丁苯酞对MPTP帕金森病模型小鼠黑质多巴胺能神经元TH、DAT、p-JNK/JNK表达的影响
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摘要
目的
帕金森病(PD)是一种常见的与年龄相关的神经变性疾病,主要特征是黑质多巴胺能神经元的进行性丢失和变性。JNK信号转导通路是MAPK通路的一条重要分支,它在细胞周期、生产、凋亡和细胞应激等多种生理和病理过程中起重要作用。目前研究证据表明帕金森病发生有JNK信号转导通路的参与。丁苯酞是从我国南方的一种水芹菜籽中分离出的有效成分,简称NBP,又名芹菜甲素,是中国医学科学院中国协和医科大学药物研究所人工合成的消旋体,从80年代开始冯亦璞带领该所开始研究NBP的药理作用：能改善缺血区局部脑血流,增加缺血区毛细血管的数量,增加缺血区脑血流量,改善缺血性脑能量代谢,缩小梗死面积,减轻神经功能损伤程度,减轻脑水肿；还可改善线粒体功能,增强呼吸链功能,能改善线粒体能量泵,增加抗氧化作用,从而发挥抗凋亡；能增加大鼠全脑缺血纹状体细胞外液氨基酸和多巴胺含量。故本试验依据JNK在PD发病的作用来研究NBP对MPTP诱导的多巴胺能神经毒性是否具保护作用。我们选择丁苯酞用于MPTP制备C57BL／6帕金森病小鼠模型,用免疫组织化学染色方法和westernblot检测帕金森病小鼠黑质多巴胺能神经元TH、DAT、p-JNK/JNK表达情况,观察并分析其表达意义。
方法
1、动物分组：30只C57BL／6小鼠采用完全随机分组法分为以下3组,每组10只。(1)正常对照组(NS+植物油)：腹腔注射与MPTP组等体积生理盐水5 d,再注射与治疗组等体积植物油14d。(2)MPTP组(MPTP+植物油)：采用MPTP(30 mg/kg)连续5 d腹腔注射,然后改用与治疗组等体积植物油注射14 d。(3)NBP治疗组(MPTP+NBP):先以MPTP(30 mg/kg)连续腹腔注射5 d,然后丁基苯酞(NBP40 mg/kg)腹腔注射14 d。每组动物于第19天处死后取脑组织进行固定石蜡包埋,取中脑黑质部位切片进行免疫组织化学染色；另外一侧脑组织提取出黑质后迅速置于-80℃冰箱冷冻用于westernblot。
2、模型制备：MPTP(30 mg/kg):连续5 d腹腔注射,注射药物后小鼠即刻出现步态跚,易激惹,毛及鼠尾竖起等反应,约5～10 min后复常态,即视为模型制备成功。
3、免疫组织化学染色方法检测TH、DAT的表达
4、Westernblot方法检测p-JNK、JNK的表达
结果
1、与正常对照组相比,MPTP组小鼠黑质多巴胺能神经元中的TH阳性神经元表达数目明显减少(P<0.05)；与MPTP组相比,NBP治疗组小鼠黑质多巴胺能神经元中TH阳性神经元表达数目增加(P<0.05),二者均具有统计学意义。
2、与正常对照组相比,MPTP组小鼠黑质纹状体多巴胺能神经纤维中的DAT阳性神经纤维表达数目明显减少(P<0.05)；与MPTP组相比,NBP治疗组小鼠黑质纹状体中DAT阳性神经纤维数目表达增加(P<0.05),二者均具有统计学意义。
3、正常对照组几乎未见p-JNK表达,MPTP组可见p-JNK/JNK的表达明显增加,而且表达较正常对照组强,二者差别有统计学意义(P<0.05),NBP治疗组p-JNK/JNK表达较MPTP组下降,二者差别有统计学意义(P<0.05)。
结论
丁苯酞可增加帕金森病小鼠黑质多巴胺能神经元TH、DAT的表达,减少p-JNK表达,拮抗JNK信号转导通路,改善多巴胺能神经元功能,这为丁苯酞可能成为治疗PD药物的临床可能性提供了实验依据。
Objectives
Parkinson's disease (PD) is a common age-related neurodegenerative disease, mainly characterized by dopaminergic neurons loss and degeneration of the sexual. JNK signal transduction pathway is an important branch of MAPK pathway, which in the cell cycle, production, apoptosis and cell stress and other physiological and pathological processes play an important role. Current research evidence suggests that occurrence of Parkinson's disease JNK signal transduction pathway involved. Butylphthalide is a kind of cress from rapeseed in South China isolated the active ingredient, referred to as NBP, a hormone known as celery, Chinese Academy of Medical Sciences Peking Union Medical College Institute of Chinese synthetic raceme, from the 80's Start Feng Yipu leading the research begun by the pharmacological effects of NBP:to improve regional cerebral blood flow in ischemic region, increasing the number of capillary ischemia, ischemic cerebral blood flow increased to improve the ischemic brain energy metabolism, reduce infarct size, reduce the neurological damage and cerebral edema; can improve mitochondrial function, enhance the respiratory chain function, can improve mitochondrial energy pumps to increase anti-oxidation, anti-apoptosis and thus play; to increase global cerebral ischemia in striatal cells extracellular amino acids and dopamine content. The purpose of this experiment based on the role of JNK in the pathogenesis of PD to study the NBP on the MPTP-induced dopaminergic neurotoxicity is a protective effect. We choose butylphthalide preparation for MPTP C57BL/6 mouse model of Parkinson's disease, by immunohistochemical staining and detection of Parkinson's disease in mice westernblot dopaminergic neurons of TH, DAT, p-JNK/JNK expression to observe and analyze its clinical significance.
Methods
1、Animal group 30 C57BL/6 mice were divided into groups using a randomized complete the following 3 groups of 10 each. (1) normal control group (NS +vegetable oil):intraperitoneal injection of saline and MPTP groups 5 d, then injected with equal volume of vegetable oil treatment group 14d. (2) MPTP group (MPTP+ vegetable oil):The MPTP (30 mg/kg) intraperitoneally consecutive 5 d, and then switch to the treatment group with equal volume of vegetable oil injection 14 d. (3) NBP treated group (MPTP+NBP):first to MPTP (30 mg/kg) by intraperitoneal injection 5 d, then NBP (NBP 40 mg/kg) intraperitoneally 14 d. Each animal was killed on day 19 were fixed after the brain tissues embedded in paraffin, to take part in the substantia nigra slices by immunohistochemical staining; other side of the substantia nigra brain tissue extracted quickly placed in-80℃freezer with in westernblot.
2、Model Preparation MPTP (30 mg/kg) intraperitoneally 5 d row [1], mice immediately after injection of gait limp, irritability, hair and tail erect reactions, about 5-10 min after the resumption of normal, that is, Preparation of success as a model.
3、Immunohistochemical staining detected TH, DAT expression 4. Westernblot to detect p-JNK, JNK expression
Results
1、With the normal control group, MPTP mice dopaminergic neurons in the TH-positive neurons and decreases the number (P<0.05); with MPTP compared, NBP treated mice substantia nigra dopaminergic neurons of TH-positive neurons increase (P <0.05), both were statistically significant.
2、With the normal control group, MPTP mice nigrostriatal dopaminergic nerve fibers in the DAT positive nerve fibers were the number decreased (P<0.05); with MPTP compared, NBP treated mice nigra profile like the body of DAT-positive nerve fibers in the number of expression (P<0.05), both were statistically significant.
3、The control group almost has no p-JNK expression, MPTP group showed p-JNK/JNK expression was significantly increased and expression than the normal control group strength, the two differences was statistically significant (P<0.05), NBP treated group p-JNK/JNK expression compared with MPTP group decreased, the two differences was statistically significant (P<0.05).
Conclusions
Butylphthalide increase Parkinsonian Mice nigral dopaminergic neurons TH, DAT expression reduce p-JNK expression, antagonistic JNK signal transduction pathway improve dopaminergic neuronal function, This butylphthalide may become treatment PD drugs clinical possibility provides experimental basis.
帕金森病(PD)是一种常见的与年龄相关的神经变性疾病,主要特征是黑质多巴胺能神经元的进行性丢失和变性。JNK信号转导通路是MAPK通路的一条重要分支,它在细胞周期、生产、凋亡和细胞应激等多种生理和病理过程中起重要作用。目前研究证据表明帕金森病发生有JNK信号转导通路的参与。丁苯酞是从我国南方的一种水芹菜籽中分离出的有效成分,简称NBP,又名芹菜甲素,是中国医学科学院中国协和医科大学药物研究所人工合成的消旋体,从80年代开始冯亦璞带领该所开始研究NBP的药理作用：能改善缺血区局部脑血流,增加缺血区毛细血管的数量,增加缺血区脑血流量,改善缺血性脑能量代谢,缩小梗死面积,减轻神经功能损伤程度,减轻脑水肿；还可改善线粒体功能,增强呼吸链功能,能改善线粒体能量泵,增加抗氧化作用,从而发挥抗凋亡；能增加大鼠全脑缺血纹状体细胞外液氨基酸和多巴胺含量。故本试验依据JNK在PD发病的作用来研究NBP对MPTP诱导的多巴胺能神经毒性是否具保护作用。我们选择丁苯酞用于MPTP制备C57BL／6帕金森病小鼠模型,用免疫组织化学染色方法和westernblot检测帕金森病小鼠黑质多巴胺能神经元TH、DAT、p-JNK/JNK表达情况,观察并分析其表达意义。
方法
1、动物分组：30只C57BL／6小鼠采用完全随机分组法分为以下3组,每组10只。(1)正常对照组(NS+植物油)：腹腔注射与MPTP组等体积生理盐水5 d,再注射与治疗组等体积植物油14d。(2)MPTP组(MPTP+植物油)：采用MPTP(30 mg/kg)连续5 d腹腔注射,然后改用与治疗组等体积植物油注射14 d。(3)NBP治疗组(MPTP+NBP):先以MPTP(30 mg/kg)连续腹腔注射5 d,然后丁基苯酞(NBP40 mg/kg)腹腔注射14 d。每组动物于第19天处死后取脑组织进行固定石蜡包埋,取中脑黑质部位切片进行免疫组织化学染色；另外一侧脑组织提取出黑质后迅速置于-80℃冰箱冷冻用于westernblot。
2、模型制备：MPTP(30 mg/kg):连续5 d腹腔注射,注射药物后小鼠即刻出现步态跚,易激惹,毛及鼠尾竖起等反应,约5～10 min后复常态,即视为模型制备成功。
3、免疫组织化学染色方法检测TH、DAT的表达
4、Westernblot方法检测p-JNK、JNK的表达
结果
1、与正常对照组相比,MPTP组小鼠黑质多巴胺能神经元中的TH阳性神经元表达数目明显减少(P<0.05)；与MPTP组相比,NBP治疗组小鼠黑质多巴胺能神经元中TH阳性神经元表达数目增加(P<0.05),二者均具有统计学意义。
2、与正常对照组相比,MPTP组小鼠黑质纹状体多巴胺能神经纤维中的DAT阳性神经纤维表达数目明显减少(P<0.05)；与MPTP组相比,NBP治疗组小鼠黑质纹状体中DAT阳性神经纤维数目表达增加(P<0.05),二者均具有统计学意义。
3、正常对照组几乎未见p-JNK表达,MPTP组可见p-JNK/JNK的表达明显增加,而且表达较正常对照组强,二者差别有统计学意义(P<0.05),NBP治疗组p-JNK/JNK表达较MPTP组下降,二者差别有统计学意义(P<0.05)。
结论
丁苯酞可增加帕金森病小鼠黑质多巴胺能神经元TH、DAT的表达,减少p-JNK表达,拮抗JNK信号转导通路,改善多巴胺能神经元功能,这为丁苯酞可能成为治疗PD药物的临床可能性提供了实验依据。
Objectives
Parkinson's disease (PD) is a common age-related neurodegenerative disease, mainly characterized by dopaminergic neurons loss and degeneration of the sexual. JNK signal transduction pathway is an important branch of MAPK pathway, which in the cell cycle, production, apoptosis and cell stress and other physiological and pathological processes play an important role. Current research evidence suggests that occurrence of Parkinson's disease JNK signal transduction pathway involved. Butylphthalide is a kind of cress from rapeseed in South China isolated the active ingredient, referred to as NBP, a hormone known as celery, Chinese Academy of Medical Sciences Peking Union Medical College Institute of Chinese synthetic raceme, from the 80's Start Feng Yipu leading the research begun by the pharmacological effects of NBP:to improve regional cerebral blood flow in ischemic region, increasing the number of capillary ischemia, ischemic cerebral blood flow increased to improve the ischemic brain energy metabolism, reduce infarct size, reduce the neurological damage and cerebral edema; can improve mitochondrial function, enhance the respiratory chain function, can improve mitochondrial energy pumps to increase anti-oxidation, anti-apoptosis and thus play; to increase global cerebral ischemia in striatal cells extracellular amino acids and dopamine content. The purpose of this experiment based on the role of JNK in the pathogenesis of PD to study the NBP on the MPTP-induced dopaminergic neurotoxicity is a protective effect. We choose butylphthalide preparation for MPTP C57BL/6 mouse model of Parkinson's disease, by immunohistochemical staining and detection of Parkinson's disease in mice westernblot dopaminergic neurons of TH, DAT, p-JNK/JNK expression to observe and analyze its clinical significance.
Methods
1、Animal group 30 C57BL/6 mice were divided into groups using a randomized complete the following 3 groups of 10 each. (1) normal control group (NS +vegetable oil):intraperitoneal injection of saline and MPTP groups 5 d, then injected with equal volume of vegetable oil treatment group 14d. (2) MPTP group (MPTP+ vegetable oil):The MPTP (30 mg/kg) intraperitoneally consecutive 5 d, and then switch to the treatment group with equal volume of vegetable oil injection 14 d. (3) NBP treated group (MPTP+NBP):first to MPTP (30 mg/kg) by intraperitoneal injection 5 d, then NBP (NBP 40 mg/kg) intraperitoneally 14 d. Each animal was killed on day 19 were fixed after the brain tissues embedded in paraffin, to take part in the substantia nigra slices by immunohistochemical staining; other side of the substantia nigra brain tissue extracted quickly placed in-80℃freezer with in westernblot.
2、Model Preparation MPTP (30 mg/kg) intraperitoneally 5 d row [1], mice immediately after injection of gait limp, irritability, hair and tail erect reactions, about 5-10 min after the resumption of normal, that is, Preparation of success as a model.
3、Immunohistochemical staining detected TH, DAT expression 4. Westernblot to detect p-JNK, JNK expression
Results
1、With the normal control group, MPTP mice dopaminergic neurons in the TH-positive neurons and decreases the number (P<0.05); with MPTP compared, NBP treated mice substantia nigra dopaminergic neurons of TH-positive neurons increase (P <0.05), both were statistically significant.
2、With the normal control group, MPTP mice nigrostriatal dopaminergic nerve fibers in the DAT positive nerve fibers were the number decreased (P<0.05); with MPTP compared, NBP treated mice nigra profile like the body of DAT-positive nerve fibers in the number of expression (P<0.05), both were statistically significant.
3、The control group almost has no p-JNK expression, MPTP group showed p-JNK/JNK expression was significantly increased and expression than the normal control group strength, the two differences was statistically significant (P<0.05), NBP treated group p-JNK/JNK expression compared with MPTP group decreased, the two differences was statistically significant (P<0.05).
Conclusions
Butylphthalide increase Parkinsonian Mice nigral dopaminergic neurons TH, DAT expression reduce p-JNK expression, antagonistic JNK signal transduction pathway improve dopaminergic neuronal function, This butylphthalide may become treatment PD drugs clinical possibility provides experimental basis.
引文
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5 Ferraz HB, Bertolucci PHF, Pereira JS, et al.Chronic exposure to the fungicide maneb may produce symptoms and signs of CNS manganese intoxication. Neurology,1988,38:550-553
6 Takahashi RN, Rogerio R, Zanin M. Maneb enhances MPTP neurotoxicity in mice. Res Commun Chem Pathol Pharmacol,1989,66 (1):167-170
7 Thiruchelvam M, Richfield EK, Baggs RB, et al. The nigrostriatal dopaminergic system as a preferntial target of repeated exposures to combined paraquat and maneb implications for Parkinson's disease. J Neurosci,2000,20(24):9207-9214
8 Gao HM, Hong JS,Zhang W, et al. Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons. J. Neruosci,2002,22:782-7,90
9 Polymeropoulos MH, Higgins JJ, Golbe LI, et al. Mapping of a gene for Parkinson's disease to chromosome 4q21-23. Science,1996,274:1197
10 Gasser T, Muller MB, Wszolek ZK, etal. A susceptibility locus for Parkinson's disease maps to chromosome 2q13. Nat Genet,1998,18:262
11 Matsumine H, Saito M, Shimoda MS, etal. Localization of a gene for an autosomal recessive form of juvenile Parkinsonismin to chromosome 6q25.2-27. Am J Hum Genet,1997,60:558
12 William KS, Martha AN, Ray LW, etal. Complete Genomic Screen in Parkinson disease. JAMA,2001,286:2239
13 Torii T, Kawarai T, Nakamura S, etal. Organization of human orphan nuclear receptor Nurrl gene [J]. Gene,1999,230:225-232.
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15 neurons in Nurrl-deficient mice [J].Exp Neurol,1999,159 (2):451-458.
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17 Bonifati V, Rizzu P, van Baren MJ, etal. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science,2003,299:256-259
18 Amier P D. Hirsch& EC. The substant nigra of the human brain. Ⅱ.Patterns of lossof
dopamine-containing neruous in Parkinson's disease. Brain.1999;122 (Pt 8):1437-1438.
19 McGeer PL. Aging and extrapyramidal function. Arch Neurol 1977;34:33.
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23 Fernandez. R. Fuente. De. La,PK. Pal,FJ. Vingerhoets. Evidence for impaired presynaptic dopamine function in Parkinsonian patients with motor fluctuations. J Neural Transm. 2000;107(1):49-57.
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33 Nagatsu T, Sawada M. Inflammatory process in Parkinson's diseas:role for cytokines. Curr
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34 Carvey PM, Chang Q, Lipton JW, etal. Prenatal exposure to the bacteriotoxin lipopolysaccharide leads to long-term losses of dopamine neurons in offspring:a potential, new model of Parkinson's diseas. Front Biosci,2003,8:s826-837
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1 J.W. Langston, P. Ballard, J.W. Tetrud, I. Irwin, Chronic parkinsonismin humans due to a product of meperidine-analog synthesis,Science 219 (1983) 979-980.
2 K.St.P. McNaught, Isoquinoline derivatives as endogenous neurotoxins in the aetiology of Parkinson's disease, Biochem. Pharmacol.56 (1998) 921-933.
3 Ballard PA, Tetrud JW, Langston JW. Permanent human parkinsonismin due to 1-methyl-4-phenyl-1,2,3,6-retrahydropyridine(MPTP):sevencases.Neurology,1985,35(7):949-9 56
4 Chronic systemic pesticide exposure reposure reproduces features of Parkinson's disease. Nat Neurosci,2000,3 (12):1301-13-6
5 Ferraz HB, Bertolucci PHF, Pereira JS, et al.Chronic exposure to the fungicide maneb may produce symptoms and signs of CNS manganese intoxication. Neurology,1988,38:550-553
6 Takahashi RN, Rogerio R, Zanin M. Maneb enhances MPTP neurotoxicity in mice. Res Commun Chem Pathol Pharmacol,1989,66 (1):167-170
7 Thiruchelvam M, Richfield EK, Baggs RB, et al. The nigrostriatal dopaminergic system as a preferntial target of repeated exposures to combined paraquat and maneb implications for Parkinson's disease. J Neurosci,2000,20(24):9207-9214
8 Gao HM, Hong JS,Zhang W, et al. Distinct role for microglia in rotenone-induced degeneration of dopaminergic neurons. J. Neruosci,2002,22:782-7,90
9 Polymeropoulos MH, Higgins JJ, Golbe LI, et al. Mapping of a gene for Parkinson's disease to chromosome 4q21-23. Science,1996,274:1197
10 Gasser T, Muller MB, Wszolek ZK, etal. A susceptibility locus for Parkinson's disease maps to chromosome 2q13. Nat Genet,1998,18:262
11 Matsumine H, Saito M, Shimoda MS, etal. Localization of a gene for an autosomal recessive form of juvenile Parkinsonismin to chromosome 6q25.2-27. Am J Hum Genet,1997,60:558
12 William KS, Martha AN, Ray LW, etal. Complete Genomic Screen in Parkinson disease. JAMA,2001,286:2239
13 Torii T, Kawarai T, Nakamura S, etal. Organization of human orphan nuclear receptor Nurrl gene [J]. Gene,1999,230:225-232.
14 Le WD, Conneely OM, Zou L, etal. SH Selective agenesis of mesencephalic dopaminergic
15 neurons in Nurrl-deficient mice [J].Exp Neurol,1999,159 (2):451-458.
16 Zetterstrom RH, Solomin L, Jansson L, etal. Dopamine neuron agenesis in Nurrl-deficient mice [J]. Science,1999,276:248-250.
17 Bonifati V, Rizzu P, van Baren MJ, etal. Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism. Science,2003,299:256-259
18 Amier P D. Hirsch& EC. The substant nigra of the human brain. Ⅱ.Patterns of lossof
dopamine-containing neruous in Parkinson's disease. Brain.1999;122 (Pt 8):1437-1438.
19 McGeer PL. Aging and extrapyramidal function. Arch Neurol 1977;34:33.
20 张一等.大鼠黑质的衰老变化—多巴胺荧光组织化学和显微荧光光度术的定量研究.解剖学报.1989；20(2)：205-209.
21 Booij J, Bergmans P, Winogrodzka A,etal. Imaging of dopamine transporters with [123I] FP-CITSPECT dose not suggest a significant effect of age no the symptomatic threshold of disease in Parkinson's disease. Synapse,2001,39(2):101-108
22 Ueda,S. Aikawa,M. Oka. A. et al. Age-related dopamine deficiencyin the mesostriatal dopamine systemof zitter mutant rats regional fiber vulnerability in the striatum and the olfactory tubercle. Neuroscience.2000;95 (2):389-398.
23 Fernandez. R. Fuente. De. La,PK. Pal,FJ. Vingerhoets. Evidence for impaired presynaptic dopamine function in Parkinsonian patients with motor fluctuations. J Neural Transm. 2000;107(1):49-57.
24 Piccine, P. Turjanski, N. Brooks. DJ. PET studies of the striatatal dopaminergic system in Parkinson's disease (PD). J Neural Transm-Suppl.1995;45:123-131.
25 Graham JM, Paley MN, Grunewald RA, etal. Brain iron deposition in Parkinson's disease imaged using the PRIME magnetic resonance sequence. Brain,2000,123 pt 12:2423-2431
26 Luigi Zecca, Mario Gallorini, Volker Schunemann, etal. Iron, neuromelanin and ferritin content in the substantia nigra of normal subjects at different ages:consequences for iron storage and neurodegenerative procesess. J. Neurochem,2001,76:1766-1773
27 Finkelstein,DI. Stanic,D. Parisn,CL. etal. Axonal sprouting following lesions of the rat substantia nigra. Neuroscience.2000; 97 (1):99-112.
28 Kingsbury,AE. Marsden,CD. Foster OJ. The vulnerability of nigral neurons to Parkinson's disease is unrealted to their intrinsic capacity for dopamine synthesis:an in situ hybridization study. Mov Disord.1999;14 (2):206-218.
29 Liu Y, Fallon L, Lashuel HA, etal. The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell, 2008,11:209-218
30 Ciechanover A,Brundin P.The ubiquitin proteasome system in neurodegenerative diseases:sometimes the chicken, sometimes the egg. Neuron,2003,40:427-446
31 Schapira AHV. Mitochondrial dysfunction and oxidative damage in Parkinson's disease. In: Beel MF, Howell N and Wollner IB. Mitochondrial and free radicals in neurodegenerative diseases. New York:Wiley-Liss, Inc,1997,343-359
32 Mitochondrial mechanisms of neural cell death and neuroprotective interventions in Parkinson's diseas. Ann NY Acad Sci,2003,991:111-119e
33 Nagatsu T, Sawada M. Inflammatory process in Parkinson's diseas:role for cytokines. Curr
Pharm Des,2005:11(8):999-1016
34 Carvey PM, Chang Q, Lipton JW, etal. Prenatal exposure to the bacteriotoxin lipopolysaccharide leads to long-term losses of dopamine neurons in offspring:a potential, new model of Parkinson's diseas. Front Biosci,2003,8:s826-837
35 汪锡金,陈生弟,刘卫国,陆国强,梁梁等..帕金森病患者血清IgG依赖补体和胶质细胞诱导多巴胺能神经元损伤.中国医学会第七次全国神经病学学术会议。
36 Gao HM, Jiang J, Wilson B, etal. Microglial activation-mediated delayed and progressive degeneration of rat nigral dopaminergic neurons:relevance to Parkinson's diseas. Acta Neurochem,2002,81(6):1285-1297
37 王丽敏,刘中霖,陶恩祥,王丽娟.不同亚型帕金森病患者血浆单胺类神经递质的研究.中国临床康复,2005,2,7
38 王丹,彭海,曹非.卒中与神经疾病。帕金森病大鼠纹状体区乙酰胆碱含量和胆碱酯酶表达的研究。2006,6,26
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