电针促进帕金森小鼠多巴胺神经元突触可塑性的细胞分子机制
|
摘要
目的：研究电针对帕金森小鼠黑质致密部多巴胺神经元突触可塑性的影响及细胞分子机制。方法：以1—甲基—4苯基—1，2，3，6四氢吡啶诱导的帕金森小鼠作为研究对象，电针“合谷”、“太冲”穴，每日1次，7次为1疗程，共3个疗程后，尼氏染色检测黑质致密部神经元变性情况；电镜检测黑质致密部突触形态变化；免疫组化检测酪氨酸羟化酶、脑源性神经营养因子、神经细胞粘附分子、多巴胺转运体、巢蛋白表达；原位杂交检测酪氨酸羟化酶、脑源性神经营养因子、神经细胞粘附分子、多巴胺转运体mRNA表达。结果：模型组小鼠尼氏染色阳性细胞计数减少，电针后增多；电针后黑质致密部突触数目增多、数密度、面密度增大；电针后帕金森小鼠与模型组比较，酪氨酸羟化酶、脑源性神经营养因子、神经细胞粘附分子、多巴胺转运体、巢蛋白表达增强；电针后酪氨酸羟化酶、脑源性神经营养因子、神经细胞粘附分子、多巴胺转运体mRNA表达也增强。结论：电针促进帕金森小鼠多巴胺神经元突触可塑性的细胞分子基础可能与脑源性神经营养因子的神经营养作用、神经细胞粘附分子的细胞粘附、对内源性神经干细胞的原位诱导和促进多巴胺的合成与重摄取有关。
Objective: To research on doparainegic neuron synapse plasticity and its celluar molecular mechanism of substantia nigra in Parkinson' s disease model mouse treated by electroacupuncture therapy. Methods:
The parkinson' s disease mouce induced by 1-methyl, 4-phenyl - 1, 2,3,6 tetrahydropyridine were treated by electroacupuncture therapy on "Hegu(LI4)" and "Taichong(LVS)" acupoints. The treatment was once daily and up to seven as one course which was lasted for 3 courses. Nissles stain for detecting dopaminergic nuron degeneration; electron microscope detecting for morphylogical changes of the dopaminegic neuron synapse plasticity in substantial nigra zone compacta; Immunohistochemistry for the exppresion of tyrosine hydroxylase, brain-derived neurotrophic factor, neural cell adhesion molecules, dopamine transpotor, nestin; in situ hybridization histochemistry was applied for testing expresion of tyrosine hydroxylase, brain-derived neurotrophic factor, neural cell adhesion molecules and dopamine
transpotor mRNA. Results: The positive cell numbers of nissles stain
in model mouce increased after electroacupuncture; The decreased dopaminergic nuron synapses in model mouse were increased in substantial nigra after acunpuncture treatment in which the number density and volume density also enlarged; Compared to model mouse, the expressions of tyrosine hydroxylase, brain-derived neurotrophic factor, neural cell adhesion molecules, dopamine transpotor, nestin were enhaced; the mRNA exression of tyrosine hydroxylase, brain-derived neurotrophic factor,
neural cell adhesion molecules and dopamine transpotor enhaced, too. Conclusions: Electroacupuncture therapy can promote the synaptic
plasticity of the degenerative dopaminergic neuron in parkinson' s disease mouse. The celluar molecular mechanism is related to the effective of neuronal nourishment by brain-derived neurotrophic factor, cell adhension of neural cell adhesion molecules, endogenous induction of nerve stem cell and acceleration of the synethis and metabolism of dopamine.
Objective: To research on doparainegic neuron synapse plasticity and its celluar molecular mechanism of substantia nigra in Parkinson' s disease model mouse treated by electroacupuncture therapy. Methods:
The parkinson' s disease mouce induced by 1-methyl, 4-phenyl - 1, 2,3,6 tetrahydropyridine were treated by electroacupuncture therapy on "Hegu(LI4)" and "Taichong(LVS)" acupoints. The treatment was once daily and up to seven as one course which was lasted for 3 courses. Nissles stain for detecting dopaminergic nuron degeneration; electron microscope detecting for morphylogical changes of the dopaminegic neuron synapse plasticity in substantial nigra zone compacta; Immunohistochemistry for the exppresion of tyrosine hydroxylase, brain-derived neurotrophic factor, neural cell adhesion molecules, dopamine transpotor, nestin; in situ hybridization histochemistry was applied for testing expresion of tyrosine hydroxylase, brain-derived neurotrophic factor, neural cell adhesion molecules and dopamine
transpotor mRNA. Results: The positive cell numbers of nissles stain
in model mouce increased after electroacupuncture; The decreased dopaminergic nuron synapses in model mouse were increased in substantial nigra after acunpuncture treatment in which the number density and volume density also enlarged; Compared to model mouse, the expressions of tyrosine hydroxylase, brain-derived neurotrophic factor, neural cell adhesion molecules, dopamine transpotor, nestin were enhaced; the mRNA exression of tyrosine hydroxylase, brain-derived neurotrophic factor,
neural cell adhesion molecules and dopamine transpotor enhaced, too. Conclusions: Electroacupuncture therapy can promote the synaptic
plasticity of the degenerative dopaminergic neuron in parkinson' s disease mouse. The celluar molecular mechanism is related to the effective of neuronal nourishment by brain-derived neurotrophic factor, cell adhension of neural cell adhesion molecules, endogenous induction of nerve stem cell and acceleration of the synethis and metabolism of dopamine.
引文
1．王新德．老年人帕金森病药物治疗进展．世界医学杂志，2002；6(11)：2-6
2．刘道宽．帕金森病的药物治疗．实用老年医学杂志，2001；15(6)：289-292
3．肖安平．老年帕金森病的外科治疗．实用老年医学杂志，2001；15(6)：292-294
4．吴小军．李立宏．帕金森与基因工程细胞移植．国外医学神经病学神经外科学分册，2002；29(3)：202-204
5. Freese A. Restorative gene therapy approaches to Parkinson's disease. Med Clin North Am, 1999;83(2):537-548
6. Arbuthott GW, Ingham CA, Wickens JR. Dopamine and synaptic plasticity in the neurostriatum. J Anat, 2000,196:587-596
7．华仲慰．神经系统可塑性研究的进展．生理科学进展，1986；17(1)：33-38
8. Kristen MH. Structure, development, and plasticity of dendritic spines. Curr opinion Neurobiol, 1999,9:343-385
9. Ingham CA, Hood SH, Mi L. Plasticity of striatopallidal terminals of following unilateral lesion of the dopaminerdic nigrostriatals pathway: a morphological study. Exp Brain Res, 1997,116:39-49
10. Finkelstein DI, Stanic D, Parish CL. Axonal sprouting following lesions of the rat substantia nigra. Neuroscience, 2000,97:99-112
11. Calabresi P, Giacomini P, Centonze D, et al. Levodopa induced dyskinesia: a pathologiacal form of striatal synaptic plasticity? Ann Neual, 2000,47(S1):60-68
12. Berretta S, Parthasarathy HB, Graybiel AM. Local realease of GABAergic inhibition in motor cortex induces immediate early gene expression in direct pathway neurons of the striatum.
Neuroscience, 1997,17:4752-4763
13. Donnan GA, Woodhouse DG, Kaczmarczyk SJ. Evidence for plasticity of the dopaminergic system in Parkinsonism. Mol Neurobiol, 1991,5:421-433
14. Tang KC, Low MJ, Grand DK. Dopamine dependent synaptic plasticity in striatum during in vivo development. Proc Natl Acad Sci USA, 2001,98:1255-1260
15．牛平，吕永利，王耀山等．帕金森病与神经营养因子的研究进展．解剖科学进展，1998；4(1)：47-53
16. Mogi M, Togari A, Kondo T, et al. Brain-derived growth factor and nerve growth factor concentrations are decreased in the substantia nigra in Parkinoson's disease. Neurosci Lett, 1999;270(1):45-48
17. Venero JL, Vizuete ML, Revuelta M, et al. Upregulation of BDNF mRNA and trk mRNA in the nigrostriatal system and in the lesion site following unilateral transection of of the medial forebrain bundle. Exp Neurol, 2000;161:38-48
18．刘爽．王亚奇．神经营养因子参与帕金森病的发生及治疗中的潜在作用．中国病理生理杂志，2002；18(1)：101-103
19．马仲才．潘卫．戚中田．脑源性神经营养因子与帕金森病．神经解剖学杂志，2002；18(1)：87-90
20. Beck KD, Knusel B, Hefti F. The nature of the trophic action of brain-derived neurophic factor, des(1-3)-insulin-like growth factor-1, and basic fibroblast growth factor on mesencephalic dopamineegic neurons developing in culture. Neuroscience, 1993;52:855-866
21. Studer L, Spenger C, Seiler RW, et al. Effects of brain-derived
neurotrophic factor on neuronal structure of dopaminergic neurons in dissociated cultures of human fetal mesencephalon. Exp Brain Res, 1996;108:328-336
22. Kontkanen O, Castren E. Trophic effects of selegiline on cultured dopaminergic neurons. Brain Res, 1999;829:190-192
23. Ostergaard K, Jones SA, Hyman C, et al. Effects of donor age and brain-derived neurotrophic facter on the survival of dopaminergic neurons and axonal growth in postnatal rat nigrostriatal cocultures. Exp Neurol, 1996;142:340-350
24. Skaper SD, Negro A, Facci L, et al. Brain-derived neurotrophic factor selectively rescues mesencephalic dopaminergic neurons from 2,4,5-trihydroxyphenylalanine-induced injury. J Neurosci Res, 1993; 34:478-487
25. Berezin V, Bock E. NCAM mimetic peptides: Pharmacological and therapeutic potential. J Mol Neurosci. 2004;22(1-2):33-39
26. Emery DL, Royo NC, Fischer I, et al. Plasticity following injury to the adult central nervous system: isrecapitulation of a developmental state worth promoting? J Neurotrauma, 2003; 20(12): 1271-92
27．胡晓燕，周严，袁建刚，等．神经细胞粘附分子的研究进展．生命科学．2001；13(5)：200
28．孟凡刚，苏万东．神经干细胞与帕金森病．国外医学神经病学神经外科学分册．2003：30(4)：392
29. Sanci V, Houle S, DaSilva JN. No change in dopamine D1 receptor in vivo binding in rats after subchronic haloperidol treatment. Can J Physiol Pharmacol. 2002,80:36-41
30. Blandini F, Greenamyre JT, Fancellu R, et al. Blockade of subthalamic glutamatergic activity corrects changes in neuronal metabolism and motor behavior in rats with nigrostriatal lesions. Neurol Sci, 2001,22:49-50
31. Nash JE, brotchie JM. A common signaling pathway for strialatal NMDA and adenosine A2 are captors: implications for the treatment of Parkinson's disease. Neuroscience, 2000,20:7782-7789
32．黄文燕．吴焕淦．针灸治疗帕金森氏病概况．中国针灸，19981 4：252-255
33．任小群．王友京．罗明富等．针刺治疗震颤麻痹临床和实验研究．中国针灸，1999；10：617-619
34．王玲玲．何崇．刘跃光等．针灸治疗帕金森病29例临床观察．中国针灸，1999；12：709-711
35．郑翎，金宇．针刺治疗震颤麻痹52例临床观察．中国针灸，1998，(2)：19-81
36．陈利国．针刺治疗震颤麻痹40例临床观察．中医杂志，1996，37(4)：216-217
37．戴若鑫．天鼎穴的临床应用．针灸临床杂志，1996，12(9)：35-36
38．王金玲，肖飞．深刺风府治疗疑难病症验案．上海针灸杂志，1996，15(2)：19-20
39．潘元侠．小儿多动症、小舞蹈病、帕金森氏病的针刺治疗体会．浙江中医学院学报，1996，(6)49-50
40．张沛霖，张勤。针刺治疗震颤麻痹的临床观察．云南中医药杂志，1996，17(5)：39-40
41．刘家瑛．针刺治疗震颤麻痹159例疗效观察．针灸临床杂志，1993，9(5)：10-11
42．李圣平．帕金森综合征的针灸康复疗法．四川中医，1993，(8)：51-52
43．王选伟．针刺治疗震颤麻痹40例．陕西中医，1994，15(4)：176
44．罗健．四关穴治疗神经系统病病应用举隅．四川中医，1996，(8)：50
45．宋南昌，宗重阳．宗瑞麟用“四关”穴的经验．广西中医药，1993．(6)：11-12
46．俞竹青．头皮针合四关穴为主治疗帕金森氏症．浙江中医学院学报，1994，(6)：45
47．奚桂芳．针刺和中药治疗帕金森病的临床疗效分析．上海针灸杂志，1995，(6)：243-244
48．王玲玲．何崇．赵玫等．针灸对帕金森病脑部血流状态的影响．中国针灸，1999：2：115-117
49．睢久红等．针刺结合复方中药对帕金森病患者血浆DA含量的影响．针刺研究，1997，(1，2)：106-107
50．张莉．针刺对帕金森病血清抗氧化酶含量的影响，上海针灸杂志，1996，15(6)：3-9
51．奚桂芳．蔡德亨．陈国美．头部穴位电刺激对帕金森病震颤肌电位的影响．上海针灸杂志，1996；(3)：5
52．马骏，王华．电针帕金森模型大鼠对黑质TH含量的影响．针刺研究，2001；26(4)：288
53．梁希彬，田德全，赵英侠等，电针后大鼠中脑腹侧部粗提液对体外培养的多巴胺能神经元生长发育的影响，针刺研究，1999；24(3)：179
54．梁希彬，刘贤宇，李丰桥，等．电针治疗部分损伤帕金森病大鼠的实验研究．针刺研究，2001；26(3)：209
55．马骏，王彦春，甘水咏．电针风府穴、太冲穴对PD大鼠黑质神经元凋亡的影响．湖北中医杂志，2003；25(11)：5
56．何崇，王玲玲，董洪涛，等．针灸对帕金森病大鼠模型脑内单胺类递质含量的影响．针刺研究，1998，23(1)：44
57．罗明富，王志英，王平．电针对震颤麻痹大鼠中脑黑质和肾上腺體质酪氨酸羟化酶的影响．针刺研究，1997，22(4)：292
58．罗松．电针对老年痴呆大鼠海马神经元突触形态可塑性的影响机制．成都
中医药大学博士学位论文．2003
59．韩婷．电针对老年痴呆大鼠海马胆碱能神经的影响研究．成都中医药大学硕士学位论文．2003
60．王廷华．吴良芳．廖德阳等．针刺对脑源性神经营养因子在脊髓Ⅱ板层可塑性中表达的影响。神经解剖学杂志，2002；18(1)：55-58
61. Nobutaka A, Kazuaki M, Yoshio G. Evaluation of a 1 methyl phenyl 1,2, 3, 6 tetrahydropyridine(MPTP) treated C57 black mouse model for Parkinsonism. Brain Res,1990,515:57～63
62. Schulz JB, et al. Mol Cell Biochem, 1997;174:193
63. Liang CL, et al. Neurodegeneration, 1996;5:313
64. Jones DG, Calverley RKS. Frequency ofoccurrence of perforated synapses in developing rat neocortex. Neurosci Lett, 1991;129:189-192
65．杨正伟，实用生物体视学，成都：四川省解剖、体视、法医、口腔学会，1991：37-68
66．郑富盛．细胞形态立体计算学[M]．北京：北京医科大学中国协和医科大学联合出版社，1999，16(3)：201
67. Giacobini E. Molecular mechanism of nervous transmission and synaptic plasticity.Progress in Brian Res, 1971,34:234
68. Zigmond MJ, Stricker EM. Animal models of Parkinson is musing selective neurotoxins: clinical and basic implications, Int Rev Neurobiol, 1989,31:1-79
69. Betarbet R, Sherer TB, Greenamyre JT. Animal models of Parkinson's disease. Bioessays, 2002,24:308-318
70. Tolwani RJ, Jakowec MW, Petzinger GM, et al. Experimental models of Parkinson's disease: insights from many models. Lab Anim Sci, 1999,49(4):363-371
71. Westlund KN, et al. Neuroscience, 1988;25:439
72．傅文玉，等．帕金森大鼠黑质和纹状体神经元的变化．解剖科学进展，1997，3(3)：208
73．伦学庆，等．损毁大鼠纹状体帕金森病模型的建立．中国病理生理杂志，1999．15(2)：188
74. Eezard E, et al. Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter. Exp Neurol, 1999;155:268
75．栗山欣弥(日)编．突触的结构与功能．人民卫生出版社．北京：1983：285
76. Tuszynski MH.Neurotrophic factors. In:Tuszynski MH, Kordower J, ed. CNS Regeneration. San Diego:Academic Press, 1999.109-158
77. Johnson JE. Neurotrophic factors. In:Zigmond MJ, ed. Fundamental Neuroscience. San Diego:Academic Press, 1999.611-635
78．何成，王成海，敖世洲．神经营养因子．生命科学，1996，8：32-35
79．盛树力主编．临床神经科学前沿．北京大学医学出版社．北京：2003：324
80．方秀彬编著．神经肽与神经营养因子．人民卫生出版社．北京：2002：274
81. Nishio T, Furukawa S, Akiguchi I, et al. Medical nigral dopamine neuron shaverich neurotrophin supporting humans. Neuroreport, 1998,9:2847～2851
82. Mogi M, Togari A, Kondo T, et al. Brain-derived growth factor and nerve growth factor concentration sare decreased in the substantia nigra in Parkinson's disease. Neurosci Lett, 1999,270:45～48
83. Parain K, Murer MG, Yah Q, et al. Reduced expression of brain-derived neurotrophic factor protein in Parkinson's disease substantia nigra. Neuroreport, 1999,10:557～561
84. Howells DW, Porritt MJ, Wong JY, et al. Reduced BDNFmRNA expression in the Parkinson's disease substantia nigra. Exp Neurol, 2000,
166:127～135
85. Venero JL, Vizuete ML, Revuelta M, et al. Upregulation of BDNFmRNA and trkBmRNA in the nigro striatal system and in the lesionsite following unilateral transection of the medial forebrain bundle. Exp Neurol, 2000,161:38～48
86. Skaper SD, Negro A, Facci L, et al. Brain-derived neurotrophic factor selectively rescues mesencephalic dopaminergic neurons from 2,4,5-trihydroxyphenylalanine induced injury. J Neurosci Res, 1993,34:478～487
87. Beck KD, Knusel B, Hefti F. The nature of the trophic action of brain-derived neurotrophic factor, des(1-3)-insulin-like growth factor-1, and basic fibroblast growth factor on mesencephalic dopaminergic neurons developing in culture. Neuroscience, 1993,52:855～866
88. Kontkanen O, Castren E. Trophic effects of selegiline on cultured dopaminergic neurons. Brain Res, 1999,829:190～192
89. Ostergaard K, Jones SA, Hyman C, et al. Effects of donorage and brain-derived neurotrophic factor on the survival of dopaminergic neurons and axonal growth in postnatal rat nigro striatal cocultures. Exp Neurol, 1996,142:340～350
90. Mark FB. Barry WC. Michaael AP. Neuroscience:Exploring the Brain, 2nd ed:高等教育出版社，北京；2002：714
91. Kiryushko D, Kofoed T, Skladchikova G, et al. A synthetic peptide ligand of neural cell adhesion molecule (NCAM), C3d, promotes neuritogenesis and synaptogenesis and modulates presynaptic function in primary cultures of rat hippocampal neurons. J Biol
Chem. 2003;278(14):12325-34
92. Son H, Seuk Kim J, Mogg Kim J, et al. Reciprocal actions of NCAM and tPA via a Ras-dependent MAPK activation in rat hippocampal neurons. Biochem Biophys Res Commun 2002;298(2):262-8
93. Fercakova A. Cell adhesion molecules in the neural development and plasticity. Bratisl Lek Listy 2001;102(12):552-5
94. Panicker AK, Buhusi M, Thelen K, et al. Cellular signalling mechanisms of neural cell adhesion moleoules. Front Biosci. 2003;8:900-11
95．蔡文琴，李海标主编．发育神经生物学．科学出版社．北京，1999：60
96．蔡文琴，李海标主编．发育神经生物学．科学出版社．北京，1999：109
97. Jones L S. Integrins: possible funtions in the adult CNS. TINS, 1996,19(1):68
98. Schmidit R, Brysch W, Rother S, et al. Inhibition of memory consolidation after active avoidance conditioning by antisense intervention with ependymin gene expression. J of Neurochemistry, 1995,65(12):1465
99. Rose S P. Cell adhesion molecules and the transition from short-to long-term memory. J Physiol Paris, 1996,90(3):387
100. Muller D, Wang C, Toni N, et al. PSA-NCAM is required for activity-induced synaptic plasticity. Neuron, 1996,17(9):413
101. Luthi A. Hippocampal long term potentiation and neural cell adhesion molecules L1 and NCAM. Nature, 1994,372(5):777
102. KasperC, RasmLisenH, Kastrup JS, etal. Structural basis of cell—cell adhe8ion by NCAM. Nature Structural Biol, 2000, 7:387—393
103. Gage FH. Brain, repair yourself. Sci Am. 2003 Sep;289(3):46-53
104．孟凡刚，苏万东．神经干细胞与帕金森病．国外医学神经病学神经外科学
分册．2003；30(4)：392
105. Kuhn HG, Palmer TD, Fuchs E. Adult neurogenesis: a compensatory mechanism for neuronal damage. Eur Arch Psychiatry Clin Neurosci. 2001 Aug; 251 (4):152-8
106. Peterson DA. Stem cells in brain plasticity and repair. Curr Opin Pharmacol. 2002 Feb;2(1):34-42
107. Kirschstein R. Skirboll LR．干细胞研究进展与未来．人民卫生出版社．2003；北京：141
108．裴雪涛主编．干细胞生物学．科学出版社．2003：北京：327
109. Kay JN, Blun M, Differential response of ventral mildbrain and straital progenitor cells to lesions of the nigro striatal dopaminergic projection. Dev Neurosci, 2000, 22:56-67
110. Dahlstrand J, Zimmerman LB. Mckay RD, et al. Chracterization of thehuman nestin gene reveal saclose evolutionary relationship to neurofilaments. J Cell Sci, 1992,103(Pt2):589-597
111. Tohyma T, Lee VM, Rorke LB, et al. Monoclonal antibodayes to a rat nestin fusion protein recognize a 220-KD apoly peptide in subsets of fetal and adult human central nervous sysytem neurons and in primitive neuroec to dermal tumoe cells. Am J Pathol, 1993, 143 (1):258-268
112．裴雪涛主编．干细胞技术．北京：化学工业出版社，2002：52
113. Petroske E, Meredith GE, Callen S, et al. Mouse model of parkinsonism: a comparison between subacute MPTP and chronic MPTP/probenecid treatment. Neurosci, 2001,106:141-153
114. Craig CG. Tropepe V. Morshead CM, et al. In vivo growth factor expansion of endogenous subependymal neural precursor cell
populations in the adult mouse brain. J eurosci. 1996,16(8):2649-2658
115. Fallon J, Reid S, Kinyamu R, et al. Invivo inductioned migration of massive proliferation, directioned midration and differentiation of neural cells in the adult mammalian brain. Proc Natl Acad Sci USA, 2000,97:14686-14691
116. Peterson DA. Stem cells in brain plasticity and repair. Curr Opin Pharmacol, 2002,2:34-42
117. Armstrong RJE, Greeza RE. Neurodegeneration: a failure of neuroregeneration. Lancet, 2001,358:1174-1176
118. Weiss S, Dunne C, Hewson J, et al. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci, 1996, 16:7599-7609
119. Palmer TD, Ray J, Gage FH. FGF-2 responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci, 1995,6:474-486
120. Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embry onic stem cell lines derived from human blastocysts, Science, 1998;282;1145-1147
121. Iwai M, Abe K, Kitagawa H, et al. Genetherapy with adenovirus mediated gial cell line derived neurotrophic factor and neural stem cells activation after ischemic brain injury. Hum Cell, 2001,14;27-38
122. Johe KK, Hazel TG, Muller t, et al. Single factors direct the diffeentiation of stem cells from the fetal and adult central nervous system. Gene & Dev, 1996, 10:3129-3140
123. Shen KZ, Zhu ZT, Munhall A, et al. Synaptic plasticity in rat
subthalamic nucleus induced by high-frequency stimulation. Synapse. 2003; 15;50(4):314-319.
124. Ciros B. et al. Tips, 1993;14:43
125．金国章．脑内多巴胺的生物医学．上海科技教育出版社．上海：1998；131
126．陈生弟主编．帕金森病临床新技术．人民军医出版社，北京：2002；14
2．刘道宽．帕金森病的药物治疗．实用老年医学杂志，2001；15(6)：289-292
3．肖安平．老年帕金森病的外科治疗．实用老年医学杂志，2001；15(6)：292-294
4．吴小军．李立宏．帕金森与基因工程细胞移植．国外医学神经病学神经外科学分册，2002；29(3)：202-204
5. Freese A. Restorative gene therapy approaches to Parkinson's disease. Med Clin North Am, 1999;83(2):537-548
6. Arbuthott GW, Ingham CA, Wickens JR. Dopamine and synaptic plasticity in the neurostriatum. J Anat, 2000,196:587-596
7．华仲慰．神经系统可塑性研究的进展．生理科学进展，1986；17(1)：33-38
8. Kristen MH. Structure, development, and plasticity of dendritic spines. Curr opinion Neurobiol, 1999,9:343-385
9. Ingham CA, Hood SH, Mi L. Plasticity of striatopallidal terminals of following unilateral lesion of the dopaminerdic nigrostriatals pathway: a morphological study. Exp Brain Res, 1997,116:39-49
10. Finkelstein DI, Stanic D, Parish CL. Axonal sprouting following lesions of the rat substantia nigra. Neuroscience, 2000,97:99-112
11. Calabresi P, Giacomini P, Centonze D, et al. Levodopa induced dyskinesia: a pathologiacal form of striatal synaptic plasticity? Ann Neual, 2000,47(S1):60-68
12. Berretta S, Parthasarathy HB, Graybiel AM. Local realease of GABAergic inhibition in motor cortex induces immediate early gene expression in direct pathway neurons of the striatum.
Neuroscience, 1997,17:4752-4763
13. Donnan GA, Woodhouse DG, Kaczmarczyk SJ. Evidence for plasticity of the dopaminergic system in Parkinsonism. Mol Neurobiol, 1991,5:421-433
14. Tang KC, Low MJ, Grand DK. Dopamine dependent synaptic plasticity in striatum during in vivo development. Proc Natl Acad Sci USA, 2001,98:1255-1260
15．牛平，吕永利，王耀山等．帕金森病与神经营养因子的研究进展．解剖科学进展，1998；4(1)：47-53
16. Mogi M, Togari A, Kondo T, et al. Brain-derived growth factor and nerve growth factor concentrations are decreased in the substantia nigra in Parkinoson's disease. Neurosci Lett, 1999;270(1):45-48
17. Venero JL, Vizuete ML, Revuelta M, et al. Upregulation of BDNF mRNA and trk mRNA in the nigrostriatal system and in the lesion site following unilateral transection of of the medial forebrain bundle. Exp Neurol, 2000;161:38-48
18．刘爽．王亚奇．神经营养因子参与帕金森病的发生及治疗中的潜在作用．中国病理生理杂志，2002；18(1)：101-103
19．马仲才．潘卫．戚中田．脑源性神经营养因子与帕金森病．神经解剖学杂志，2002；18(1)：87-90
20. Beck KD, Knusel B, Hefti F. The nature of the trophic action of brain-derived neurophic factor, des(1-3)-insulin-like growth factor-1, and basic fibroblast growth factor on mesencephalic dopamineegic neurons developing in culture. Neuroscience, 1993;52:855-866
21. Studer L, Spenger C, Seiler RW, et al. Effects of brain-derived
neurotrophic factor on neuronal structure of dopaminergic neurons in dissociated cultures of human fetal mesencephalon. Exp Brain Res, 1996;108:328-336
22. Kontkanen O, Castren E. Trophic effects of selegiline on cultured dopaminergic neurons. Brain Res, 1999;829:190-192
23. Ostergaard K, Jones SA, Hyman C, et al. Effects of donor age and brain-derived neurotrophic facter on the survival of dopaminergic neurons and axonal growth in postnatal rat nigrostriatal cocultures. Exp Neurol, 1996;142:340-350
24. Skaper SD, Negro A, Facci L, et al. Brain-derived neurotrophic factor selectively rescues mesencephalic dopaminergic neurons from 2,4,5-trihydroxyphenylalanine-induced injury. J Neurosci Res, 1993; 34:478-487
25. Berezin V, Bock E. NCAM mimetic peptides: Pharmacological and therapeutic potential. J Mol Neurosci. 2004;22(1-2):33-39
26. Emery DL, Royo NC, Fischer I, et al. Plasticity following injury to the adult central nervous system: isrecapitulation of a developmental state worth promoting? J Neurotrauma, 2003; 20(12): 1271-92
27．胡晓燕，周严，袁建刚，等．神经细胞粘附分子的研究进展．生命科学．2001；13(5)：200
28．孟凡刚，苏万东．神经干细胞与帕金森病．国外医学神经病学神经外科学分册．2003：30(4)：392
29. Sanci V, Houle S, DaSilva JN. No change in dopamine D1 receptor in vivo binding in rats after subchronic haloperidol treatment. Can J Physiol Pharmacol. 2002,80:36-41
30. Blandini F, Greenamyre JT, Fancellu R, et al. Blockade of subthalamic glutamatergic activity corrects changes in neuronal metabolism and motor behavior in rats with nigrostriatal lesions. Neurol Sci, 2001,22:49-50
31. Nash JE, brotchie JM. A common signaling pathway for strialatal NMDA and adenosine A2 are captors: implications for the treatment of Parkinson's disease. Neuroscience, 2000,20:7782-7789
32．黄文燕．吴焕淦．针灸治疗帕金森氏病概况．中国针灸，19981 4：252-255
33．任小群．王友京．罗明富等．针刺治疗震颤麻痹临床和实验研究．中国针灸，1999；10：617-619
34．王玲玲．何崇．刘跃光等．针灸治疗帕金森病29例临床观察．中国针灸，1999；12：709-711
35．郑翎，金宇．针刺治疗震颤麻痹52例临床观察．中国针灸，1998，(2)：19-81
36．陈利国．针刺治疗震颤麻痹40例临床观察．中医杂志，1996，37(4)：216-217
37．戴若鑫．天鼎穴的临床应用．针灸临床杂志，1996，12(9)：35-36
38．王金玲，肖飞．深刺风府治疗疑难病症验案．上海针灸杂志，1996，15(2)：19-20
39．潘元侠．小儿多动症、小舞蹈病、帕金森氏病的针刺治疗体会．浙江中医学院学报，1996，(6)49-50
40．张沛霖，张勤。针刺治疗震颤麻痹的临床观察．云南中医药杂志，1996，17(5)：39-40
41．刘家瑛．针刺治疗震颤麻痹159例疗效观察．针灸临床杂志，1993，9(5)：10-11
42．李圣平．帕金森综合征的针灸康复疗法．四川中医，1993，(8)：51-52
43．王选伟．针刺治疗震颤麻痹40例．陕西中医，1994，15(4)：176
44．罗健．四关穴治疗神经系统病病应用举隅．四川中医，1996，(8)：50
45．宋南昌，宗重阳．宗瑞麟用“四关”穴的经验．广西中医药，1993．(6)：11-12
46．俞竹青．头皮针合四关穴为主治疗帕金森氏症．浙江中医学院学报，1994，(6)：45
47．奚桂芳．针刺和中药治疗帕金森病的临床疗效分析．上海针灸杂志，1995，(6)：243-244
48．王玲玲．何崇．赵玫等．针灸对帕金森病脑部血流状态的影响．中国针灸，1999：2：115-117
49．睢久红等．针刺结合复方中药对帕金森病患者血浆DA含量的影响．针刺研究，1997，(1，2)：106-107
50．张莉．针刺对帕金森病血清抗氧化酶含量的影响，上海针灸杂志，1996，15(6)：3-9
51．奚桂芳．蔡德亨．陈国美．头部穴位电刺激对帕金森病震颤肌电位的影响．上海针灸杂志，1996；(3)：5
52．马骏，王华．电针帕金森模型大鼠对黑质TH含量的影响．针刺研究，2001；26(4)：288
53．梁希彬，田德全，赵英侠等，电针后大鼠中脑腹侧部粗提液对体外培养的多巴胺能神经元生长发育的影响，针刺研究，1999；24(3)：179
54．梁希彬，刘贤宇，李丰桥，等．电针治疗部分损伤帕金森病大鼠的实验研究．针刺研究，2001；26(3)：209
55．马骏，王彦春，甘水咏．电针风府穴、太冲穴对PD大鼠黑质神经元凋亡的影响．湖北中医杂志，2003；25(11)：5
56．何崇，王玲玲，董洪涛，等．针灸对帕金森病大鼠模型脑内单胺类递质含量的影响．针刺研究，1998，23(1)：44
57．罗明富，王志英，王平．电针对震颤麻痹大鼠中脑黑质和肾上腺體质酪氨酸羟化酶的影响．针刺研究，1997，22(4)：292
58．罗松．电针对老年痴呆大鼠海马神经元突触形态可塑性的影响机制．成都
中医药大学博士学位论文．2003
59．韩婷．电针对老年痴呆大鼠海马胆碱能神经的影响研究．成都中医药大学硕士学位论文．2003
60．王廷华．吴良芳．廖德阳等．针刺对脑源性神经营养因子在脊髓Ⅱ板层可塑性中表达的影响。神经解剖学杂志，2002；18(1)：55-58
61. Nobutaka A, Kazuaki M, Yoshio G. Evaluation of a 1 methyl phenyl 1,2, 3, 6 tetrahydropyridine(MPTP) treated C57 black mouse model for Parkinsonism. Brain Res,1990,515:57～63
62. Schulz JB, et al. Mol Cell Biochem, 1997;174:193
63. Liang CL, et al. Neurodegeneration, 1996;5:313
64. Jones DG, Calverley RKS. Frequency ofoccurrence of perforated synapses in developing rat neocortex. Neurosci Lett, 1991;129:189-192
65．杨正伟，实用生物体视学，成都：四川省解剖、体视、法医、口腔学会，1991：37-68
66．郑富盛．细胞形态立体计算学[M]．北京：北京医科大学中国协和医科大学联合出版社，1999，16(3)：201
67. Giacobini E. Molecular mechanism of nervous transmission and synaptic plasticity.Progress in Brian Res, 1971,34:234
68. Zigmond MJ, Stricker EM. Animal models of Parkinson is musing selective neurotoxins: clinical and basic implications, Int Rev Neurobiol, 1989,31:1-79
69. Betarbet R, Sherer TB, Greenamyre JT. Animal models of Parkinson's disease. Bioessays, 2002,24:308-318
70. Tolwani RJ, Jakowec MW, Petzinger GM, et al. Experimental models of Parkinson's disease: insights from many models. Lab Anim Sci, 1999,49(4):363-371
71. Westlund KN, et al. Neuroscience, 1988;25:439
72．傅文玉，等．帕金森大鼠黑质和纹状体神经元的变化．解剖科学进展，1997，3(3)：208
73．伦学庆，等．损毁大鼠纹状体帕金森病模型的建立．中国病理生理杂志，1999．15(2)：188
74. Eezard E, et al. Absence of MPTP-induced neuronal death in mice lacking the dopamine transporter. Exp Neurol, 1999;155:268
75．栗山欣弥(日)编．突触的结构与功能．人民卫生出版社．北京：1983：285
76. Tuszynski MH.Neurotrophic factors. In:Tuszynski MH, Kordower J, ed. CNS Regeneration. San Diego:Academic Press, 1999.109-158
77. Johnson JE. Neurotrophic factors. In:Zigmond MJ, ed. Fundamental Neuroscience. San Diego:Academic Press, 1999.611-635
78．何成，王成海，敖世洲．神经营养因子．生命科学，1996，8：32-35
79．盛树力主编．临床神经科学前沿．北京大学医学出版社．北京：2003：324
80．方秀彬编著．神经肽与神经营养因子．人民卫生出版社．北京：2002：274
81. Nishio T, Furukawa S, Akiguchi I, et al. Medical nigral dopamine neuron shaverich neurotrophin supporting humans. Neuroreport, 1998,9:2847～2851
82. Mogi M, Togari A, Kondo T, et al. Brain-derived growth factor and nerve growth factor concentration sare decreased in the substantia nigra in Parkinson's disease. Neurosci Lett, 1999,270:45～48
83. Parain K, Murer MG, Yah Q, et al. Reduced expression of brain-derived neurotrophic factor protein in Parkinson's disease substantia nigra. Neuroreport, 1999,10:557～561
84. Howells DW, Porritt MJ, Wong JY, et al. Reduced BDNFmRNA expression in the Parkinson's disease substantia nigra. Exp Neurol, 2000,
166:127～135
85. Venero JL, Vizuete ML, Revuelta M, et al. Upregulation of BDNFmRNA and trkBmRNA in the nigro striatal system and in the lesionsite following unilateral transection of the medial forebrain bundle. Exp Neurol, 2000,161:38～48
86. Skaper SD, Negro A, Facci L, et al. Brain-derived neurotrophic factor selectively rescues mesencephalic dopaminergic neurons from 2,4,5-trihydroxyphenylalanine induced injury. J Neurosci Res, 1993,34:478～487
87. Beck KD, Knusel B, Hefti F. The nature of the trophic action of brain-derived neurotrophic factor, des(1-3)-insulin-like growth factor-1, and basic fibroblast growth factor on mesencephalic dopaminergic neurons developing in culture. Neuroscience, 1993,52:855～866
88. Kontkanen O, Castren E. Trophic effects of selegiline on cultured dopaminergic neurons. Brain Res, 1999,829:190～192
89. Ostergaard K, Jones SA, Hyman C, et al. Effects of donorage and brain-derived neurotrophic factor on the survival of dopaminergic neurons and axonal growth in postnatal rat nigro striatal cocultures. Exp Neurol, 1996,142:340～350
90. Mark FB. Barry WC. Michaael AP. Neuroscience:Exploring the Brain, 2nd ed:高等教育出版社，北京；2002：714
91. Kiryushko D, Kofoed T, Skladchikova G, et al. A synthetic peptide ligand of neural cell adhesion molecule (NCAM), C3d, promotes neuritogenesis and synaptogenesis and modulates presynaptic function in primary cultures of rat hippocampal neurons. J Biol
Chem. 2003;278(14):12325-34
92. Son H, Seuk Kim J, Mogg Kim J, et al. Reciprocal actions of NCAM and tPA via a Ras-dependent MAPK activation in rat hippocampal neurons. Biochem Biophys Res Commun 2002;298(2):262-8
93. Fercakova A. Cell adhesion molecules in the neural development and plasticity. Bratisl Lek Listy 2001;102(12):552-5
94. Panicker AK, Buhusi M, Thelen K, et al. Cellular signalling mechanisms of neural cell adhesion moleoules. Front Biosci. 2003;8:900-11
95．蔡文琴，李海标主编．发育神经生物学．科学出版社．北京，1999：60
96．蔡文琴，李海标主编．发育神经生物学．科学出版社．北京，1999：109
97. Jones L S. Integrins: possible funtions in the adult CNS. TINS, 1996,19(1):68
98. Schmidit R, Brysch W, Rother S, et al. Inhibition of memory consolidation after active avoidance conditioning by antisense intervention with ependymin gene expression. J of Neurochemistry, 1995,65(12):1465
99. Rose S P. Cell adhesion molecules and the transition from short-to long-term memory. J Physiol Paris, 1996,90(3):387
100. Muller D, Wang C, Toni N, et al. PSA-NCAM is required for activity-induced synaptic plasticity. Neuron, 1996,17(9):413
101. Luthi A. Hippocampal long term potentiation and neural cell adhesion molecules L1 and NCAM. Nature, 1994,372(5):777
102. KasperC, RasmLisenH, Kastrup JS, etal. Structural basis of cell—cell adhe8ion by NCAM. Nature Structural Biol, 2000, 7:387—393
103. Gage FH. Brain, repair yourself. Sci Am. 2003 Sep;289(3):46-53
104．孟凡刚，苏万东．神经干细胞与帕金森病．国外医学神经病学神经外科学
分册．2003；30(4)：392
105. Kuhn HG, Palmer TD, Fuchs E. Adult neurogenesis: a compensatory mechanism for neuronal damage. Eur Arch Psychiatry Clin Neurosci. 2001 Aug; 251 (4):152-8
106. Peterson DA. Stem cells in brain plasticity and repair. Curr Opin Pharmacol. 2002 Feb;2(1):34-42
107. Kirschstein R. Skirboll LR．干细胞研究进展与未来．人民卫生出版社．2003；北京：141
108．裴雪涛主编．干细胞生物学．科学出版社．2003：北京：327
109. Kay JN, Blun M, Differential response of ventral mildbrain and straital progenitor cells to lesions of the nigro striatal dopaminergic projection. Dev Neurosci, 2000, 22:56-67
110. Dahlstrand J, Zimmerman LB. Mckay RD, et al. Chracterization of thehuman nestin gene reveal saclose evolutionary relationship to neurofilaments. J Cell Sci, 1992,103(Pt2):589-597
111. Tohyma T, Lee VM, Rorke LB, et al. Monoclonal antibodayes to a rat nestin fusion protein recognize a 220-KD apoly peptide in subsets of fetal and adult human central nervous sysytem neurons and in primitive neuroec to dermal tumoe cells. Am J Pathol, 1993, 143 (1):258-268
112．裴雪涛主编．干细胞技术．北京：化学工业出版社，2002：52
113. Petroske E, Meredith GE, Callen S, et al. Mouse model of parkinsonism: a comparison between subacute MPTP and chronic MPTP/probenecid treatment. Neurosci, 2001,106:141-153
114. Craig CG. Tropepe V. Morshead CM, et al. In vivo growth factor expansion of endogenous subependymal neural precursor cell
populations in the adult mouse brain. J eurosci. 1996,16(8):2649-2658
115. Fallon J, Reid S, Kinyamu R, et al. Invivo inductioned migration of massive proliferation, directioned midration and differentiation of neural cells in the adult mammalian brain. Proc Natl Acad Sci USA, 2000,97:14686-14691
116. Peterson DA. Stem cells in brain plasticity and repair. Curr Opin Pharmacol, 2002,2:34-42
117. Armstrong RJE, Greeza RE. Neurodegeneration: a failure of neuroregeneration. Lancet, 2001,358:1174-1176
118. Weiss S, Dunne C, Hewson J, et al. Multipotent CNS stem cells are present in the adult mammalian spinal cord and ventricular neuroaxis. J Neurosci, 1996, 16:7599-7609
119. Palmer TD, Ray J, Gage FH. FGF-2 responsive neuronal progenitors reside in proliferative and quiescent regions of the adult rodent brain. Mol Cell Neurosci, 1995,6:474-486
120. Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Embry onic stem cell lines derived from human blastocysts, Science, 1998;282;1145-1147
121. Iwai M, Abe K, Kitagawa H, et al. Genetherapy with adenovirus mediated gial cell line derived neurotrophic factor and neural stem cells activation after ischemic brain injury. Hum Cell, 2001,14;27-38
122. Johe KK, Hazel TG, Muller t, et al. Single factors direct the diffeentiation of stem cells from the fetal and adult central nervous system. Gene & Dev, 1996, 10:3129-3140
123. Shen KZ, Zhu ZT, Munhall A, et al. Synaptic plasticity in rat
subthalamic nucleus induced by high-frequency stimulation. Synapse. 2003; 15;50(4):314-319.
124. Ciros B. et al. Tips, 1993;14:43
125．金国章．脑内多巴胺的生物医学．上海科技教育出版社．上海：1998；131
126．陈生弟主编．帕金森病临床新技术．人民军医出版社，北京：2002；14