利福平保护MPTP所致小鼠中脑多巴胺能神经元凋亡的实验研究
|
摘要
研究背景
帕金森病(PD)又名震颤麻痹，是一种中老年人常见的慢性黑质和黑质纹状体通路变性的神经系统疾病，主要病理改变是中脑黑质致密部(SNc)多巴胺(DA)能神经元选择性地变性、死亡、缺失，以及残存神经元细胞DA生物合成能力下降，致纹状体DA不足，从而导致基底节神经调节功能的紊乱。在临床上表现为静止性震颤、肌强直、运动迟缓和姿势不稳等四大主要特征。国外的统计资料表明，PD发病率占总人数的0.1％-0.2％，其中55岁以上人口占1.4％。随着社会逐步进入老龄化，PD患者的人数也在日趋增加。
目前PD的病因尚未清楚，一股认为是由遗传、年龄、环境、氧化应激、免疫异常、兴奋性氨皋酸毒性、线粒体功能障碍等多种因素所致的中脑黑质DA能神经元死亡，而细胞凋亡是这种细胞死亡的主要方式。对神经元的保护和抗细胞凋亡的治疗已成为PD治疗的主要思路。目前PD细胞凋亡的常用治疗方案有：1．抗氧化剂。2．神经营养因子。3．中药。4．基因治疗。5．对凋亡过程的调控，如凋亡起始因子的抑制剂、抗凋亡基因的促进剂等。神经保护剂的抗凋亡治疗已在临床上开始使用，并取得了一些疗效，但仍存在异议。
由于PD病人死后脑标本难以获得，因此建立动物模型是研究该病发病机制和治疗方法的重要手段。1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)是一种神经
Background
Parkinson's disease(PD), also named "paralysis agitans", is a degeneration disease of the central neural system with high morbidity in the elders. The selective degeneration, death and depletion of the dopamine (DA) energetic neurons in the compact part of substantia nigra of midbrain accounts the most for the pathology of PD. The disorder of the function of basal nuclei with deficient DA in corpora striata caused by the remnant DA neurons' decreasing capability of DA generation also contributes to the disease. PD has four essential characteristics, such as static tremor, rigidity, bradykinesia and postural unsteadiness. The foreign statistic data indicates that the morbidity of PD is 0.1% to 0.2%, and amounts to 1.4% in the people over 55 years old. The patients of PD become more and more with the aging of the society.
The aetiology of PD has not been identified yet by now. It is considered that the death (mainly apoptosis) of DA energetic neurons in substantia nigra of midbrain caused by heredity, aging, environment, oxidative stress, immune abnormality, excitory amino acids toxicity and dysfunction of mitochondria may be answer. So, the comprehensive route to treat PD is the protection of neuron and the fight against cell apoptosis. Now, there are 5 therapeutic methods coming into being, including
帕金森病(PD)又名震颤麻痹，是一种中老年人常见的慢性黑质和黑质纹状体通路变性的神经系统疾病，主要病理改变是中脑黑质致密部(SNc)多巴胺(DA)能神经元选择性地变性、死亡、缺失，以及残存神经元细胞DA生物合成能力下降，致纹状体DA不足，从而导致基底节神经调节功能的紊乱。在临床上表现为静止性震颤、肌强直、运动迟缓和姿势不稳等四大主要特征。国外的统计资料表明，PD发病率占总人数的0.1％-0.2％，其中55岁以上人口占1.4％。随着社会逐步进入老龄化，PD患者的人数也在日趋增加。
目前PD的病因尚未清楚，一股认为是由遗传、年龄、环境、氧化应激、免疫异常、兴奋性氨皋酸毒性、线粒体功能障碍等多种因素所致的中脑黑质DA能神经元死亡，而细胞凋亡是这种细胞死亡的主要方式。对神经元的保护和抗细胞凋亡的治疗已成为PD治疗的主要思路。目前PD细胞凋亡的常用治疗方案有：1．抗氧化剂。2．神经营养因子。3．中药。4．基因治疗。5．对凋亡过程的调控，如凋亡起始因子的抑制剂、抗凋亡基因的促进剂等。神经保护剂的抗凋亡治疗已在临床上开始使用，并取得了一些疗效，但仍存在异议。
由于PD病人死后脑标本难以获得，因此建立动物模型是研究该病发病机制和治疗方法的重要手段。1-甲基-4-苯基-1，2，3，6-四氢吡啶(MPTP)是一种神经
Background
Parkinson's disease(PD), also named "paralysis agitans", is a degeneration disease of the central neural system with high morbidity in the elders. The selective degeneration, death and depletion of the dopamine (DA) energetic neurons in the compact part of substantia nigra of midbrain accounts the most for the pathology of PD. The disorder of the function of basal nuclei with deficient DA in corpora striata caused by the remnant DA neurons' decreasing capability of DA generation also contributes to the disease. PD has four essential characteristics, such as static tremor, rigidity, bradykinesia and postural unsteadiness. The foreign statistic data indicates that the morbidity of PD is 0.1% to 0.2%, and amounts to 1.4% in the people over 55 years old. The patients of PD become more and more with the aging of the society.
The aetiology of PD has not been identified yet by now. It is considered that the death (mainly apoptosis) of DA energetic neurons in substantia nigra of midbrain caused by heredity, aging, environment, oxidative stress, immune abnormality, excitory amino acids toxicity and dysfunction of mitochondria may be answer. So, the comprehensive route to treat PD is the protection of neuron and the fight against cell apoptosis. Now, there are 5 therapeutic methods coming into being, including
引文
[1] Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism[J]. Nature, 1998, 392(6676): 605-608
[2] Qian ZM, Shen X. Brain iron transport and neurodegeneration[J]. Trend Mol Med, 2001, 7(6): 103-108
[3] Olanow C W, Tatton W G. Etiology and pathogenesis of Parkinson's disease[J]. Annu Rev Neurosci, 1999, 22(10): 123-144
[4] Ball J. Current advances in Parkinson's disease[J]. Trends Neurosci, 2001, 24(7): 367
[5] 罗毅，黄新德．原发性帕金森病治疗的建议(1998年)[J]．中风与神经病症杂 志，1999，16(2)：114
[6] Paola RD, Uitti RJ. Treatment implications in the early detection of Parkinson's disease[J]. Med Pro Sea, 1997, 24(1): 8-11
[7] 张世忠，郭燕舞，张旺明等．帕金森病外科治疗中苍白球内侧部神经元电生理记录的有效针道方法[J]．中华神经医学杂志．2003，2(3)：180-182
[8] 张世忠，徐如祥．帕金森病的外科治疗[J]．中华神经医学杂志，2003，2(5)：383-389
[9] Panikar D, Kishore A. Deep brain stimulation for Parkinson's disease[J]. Neurol India, 2003, 51(2): 167-75
[10] 董继宏，蒋雨平．脑深部电刺激治疗PD和特发性震颤的近期和远期疗效[J]．中华临床神经科学，2005，13(1)：86-91
[11] 张世忠，徐强，徐如祥等．脑深部刺激电极埋置术治疗帕金森病疗效研究[J]．中国神经精神疾病杂志，2003，29(6)：404-406
[12] Burke RE, Kholodilov NG. Programmed cell death: does it play a role in Parkinson's disease[J]. Ann Neurol, 1998, 44(Suppl 1): 160-166
[13] Delanty N, Dichter MA. Antioxidant therapy in neurologic disease[J]. Arch Neurol, 2000, 68(4): 685-690
[14] Parkinson study Group. Evaluation of dyskinesias in a pilot, randomized, placebo-controlled trial of remacemide in advanced Parkinson disease [J]. Arch Neurol, 2001, 58(10): 1660-1668
[15] Doble A. The role of excitotoxicity in neurodegenerative disease: Implications for therapy[J]. Pharm acol Ther, 1999, 81(6): 163
[16] Shoulson I, Penney J, McDermott M, et al. A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease[J]. Neurology, 2001, 56(4): 455
[17] Factor SA, Molho ES. Transient benefit of amantadine in Parkinson's disease: The facts about the myth[J]. Mov Disord, 1999, 14(12): 515
[18] Moosmann B, Skutella T, Beyer K, et al. Protective activity of aromatic amines and imines against oxidative nerve cell death[J]. Biol Chem, 2001, 38(11): 1601-1612
[19] 李玉芝，高霞，李国庆．还原型谷胱甘肽治疗PD临床疗效观察[J]．中国煤炭工业医学杂志，2005，8(8)：870-871
[20] 田学文，章翔，张剑宁，等．雌激素对PD大鼠中脑黑质DA能神经元的保护作用[J]．中国临床康复，2005，9(9)：193-195
[21] Bottcher T, Gerber J, Wellmer A, et al. Rifampin reduces production of reactive oxygen species of cerebrospinal fluid phagocytes and hippocampal neuronal apoptosis in experimental Streptococcus pneumoniae meningitis[J]. J Infect Dis, 2000, 181(6): 2095-2098
[22] Gerber J, Pohl K, Sander V, et al. Rifampin followed by ceftriaxone for experimental meningitis decreases lipoteichoic acid concentrations in cerebrospinal fluid and reduces neuronal damage in comparison to ceftriaxone alone[J]. Antimicrob Agents Chemother, 2003, 47(4): 1313-1317
[23] Yulug B, Kilic U, Kilic E, et al. Rifampicin attenuates brain damage in focal ischemia[J]. BRAIN RES, 2004, 996(1): 76-80
[24] Kilic U, Kilic E, Lingor P, et al. Rifampicin inhibits neurodegeneration in the optic nerve transection model in vivo and after 1-methyl-4-phenylpyridinium intoxication in vitro[J]. Acta Neuropathol, 2004, 108(1): 65-68
[25] Fuchs E, Segre JA. Stem cell: a new release on life[J]. Cell, 2000, 100:143-155
[26] 束汉生，曾水林，李涛．神经干细胞治疗帕金森病的可行性探究[J]．中华老年医学杂志，2003，22(1)：56-57
[27] Kang UJ, Lee WY, Chang JW. Gene therapy for Parkinson's disease: determining the genes necessary for optimal dopamine replacement in rat models[J]. Hum Cell, 2001, 14(1): 39-48
[28] Kordower JH, Emborg ME, Bloch J, et al. Neurodegeneration prevented by lentivirai vector delivery of GDNF in primate model of Parkinson's disease[J]. Science, 2000, 290(5492): 767-773
[29] 曲伸，何小龙，何成．脑源性神经营养因子基因工程细胞脑内移植治疗PD大鼠的实验研究[J]．中华神经科杂志，1999，32(1)：13-16
[30]Yamada M, Oligino T, Mata M, et al. Herpes simplex virus vecto-mediated expression of Bcl-2 prevents 6-hydroxydopamine induced degeneration of neurons in the substantia nigra in vivo [J].Proc Natl Acad Sci, 1999, 96(7): 4078-4083
[31]Gilgun-Sherki Y, Djaldetti R, Melamed E, et al. Polymorphism in candidate genes: implications for the risk and treatment of idiopathic Parkinson's disease[J]. Pharmacogenomics J. 2004, 4(5): 291-306
[32]Tatton NA, Kish SJ. In situ detection of apoptotic nuclei in the substantia nigra compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using terminal deoxynucleotidyl transferase labelling and acridine orange staining[J].Neuroscience, 1997, 77(4): 1037-1048
[1] 陈滢，陈晓春．MPTP诱导小鼠黑质神经元凋亡[J]．福建医科大学学报，2001，35(2)：105-108
[2] Tatton NA, Kish SJ. In situ detection of apoptotic nuclei in the substantia nigra compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using terminal deoxynucleotidyl transferase labelling and acridine orange staining[J]. Neuroscience, 1997, 77(4): 1037-1048
[3] 姚庆和，高国栋．MPTP的毒性机制与帕金森病动物模型[J]．国外医学神经病学神经外科学分册，2004，31(1)：45-48
[4] 梁晓俐主编．病理学基础与实验技术[M]．北京：军事医学科学出版社，2003，152-153
[5] Ungerstedt U. 6-Hydroxydopamine induced degeneration of central monomine neurons[J]. Eur J Pharmacol, 1968,5(1): 107-110
[6] Betarbet R, Sherer TB, Greenamyre JT. Animalmodels of Parkinson's disease[J]. Bioessays, 2002, 24(5):308-318
[7] Vander P, Wiederhold KH, Probst A, et al. Neurolpathology in mice expressing human alphasynuclein[J]. Neuroscience, 2000, 20(2): 6021-6029
[8] Schmidt RH, Bjobrklund A, Stenevi U, et al. Intracerebral grafting of neuronal cell suspension Ⅲ, A ctivity of intrastrial nigral suspension implants assessed by measurements of dopamine synthesis and metabolism[J]. Acta Physioi Scand, 1983, 522(supp 1): 19-28
[9] Brecknell JE, Dunnett SB, Fawcett JW, et al. A quantitative study of cell death in the substantia nigra following amechanical lesion of the medial forebrain bundle[J]. Neuroscience, 1995,64(7): 219-227
[10] Tseng JL, Baetge EE, Zurn AD, et al. GDNF reduces drug-induced rotational behavior after medial forebrain bundle transection by a mechanism not involving striatal dopamine [J]. J Neurosci, 1997, 17(12): 325-333
[11] 梁希彬，罗涌，卢峻，等．线刀毁损大鼠内侧前脑束建立部分损伤的帕金森病模型[J]．神经解剖学杂志，2001，17(3)：199-204
[12] Olanow CW, Tatton WG. Etiology and pathogenesis of Parkinson's disease[J]. Annu Rev Neurosci, 1999, 22(4): 123-144
[13] Yang SC, Markey SP. Recommented safe practices for using the neurotoxin MPTP in animal experinents[J]. Lab Anim Sci, 1988, 38: 563-567] [Przedorsle S, Jaclcson VL, The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydoyndine (MPTP): a technical review of its utility and safety[J]. J Neurochem, 2001, 76(3): 1265-1274
[14] Langston JW, Irwin I. MPTP: current concepts and controversies[J]. Clin Neropharmaeol, 1986, 9(8): 485-507
[15] Kopin IJ, Markey SP. MPTP toxicity: implication for research in Pakinson's diseare[J]. Annu Rev Neurosci, 1985,11 (6): 81-90
[16] Gerlach M, Riedererer P, Przuntek H. MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease[J]. Europeam J Pharm, 1991, 208(9): 273-286
[17] Giovann A, Sieber BA. Correlation between the neostriatal content of the 1-methyl-4-phenyl-1,2,3,6-tetrahydoyndine species and dopminergic neuron-toxicity following 1-methyl-4-phenyl-1,2,3,6-tetrahydoyndine administration to several strains of mice[J]. J pharma Exp Ther, 1991 , 257(10): 691-697
[18] 邹春林，孙异临．MPTP与帕金森小鼠模型的研究进展[J]．国外医学神经病学神经外科学分册，2000，27(6)：330-333
[19] Heikkila RE, Manzino L. Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydoyndine by monoamine oxidase inhibiters[J]. Nature, 1984, 311(2): 467-469
[20] Burke RE, Kholodilov NG. Programmed cell death: does it play a role in Parkinson's disease[J]. Ann Neurol, 1998, 44(Suppl 1): 160-166
[21] Hengartner MO. The biochemistry of apoptosis[J]. Nature, 2000, 407(4089): 770-774
[22] Jaattela M. Programmed cell death: many ways for cells to die decently[J]. Ann Med, 2002, 34(6): 480-488
[23] Kroemer G. The proto-oncogene Bcl-2 and its role in regulating apoptosis[J]. Nat Med, 1997, 3(11): 614-620
[24]Kitagawa K, Matsumoto M, Tsujimoto Y, et al. Amelioration of hippocampal neuronal damage after global ischemia by neuronal overexpression of bcl-2 in transgenic mice[J]. Stroke, 1998, 29(12): 2616-2621
[25]Veech GA, Dennis J, Keeney PM, et al. Disrupted mitochondrial electron transport function increases expression of anti-apoptotic bcl-2 and bcl-X(L) proteins in SH-SY5Y neuroblastoma and in Parkinson disease cybrid cells through oxidative stress[J]. J Neurosci Res, 2000, 61(6): 693-700
[26] Huang Y, Ray S, Reed JC, et al. Estrogen increases intracellar Bcl-2 to Bax ratios and inhibits taxol-induced apoptosis of human breast cancer MCF-7 cells[J]. Breast Cancer Res Treat, 1997, 42(4): 73-81
[27]Hassouna I, Wickert H, Zimmermann M, et al. Increase in bax expression in substantia nigra following 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine(MPTP) treatment of mice[J]. Neurosci Lett, 1996, 204(122):85-88
[28]Offen D, Beart PM, Cheung NS, et al. Transgenic mice expressing human Bcl-2 in their neurons are resistant to 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity [J]. Proc Natl Acad Sci USA, 1998, 95(10): 5789-5794
[29]Hartmann A, Mouatt Prigent A, Vila M, et al. Increased expression and redistribution of the antiapoptotic molecule Bcl-xL in Parkinson's disease[J]. Neurobiol Dis, 2002, 10(1): 28-32
[30]Mogi M, Togari A, Kondo T, et al. Caspase activities and tumor necrosis factor receptor Rl(p55) level are elevated in the substantia nigra from parkinsonian brain[J]. J Neural Transm, 2000, 107(3):335-341
[31]Du Y, Dodel RC, Bales KR, et al. Involvement of a caspase-3-like cysteine protease in 1-methyl-4-phenyipyridinium-mediated apoptosis of cultured cerebellar granule neurons [J]. J Neuro Chem, 1997, 69(4): 1382-1388
[32]Bilsland J, Roy S, Xanthoudakis S, et al. Caspase inhibitors attenuate 1-methyl-4-phenylpyridinium toxicity in primary cultures of mesencephalic dopaminergic neurons[J]. J Neurosci, 2002, 22(7): 2637-2649
[1] Burke RE, Kholodilov NG. Programmed cell death: does it play a role in Parkinson's disease[J]. Ann Neurol, 1998, 44(Suppl 1): 160-166
[2] Bottcher T, Gerber J, Wellmer A, et al. Rifampin reduces production of reactive oxygen species of cerebrospinal fluid phagocytes and hippocampal neuronal apoptosis in experimental Streptococcus pneumoniae meningitis[J]. J Infect Dis, 2000, 181 (6):2095-2098
[3] Gerber J, Pohl K, Sander V, et al. Rifampin followed by ceftriaxone for experimental meningitis decreases lipoteichoic acid concentrations in cerebrospinal fluid and reduces neuronal damage in comparison to ceftriaxone alone[J]. Antimicrob Agents Chemother, 2003, 47(4):1313-1317
[4] Yulug B, Kilic U, Kilic E, et al. Rifampicin attenuates brain damage in focal ischemia[J]. Brain Res, 2004, 996(1):76-80
[5] Kilic U, Kilic E, Lingor P, et al. Rifampicin inhibits neurodegeneration in the optic nerve transection model in vivo and after 1-methyl-4-phenylpyridinium intoxication in vitro[J]. Acta Neuropathol, 2004, 108(1):65-68
[6] Delanty N, Dichter MA. Antioxidant therapy in neurologic disease[J]. Arch Neurol, 2000, 68(5): 685-690
[7] Parkinson study Group. Evaluation of dyskinesias in a pilot, randomized, placebo-controlled trial of remacemide in advanced Parkinson disease [J]. Arch Neurol, 2001, 58(10): 1660-1668
[8] Doble A. The role of excitotoxicity in neurodegenerative disease: Implications for therapy[J]. Pharm acol Ther, 1999, 81(2): 163
[9] Factor SA, Molho ES. Transient benefit of amantadine in Parkinson's disease: The facts about the myth[J]. Mov Disord, 1999, 14(8): 515
[10] Shoulson I, Penney J, McDermott M, et al. A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease[J]. Neurology, 2001, 56(4): 455
[11] 田学文，章翔，张剑宁，等．雌激素对PD大鼠中脑黑质DA能神经元的保护作用[J]．中国临床康复，2005，9(9)：193-195
[12] Moosmann B, Skutella T, Beyer K, et al. Protective activity of aromatic amines and imines against oxidative nerve cell death[J]. Biol Chem, 2001, 38(11): 1601-1612
[13] 李玉芝，高霞，李国庆．还原型谷胱甘肽治疗PD临床疗效观察[J]．中国煤炭工业医学杂志，2005，8(8)：870-871
[14] 任雷明．抗结核病药与抗麻风病药[M]．见：李端，主编．药理学．第五版．北京：人民卫生出版社，2003．407-408
[15] World Health Organization. WHO Expert Committee on leprosy, sixth report. Tech.Rep.Ser.1988.768. WHO,Geneva
[16] Namba Y, Kawatsu K, Izumi S, et al. Neurofibrillary tangles and senile plaques in brain of elderly leprosy patients[J]. Lancet, 1992, 340(8825): 978
[17] Tomiyama T, Shoji A, Kataoka K, et al. Inhibition of amyloid β protein aggregation and neurotoxicity by rifampicin[J]. J Biol Chem, 1996, 271(12): 6839-6845
[18] Hal ED. Antioxidant pharmacotherapy. In: Ginsberg M, Bogousslavsky J. Cerebrovascular disease: pathophysiology, diagnosis and management[M]. Blackwell Science, 1997. Malden
[19] Calleja C, Pascussi JM, Mani JC, et al. The antibiotic rifampicin is a non-steroidal ligand and activator of the human glucocorticoid receptor[J]. Nature Med, 1998, 4(1): 92-96
[20] YangY, Ashwell JD. Thymocyte apoptosis[J]. J Clin Immunol, 1999, 19(6): 337-349
[21] Andreau K, Lemaire C, Souvannavong V, et al. Induction of apoptosis by dexamethasone in the B cell lineage[J]. Immunopharmacology, 1998, 40(1): 67-76
[22] Schmidt M, Pauels H-G, Lugering N, et al. Glucocorticoids induce apoptosis in human monocytes: Potential role of IL-1 beta[J]. J Immunol, 1999, 163(6): 3484-3490
[23] Migriorati G, Nicoletti I, D'Adamio F, et al. Dexamethsone-induced apoptosis in mouse natural killer cells and cytotoxic T lymphocytes[J]. Immunology, 1994, 81(1): 21-26
[24] Yang Y, Mercep M, Ware CF, et al. Fas and activationinduced Fas ligand mediated apoptosis of T cell hybridomas: Inhibition of Fas ligand expression by retinoic acid and glucocorticoids[J]. J Exp Med, 1995, 181(5): 1673-1682
[25]Huang ST, Cidlowski JA. Glucocorticoids inhibit serum depletion-induced apoptosis in T lymphocytes expressing Bcl-2[J]. Faseb J, 1999, 13(3): 467-476
[26]Yamamoto M, Fukuda K, Miura N, et al. Inhibition by dexamethasone of transforming growth factor-induced apoptosis in rat hepatoma cells: a possible association with Bcl-xL induction[J]. Hepatology, 1998, 27(4): 959-966
[27] Chang TC, Hung MW, Jiang SY, et al. Dexamethasone suppresses apoptosis in a human gastric cancer cell line through modulation of Bcl-x gene expression[J]. Febs Lett, 1997,415(1): 11-15
[28]Nittoh T, Fujimori H, Kozumi Y, et al. Effects of glucocorticoids on apoptosis of infiltrated eosinophils and neutrophils in rats[J]. Eur J Pharm, 1998, 354(1):73-81
[29] Meagher LC, Cousin J, Secki JR, et al. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophils and eosinophils[J]. J Immunol, 1996, 156(11): 4422-4428
[30] Iwata M, Hanaoke S, Sato K. Rescue of thymocytes and T cell hybridomas from glucocorticoid-induced apoptosis by stimulation via the T cell receptor/CD3 complex: A possible in vitro model for positive selection of the T cell repertoire[J].Eur J Immunol, 1991, 21(3): 643-648
[31]Jaidka S, Gollapudi SV, Gupta S. Rifampicin inhibits anti-CD95-induced apoptosis in T cells by activating glucocorticoid receptor[J]. Faseb J, 2001, 15(4): 313
[1] Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism[J]. Nature, 1998, 392(6676): 605-608
[2] Ball J. Current advances in Parkinson's disease[J]. Trends Neurosci, 2001, 24(7): 367
[3] 罗毅，黄新德．原发性帕金森病治疗的建议(1998年)[J]．中风与神经病症杂志，1999，16(2)：114
[4] Regina K, Andrew J. Treatment of Parkinson's disease: levodopa as the first choice[J]. J Neurology, 2002, 249(Suppl 2): 19-24
[5] Jankovic, Joseph. Levodopa strengths and weaknesses[J]. Neurology, 2002, 58(3): S19
[6] Lewitt PA, Nyholm D. New developments in levodopa therapy[J]. Neurology, 2004, 62(suppl. 1): S9
[7] Sorbera LA, Martin L. Etilevodopa: Antiparkinsonian dopamine precursor[J]. Drugs Future, 2001, 26(9): 219
[8] Jenner P. Pharmacology of dopamine agonists in the treatment of Parkinson's disease[J]. Neurology, 2002, 58(11): S1
[9] Whone AL, Remy P, Davis MR, et al. The REAL-PET study: slower progression in early Parkinson's disease treated with ropinirole compared with L-dopa[J]. Neurology, 2002, 58(suppl 3): S82-S83
[10] Parkinson Study Group. Dopamine transporter brain imaging to assess the effect of pramipexole vs levodopa on Parkinson disease progression[J]. Jama, 2002, 287(13): 1653-1661
[11] Ziegler N, Castro CA, Del SS, et al. Efficacy of piribedil as early combination to levodopa in patients with stable Parkinson's disease: a 6-month, randomized, placebo-controlled study[J]. Movement Disorders, 2003, 18(4): 418-425 Contin M, Riva R, Albani F. Pharmacokinetic optimization of dopamine receptor agonist therapy for Parkinson's disease[J]. CNS Drugs, 2000, 14(12): 439
[12] Schapira AH. Neuroprotection and dopamine agonists[J]. Neurology, 2002, 58:S9
[13] Yu P. Brasofensine Neurosearch[J]. Curr Opin Invest Drugs, 2000, 1(6): 504
[14] Negrotti A, Bizzarri G, Calzetti S. Long-term persistence of symptomatic effect of selegiline in Parkinson's disease. A two-months placebo-controlled withdrawal stusy[J]. J Neural Transm, 2001, 108(6): 215
[15] Rnoll J. Deprenyl(selegiline): past present and future[J]. J Neurobiology, 2000, 8(2): 179
[16] Parkinson Study Group. A controlled, randomized, delayed-Start Study of rasagiline in early Parkinson disease[J]. Archives of Neurology, 2004, 1(4): 561-566
[17] Power W. The role of COMT inhibiton in the treatment of Parkinson's disease[J]. Neurology, 2004, 62(suppl 1): S33
[18] Chanhan NB, Siegel GJ, Lee JM. Depletion of glial cell line-derived neurotrophic factor in substantia nigra neurons of Parkinson's disease brain[J]. J Chem Neuroanat, 2001, 21(1): 277
[19] 陈萍，李作汉．神经节苷脂GM1 治疗帕金森病的基础与临床[J]．国外医学-神经病、神经外科学分册，1999，26(5)：251
[20] 曲伸，何小龙，何成．脑源性神经营养因子基因工程细胞脑内移植治疗 PD大鼠的实验研究[J]．中华神经科杂志，1999，32(1)：13-16
[21] Shiozaki S, Ichikawa S, Nakamura J, et al. Actions of adenosine A-a receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP[J]. Psychopharmacology, 1999, 147(5): 90
[22] Kanda T, Jackson MJ, Smith L, et al. Combined use of the adenosine A-a antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not Dyskinesia in MPTP-treated monkeys[J]. Exp Neurol, 2000, 162(4): 321
[23] 罗京京．抗PD药 Istradefylline[J]．药学进展，2004，28(12)：574
[24] Chen LW, Yung KK, Chan YS. Neurokinin peptides and neurokinin receptors as potential therapeutic intervention targets of basal ganglia in the prevention and treatment of Parkinson's disease[J]. Curr Drug Targets. 2004, 5(2): 197-206
[25] Burke RE, Kholodilov NG. Programmed cell death: does it play a role in Parkinson's disease[J]. Ann Neurol, 1998, 44(Suppl 1): 160-166
[26] Delanty N, Dichter MA. Antioxidant therapy in neurologic disease[J]. Arch Neurol, 2000, 68(4): 685-690
[27] Parkinson study Group. Evaluation of dyskinesias in a pilot, randomized, placebo-controlled trial of remacemide in advanced Parkinson disease [J]. Arch Neurol, 2001, 58(10): 1660-1668
[28] Shoulson I, Penney J, McDermott M, et al. A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease[J]. Neurology, 2001, 56(4): 455
[29] Factor SA, Molho ES. Transient benefit of amantadine in Parkinson's disease: The facts about the myth[J]. Mov Disord, 1999, 14(2): 515
[30] Moosmann B, Skutella T, Beyer K, et al. Protective activity of aromatic amines and imines against oxidative nerve cell death[J]. Biol Chem, 2001, 38(11): 1601-1612
[31] 李玉芝，高霞，李国庆．还原型谷胱甘肽治疗PD临床疗效观察[J]．中国煤炭工业医学杂志，2005，8(8)：870-871
[32] 田学文，章翔，张剑宁，等．雌激素对PD大鼠中脑黑质DA能神经元的保护作用[J]．中国临床康复，2005，9(9)：193-195
[33] Kilic U, Kilic E, Lingor P, et al. Rifampicin inhibits neurodegeneration in the optic nerve transection model in vivo and after 1-methyl-4-phenylpyridinium intoxication in vitro[J]. Acta Neuropathol, 2004, 108(1): 65-68
[34] 张世忠，郭燕舞，张旺明等．帕金森病外科治疗中苍白球内侧部神经元电生理记录的有效针道方法[J]．中华神经医学杂志．2003，2(3)：180-182
[35] 董继宏，蒋雨平．脑深部电刺激治疗PD和特发性震颤的近期和远期疗效[J]．中华临床神经科学，2005，13(1)：86-91
[36] 张世忠，徐强，徐如祥等．脑深部刺激电极埋置术治疗帕金森病疗效研究[J]．中国神经精神疾病杂志．2003，29(6)：404-406
[37] Fuchs E, Segre JA. Stem cell: a new release on life[J]. Cell, 2000, 100(1): 143-155
[38] 束汉生，曾水林，李涛．神经干细胞治疗帕金森病的可行性探究[J]．中华老年医学杂志，2003，22(1)：56-57
[39] Gilgun-Sherki Y, Djaldetti R, Melamed E, et al. Polymorphism in candidate genes: implications for the risk and treatment of idiopathic Parkinson's disease[J]. Pharmacogenomics J. 2004, 4(5): 291-306
[40] Yamada M, Oligino T, Mata M, et al. Herpes simplex virus vecto-mediated expression of Bcl-2 prevents 6-hydroxydopamine induced degeneration of neurons in the substantia nigra in vivo [J].Proc Natl Acad Sci, 1999, 96(7): 4078-4083
[2] Qian ZM, Shen X. Brain iron transport and neurodegeneration[J]. Trend Mol Med, 2001, 7(6): 103-108
[3] Olanow C W, Tatton W G. Etiology and pathogenesis of Parkinson's disease[J]. Annu Rev Neurosci, 1999, 22(10): 123-144
[4] Ball J. Current advances in Parkinson's disease[J]. Trends Neurosci, 2001, 24(7): 367
[5] 罗毅，黄新德．原发性帕金森病治疗的建议(1998年)[J]．中风与神经病症杂 志，1999，16(2)：114
[6] Paola RD, Uitti RJ. Treatment implications in the early detection of Parkinson's disease[J]. Med Pro Sea, 1997, 24(1): 8-11
[7] 张世忠，郭燕舞，张旺明等．帕金森病外科治疗中苍白球内侧部神经元电生理记录的有效针道方法[J]．中华神经医学杂志．2003，2(3)：180-182
[8] 张世忠，徐如祥．帕金森病的外科治疗[J]．中华神经医学杂志，2003，2(5)：383-389
[9] Panikar D, Kishore A. Deep brain stimulation for Parkinson's disease[J]. Neurol India, 2003, 51(2): 167-75
[10] 董继宏，蒋雨平．脑深部电刺激治疗PD和特发性震颤的近期和远期疗效[J]．中华临床神经科学，2005，13(1)：86-91
[11] 张世忠，徐强，徐如祥等．脑深部刺激电极埋置术治疗帕金森病疗效研究[J]．中国神经精神疾病杂志，2003，29(6)：404-406
[12] Burke RE, Kholodilov NG. Programmed cell death: does it play a role in Parkinson's disease[J]. Ann Neurol, 1998, 44(Suppl 1): 160-166
[13] Delanty N, Dichter MA. Antioxidant therapy in neurologic disease[J]. Arch Neurol, 2000, 68(4): 685-690
[14] Parkinson study Group. Evaluation of dyskinesias in a pilot, randomized, placebo-controlled trial of remacemide in advanced Parkinson disease [J]. Arch Neurol, 2001, 58(10): 1660-1668
[15] Doble A. The role of excitotoxicity in neurodegenerative disease: Implications for therapy[J]. Pharm acol Ther, 1999, 81(6): 163
[16] Shoulson I, Penney J, McDermott M, et al. A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease[J]. Neurology, 2001, 56(4): 455
[17] Factor SA, Molho ES. Transient benefit of amantadine in Parkinson's disease: The facts about the myth[J]. Mov Disord, 1999, 14(12): 515
[18] Moosmann B, Skutella T, Beyer K, et al. Protective activity of aromatic amines and imines against oxidative nerve cell death[J]. Biol Chem, 2001, 38(11): 1601-1612
[19] 李玉芝，高霞，李国庆．还原型谷胱甘肽治疗PD临床疗效观察[J]．中国煤炭工业医学杂志，2005，8(8)：870-871
[20] 田学文，章翔，张剑宁，等．雌激素对PD大鼠中脑黑质DA能神经元的保护作用[J]．中国临床康复，2005，9(9)：193-195
[21] Bottcher T, Gerber J, Wellmer A, et al. Rifampin reduces production of reactive oxygen species of cerebrospinal fluid phagocytes and hippocampal neuronal apoptosis in experimental Streptococcus pneumoniae meningitis[J]. J Infect Dis, 2000, 181(6): 2095-2098
[22] Gerber J, Pohl K, Sander V, et al. Rifampin followed by ceftriaxone for experimental meningitis decreases lipoteichoic acid concentrations in cerebrospinal fluid and reduces neuronal damage in comparison to ceftriaxone alone[J]. Antimicrob Agents Chemother, 2003, 47(4): 1313-1317
[23] Yulug B, Kilic U, Kilic E, et al. Rifampicin attenuates brain damage in focal ischemia[J]. BRAIN RES, 2004, 996(1): 76-80
[24] Kilic U, Kilic E, Lingor P, et al. Rifampicin inhibits neurodegeneration in the optic nerve transection model in vivo and after 1-methyl-4-phenylpyridinium intoxication in vitro[J]. Acta Neuropathol, 2004, 108(1): 65-68
[25] Fuchs E, Segre JA. Stem cell: a new release on life[J]. Cell, 2000, 100:143-155
[26] 束汉生，曾水林，李涛．神经干细胞治疗帕金森病的可行性探究[J]．中华老年医学杂志，2003，22(1)：56-57
[27] Kang UJ, Lee WY, Chang JW. Gene therapy for Parkinson's disease: determining the genes necessary for optimal dopamine replacement in rat models[J]. Hum Cell, 2001, 14(1): 39-48
[28] Kordower JH, Emborg ME, Bloch J, et al. Neurodegeneration prevented by lentivirai vector delivery of GDNF in primate model of Parkinson's disease[J]. Science, 2000, 290(5492): 767-773
[29] 曲伸，何小龙，何成．脑源性神经营养因子基因工程细胞脑内移植治疗PD大鼠的实验研究[J]．中华神经科杂志，1999，32(1)：13-16
[30]Yamada M, Oligino T, Mata M, et al. Herpes simplex virus vecto-mediated expression of Bcl-2 prevents 6-hydroxydopamine induced degeneration of neurons in the substantia nigra in vivo [J].Proc Natl Acad Sci, 1999, 96(7): 4078-4083
[31]Gilgun-Sherki Y, Djaldetti R, Melamed E, et al. Polymorphism in candidate genes: implications for the risk and treatment of idiopathic Parkinson's disease[J]. Pharmacogenomics J. 2004, 4(5): 291-306
[32]Tatton NA, Kish SJ. In situ detection of apoptotic nuclei in the substantia nigra compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using terminal deoxynucleotidyl transferase labelling and acridine orange staining[J].Neuroscience, 1997, 77(4): 1037-1048
[1] 陈滢，陈晓春．MPTP诱导小鼠黑质神经元凋亡[J]．福建医科大学学报，2001，35(2)：105-108
[2] Tatton NA, Kish SJ. In situ detection of apoptotic nuclei in the substantia nigra compacta of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice using terminal deoxynucleotidyl transferase labelling and acridine orange staining[J]. Neuroscience, 1997, 77(4): 1037-1048
[3] 姚庆和，高国栋．MPTP的毒性机制与帕金森病动物模型[J]．国外医学神经病学神经外科学分册，2004，31(1)：45-48
[4] 梁晓俐主编．病理学基础与实验技术[M]．北京：军事医学科学出版社，2003，152-153
[5] Ungerstedt U. 6-Hydroxydopamine induced degeneration of central monomine neurons[J]. Eur J Pharmacol, 1968,5(1): 107-110
[6] Betarbet R, Sherer TB, Greenamyre JT. Animalmodels of Parkinson's disease[J]. Bioessays, 2002, 24(5):308-318
[7] Vander P, Wiederhold KH, Probst A, et al. Neurolpathology in mice expressing human alphasynuclein[J]. Neuroscience, 2000, 20(2): 6021-6029
[8] Schmidt RH, Bjobrklund A, Stenevi U, et al. Intracerebral grafting of neuronal cell suspension Ⅲ, A ctivity of intrastrial nigral suspension implants assessed by measurements of dopamine synthesis and metabolism[J]. Acta Physioi Scand, 1983, 522(supp 1): 19-28
[9] Brecknell JE, Dunnett SB, Fawcett JW, et al. A quantitative study of cell death in the substantia nigra following amechanical lesion of the medial forebrain bundle[J]. Neuroscience, 1995,64(7): 219-227
[10] Tseng JL, Baetge EE, Zurn AD, et al. GDNF reduces drug-induced rotational behavior after medial forebrain bundle transection by a mechanism not involving striatal dopamine [J]. J Neurosci, 1997, 17(12): 325-333
[11] 梁希彬，罗涌，卢峻，等．线刀毁损大鼠内侧前脑束建立部分损伤的帕金森病模型[J]．神经解剖学杂志，2001，17(3)：199-204
[12] Olanow CW, Tatton WG. Etiology and pathogenesis of Parkinson's disease[J]. Annu Rev Neurosci, 1999, 22(4): 123-144
[13] Yang SC, Markey SP. Recommented safe practices for using the neurotoxin MPTP in animal experinents[J]. Lab Anim Sci, 1988, 38: 563-567] [Przedorsle S, Jaclcson VL, The parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydoyndine (MPTP): a technical review of its utility and safety[J]. J Neurochem, 2001, 76(3): 1265-1274
[14] Langston JW, Irwin I. MPTP: current concepts and controversies[J]. Clin Neropharmaeol, 1986, 9(8): 485-507
[15] Kopin IJ, Markey SP. MPTP toxicity: implication for research in Pakinson's diseare[J]. Annu Rev Neurosci, 1985,11 (6): 81-90
[16] Gerlach M, Riedererer P, Przuntek H. MPTP mechanisms of neurotoxicity and their implications for Parkinson's disease[J]. Europeam J Pharm, 1991, 208(9): 273-286
[17] Giovann A, Sieber BA. Correlation between the neostriatal content of the 1-methyl-4-phenyl-1,2,3,6-tetrahydoyndine species and dopminergic neuron-toxicity following 1-methyl-4-phenyl-1,2,3,6-tetrahydoyndine administration to several strains of mice[J]. J pharma Exp Ther, 1991 , 257(10): 691-697
[18] 邹春林，孙异临．MPTP与帕金森小鼠模型的研究进展[J]．国外医学神经病学神经外科学分册，2000，27(6)：330-333
[19] Heikkila RE, Manzino L. Protection against the dopaminergic neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydoyndine by monoamine oxidase inhibiters[J]. Nature, 1984, 311(2): 467-469
[20] Burke RE, Kholodilov NG. Programmed cell death: does it play a role in Parkinson's disease[J]. Ann Neurol, 1998, 44(Suppl 1): 160-166
[21] Hengartner MO. The biochemistry of apoptosis[J]. Nature, 2000, 407(4089): 770-774
[22] Jaattela M. Programmed cell death: many ways for cells to die decently[J]. Ann Med, 2002, 34(6): 480-488
[23] Kroemer G. The proto-oncogene Bcl-2 and its role in regulating apoptosis[J]. Nat Med, 1997, 3(11): 614-620
[24]Kitagawa K, Matsumoto M, Tsujimoto Y, et al. Amelioration of hippocampal neuronal damage after global ischemia by neuronal overexpression of bcl-2 in transgenic mice[J]. Stroke, 1998, 29(12): 2616-2621
[25]Veech GA, Dennis J, Keeney PM, et al. Disrupted mitochondrial electron transport function increases expression of anti-apoptotic bcl-2 and bcl-X(L) proteins in SH-SY5Y neuroblastoma and in Parkinson disease cybrid cells through oxidative stress[J]. J Neurosci Res, 2000, 61(6): 693-700
[26] Huang Y, Ray S, Reed JC, et al. Estrogen increases intracellar Bcl-2 to Bax ratios and inhibits taxol-induced apoptosis of human breast cancer MCF-7 cells[J]. Breast Cancer Res Treat, 1997, 42(4): 73-81
[27]Hassouna I, Wickert H, Zimmermann M, et al. Increase in bax expression in substantia nigra following 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine(MPTP) treatment of mice[J]. Neurosci Lett, 1996, 204(122):85-88
[28]Offen D, Beart PM, Cheung NS, et al. Transgenic mice expressing human Bcl-2 in their neurons are resistant to 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity [J]. Proc Natl Acad Sci USA, 1998, 95(10): 5789-5794
[29]Hartmann A, Mouatt Prigent A, Vila M, et al. Increased expression and redistribution of the antiapoptotic molecule Bcl-xL in Parkinson's disease[J]. Neurobiol Dis, 2002, 10(1): 28-32
[30]Mogi M, Togari A, Kondo T, et al. Caspase activities and tumor necrosis factor receptor Rl(p55) level are elevated in the substantia nigra from parkinsonian brain[J]. J Neural Transm, 2000, 107(3):335-341
[31]Du Y, Dodel RC, Bales KR, et al. Involvement of a caspase-3-like cysteine protease in 1-methyl-4-phenyipyridinium-mediated apoptosis of cultured cerebellar granule neurons [J]. J Neuro Chem, 1997, 69(4): 1382-1388
[32]Bilsland J, Roy S, Xanthoudakis S, et al. Caspase inhibitors attenuate 1-methyl-4-phenylpyridinium toxicity in primary cultures of mesencephalic dopaminergic neurons[J]. J Neurosci, 2002, 22(7): 2637-2649
[1] Burke RE, Kholodilov NG. Programmed cell death: does it play a role in Parkinson's disease[J]. Ann Neurol, 1998, 44(Suppl 1): 160-166
[2] Bottcher T, Gerber J, Wellmer A, et al. Rifampin reduces production of reactive oxygen species of cerebrospinal fluid phagocytes and hippocampal neuronal apoptosis in experimental Streptococcus pneumoniae meningitis[J]. J Infect Dis, 2000, 181 (6):2095-2098
[3] Gerber J, Pohl K, Sander V, et al. Rifampin followed by ceftriaxone for experimental meningitis decreases lipoteichoic acid concentrations in cerebrospinal fluid and reduces neuronal damage in comparison to ceftriaxone alone[J]. Antimicrob Agents Chemother, 2003, 47(4):1313-1317
[4] Yulug B, Kilic U, Kilic E, et al. Rifampicin attenuates brain damage in focal ischemia[J]. Brain Res, 2004, 996(1):76-80
[5] Kilic U, Kilic E, Lingor P, et al. Rifampicin inhibits neurodegeneration in the optic nerve transection model in vivo and after 1-methyl-4-phenylpyridinium intoxication in vitro[J]. Acta Neuropathol, 2004, 108(1):65-68
[6] Delanty N, Dichter MA. Antioxidant therapy in neurologic disease[J]. Arch Neurol, 2000, 68(5): 685-690
[7] Parkinson study Group. Evaluation of dyskinesias in a pilot, randomized, placebo-controlled trial of remacemide in advanced Parkinson disease [J]. Arch Neurol, 2001, 58(10): 1660-1668
[8] Doble A. The role of excitotoxicity in neurodegenerative disease: Implications for therapy[J]. Pharm acol Ther, 1999, 81(2): 163
[9] Factor SA, Molho ES. Transient benefit of amantadine in Parkinson's disease: The facts about the myth[J]. Mov Disord, 1999, 14(8): 515
[10] Shoulson I, Penney J, McDermott M, et al. A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease[J]. Neurology, 2001, 56(4): 455
[11] 田学文，章翔，张剑宁，等．雌激素对PD大鼠中脑黑质DA能神经元的保护作用[J]．中国临床康复，2005，9(9)：193-195
[12] Moosmann B, Skutella T, Beyer K, et al. Protective activity of aromatic amines and imines against oxidative nerve cell death[J]. Biol Chem, 2001, 38(11): 1601-1612
[13] 李玉芝，高霞，李国庆．还原型谷胱甘肽治疗PD临床疗效观察[J]．中国煤炭工业医学杂志，2005，8(8)：870-871
[14] 任雷明．抗结核病药与抗麻风病药[M]．见：李端，主编．药理学．第五版．北京：人民卫生出版社，2003．407-408
[15] World Health Organization. WHO Expert Committee on leprosy, sixth report. Tech.Rep.Ser.1988.768. WHO,Geneva
[16] Namba Y, Kawatsu K, Izumi S, et al. Neurofibrillary tangles and senile plaques in brain of elderly leprosy patients[J]. Lancet, 1992, 340(8825): 978
[17] Tomiyama T, Shoji A, Kataoka K, et al. Inhibition of amyloid β protein aggregation and neurotoxicity by rifampicin[J]. J Biol Chem, 1996, 271(12): 6839-6845
[18] Hal ED. Antioxidant pharmacotherapy. In: Ginsberg M, Bogousslavsky J. Cerebrovascular disease: pathophysiology, diagnosis and management[M]. Blackwell Science, 1997. Malden
[19] Calleja C, Pascussi JM, Mani JC, et al. The antibiotic rifampicin is a non-steroidal ligand and activator of the human glucocorticoid receptor[J]. Nature Med, 1998, 4(1): 92-96
[20] YangY, Ashwell JD. Thymocyte apoptosis[J]. J Clin Immunol, 1999, 19(6): 337-349
[21] Andreau K, Lemaire C, Souvannavong V, et al. Induction of apoptosis by dexamethasone in the B cell lineage[J]. Immunopharmacology, 1998, 40(1): 67-76
[22] Schmidt M, Pauels H-G, Lugering N, et al. Glucocorticoids induce apoptosis in human monocytes: Potential role of IL-1 beta[J]. J Immunol, 1999, 163(6): 3484-3490
[23] Migriorati G, Nicoletti I, D'Adamio F, et al. Dexamethsone-induced apoptosis in mouse natural killer cells and cytotoxic T lymphocytes[J]. Immunology, 1994, 81(1): 21-26
[24] Yang Y, Mercep M, Ware CF, et al. Fas and activationinduced Fas ligand mediated apoptosis of T cell hybridomas: Inhibition of Fas ligand expression by retinoic acid and glucocorticoids[J]. J Exp Med, 1995, 181(5): 1673-1682
[25]Huang ST, Cidlowski JA. Glucocorticoids inhibit serum depletion-induced apoptosis in T lymphocytes expressing Bcl-2[J]. Faseb J, 1999, 13(3): 467-476
[26]Yamamoto M, Fukuda K, Miura N, et al. Inhibition by dexamethasone of transforming growth factor-induced apoptosis in rat hepatoma cells: a possible association with Bcl-xL induction[J]. Hepatology, 1998, 27(4): 959-966
[27] Chang TC, Hung MW, Jiang SY, et al. Dexamethasone suppresses apoptosis in a human gastric cancer cell line through modulation of Bcl-x gene expression[J]. Febs Lett, 1997,415(1): 11-15
[28]Nittoh T, Fujimori H, Kozumi Y, et al. Effects of glucocorticoids on apoptosis of infiltrated eosinophils and neutrophils in rats[J]. Eur J Pharm, 1998, 354(1):73-81
[29] Meagher LC, Cousin J, Secki JR, et al. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophils and eosinophils[J]. J Immunol, 1996, 156(11): 4422-4428
[30] Iwata M, Hanaoke S, Sato K. Rescue of thymocytes and T cell hybridomas from glucocorticoid-induced apoptosis by stimulation via the T cell receptor/CD3 complex: A possible in vitro model for positive selection of the T cell repertoire[J].Eur J Immunol, 1991, 21(3): 643-648
[31]Jaidka S, Gollapudi SV, Gupta S. Rifampicin inhibits anti-CD95-induced apoptosis in T cells by activating glucocorticoid receptor[J]. Faseb J, 2001, 15(4): 313
[1] Kitada T, Asakawa S, Hattori N, et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism[J]. Nature, 1998, 392(6676): 605-608
[2] Ball J. Current advances in Parkinson's disease[J]. Trends Neurosci, 2001, 24(7): 367
[3] 罗毅，黄新德．原发性帕金森病治疗的建议(1998年)[J]．中风与神经病症杂志，1999，16(2)：114
[4] Regina K, Andrew J. Treatment of Parkinson's disease: levodopa as the first choice[J]. J Neurology, 2002, 249(Suppl 2): 19-24
[5] Jankovic, Joseph. Levodopa strengths and weaknesses[J]. Neurology, 2002, 58(3): S19
[6] Lewitt PA, Nyholm D. New developments in levodopa therapy[J]. Neurology, 2004, 62(suppl. 1): S9
[7] Sorbera LA, Martin L. Etilevodopa: Antiparkinsonian dopamine precursor[J]. Drugs Future, 2001, 26(9): 219
[8] Jenner P. Pharmacology of dopamine agonists in the treatment of Parkinson's disease[J]. Neurology, 2002, 58(11): S1
[9] Whone AL, Remy P, Davis MR, et al. The REAL-PET study: slower progression in early Parkinson's disease treated with ropinirole compared with L-dopa[J]. Neurology, 2002, 58(suppl 3): S82-S83
[10] Parkinson Study Group. Dopamine transporter brain imaging to assess the effect of pramipexole vs levodopa on Parkinson disease progression[J]. Jama, 2002, 287(13): 1653-1661
[11] Ziegler N, Castro CA, Del SS, et al. Efficacy of piribedil as early combination to levodopa in patients with stable Parkinson's disease: a 6-month, randomized, placebo-controlled study[J]. Movement Disorders, 2003, 18(4): 418-425 Contin M, Riva R, Albani F. Pharmacokinetic optimization of dopamine receptor agonist therapy for Parkinson's disease[J]. CNS Drugs, 2000, 14(12): 439
[12] Schapira AH. Neuroprotection and dopamine agonists[J]. Neurology, 2002, 58:S9
[13] Yu P. Brasofensine Neurosearch[J]. Curr Opin Invest Drugs, 2000, 1(6): 504
[14] Negrotti A, Bizzarri G, Calzetti S. Long-term persistence of symptomatic effect of selegiline in Parkinson's disease. A two-months placebo-controlled withdrawal stusy[J]. J Neural Transm, 2001, 108(6): 215
[15] Rnoll J. Deprenyl(selegiline): past present and future[J]. J Neurobiology, 2000, 8(2): 179
[16] Parkinson Study Group. A controlled, randomized, delayed-Start Study of rasagiline in early Parkinson disease[J]. Archives of Neurology, 2004, 1(4): 561-566
[17] Power W. The role of COMT inhibiton in the treatment of Parkinson's disease[J]. Neurology, 2004, 62(suppl 1): S33
[18] Chanhan NB, Siegel GJ, Lee JM. Depletion of glial cell line-derived neurotrophic factor in substantia nigra neurons of Parkinson's disease brain[J]. J Chem Neuroanat, 2001, 21(1): 277
[19] 陈萍，李作汉．神经节苷脂GM1 治疗帕金森病的基础与临床[J]．国外医学-神经病、神经外科学分册，1999，26(5)：251
[20] 曲伸，何小龙，何成．脑源性神经营养因子基因工程细胞脑内移植治疗 PD大鼠的实验研究[J]．中华神经科杂志，1999，32(1)：13-16
[21] Shiozaki S, Ichikawa S, Nakamura J, et al. Actions of adenosine A-a receptor antagonist KW-6002 on drug-induced catalepsy and hypokinesia caused by reserpine or MPTP[J]. Psychopharmacology, 1999, 147(5): 90
[22] Kanda T, Jackson MJ, Smith L, et al. Combined use of the adenosine A-a antagonist KW-6002 with L-DOPA or with selective D1 or D2 dopamine agonists increases antiparkinsonian activity but not Dyskinesia in MPTP-treated monkeys[J]. Exp Neurol, 2000, 162(4): 321
[23] 罗京京．抗PD药 Istradefylline[J]．药学进展，2004，28(12)：574
[24] Chen LW, Yung KK, Chan YS. Neurokinin peptides and neurokinin receptors as potential therapeutic intervention targets of basal ganglia in the prevention and treatment of Parkinson's disease[J]. Curr Drug Targets. 2004, 5(2): 197-206
[25] Burke RE, Kholodilov NG. Programmed cell death: does it play a role in Parkinson's disease[J]. Ann Neurol, 1998, 44(Suppl 1): 160-166
[26] Delanty N, Dichter MA. Antioxidant therapy in neurologic disease[J]. Arch Neurol, 2000, 68(4): 685-690
[27] Parkinson study Group. Evaluation of dyskinesias in a pilot, randomized, placebo-controlled trial of remacemide in advanced Parkinson disease [J]. Arch Neurol, 2001, 58(10): 1660-1668
[28] Shoulson I, Penney J, McDermott M, et al. A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease[J]. Neurology, 2001, 56(4): 455
[29] Factor SA, Molho ES. Transient benefit of amantadine in Parkinson's disease: The facts about the myth[J]. Mov Disord, 1999, 14(2): 515
[30] Moosmann B, Skutella T, Beyer K, et al. Protective activity of aromatic amines and imines against oxidative nerve cell death[J]. Biol Chem, 2001, 38(11): 1601-1612
[31] 李玉芝，高霞，李国庆．还原型谷胱甘肽治疗PD临床疗效观察[J]．中国煤炭工业医学杂志，2005，8(8)：870-871
[32] 田学文，章翔，张剑宁，等．雌激素对PD大鼠中脑黑质DA能神经元的保护作用[J]．中国临床康复，2005，9(9)：193-195
[33] Kilic U, Kilic E, Lingor P, et al. Rifampicin inhibits neurodegeneration in the optic nerve transection model in vivo and after 1-methyl-4-phenylpyridinium intoxication in vitro[J]. Acta Neuropathol, 2004, 108(1): 65-68
[34] 张世忠，郭燕舞，张旺明等．帕金森病外科治疗中苍白球内侧部神经元电生理记录的有效针道方法[J]．中华神经医学杂志．2003，2(3)：180-182
[35] 董继宏，蒋雨平．脑深部电刺激治疗PD和特发性震颤的近期和远期疗效[J]．中华临床神经科学，2005，13(1)：86-91
[36] 张世忠，徐强，徐如祥等．脑深部刺激电极埋置术治疗帕金森病疗效研究[J]．中国神经精神疾病杂志．2003，29(6)：404-406
[37] Fuchs E, Segre JA. Stem cell: a new release on life[J]. Cell, 2000, 100(1): 143-155
[38] 束汉生，曾水林，李涛．神经干细胞治疗帕金森病的可行性探究[J]．中华老年医学杂志，2003，22(1)：56-57
[39] Gilgun-Sherki Y, Djaldetti R, Melamed E, et al. Polymorphism in candidate genes: implications for the risk and treatment of idiopathic Parkinson's disease[J]. Pharmacogenomics J. 2004, 4(5): 291-306
[40] Yamada M, Oligino T, Mata M, et al. Herpes simplex virus vecto-mediated expression of Bcl-2 prevents 6-hydroxydopamine induced degeneration of neurons in the substantia nigra in vivo [J].Proc Natl Acad Sci, 1999, 96(7): 4078-4083