二甲双胍对1型糖尿病大鼠周围神经病变的影响及机制初探  

The effect and mechanism of metformin on peripheral neuropathy in type 1 diabetic rats

作　　者：王星 李彩娜 张琳[3,4] 纪文明 雷蕾 曹慧 刘泉 环奕 孙素娟 刘率男 申竹芳 WANG Xing;LI Cai-na;ZHANG Lin;JI Wen-ming;LEI Lei;CAO Hui;LIU Quan;HUAN Yi;SUN Su-juan;LIU Shuai-nan;SHEN Zhu-fang(Department of Pharmacy,North Sichuan Medical College,Nanchong 637100,China;Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Beijing Key Laboratory of Polymorphic Drugs,Beijing 100050,China;Beijing Tongren Hospital,Capital Medical University,Beijing 100730,China;Beijing Key Laboratory of Diabetes Research and Care,Beijing 100730,China)

机构地区：[1]川北医学院药学院,四川南充637100 [2]中国医学科学院药物研究所,天然药物活性物质与功能国家重点实验室,晶型药物研究北京市重点实验室,北京100050 [3]首都医科大学附属北京同仁医院,北京100730 [4]糖尿病防治研究北京市重点实验室,北京100730

出　　处：《药学学报》2023年第2期386-395,共10页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金面上资助项目(81973379);北京市中医药科技发展资金项目(JJ-2020-25);中国学科学院医学与健康科技创新工程项目(2021-I2M-1-026,2022-I2M-JB0011);南充市市校合作项目(22SXZRKX0012);川北医学院博士科研启动基金(CBY21-QD16).

摘　　要：糖尿病周围神经病变(diabetic peripheral neuropathy,DPN)是1型和2型糖尿病中最常见的微血管并发症之一,常导致患者遭受严重的痛觉过敏和异常性疼痛。迄今为止,DPN的临床治疗效果仍不令人满意。二甲双胍是一种几十年来一直被安全、广泛地用于治疗2型糖尿病的抗糖尿病药物。研究表明二甲双胍可改善DPN引起的疼痛,但是其对DPN神经传导速度、坐骨神经形态的影响及改善DPN的机制还不清楚。因此,本研究以链脲佐菌素(streptozotocin,STZ)诱导SD大鼠形成的1型DPN模型为对象,考察二甲双胍对糖尿病周围神经病变的影响及探讨初步作用机制。所有动物实验操作和福利均遵循中国医学科学院、北京协和医学院药物研究所实验动物伦理与动物福利委员会的规定。模型形成成功后,将STZ糖尿病大鼠随机分为模型组和二甲双胍治疗组,另取10只正常SD大鼠为正常对照组,连续灌胃给药12周。结果表明:二甲双胍可显著降低STZ大鼠血糖、糖化血红蛋白、摄食量和饮水量;二甲双胍明显增大STZ大鼠神经传导速度和机械刺痛阈值,延长热板潜伏期阈值,且改善坐骨神经病理形态异常;此外,二甲双胍增加STZ糖尿病大鼠血清和坐骨神经中还原型谷胱甘肽(glutathione,GSH)含量,增强抗氧化酶超氧化物歧化酶(superoxide dismutase,SOD)、过氧化氢酶(catalase,CAT)活性,降低丙二醛(malondialdehyde,MDA)含量,调节坐骨神经中氧化应激相关基因的表达;二甲双胍可显著降低STZ大鼠血清中促炎因子肿瘤坏死因子α(tumor necrosis factorα,TNF-α)、白介素(interleukin,IL)-1β、IL-6水平,并抑制坐骨神经中这些炎症因子的基因表达水平。综上,二甲双胍明显增大DPN大鼠神经传导速度,改善坐骨神经形态异常和疼痛,其作用机制可能与改善氧化应激和减轻炎症有关。Diabetic peripheral neuropathy(DPN)is one of the most common microvascular complications occurring in both type 1 and type 2 diabetes mellitus patients,which often results in patients suffering from severe hyperalgesia and allodynia.Up to now,the clinical therapeutic effect of DPN is still unsatisfactory.Metformin is an anti-diabetic drug that has been safely and widely used for the treatment of type 2 diabetes for decades.Studies have shown that metformin can improve pain caused by DPN,but its effects on the nerve conduction velocity and morphology of the sciatic nerve of DPN,and the mechanism for improving DPN are not clear.Therefore,the STZinduced model of type 1 DPN in SD rats was used to study the effects of metformin on DPN,and to preliminarily explore its mechanism in this study.All animal experiments were carried out with approval of the Experimental Animal Welfare Ethics Committee of the Institute of Materia Medica(Chinese Academy of Medical Sciences and Peking Union Medical College).After the model was established successfully,STZ diabetic rats were randomly divided into a model group and a metformin treatment group,and 10 normal SD rats were selected as the normal control group,and the rats were intragastrically administered for 12 weeks.The results showed that metformin significantly reduced blood glucose,glycosylated hemoglobin,food consumption and water consumption in STZ rats.Metformin markedly increased the motor nerve conduction velocity and mechanical stabbing pain threshold,prolonged the hot plate latency threshold,and improved the pathological morphological abnormalities of the sciatic nerve in STZ rats.In addition,metformin increased the content of glutathione(GSH),enhanced the activities of antioxidant enzymes superoxide dismutase(SOD)and catalase(CAT),and reduced the content of malondialdehyde(MDA)in serum and sciatic nerve of STZ diabetic rats,as well as regulating the expression of genes related to oxidative stress in the sciatic nerve.Metformin obviously reduced the levels of pro-inflamm

关 键 词：二甲双胍 糖尿病 糖尿病周围神经病变 炎症反应 氧化应激 

分 类 号：R966[医药卫生—药理学]