynia decreased (P < 0.05), which was more obvious with the oxaliplatin dose accumulation. The arrangement of sciatic nerve fibers was disorganized, the nucleoli of dorsal root ganglion cells were reduced, mitochondria were swollen, and the content of platinum in the dorsal root ganglion was significantly increased (P < 0.01). The expression of OCT2mRNA was increased (P < 0.05). The expression of ATP7A was not significantly changed (P > 0.05). Compared with the model group, there was no significant difference in body weight (P > 0.05) in the Huangqi Guizhi Wuwu Decoction group and no significant decrease in the mechanical allodynia foot contraction (P > 0.05). The pathological damage of sciatic nerve and dorsal root ganglion cells was mild, and the content of platinum in the dorsal root ganglion was significantly decreased (P < 0.05), the expression of OCT2mRNA was decreased (P < 0.05), and the expression of ATP7A mRNA was increased (P < 0.05). Conclusion Huangqi Guizhi Wuwu Decoction may down-regulate the expression of OCT2 in dorsal root ganglion cells to reduce the intake of platinum, and up-regulate the expression of ATP7A mRNA to promote platinum pumping, so as to reduce the accumulation of platinum in dorsal root ganglion and play a role in preventing oxaliplatin-induced chronic peripheral neuropathy.
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