帕金森病防治方药的文献研究和定颤饮对帕金森病防治机理的探讨
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摘要
帕金森病(Parkinson's diseaise)是影响中老年人身体健康的主要神经退行性疾病，其病因及发病机制仍不清楚。祖国医学对该病认识较为久远，大量防治经验散在于颤振、振掉、震颤、肝风等相关文献中．
因左旋多巴治疗存在严重的副作用，人们普遍看重PD的神经保护性治疗。纵观多年的临床实践证明中药治疗PD的效果是确切的，不仅能有效拮抗和治疗西药所引起的毒副反应，并具有治疗原发病和并发症的双重作用。但目前对中药治疗PD的机理研究则相对较少，中药复方“定颤饮”在前期临床治疗中取得了较好的疗效，本课题欲从动物实验角度探讨“定颤饮”对原发性PD的保护与治疗机理，以期更好地服务于临床。
本研究采用除草剂“百草枯”(PQ)腹腔注射C57BL／6J小鼠制作PD模型，利用行为学检测、生化检测、免疫组化等方法，在抗氧化、抗凋亡等方面对“定颤饮”防治PD的机理进行了系统研究。旨在为中药复方“定颤饮”防冶PD提供实验数据，为PD治疗提供新思路。研究分为如下几部分：
第一部分帕金森病防治方药的中医文献研究
运用文献研究和统计学分析相结合的方法，对古代中医防治颤证的相关文献进行系统研究，同时对1990年以来十几年间中医药防治颤证的现代文献进行系统研究，从古代文献相关病名、病因病机、防治方药几方面探寻颤证辨证论治的发展规律及其脉络。古今文献进行对比分析研究，以明辨其异同。分别建立古今颤证防治方药数据库，运用统计学方法，从方药角度出发，分析研究古代及现代两个时期的用药特色，并对古今防治颤证之高频药物进行分析研究和整理，分别析出了古今防治颤证的高频药物，从中组合出防治颤证的基本方药。通过上述系统分析方药统计结果，结合文献研究和相关中医药理论，提出了防治颤证的基本思路：益气养血、培补脾肾、清热熄风、涤痰化瘀是防治颤证的基本方法；权衡标本，治分先后是防治颤证的基本原则；固源培本，缓图其功是防治颤证的主导思想。
第二部分动物实验研究
实验动物：本实验采用健康雄性C57BL／6J小鼠，7～9周龄，体质量18～22g，a级。购于上海斯莱克实验动物有限责任公司，许可证号为SCXX(沪)2003-0003。实验动物在本校清洁级安静动物饲养室喂养，每天保持12小时明暗环境，自由饮水取食5天，以保持体内单胺类神经递质的稳定。实验室温度18℃-21℃，相对湿度45％-55％。
动物分组：阴性对照组(NS组)：每天上午给予C57BL／6J小鼠生理盐水0.5ml／20g体重灌胃，连续14天，于第15天小鼠灌胃后1小时给予生理盐水腹腔注射，剂量10mg／Kg，隔天一次，共4次。模型组(M)：每天上午给予C57BL／6J小鼠生理盐水0.5ml／20g体重灌胃，连续14天，第15天小鼠灌胃后1小时给予PQ腹腔注射，剂量10mg／Kg，隔天一次，共4次。定颤饮预防给药组：每天上午8：00给予C57BL／6J小鼠不同浓度的定颤饮0.5ml／20g体重灌胃，连续两周，第15天小鼠灌胃后1小时给予PQ腹腔注射，剂量10mg／Kg，隔天一次，共4次。
实验方法：本实验中，对造模成功的PD小鼠首先行自主活动能力和平衡功能检测。部分小鼠分离血清、双侧黑质进行GSH、MDA、SOD检测。其余部分小鼠用4％多聚甲醛进行全身灌注，观察黑质致密部TH、caspase-3阳性神经元的表达。
结论：
①中药复方定颤饮可减轻PD小鼠注射PQ后的症状，改善小鼠的自主活动能力和平衡协调功能。
②小鼠黑质GSH浓度有所升高，而SOD、MDA浓度下降；而血清GSH、SOD、MDA水平却无特异性改变。
③中药复方定颤饮可有效增加PD小鼠黑质TH免疫反应阳性神经元面积及平均密度，有效抑制caspase-3阳性神经元的表达。
研究总结
帕金森病是临床常见病，古今中医文献积累了较多关于本病成因证治的论述，但一直缺少系统的研究和整理。本次研究从历史发展和现代医学动物实验的角度，运用文献学和统计学等相关方法进行了较为系统的整理和研究，综合起来，本次研究的主要成果及结论如下。
1．运用文献学方法，系统收集整理了大略相当于现今帕金森病的相关文献资料，分析研究了本病的病名沿革、病因病机、防治方药，从整体上把握了该病的证治发展规律，为今后的研究奠定了理论和文献学基础。
2．运用统计学方法，系统整理研究古代、现代两个时期临床医家遣方用药的总体规律及其特点，通过分析统计结果，结合文献研究，基本理清了帕金森病防治方药的发展脉络及其演变规律并．分别建立了古今防治颤证方药数据库，分析古今防治颤证的高频药物，从中得出了防治本病的基本药物组合。
3．通过对古今防治颤证文献的系统分析研究，提出了防治帕金森病的基本思路，即：益气养血、培补脾肾、清热熄风、涤痰化瘀是PD基本方法；权衡标本，治分先后是防治PD的基本原则；固源培本，缓图其功是防治PD的主导思想。
4．借鉴现代医学研究手段，从动物实验的角度探讨临床行之有效的中药复方定颤饮防治PD的机理。认为定颤饮能改善PD模型小鼠的行为能力和平衡功能，有效增加PD模型小鼠黑质致密部TH阳性神经元的表达，升高GSH浓度，降低MDA浓度和SOD活力。进一步证明PQ导致的PD发病过程中，抗自由基酶活力下降，脂质过氧化反应增强。提示定颤饮可明显调节PD黑质部位抗氧化应激的酶系统，增加抵抗自由基损伤的能力，有效减少MDA的生成。
5．黑质多巴胺能神经元凋亡的细胞内部调控是一个极其复杂的过程，caspase-3充当了重要角色，中药复方定颤饮可有效抑制帕金森病模型小鼠黑质神经元细胞的caspase-3表达，从根本上阻止黑质多巴胺能神经元的细胞凋亡。
6．本实验中我们选择给予C57BL／6J小鼠腹腔注射PQ(10 mg／kg体重)隔天一次模拟临床PD患者，证明该模型是成功的。该模型的可能作用机理是：在PD模型中，脑组织中因PQ的作用而导致抗氧化能力降低，自由基积累，攻击生物膜中多不饱和脂肪酸，引发脂质过氧化反应，产生高水平的脂质过氧化物，参与PD的发病。
The Parkinson's disease is a main nerve recession disease which is affecting themiddle-aged person and old person, the cause of disease and the pathogenesis were notstill clear. There are a lot of accounts in the TCM literature, much experience ofpreventing and controls lies in the flutter, inspires, trembles and ganfeng, and so on in therelated literature.
Besides the L-dopamine, the current strategy is the neuroprotective therapy.Some experiments reported that Chinese medicine had obvious therapeutic effect on PD,which is regarded as one of the neuroprotective therapy. However, there is few study onthe mechanism of Chinese medicine's therapeutic effect of PD. Chinese medicine"Dingchanyin" has a beneficial effect on treating PD. It could not only improve theclinical symptoms of PD patients, but also remarkably enhance the immune systemfunction.
In this topic, we used paraquat (PQ) to inject the C57BL/6J mouse fromabdominal to manufacture the PD model, using behavior examination, biochemistryexamination, immunity group methods to study the mechanism of Dingchanyin onprevents and controls, so that we can provide the empirical datum and new mentality.This experiment divides into the following several parts:
PARTI The Literature Study of Herbs and Formulas for Chanzheng's Preventionand Treatment.
The article which is based on systematically review of past dynasties and modembibliography and tutor's many years experience studies the laws of prevention and treatment in each epoch from the history of the name, the causes and the mechanism ofthe disease, the formula and medicine of prevention and treatment. At the same time,compared with Chinese traditional medicine used in modem times to prevent and treatthe PD, the same and difference between the two groups are studied, and the reasons forthese are explained too.
With the aim of showing some useful references for PD prevention and treatment,146 formulas are collected from the classical documents and 232 are selected frommodem bibliography used for prevention and treatment. With the computer, twodatabases of the formulas and medicine are founded. The frequencies of herbs areanalyzed by SPSS10.5 statistic method. At the same time, the characters ofmedicine-using in each epoch are studied. What's more, the high frequent herbs areselected. From the results of analysis,it is showed that a basic prescription can be used inthe prevention and treatment of the PD. And this result conforms to modem studies.
There are 3 basic methods are put forward in the last part of the article, and I thinkthey are important principals to prevent and treat PD, they will direct clinicians well too.
PARTⅡThe animal experimentation studies
This experiment uses the healthy male C57BL/6J mouse, 7～9 weeks ages, thephysique measures 18～22 grams, a level.Buy from Shanghai Slack Experimental animalLimited liability company; the permit number is SCXX (Shanghai) 2003-0003. Theexperimental animal feeds in this school clean level peaceful animal feed room, everyday maintains 12 hour light and shade environment, the free potable water takes food 5day to maintain in vivo single amines nerve to hand over the archery target to bestable.Laboratory temperature 18～21℃, relative humidity 45%-55%.
Animal grouping: Negative control group (NS group): Every day in the morning,gives the C57BL/6J mouse are given physiological saline 0.5ml/20g body weight to fillthe stomach, continual 14 days, after 1 hour in the 15th day the mice are given thephysiological saline, dosage 10mg/kg, previous day one time, altogether 4 times.
Model group (M): every day in the morning, the C57BL/6J mice are givenphysiological saline 0.5ml/20g body weight to fill the stomach, continual 14 days, the15th day the mice are injected PQ abdominal cavity ion, dosage 10mg/kg, previous day one time, altogether 4 times.
Protecting group: In the morning 8:00 gives the C57BL/6J mouse different densityDingchanyin 0.5ml/20g body weight, the continual two weeks, the 15th day mouse areinjected PQ abdominal cavity, dosage 10mg/kg, previous day one time, altogether 4times.
Experimental technique: In this experiment, to makes the PD mouse advanceindependent energy and the balanced function examination, which the mold succeeds.The partial mouse separation blood serum, the two-sided opsoninum carry on GSH,MDA, and the SOD examination. Other parts of mice carry on the whole body irrigationwith 4% paraformaldehyde, observation opsoninum compact TH, the caspase-3masculine neuron expression.
Conclusion:
The Dingchanyin may mitigate the symptom of the PD mouse, improve itsindependent motion and the balance coordinated function. The GSH density has beenascened, but SOD, the MDA density drops; But blood serum GSH, SOD, the MDA leveldoes not have the specificity change actually. The Dingchanyin may increase effectivelythe opsoninum TH immune response masculine neuron area and the average light density,suppresses the caspase-3 masculine neuron effectively the expression.
Research summary
PD is the clinical common disease, many literature has been accumulated, but thereare less systematic research .In this research, we use statistics correlation methods toanalyze the sickness evolution, the cause of disease pathogenesis, the prevention andcontrolling of the sick, and we has established the theory and the literature studyfoundation for the next research. Using the statistical method, we has established theancient and modem preventing and controlling medicine database, and analyzed theancient and modem preventing and controlling medicine of the high frequency, and hasobtained a permanent medicine combination. The Dingchanyin can improve the PDmodel mouse's capacity and the balance function, increases PD effectively the modelmouse opsoninum compact TH masculine neuron the expression, elevates the GSHdensity, reduces the MDA density and the SOD. caspase-3 plays the strong character in PD. The Dingchanyin can suppress the Parkinson sickness model mouse opsoninumneuron cell the caspase-3 expression, fundamentally prevented the opsoninummulti-Pakistan amine to be able the neuron cell to perish weakly. In this experiment, themodel which C57BL/6J mouse is injected PQ (10 mg/kg body weights) is proved to be asuccessful one.
因左旋多巴治疗存在严重的副作用，人们普遍看重PD的神经保护性治疗。纵观多年的临床实践证明中药治疗PD的效果是确切的，不仅能有效拮抗和治疗西药所引起的毒副反应，并具有治疗原发病和并发症的双重作用。但目前对中药治疗PD的机理研究则相对较少，中药复方“定颤饮”在前期临床治疗中取得了较好的疗效，本课题欲从动物实验角度探讨“定颤饮”对原发性PD的保护与治疗机理，以期更好地服务于临床。
本研究采用除草剂“百草枯”(PQ)腹腔注射C57BL／6J小鼠制作PD模型，利用行为学检测、生化检测、免疫组化等方法，在抗氧化、抗凋亡等方面对“定颤饮”防治PD的机理进行了系统研究。旨在为中药复方“定颤饮”防冶PD提供实验数据，为PD治疗提供新思路。研究分为如下几部分：
第一部分帕金森病防治方药的中医文献研究
运用文献研究和统计学分析相结合的方法，对古代中医防治颤证的相关文献进行系统研究，同时对1990年以来十几年间中医药防治颤证的现代文献进行系统研究，从古代文献相关病名、病因病机、防治方药几方面探寻颤证辨证论治的发展规律及其脉络。古今文献进行对比分析研究，以明辨其异同。分别建立古今颤证防治方药数据库，运用统计学方法，从方药角度出发，分析研究古代及现代两个时期的用药特色，并对古今防治颤证之高频药物进行分析研究和整理，分别析出了古今防治颤证的高频药物，从中组合出防治颤证的基本方药。通过上述系统分析方药统计结果，结合文献研究和相关中医药理论，提出了防治颤证的基本思路：益气养血、培补脾肾、清热熄风、涤痰化瘀是防治颤证的基本方法；权衡标本，治分先后是防治颤证的基本原则；固源培本，缓图其功是防治颤证的主导思想。
第二部分动物实验研究
实验动物：本实验采用健康雄性C57BL／6J小鼠，7～9周龄，体质量18～22g，a级。购于上海斯莱克实验动物有限责任公司，许可证号为SCXX(沪)2003-0003。实验动物在本校清洁级安静动物饲养室喂养，每天保持12小时明暗环境，自由饮水取食5天，以保持体内单胺类神经递质的稳定。实验室温度18℃-21℃，相对湿度45％-55％。
动物分组：阴性对照组(NS组)：每天上午给予C57BL／6J小鼠生理盐水0.5ml／20g体重灌胃，连续14天，于第15天小鼠灌胃后1小时给予生理盐水腹腔注射，剂量10mg／Kg，隔天一次，共4次。模型组(M)：每天上午给予C57BL／6J小鼠生理盐水0.5ml／20g体重灌胃，连续14天，第15天小鼠灌胃后1小时给予PQ腹腔注射，剂量10mg／Kg，隔天一次，共4次。定颤饮预防给药组：每天上午8：00给予C57BL／6J小鼠不同浓度的定颤饮0.5ml／20g体重灌胃，连续两周，第15天小鼠灌胃后1小时给予PQ腹腔注射，剂量10mg／Kg，隔天一次，共4次。
实验方法：本实验中，对造模成功的PD小鼠首先行自主活动能力和平衡功能检测。部分小鼠分离血清、双侧黑质进行GSH、MDA、SOD检测。其余部分小鼠用4％多聚甲醛进行全身灌注，观察黑质致密部TH、caspase-3阳性神经元的表达。
结论：
①中药复方定颤饮可减轻PD小鼠注射PQ后的症状，改善小鼠的自主活动能力和平衡协调功能。
②小鼠黑质GSH浓度有所升高，而SOD、MDA浓度下降；而血清GSH、SOD、MDA水平却无特异性改变。
③中药复方定颤饮可有效增加PD小鼠黑质TH免疫反应阳性神经元面积及平均密度，有效抑制caspase-3阳性神经元的表达。
研究总结
帕金森病是临床常见病，古今中医文献积累了较多关于本病成因证治的论述，但一直缺少系统的研究和整理。本次研究从历史发展和现代医学动物实验的角度，运用文献学和统计学等相关方法进行了较为系统的整理和研究，综合起来，本次研究的主要成果及结论如下。
1．运用文献学方法，系统收集整理了大略相当于现今帕金森病的相关文献资料，分析研究了本病的病名沿革、病因病机、防治方药，从整体上把握了该病的证治发展规律，为今后的研究奠定了理论和文献学基础。
2．运用统计学方法，系统整理研究古代、现代两个时期临床医家遣方用药的总体规律及其特点，通过分析统计结果，结合文献研究，基本理清了帕金森病防治方药的发展脉络及其演变规律并．分别建立了古今防治颤证方药数据库，分析古今防治颤证的高频药物，从中得出了防治本病的基本药物组合。
3．通过对古今防治颤证文献的系统分析研究，提出了防治帕金森病的基本思路，即：益气养血、培补脾肾、清热熄风、涤痰化瘀是PD基本方法；权衡标本，治分先后是防治PD的基本原则；固源培本，缓图其功是防治PD的主导思想。
4．借鉴现代医学研究手段，从动物实验的角度探讨临床行之有效的中药复方定颤饮防治PD的机理。认为定颤饮能改善PD模型小鼠的行为能力和平衡功能，有效增加PD模型小鼠黑质致密部TH阳性神经元的表达，升高GSH浓度，降低MDA浓度和SOD活力。进一步证明PQ导致的PD发病过程中，抗自由基酶活力下降，脂质过氧化反应增强。提示定颤饮可明显调节PD黑质部位抗氧化应激的酶系统，增加抵抗自由基损伤的能力，有效减少MDA的生成。
5．黑质多巴胺能神经元凋亡的细胞内部调控是一个极其复杂的过程，caspase-3充当了重要角色，中药复方定颤饮可有效抑制帕金森病模型小鼠黑质神经元细胞的caspase-3表达，从根本上阻止黑质多巴胺能神经元的细胞凋亡。
6．本实验中我们选择给予C57BL／6J小鼠腹腔注射PQ(10 mg／kg体重)隔天一次模拟临床PD患者，证明该模型是成功的。该模型的可能作用机理是：在PD模型中，脑组织中因PQ的作用而导致抗氧化能力降低，自由基积累，攻击生物膜中多不饱和脂肪酸，引发脂质过氧化反应，产生高水平的脂质过氧化物，参与PD的发病。
The Parkinson's disease is a main nerve recession disease which is affecting themiddle-aged person and old person, the cause of disease and the pathogenesis were notstill clear. There are a lot of accounts in the TCM literature, much experience ofpreventing and controls lies in the flutter, inspires, trembles and ganfeng, and so on in therelated literature.
Besides the L-dopamine, the current strategy is the neuroprotective therapy.Some experiments reported that Chinese medicine had obvious therapeutic effect on PD,which is regarded as one of the neuroprotective therapy. However, there is few study onthe mechanism of Chinese medicine's therapeutic effect of PD. Chinese medicine"Dingchanyin" has a beneficial effect on treating PD. It could not only improve theclinical symptoms of PD patients, but also remarkably enhance the immune systemfunction.
In this topic, we used paraquat (PQ) to inject the C57BL/6J mouse fromabdominal to manufacture the PD model, using behavior examination, biochemistryexamination, immunity group methods to study the mechanism of Dingchanyin onprevents and controls, so that we can provide the empirical datum and new mentality.This experiment divides into the following several parts:
PARTI The Literature Study of Herbs and Formulas for Chanzheng's Preventionand Treatment.
The article which is based on systematically review of past dynasties and modembibliography and tutor's many years experience studies the laws of prevention and treatment in each epoch from the history of the name, the causes and the mechanism ofthe disease, the formula and medicine of prevention and treatment. At the same time,compared with Chinese traditional medicine used in modem times to prevent and treatthe PD, the same and difference between the two groups are studied, and the reasons forthese are explained too.
With the aim of showing some useful references for PD prevention and treatment,146 formulas are collected from the classical documents and 232 are selected frommodem bibliography used for prevention and treatment. With the computer, twodatabases of the formulas and medicine are founded. The frequencies of herbs areanalyzed by SPSS10.5 statistic method. At the same time, the characters ofmedicine-using in each epoch are studied. What's more, the high frequent herbs areselected. From the results of analysis,it is showed that a basic prescription can be used inthe prevention and treatment of the PD. And this result conforms to modem studies.
There are 3 basic methods are put forward in the last part of the article, and I thinkthey are important principals to prevent and treat PD, they will direct clinicians well too.
PARTⅡThe animal experimentation studies
This experiment uses the healthy male C57BL/6J mouse, 7～9 weeks ages, thephysique measures 18～22 grams, a level.Buy from Shanghai Slack Experimental animalLimited liability company; the permit number is SCXX (Shanghai) 2003-0003. Theexperimental animal feeds in this school clean level peaceful animal feed room, everyday maintains 12 hour light and shade environment, the free potable water takes food 5day to maintain in vivo single amines nerve to hand over the archery target to bestable.Laboratory temperature 18～21℃, relative humidity 45%-55%.
Animal grouping: Negative control group (NS group): Every day in the morning,gives the C57BL/6J mouse are given physiological saline 0.5ml/20g body weight to fillthe stomach, continual 14 days, after 1 hour in the 15th day the mice are given thephysiological saline, dosage 10mg/kg, previous day one time, altogether 4 times.
Model group (M): every day in the morning, the C57BL/6J mice are givenphysiological saline 0.5ml/20g body weight to fill the stomach, continual 14 days, the15th day the mice are injected PQ abdominal cavity ion, dosage 10mg/kg, previous day one time, altogether 4 times.
Protecting group: In the morning 8:00 gives the C57BL/6J mouse different densityDingchanyin 0.5ml/20g body weight, the continual two weeks, the 15th day mouse areinjected PQ abdominal cavity, dosage 10mg/kg, previous day one time, altogether 4times.
Experimental technique: In this experiment, to makes the PD mouse advanceindependent energy and the balanced function examination, which the mold succeeds.The partial mouse separation blood serum, the two-sided opsoninum carry on GSH,MDA, and the SOD examination. Other parts of mice carry on the whole body irrigationwith 4% paraformaldehyde, observation opsoninum compact TH, the caspase-3masculine neuron expression.
Conclusion:
The Dingchanyin may mitigate the symptom of the PD mouse, improve itsindependent motion and the balance coordinated function. The GSH density has beenascened, but SOD, the MDA density drops; But blood serum GSH, SOD, the MDA leveldoes not have the specificity change actually. The Dingchanyin may increase effectivelythe opsoninum TH immune response masculine neuron area and the average light density,suppresses the caspase-3 masculine neuron effectively the expression.
Research summary
PD is the clinical common disease, many literature has been accumulated, but thereare less systematic research .In this research, we use statistics correlation methods toanalyze the sickness evolution, the cause of disease pathogenesis, the prevention andcontrolling of the sick, and we has established the theory and the literature studyfoundation for the next research. Using the statistical method, we has established theancient and modem preventing and controlling medicine database, and analyzed theancient and modem preventing and controlling medicine of the high frequency, and hasobtained a permanent medicine combination. The Dingchanyin can improve the PDmodel mouse's capacity and the balance function, increases PD effectively the modelmouse opsoninum compact TH masculine neuron the expression, elevates the GSHdensity, reduces the MDA density and the SOD. caspase-3 plays the strong character in PD. The Dingchanyin can suppress the Parkinson sickness model mouse opsoninumneuron cell the caspase-3 expression, fundamentally prevented the opsoninummulti-Pakistan amine to be able the neuron cell to perish weakly. In this experiment, themodel which C57BL/6J mouse is injected PQ (10 mg/kg body weights) is proved to be asuccessful one.
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