不同通络中药对糖尿病大鼠周围神经病变的保护作用及其机制研究
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摘要
目的(背景):糖尿病周围神经病变(DPN)是糖尿病(DM)最常见的慢性并发症之一,严重影响糖尿病患者的生活质量,是糖尿病患者致残的主要因素。寻找一有效的治疗途径是目前国内外研究的热点。现在国外的研究多集中在糖尿病周围神经病变的细胞内信号传导机制,以期寻找共同通路,为糖尿病神经病变的防治寻找新的途径。中医治疗DPN有三类不同通络中药,但是何者为优,尚未见报道。本实验通过观察不同通络中药(辛味、藤类、虫类)对链脲佐霉素(STZ)诱导的糖尿病周围神经病变大鼠坐骨神经的病理形态改变,以及对坐骨神经中核转录因子NF-κB、IκBa、Ikka蛋白表达的影响,来探讨不同通络中药对DPN大鼠的防治作用及其机制。
方法:187只雄性Wistar大鼠,以STZ诱导糖尿病模型,随机分为正常对照组、模型组、辛味通络组、藤类通络组、虫类通络组。①分别于治疗前、治疗后2w、4w、8w尾静脉采血测定血糖值及称重.②分别于治疗后2w、4w、8w测定大鼠坐骨神经传导速度(MNCV),之后处死大鼠取坐骨神经制备光镜及电镜标本行组织学观察,并用免疫组织化学法和蛋白印记方法观察坐骨神经中核转录因子NF-κB、IκBa、Ikka的蛋白表达。
结果:①造模之后各组大鼠血糖水平、体重与正常对照组相比均有显著差异(P<0.01)。模型组2w、4w、8w血糖水平逐渐升高,体重增长缓慢。辛味通络组、藤类通络组、虫类通络组与同期模型组相比,血糖略有下降,体重略有增加,但无统计学意义,同期三治疗组之间比较血糖、体重差异均不显著(均P>0.05)。②不同通络中药对坐骨神经传导速度的影响:与正常对照组相比,模型组大鼠坐骨神经传导速度在造模后2w(26.66m/s)、4w(25.59m/s)、8w(22.22m/s)明显减慢,而且呈下降趋势(P<0.01)。各治疗组经不同通络中药干预后均能提高神经传导速度,与同期模型组比较均有显著性差异(P<0.01),同期各治疗组之间MNCV比较无显著性差异(P>0.05)。③形态学观察:与正常对照组相比,模型组、辛味通络组、藤类通络组、虫类通络组大鼠在2w开始逐渐表现有病理损伤反应,模型组随着病程延长病理损伤程度逐渐加重,经不同通络中药干预后病变程度明显减轻,同期治疗组之间病理损伤程度相近。④免疫组化及蛋白印记结果显示:造模组坐骨神经中NF-κB水平明显高于同期正常组(P<0.01),而IκBa、Ikka水平明显低于同期正常组(P<0.01),随着病程延长,模型组大鼠坐骨神经中NF-κB蛋白表达水平逐渐增加,IκBa、Ikka表达水平逐渐降低,与同期模型组比较,2周不同通络组与模型组相比坐骨神经中NF-κB、IκBa、Ikka的表达无显著性差异(均P>0.05),4周、8周不同通络中药组均能降低坐骨神经中NF-κB的表达(P<0.01),提高IκBa、Ikka的表达(P<0.01)。同期治疗组之间比较坐骨神经中NF-κB、IκBa、Ikka的表达无显著性差异(均P>0.05)。
结论:不同通络中药随着疗程延长均具有减轻糖尿病模型大鼠周围神经结构和功能损伤,延缓神经病变进程的作用,其保护机制可能与调节NF-κB信号系统有关。
Objective: Diabetic peripheral neuropathy(DPN)is one of the most common and chronic complication of Diabetes mellitus(DM),which seriously influence on the life quality of diabetic patients, and be the major factor of mutilation of diabetic patients. Finding an effective way to treat DPN is the researching hot spot of internal and external.Despite the research of the mechanism on the DPN have achieved some results, the therapy to DPN is still poor in the clinic. Now,the research of DPN focus on the endocelluar signal transduction , in order to find the common way , and the new therapy method for the prevention and cure of DPN. This experiment approaches the role of the prevention and cure of the different smoothing collaterals Chinese medicine to DPN mice, and its mechanism, through observing the different smoothing collaterals Chinese medicine to DPN mice induced by STZ, the pathomorph change of sciatic nerve and the albumen expression of NF-κB、IκBa、Ikka in the sciatic nerve.
Method: 187 male Wistar rats were randomly divided into five groups, including normal-control group , model-control group , XingWeiTongLuo(XWTL) group , TengLeiTongLuo(TLTL) group, CHongLeiTongLuo(CLTL) group, and diabetic model were induced by STZ.①nonfasting plasma glucose and weigh were measured by vena caudalis in the 2th、4th、8th week and before treatment respectively.②the speed of conduction in sciatic nerve was detected in 2th、4th、8th week, and then the rats were killed in 2th、4th、8th week, the sciatic nerve was taken out ,which was observed by Morphometric evaluation under light microscope and transmission electron microscope, and observed NF-κB、IκBa、Ikka albumen express of the sciatic nerve by immunohistochemical method and western blotting method.
Results:①There were a significantly difference between normal-control group and model-control group in the level on plasma glucose and weight after making model. There was a raising up tendency in the level of in the plasma glucose, but weight increased slowly in 2th、4th、8th week. compared with model-control group, there were a bit lower in the level of plasma glucose and a bit grower in the weight, but not statistically significant , and there were not a significantly difference on the plasma glucose and weight in the XWTL group, TLTL group, CLTL group.②The effects of different smoothing collaterals Chinese medicine on the sciatic nerve conduction velocity: compared with the normal group, the sciatic nerve conduction velocity of the model group is significantly slow on the 2th、4th、8th week after successful induction by STZ(P<0.01).The different smoothing collaterals Chinese medicine groups could accelerate the nerve conduction velocity .And at the same time there also was a significant difference between the different smoothing collaterals Chinese medicine groups and model group(P<0.01 ).③Observation on pathological change: Compared with normal-control group, there were obvious reactions to the damage all in model group, XWTL group, TLTL group, CLTL group in the 2th、4th、8th week, however the reaction in the different smoothing collaterals Chinese medicine groups is weaker obviously,the damage of the therapeutic groups is similar.④The results of immunohistochemical and western blotting method show: The level NF-κB of sciatic nerve in the making model group is obviously higher than the normal-control group in the corresponding time period (P<0.01),however the level of IκBa、Ikka is lower obviously than the normal-control group in the corresponding time period(P<0.01), and following the prolongation of the disease course, the level NF-κB of sciatic nerve in the model-control group was increased gradually, the level IκBa、Ikka is lower gradually. Compared with the model-control group in the corresponding time period, the different smoothing collaterals Chinese medicine groups in the 4th and 8th week can lower the expression of NF-κB in the sciatic nerve(P<0.01), and elevate the expression of IκBa、Ikka(P<0.01), in the 2th week between the therapeutic groups and model-contrio group has no defference(P>0.05 ). There were no obviously different during the three therapeutic groups(P>0.05 ).
Conclusion: The different smoothing collaterals Chinese medicine can lessen the damages to structure and function of peripheral nerves in diabetic rats and postpone the development of neuropathy. The protective effects of the different smoothing collaterals Chinese medicine on diabetic peripheral neuropathy is possibly related with regulating the NF-κB signal transduction system.
方法:187只雄性Wistar大鼠,以STZ诱导糖尿病模型,随机分为正常对照组、模型组、辛味通络组、藤类通络组、虫类通络组。①分别于治疗前、治疗后2w、4w、8w尾静脉采血测定血糖值及称重.②分别于治疗后2w、4w、8w测定大鼠坐骨神经传导速度(MNCV),之后处死大鼠取坐骨神经制备光镜及电镜标本行组织学观察,并用免疫组织化学法和蛋白印记方法观察坐骨神经中核转录因子NF-κB、IκBa、Ikka的蛋白表达。
结果:①造模之后各组大鼠血糖水平、体重与正常对照组相比均有显著差异(P<0.01)。模型组2w、4w、8w血糖水平逐渐升高,体重增长缓慢。辛味通络组、藤类通络组、虫类通络组与同期模型组相比,血糖略有下降,体重略有增加,但无统计学意义,同期三治疗组之间比较血糖、体重差异均不显著(均P>0.05)。②不同通络中药对坐骨神经传导速度的影响:与正常对照组相比,模型组大鼠坐骨神经传导速度在造模后2w(26.66m/s)、4w(25.59m/s)、8w(22.22m/s)明显减慢,而且呈下降趋势(P<0.01)。各治疗组经不同通络中药干预后均能提高神经传导速度,与同期模型组比较均有显著性差异(P<0.01),同期各治疗组之间MNCV比较无显著性差异(P>0.05)。③形态学观察:与正常对照组相比,模型组、辛味通络组、藤类通络组、虫类通络组大鼠在2w开始逐渐表现有病理损伤反应,模型组随着病程延长病理损伤程度逐渐加重,经不同通络中药干预后病变程度明显减轻,同期治疗组之间病理损伤程度相近。④免疫组化及蛋白印记结果显示:造模组坐骨神经中NF-κB水平明显高于同期正常组(P<0.01),而IκBa、Ikka水平明显低于同期正常组(P<0.01),随着病程延长,模型组大鼠坐骨神经中NF-κB蛋白表达水平逐渐增加,IκBa、Ikka表达水平逐渐降低,与同期模型组比较,2周不同通络组与模型组相比坐骨神经中NF-κB、IκBa、Ikka的表达无显著性差异(均P>0.05),4周、8周不同通络中药组均能降低坐骨神经中NF-κB的表达(P<0.01),提高IκBa、Ikka的表达(P<0.01)。同期治疗组之间比较坐骨神经中NF-κB、IκBa、Ikka的表达无显著性差异(均P>0.05)。
结论:不同通络中药随着疗程延长均具有减轻糖尿病模型大鼠周围神经结构和功能损伤,延缓神经病变进程的作用,其保护机制可能与调节NF-κB信号系统有关。
Objective: Diabetic peripheral neuropathy(DPN)is one of the most common and chronic complication of Diabetes mellitus(DM),which seriously influence on the life quality of diabetic patients, and be the major factor of mutilation of diabetic patients. Finding an effective way to treat DPN is the researching hot spot of internal and external.Despite the research of the mechanism on the DPN have achieved some results, the therapy to DPN is still poor in the clinic. Now,the research of DPN focus on the endocelluar signal transduction , in order to find the common way , and the new therapy method for the prevention and cure of DPN. This experiment approaches the role of the prevention and cure of the different smoothing collaterals Chinese medicine to DPN mice, and its mechanism, through observing the different smoothing collaterals Chinese medicine to DPN mice induced by STZ, the pathomorph change of sciatic nerve and the albumen expression of NF-κB、IκBa、Ikka in the sciatic nerve.
Method: 187 male Wistar rats were randomly divided into five groups, including normal-control group , model-control group , XingWeiTongLuo(XWTL) group , TengLeiTongLuo(TLTL) group, CHongLeiTongLuo(CLTL) group, and diabetic model were induced by STZ.①nonfasting plasma glucose and weigh were measured by vena caudalis in the 2th、4th、8th week and before treatment respectively.②the speed of conduction in sciatic nerve was detected in 2th、4th、8th week, and then the rats were killed in 2th、4th、8th week, the sciatic nerve was taken out ,which was observed by Morphometric evaluation under light microscope and transmission electron microscope, and observed NF-κB、IκBa、Ikka albumen express of the sciatic nerve by immunohistochemical method and western blotting method.
Results:①There were a significantly difference between normal-control group and model-control group in the level on plasma glucose and weight after making model. There was a raising up tendency in the level of in the plasma glucose, but weight increased slowly in 2th、4th、8th week. compared with model-control group, there were a bit lower in the level of plasma glucose and a bit grower in the weight, but not statistically significant , and there were not a significantly difference on the plasma glucose and weight in the XWTL group, TLTL group, CLTL group.②The effects of different smoothing collaterals Chinese medicine on the sciatic nerve conduction velocity: compared with the normal group, the sciatic nerve conduction velocity of the model group is significantly slow on the 2th、4th、8th week after successful induction by STZ(P<0.01).The different smoothing collaterals Chinese medicine groups could accelerate the nerve conduction velocity .And at the same time there also was a significant difference between the different smoothing collaterals Chinese medicine groups and model group(P<0.01 ).③Observation on pathological change: Compared with normal-control group, there were obvious reactions to the damage all in model group, XWTL group, TLTL group, CLTL group in the 2th、4th、8th week, however the reaction in the different smoothing collaterals Chinese medicine groups is weaker obviously,the damage of the therapeutic groups is similar.④The results of immunohistochemical and western blotting method show: The level NF-κB of sciatic nerve in the making model group is obviously higher than the normal-control group in the corresponding time period (P<0.01),however the level of IκBa、Ikka is lower obviously than the normal-control group in the corresponding time period(P<0.01), and following the prolongation of the disease course, the level NF-κB of sciatic nerve in the model-control group was increased gradually, the level IκBa、Ikka is lower gradually. Compared with the model-control group in the corresponding time period, the different smoothing collaterals Chinese medicine groups in the 4th and 8th week can lower the expression of NF-κB in the sciatic nerve(P<0.01), and elevate the expression of IκBa、Ikka(P<0.01), in the 2th week between the therapeutic groups and model-contrio group has no defference(P>0.05 ). There were no obviously different during the three therapeutic groups(P>0.05 ).
Conclusion: The different smoothing collaterals Chinese medicine can lessen the damages to structure and function of peripheral nerves in diabetic rats and postpone the development of neuropathy. The protective effects of the different smoothing collaterals Chinese medicine on diabetic peripheral neuropathy is possibly related with regulating the NF-κB signal transduction system.
引文
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