雷公藤多甙对肌收缩影响及对治疗MG机理探讨
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摘要
重症肌无力(myasthenia gravis，MG)是一种自身免疫性疾病，其主要表现为肌收缩无力，易疲劳。目前，用激素等免疫抑制剂治疗MG仍是主要方法之一，但其副作用明显且不易消除，使临床工作者治疗MG受到一定程度的困扰。近年来，大量研究已经证实雷公藤多甙(Tripterygium Wilfordii Polyglycosidium，TWP)具有明确的抗炎、免疫抑制作用，且临床研究也已显示其治疗MG效果好、毒副作用少，是治疗MG安全有效的药物，其避免了糖皮质激素及细胞毒性药物所引起的难以克服的毒副作用，其作用范围及作用疗效日渐被人们所重视，但其具体作用机制，到目前为止还不是十分清楚。本课题组前面的研究发现，TWP能通过提高神经-肌接头处兴奋传递，增强肌肉的收缩。但是，TWP对肌收缩本身是否有影响，尚存在疑问。而且，TWP治疗MG的药效学作用的客观参数和依据，鲜有报道。因此，本实验的目的是深入探讨TWP的药理作用，及其可能的作用机制，为反映TWP的药效提供一个客观方法和客观依据，并为临床应用TWP治疗MG提供直接的实验和理论基础。
本研究分两部分内容：
第一部分：用电生理学方法，研究TWP对蟾蜍腓肠肌收缩张力的影响。研究结果表明：
1．TWP不仅可促进神经-肌接头间兴奋传递，还可直接增强肌
四少11大学硕士学位论文
肉本身的收缩力。
2.溶剂二甲亚酚(DMSO)对肌收缩本身有抑制作用
第二部分:利用从小牛肌肉组织提取的AchR作为抗原，免疫
C57BL/6小鼠，建立实验性自身免疫性重症肌无力(experimental
autoimmune myas出enia盯avis，EAMG)动物模型;用电生理学方法检
测TWP对EANIG动物模型排肠肌和旋前圆肌复合动作电位的影响。
研究结果表明:
1.EAMG动物模型建立成功。
2.TWP可增大EAMG动物胖肠肌和旋前圆肌复合动作电位
的幅度。
3.TWP对不同肌肉间复合动作电位的影响没有差异。
4.TWP可能不仅通过促进神经一肌接头间兴奋传递，还通过其
它作用机理，联合作用增加肌肉复合动作电位幅度。
5.检测多组神经肌肉肌电图，可提高MG诊断阳性率。
Myasthenis gravis (MG) is an autoimmune disease. It manifests
itself by varying weakness of muscle under voluntery control. Prednisone is one of the most effective treatments for MG. However, it has relatively severe side effects. A great deal of researchs has confirmed that Tripterygium Wilfordii Polyglycosidium (TWP) has strong anti-inflammatory and immunosuppressing effect. Clinical researchs have showed that TWP is a kind of safe and effective herb medicine in treating MG, which decreases or avoids side effects produced by such as glucocorticosteroid or cytotoxicity. Its scope of influence and effects has been increasingly received recognition. But we still know little about its specific mechanism. The studies, which have been done earlier in our research group, showed that TWP could increase muscle contraction by promoting the transmission at neuromusclar junction. However, there is no report reported about TWP's influence on capability of muscle contraction and also still lack of objective parameter about TWP's effect on MG. So this experiment aims at studying th
e effects and mechanism of TWP on capability of muscle contraction and compound muscle action potential, so as to understand TWP's influence and mechanism on muscle contraction more and establish a method and a kind of objective evidence for clinical treament on MG.
This study consists of two parts:
Part I : Effects of TWP on capability of muscle contraction of isolated gastrocnemius muscle preparation of toad were observed and recorded by using equilength transfering energy equipment.
The results and conclusion are as follows:
1. TWP not noly can stimulate the trasmission at neurornusclar junction, but also can enhance the inner ability of muscle contraction.
2. Solvent DMSO can restrain muscle contraction.
Part II: Experimental autoimmune myasthenia gravis (EAMG) was establited by injecting anitigen of AchR extracted from the muscle of calf; Influence of TWP on compound muscle action potential of gastrocnemius muscle and pronator teres muscle were observed and recorded by using neuroelectrophysiological method in established EAMG.
The results and conclusion are as follows:
1. EAMG was established successfully.
2. TWP can increase the amplitude of compound muscle action potential of gastrocnemius muscle and pronator teres muscle.
3. The effect of TWP on compound muscle action potential in different muscle has no different.
4. TWP can enhence compound muscle action potential possibly not only by promoting transmission at neurornusclar junction but also by other mechanisms.
5. Examining electromyography in more than one nerve-muscle group
can increase diagnosis rate of MG.
本研究分两部分内容：
第一部分：用电生理学方法，研究TWP对蟾蜍腓肠肌收缩张力的影响。研究结果表明：
1．TWP不仅可促进神经-肌接头间兴奋传递，还可直接增强肌
四少11大学硕士学位论文
肉本身的收缩力。
2.溶剂二甲亚酚(DMSO)对肌收缩本身有抑制作用
第二部分:利用从小牛肌肉组织提取的AchR作为抗原，免疫
C57BL/6小鼠，建立实验性自身免疫性重症肌无力(experimental
autoimmune myas出enia盯avis，EAMG)动物模型;用电生理学方法检
测TWP对EANIG动物模型排肠肌和旋前圆肌复合动作电位的影响。
研究结果表明:
1.EAMG动物模型建立成功。
2.TWP可增大EAMG动物胖肠肌和旋前圆肌复合动作电位
的幅度。
3.TWP对不同肌肉间复合动作电位的影响没有差异。
4.TWP可能不仅通过促进神经一肌接头间兴奋传递，还通过其
它作用机理，联合作用增加肌肉复合动作电位幅度。
5.检测多组神经肌肉肌电图，可提高MG诊断阳性率。
Myasthenis gravis (MG) is an autoimmune disease. It manifests
itself by varying weakness of muscle under voluntery control. Prednisone is one of the most effective treatments for MG. However, it has relatively severe side effects. A great deal of researchs has confirmed that Tripterygium Wilfordii Polyglycosidium (TWP) has strong anti-inflammatory and immunosuppressing effect. Clinical researchs have showed that TWP is a kind of safe and effective herb medicine in treating MG, which decreases or avoids side effects produced by such as glucocorticosteroid or cytotoxicity. Its scope of influence and effects has been increasingly received recognition. But we still know little about its specific mechanism. The studies, which have been done earlier in our research group, showed that TWP could increase muscle contraction by promoting the transmission at neuromusclar junction. However, there is no report reported about TWP's influence on capability of muscle contraction and also still lack of objective parameter about TWP's effect on MG. So this experiment aims at studying th
e effects and mechanism of TWP on capability of muscle contraction and compound muscle action potential, so as to understand TWP's influence and mechanism on muscle contraction more and establish a method and a kind of objective evidence for clinical treament on MG.
This study consists of two parts:
Part I : Effects of TWP on capability of muscle contraction of isolated gastrocnemius muscle preparation of toad were observed and recorded by using equilength transfering energy equipment.
The results and conclusion are as follows:
1. TWP not noly can stimulate the trasmission at neurornusclar junction, but also can enhance the inner ability of muscle contraction.
2. Solvent DMSO can restrain muscle contraction.
Part II: Experimental autoimmune myasthenia gravis (EAMG) was establited by injecting anitigen of AchR extracted from the muscle of calf; Influence of TWP on compound muscle action potential of gastrocnemius muscle and pronator teres muscle were observed and recorded by using neuroelectrophysiological method in established EAMG.
The results and conclusion are as follows:
1. EAMG was established successfully.
2. TWP can increase the amplitude of compound muscle action potential of gastrocnemius muscle and pronator teres muscle.
3. The effect of TWP on compound muscle action potential in different muscle has no different.
4. TWP can enhence compound muscle action potential possibly not only by promoting transmission at neurornusclar junction but also by other mechanisms.
5. Examining electromyography in more than one nerve-muscle group
can increase diagnosis rate of MG.
引文
1. Grob D. Course and treatment of myasthenia gravis. JAMA, 1953; 153: 529
2．粟秀处，吴保仁，黄远桂．新编神经病学．第四军医大学出版社，2002，8：419
3．舒志荣．重症肌无力．山东医药．2001；41(11)：49-50
4．李淑英，宋文燕．重症肌无力患者的临床特点及护理体会．中国误诊学杂志，2001；1(11)：1701
5．金凤艳．重症肌无力基础研究及最新进展．中华实用医学，2002；4(5)：58-60
6. Patrick J, et at. Studies on purified eel anttiacctylcholine receptor antibody. Proc Natl Acad Sci, 1973; 70:3334
7. Lennon, V., Lindstrom, J., and Seybold, M. E. Experimental autoimmune myasthenia gravis (EAMG): A model of myasthenia gravis in rats and guine pigs. J. Exp. Med, 1975; 141:1365-1375
8. Christadoss, P., Lennon, V. A., Lambert, E. H., et al. Genetic control of experimental autoimmune myasthenia gravis in mice. In "T and B Lymphocytes: Recognition and function". Academic Press, NewYork, 1979; 249
9. Berman, P. W., and Patrick, J. Linkage between the frequency of muscle weakness and loci that regulate immune responsiveness in murine experimential autoimmune myasthenia gravis. J. Exp. Med, 1980; 152:507-520
10. Christadoss, P., Lennon, V.A., Kreo, C.J. et al. Genetic contral of
autoimmunity to acetylcholine. Role of Ia molecules. Ann. NY Acad. Sci, 1981; 377:258-277
11．郭东华．雷公藤研究现状与展望．职业与健康，1998；14(2)：51-52
12．林琳，姜济民，载惠珍．介绍我国独创的抗炎药—雷公藤多甙片．江苏医药，1985；11(3)：39
13．顾克显．雷酚内酯的抗炎免疫药理作用．中草药，1995；10(1)，54
14．赵仲坤，王玉玺．雷公藤的药用研究概．药学情报通讯，1999；9(1)：58-62
15．范勇毅，陈绍先．TWP 的免疫学效应．中国实验临床免疫学杂志，1990；2(6)：40-43
16．力弘，贾永峰，李端．雷公藤多甙的抗炎和免疫抑制作用．上海医科大学学报，2000；27(6)：502-505
17．李作孝，熊先骥，张泽兰等．雷公藤多甙治疗重症肌无力临床疗效及其免疫机制探讨．中国中西医结合杂志，1997；17(12)：754
18．叶礼燕，吴荔琼．雷公藤多甙临床应用与机理研究综述．福建中医学院学报，2002；12(12)：60-62
19．郑家润，李季和，徐兰芳等．雷公藤总甙的毒理研究．中国医学科学院学报，1983；5(2)：1
20．孙赢斌，葛茂振，吴长有等．雷公藤片治疗多发性硬化的初步探讨．中西医结合杂志，1988；8(2)：87
21．谢道孚．沈金望．裴家风等．雷公藤总甙治疗白塞氏病的体会．中西医结合杂志，1983；3(6)：249
22．黄德仁．白细胞介素2及其受体在神经科学中应用．国外医学．神经病学神经外科学分册，1993；20：300
23．秦凤华，谢蜀生，龙振洲．雷公藤总甙免疫抑制作用的机制．中国
药理学通报，1991；7，433
24．李作孝，熊先骥，张泽兰等．重症肌无力患者雷公藤多甙治疗前后周围血自然杀伤细胞含量变化的研究．临床神经病学杂志，1999；12(4)：216-218
25．陈正君．雷公藤多甙对重症肌无力患者血清 sIL-2R 水平的影响．中国航天工业医药，20002；2(5)：20-21
26．吕广能，周玲，徐建国．雷公藤多甙影响蟾蜍神经-肌接头传递初探．华西医科大学学报，1997；28(2)：145-148
27．邓清委．雷公藤多甙影响蟾蜍神经-肌接头兴奋传递机理探讨．学位论文，华西医科大学．1996；6，1
28．喻璟瑞．雷公藤多甙影响神经肌接头兴奋传递机理探讨．学位论文，华西医科大学．2001；5，1
29．张镜如，乔健天．生理学．人民卫生出版社，1999；10：41-50
30．袁必文，陈平，杨晓红等．雷公藤多甙对实验性重症肌无力的防治研究．中国免疫杂志，1995；11(增刊)：53
31．施昌年．雷公藤药理作用研究进展．中国医院药学杂志，1989；9(3)：11
32．金忱．雷公藤实验研究与临床应用的进展．国外医学·外科学分册，1998；25(5)：284
33．童建孙，秦进喜．雷公藤多甙对大鼠支持细胞功能的影响．实用男科杂志，1996；2(1)：6
34．姚泰．人体生理学．人民卫生出版社，2001；117-130
35．朱思明．医用生理学．科学技术出版社，2002；40-50
2．粟秀处，吴保仁，黄远桂．新编神经病学．第四军医大学出版社，2002，8：419
3．舒志荣．重症肌无力．山东医药．2001；41(11)：49-50
4．李淑英，宋文燕．重症肌无力患者的临床特点及护理体会．中国误诊学杂志，2001；1(11)：1701
5．金凤艳．重症肌无力基础研究及最新进展．中华实用医学，2002；4(5)：58-60
6. Patrick J, et at. Studies on purified eel anttiacctylcholine receptor antibody. Proc Natl Acad Sci, 1973; 70:3334
7. Lennon, V., Lindstrom, J., and Seybold, M. E. Experimental autoimmune myasthenia gravis (EAMG): A model of myasthenia gravis in rats and guine pigs. J. Exp. Med, 1975; 141:1365-1375
8. Christadoss, P., Lennon, V. A., Lambert, E. H., et al. Genetic control of experimental autoimmune myasthenia gravis in mice. In "T and B Lymphocytes: Recognition and function". Academic Press, NewYork, 1979; 249
9. Berman, P. W., and Patrick, J. Linkage between the frequency of muscle weakness and loci that regulate immune responsiveness in murine experimential autoimmune myasthenia gravis. J. Exp. Med, 1980; 152:507-520
10. Christadoss, P., Lennon, V.A., Kreo, C.J. et al. Genetic contral of
autoimmunity to acetylcholine. Role of Ia molecules. Ann. NY Acad. Sci, 1981; 377:258-277
11．郭东华．雷公藤研究现状与展望．职业与健康，1998；14(2)：51-52
12．林琳，姜济民，载惠珍．介绍我国独创的抗炎药—雷公藤多甙片．江苏医药，1985；11(3)：39
13．顾克显．雷酚内酯的抗炎免疫药理作用．中草药，1995；10(1)，54
14．赵仲坤，王玉玺．雷公藤的药用研究概．药学情报通讯，1999；9(1)：58-62
15．范勇毅，陈绍先．TWP 的免疫学效应．中国实验临床免疫学杂志，1990；2(6)：40-43
16．力弘，贾永峰，李端．雷公藤多甙的抗炎和免疫抑制作用．上海医科大学学报，2000；27(6)：502-505
17．李作孝，熊先骥，张泽兰等．雷公藤多甙治疗重症肌无力临床疗效及其免疫机制探讨．中国中西医结合杂志，1997；17(12)：754
18．叶礼燕，吴荔琼．雷公藤多甙临床应用与机理研究综述．福建中医学院学报，2002；12(12)：60-62
19．郑家润，李季和，徐兰芳等．雷公藤总甙的毒理研究．中国医学科学院学报，1983；5(2)：1
20．孙赢斌，葛茂振，吴长有等．雷公藤片治疗多发性硬化的初步探讨．中西医结合杂志，1988；8(2)：87
21．谢道孚．沈金望．裴家风等．雷公藤总甙治疗白塞氏病的体会．中西医结合杂志，1983；3(6)：249
22．黄德仁．白细胞介素2及其受体在神经科学中应用．国外医学．神经病学神经外科学分册，1993；20：300
23．秦凤华，谢蜀生，龙振洲．雷公藤总甙免疫抑制作用的机制．中国
药理学通报，1991；7，433
24．李作孝，熊先骥，张泽兰等．重症肌无力患者雷公藤多甙治疗前后周围血自然杀伤细胞含量变化的研究．临床神经病学杂志，1999；12(4)：216-218
25．陈正君．雷公藤多甙对重症肌无力患者血清 sIL-2R 水平的影响．中国航天工业医药，20002；2(5)：20-21
26．吕广能，周玲，徐建国．雷公藤多甙影响蟾蜍神经-肌接头传递初探．华西医科大学学报，1997；28(2)：145-148
27．邓清委．雷公藤多甙影响蟾蜍神经-肌接头兴奋传递机理探讨．学位论文，华西医科大学．1996；6，1
28．喻璟瑞．雷公藤多甙影响神经肌接头兴奋传递机理探讨．学位论文，华西医科大学．2001；5，1
29．张镜如，乔健天．生理学．人民卫生出版社，1999；10：41-50
30．袁必文，陈平，杨晓红等．雷公藤多甙对实验性重症肌无力的防治研究．中国免疫杂志，1995；11(增刊)：53
31．施昌年．雷公藤药理作用研究进展．中国医院药学杂志，1989；9(3)：11
32．金忱．雷公藤实验研究与临床应用的进展．国外医学·外科学分册，1998；25(5)：284
33．童建孙，秦进喜．雷公藤多甙对大鼠支持细胞功能的影响．实用男科杂志，1996；2(1)：6
34．姚泰．人体生理学．人民卫生出版社，2001；117-130
35．朱思明．医用生理学．科学技术出版社，2002；40-50
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