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研究生:姜函芸
研究生(外文):Han-Yun Chiang
論文名稱:鋅離子和多巴胺造成多巴胺神元退化之研究—一個可能的帕金森氏症研究模式系統
論文名稱(外文):Zn2+ and dopamine-induced degeneration of dopaminergic neurons –A potential model for Parkinson’s disease
指導教授:高閬仙高閬仙引用關係
指導教授(外文):Lung-Sen Kao
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生物化學研究所
學門:生命科學學門
學類:生物化學學類
論文種類:學術論文
論文出版年:2004
畢業學年度:92
語文別:中文
論文頁數:54
中文關鍵詞:帕金森氏症多巴胺鋅離子
外文關鍵詞:Parkinson's diseasedopamineZn(2+)
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摘要
帕金森氏症是一神經退化性疾病,其主要是因為黑質區中的多巴胺神經元大量死亡,導致其下游的紋狀體接收到的多巴胺濃度降低所引起運動不協調的疾病。一般認為多巴胺引起氧化壓力升高造成細胞傷害,是造成多巴胺神經元死亡的原因之一。此外在帕金森氏病人腦組織中觀察到在黑質區和紋狀體有累積大量的鋅。然而到目前為止對於帕金森氏症的致病機轉尚未明瞭,也沒有一個有效的方法可以保護多巴胺神經元。本論文利用PC12細胞作為模式想要瞭解(一)Zn2+和多巴胺在所引起的細胞毒殺中所扮演的角色。(二)找出有效保護細胞免於多巴胺所造成的傷害。在第一部份,多巴胺造成PC12細胞死亡的現象與處理多巴胺的濃度成正相關,可推測多巴胺神經元可能分泌過多的多巴胺造成細胞死亡。且在實驗中觀察到Zn2+可以大量增加多巴胺對於PC12細胞的毒殺作用,換句話說,也就是Zn2+和多巴胺對於細胞傷害有協同作用,而這個現象也在動物模式中的到證實。另外Zn2+增強多巴胺的神經毒性可能是透過增加ROS的產生所致,且含有thiol官能基的抗氧化物可以回復Zn2+和多巴胺所引起的細胞傷害。在實驗第二部分,利用離體實驗找出可以保護細胞免於多巴胺傷害的藥物。在篩選中草藥中找到一種中草藥--牛乳埔的粗略萃取物,在含有Zn2+的情況下具有保護的功效。在本實驗中可以更進一步瞭解在帕金森氏症中Zn2+中可能所扮演的角色,可能是增加多巴胺的毒性傷害細胞,並且進一步找出一個有效治療帕金森氏症的方法。
Abstract
Parkinson’s disease (PD) is a neurodegenative disorder characterized by a preferential loss of dopaminergic neurons of substantia nigra par compacta (SNpc). The mechanism causing PD is still unknown, and there is no efficient therapy to cure PD. Dopamine (DA) is thought to cause neuronal toxicity via production of reactive oxygen species (ROS). In postmortem brain tissue of PD patients, zinc level was increased in substantia nigra and in striatum (ST). In this study, I have established a cell model to study the pathogenesis of PD. Dopamine induced a dose-dependent PC12 cells death, which was synergistically enhanced by zinc. The ROS generation in PC12 cells was also synergistically increased by zinc and dopamine. The cells death could be reversed by thiol antioxidant (glutathione, dithiothreithone, and N-acetyl-cysteine). Using the PC12 cell model established, I have screened an assay of herbal extracts and found a fraction of Ficus erecta Thunb. Ex Kaempf, protected PC12 cells from dopamine plus zinc-induced toxic effect. The synergistic effect between zinc and dopamine was also shown in rats when the two agents were infused into SN and ST, respectively or co –infused into ST. Results from my study could help the future study of the mechanisms involved in zinc plus dopamine-induced neurotoxicity and find a way to prevent the cells form unwanted death.
參考文獻
Agid, Y., Ruberg, M., Raisman-Vozari, R., Hirsch, E.C., Javoy-Agid, F. (1990). The biochemistry of Parkinson’s disease. In: Stern, GM (Ed.), Parkinson’s Disease. Chapman & Hall, London, pp.99-125.
Beckman and Ames. (1998). The free radical theory of aging matures.
Physiol Rev. 78, 547-581.
Blum, D., Torch, S., Lambeng, N., Nissou, M., Benabid, A.L., Sadoul, R., Verna, J.M. (2001). Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson's disease. Prog Neurobiol. 65, 135-172.
Blum D, Torch S, Nissou MF, Benabid AL, Verna JM. (2000). Extracellular toxicity of 6-hydroxydopamine on PC12 cells.
Neurosci Lett. 283, 193-196.
Bonnet, A.M., Houeto, J.L. (1999). Pathophysiology of Parkinson's disease.
Biomed Pharmacother. 53, 117-121.
Bussell, R., Jr., and Eliezer, D. (2001). Residual structure and dynamics in Parkinson’s disease-associated mutants of alpha-synuclein. J. Bio. Chem. 276, 46996-46003.
Cassarino, D.S., Bennett, J.P. Jr. (1999) An evaluation of the role of mitochondria in neurodegenerative diseases: mitochondrial mutations and oxidative pathology, protective nuclear responses, and cell death in neurodegeneration. Brain Res Brain Res Rev. 25, 1-25
Choi, D.W.,and Koh, J.Y. (1998) Zinc and brain injury. Annu Rev Neurosci. 21, 347-75.
Choi, D.W., Yokoyama, M., Koh, J. (1988). Zinc neurotoxicity in cortical cell culture. Neuroscience. 24, 67-79.
Dauer, W., Przedborski, S. (2003). Parkinson’s disease: mechanisms and models. Neuron. 39, 889-909.
Dexter, D.T., Carayon, A., Javoy-Agid, F., Agid, Y., Wells, F.R., Daniel, S.E., Lees, A.J., Jenner, P., Marsden, C.D. (1991) Alterations in the levels of iron, ferritin and other trace metals in Parkinson's disease and other neurodegenerative diseases affecting the basal ganglia. Brain. 114, 1953-1975.
Fahn, S. and Cohen, G. (1992). The oxidant stress hypothesis in Parkinson's disease: evidence supporting it. Ann. Neurol. 32, 804-812.
Fearnley, J.M. and Lees, A.J. (1991). Ageing and Parkinson's disease: substantia nigra regional selectivity. Brain 114 ( Pt 5), 2283-2301.
Filloux, F., Townsend, J.J. (1993) Pre- and postsynaptic neurotoxic effects of dopamine demonstrated by intrastriatal injection. Exp Neurol. 119, 79-88.
Gaskin, F., Kress, Y., Brosnan, C., Bornstein, M. (1978). Abnormal tublin aggregates induced by zinc sulfate in organotypic cultures of nerve tissue. Neuroscience. 3, 1117-1128.
Goble, L.I. (1991). Young-onset Parkinson’s disease: a clinical review. Neurology. 41, 168-173.
Goto,S., Hirano,A., and Matsumoto, S. (1989). Subdivisional involvement of nigrostriatal loop in idiopathic Parkinson's disease and striatonigral degeneration. Ann. Neurol. 26, 766-770.
Gotz, M.E., Kunig, G., Riederer, P., Youdim, M.B. (1994) Oxidative stress: free radical production in neural degeneration. Pharmacol Ther. 63, 37-122.
Halliwell, B. (1992). Reactive oxygen species and the central nervous system.
J Neurochem. 59,1609-1623.
Hastings, T.G., and Zigmond, M.J. (1994). Identification of catechol-protein conjucates in neostriatalslices incubated with [3H]dopamine: impact of ascorbic and glutathione. 63,1126-1132.
Hattori, N., Tanaka, M., Ozawa, T., Mizuno, Y. (1991). Immunohistochemical studies on complexs I, II, III, and IV of mitochondria in Parkinson’s disease. Ann. Neurol. 30, 563-571.
Hirsch, E., Graybiel, A.M., and Agid, Y.A. (1988). Melanized dopaminergic neurons are differentially susceptible to degeneration in Parkinson's disease. Nature 334, 345-348.
Huang, C.M., Tsai, K.E., and Kao, L.S. (1996). Role of Ca2+ in differentiation mediated by nerve growth factor and dibutyryl cyclic AMP in PC12 cells. J. Neuronchem. 67, 530-539.
Hughes, A.J., Daniel, S.E., Blankson, S., and Lees, A.J. (1993). A clinicopathologic study of 100 cases of Parkinson's disease. Arch. Neurol. 50, 140-148.
Hunot, S., Boissiere, F., Faucheux, B., Brugg, B., Mouatt-Prigent, A., Agid, Y., and Hirsch, E.C. (1996). Nitric oxide synthase and neuronal vulnerability in Parkinson's disease. Neuroscience 72, 355-363.
Jellinger, K., Kienzl, E., Rumpelmair, G., Riederer, P., Stachelberger, H., Ben Shachar, D., and Youdim, M.B. (1992). Iron-melanin complex in substantia nigra of parkinsonian brains: an x-ray microanalysis. J. Neurochem. 59, 1168-1171.
Jenner, P. (2003). Oxidative stress in Parkinson’s disease. Ann. Neurol. 53 (suppl 3), s26-s38.
Jenner, P., Dexter, D.T., Sian, J., Schapira, A.H., and Marsden, C.D. (1992). Oxidative stress as a cause of nigral cell death in Parkinson's disease and incidental Lewy body disease. The Royal Kings and Queens Parkinson's Disease Research Group. Ann. Neurol. 32 Suppl, S82-S87.
Jones, P.D. (1995). Glutathione distribution in natural products: Absorption and tissue distribution. Methods Enzymol. 252, 3-25.
Kamata, H., Tanaka, C., Yagisawa, H., Hirata, H. (1996) Nerve growth factor and forskolin prevent H2O2-induced apoptosis in PC12 cells by glutathione independent mechanism. Neurosci Lett. 212, 179-82.
Kim, E.Y., Koh, J.Y., Kim, Y.H., Shon, S., Joe, E., Gwag, B.J. (1999). Zn2+ entry produces oxidative neuronal necrosis in cortical cell cultures. Eur. J. Neurosci. 11, 327-334.
Kitazawa M, Wagner JR, Kirby ML, Anantharam V, Kanthasamy AG. (2002). Oxidative stress and mitochondrial-mediated apoptosis in dopaminergic cells exposed to methylcyclopentadienyl manganese tricarbonyl. J Pharmacol Exp Ther. 1, 26-35.
Kitazawa, M., Anantharam, V., Kanthasamy, A.G. (2001). Dieldrin-induced oxidative stress and neurochemical changes contribute to apoptotic cell death in dopaminergic cells. Free Radical Biology and Medicine. 31, 1473-1485.
Koh, J.Y. (2001). Zinc and disease of the brain. Mol. Neurol. 24, 99-106.
Kuo, J.S., Cheng, F.C., Shen, C.C., Ou, H.C., Wu, T.F., Huang, H.M.
(2000). Differential alteration of catecholamine release during chemical hypoxia is correlated with cell toxicity and is blocked by protein kinase C inhibitors in PC12 cells. J Cell Biochem. 79, 191-201.
Lee, C.S., Schulzer, M., Mak, E.K., Snow, B.J., Tsui, J.K., Calne, S., Hammerstad, J., and Calne, D.B. (1994). Clinical observations on the rate of progression of idiopathic parkinsonism. Brain 117, 501-507.
Levay, G. and Bodell, W.J. (1993). Detection of dopamine--DNA adducts: potential role in Parkinson's disease. Carcinogenesis 14, 1241-1245.
Leveugle, B., Faucheux, B.A., Bouras, C., Nillesse, N., Spik, G., Hirsch, E.C., Agid, Y., and Hof, P.R. (1996). Cellular distribution of the iron-binding protein lactotransferrin in the mesencephalon of Parkinson's disease cases. Acta Neuropathol. (Berl) 91, 566-572.
Lin, A.M.Y. (2001). Coexistence of zinc and iron augmented oxidative injuries in the nigrostriatal dopaminergic system of SD rats.
Free Radic Biol Med. 30, 225-31.
Lo, H.S., Chiang, H.C., Lin, A.M.Y., Chiang, H.Y., Chu, Y.C., Kao, L.S.(2004). Synergistic effects of dopamine and Zn2+ on the induction of PC12 cell death and dopamine depletion in the striatum: possible implication in the pathogenesis of Parkinson’s disease. Neurobiol. Dis. in press.
McGeer, P.L., Itagaki, S., Akiyama, H., and McGeer, E.G. (1988). Rate of cell death in parkinsonism indicates active neuropathological process. Ann. Neurol. 24, 574-576.
McNaught, K.S., Olanow, C.W., Halliwell, B., et al. (2001). Failure of the ubiguitin-proteasome system in Parkinson’s disease. Nat. Rev. Neurosci. 2, 589-594.
Manev, H., Kharlamov, E., Uz, T., Mason, R.P., Cagnoli, C.M. (1997 ). Characterization of zinc-induced neuronal death in primary cultures of rat cerebellar granule cells. Exp Neurol. 46, 171-8.
Mattammal, M.B., Haring, J.H., Chung, H.D., Raghu, G., Strong, R. (1995). An endogeneous dpaminergic neurotoxin: implication for Parkinson’s disease. Neurodegeneration 4, 271-281.
Michel, P.P., Hefti, F. (1990). Toxicity of 6-hydroxydopamine and dopamine for dopaminergic neurons in culture. J. Neurosci. Res. 26, 428-35.
Noh, K.M., Kim, Y.H., Koh, J.Y. (1999). Mediation by membrane protein kinase C of zinc-induced oxidative neuronal injury in mouse cortical cultures. J. Neurochem. 72, 1609-1616.
Noh, K.M., Koh, J.Y. (2000). Induction and activation by zinc of NADPH oxidase in culture cortical neuron and astrocytes. J. Neurosci. 20, RC111.
O’Halloran, T.V. (1993). Transition metals in control of gene expression. Science 261, 715-725.
Offen, D., Ziv, I., Sternin, H., Melamed, E., Hochman, A. (1996). Prevention of dopamine-induced cell death by thiol antioxidants: possible implications for treatment of Parkinson’s disease. Exp. Neurol. 141, 32-39.
Park, J.A., Koh, J.Y. (1999). Induction of an immediate early gene egr-1 by zinc through extracellular signal-regulated kinase activation in cortical culture: its role in zinc-induced neuronal death.
Przedborski, S., and Jackson-Lewis, V. (2000).ROS and Parkinson’s disease: a view to kill. In Free Radicals in Brain Pathophysiology, G. Poli, E.Cadenas, and L. Paker, eds. (New York: Marcel Dekker, Inc.), pp.273-290
Sanchez-Ramos, J.R., Övervik, E., Ames, B.N. (1994). A maker of oxyradical-mediated DNA damage (8-hydroxy-2’deoxyguanosine)increased in nigro-striatum of Parkinson’s disease brain. Neurodegeneration 3, 197-204.
Schapira,A.H., Cooper,J.M., Dexter,D., Clark,J.B., Jenner,P., and Marsden,C.D. (1990). Mitochondrial complex I deficiency in Parkinson's disease. J. Neurochem. 54, 823-827.
Schapira,A.H. (1998). Mitochondrial dysfunction in neurodegenerative disorders. Biochem. Biophys. Acta. 1366, 225-233.
Sensi, S.L., Canzoniero, L.M.T., Yu, S.P., Ying, H., Koh, J.Y. (1997). Measurement of intracellular free zinc in living cortical neurons: routes of entry. J. Neurosci. 17, 9554-9564.
Shadel, G.S. and Clayton, D.A. (1997). Mitochondrial DNA maintenance in vertebrates. Annu. Rev. Biochem. 66, 409-435.
Sheline CT, Behrens MM, Choi DW. (2000)Zinc-induced cortical neuronal death: contribution of energy failure attributable to loss of NAD(+) and inhibition of glycolysis. J. Neurosci. 20, 3139-3146.
Spencer ,J.P., Jenner, P., Halliwell, B. (1995). Superoxide-dependent depletion of reduced glutathione by L-DOPA and dopamine. Relevance to Parkinson's disease. Neuroreport. 31, 1480-1484.
Stokes, A.H., Hastings, T.G., Vrana, K.E. (1999). Cytotoxic and genotoxic potential of dopamine. J Neurosci Res. 55, 659-65.
Sudo M, Tsuzuki K, Okado H, Miwa A, Ozawa S. (1997). Adenovirus-mediated expression of AMPA-type glutamate receptor channels in PC12 cells. Brain Res Mol Brain Res. 50, 91-99.
Takahashi, K., Taira, T., Niki, T., Seino, C., Iguchi-Ariga, S.M., Ariga, H. (2001). DJ-1 positively regulates the androgen receptor by impairing the binding of PIASx alpha to the receptor. J. Biol. Chem. 276, 37556-37563.
Tonder, N., Johansen, F.F., Frederickson, C.J., Zimmer, J., Diemer, N.H. (1990). Possible role of zinc in the selective degeneration of dentate hilar neurons after cerebral ischemia in the adult rat. Neurosci. Lett. 109, 247-252.
Velez-Pardo, C., Jimenez, D.R., Verschueren, H., Ebinger, G., Vauquelin, G. (1997). Dopamine and iron induce apoptosis in PC12 cells. Parmacol. Toxicol. 80, 76-84.
Weiss, J.H., Sensi, S.L., Koh, J.Y. (2000). Zn2+: a novel ionic mediator of neural injury in brain disease. Trends Pharmacol Sci. 21, 395-401.
Wenzel, H.J., Cole, T.B., Born, D.E., Schwartzkroin, P.A., Palmiter, R.D. (1997). Ultrastructural localization of zinc transporter-3 (ZnT-3)to synaptic vesicle membranes within mossy fiber boutons in hippocampus of mouse and monkey. Proc. Natl. Acad. Sci. USA 94, 12676-81.
Youdim, M.B., Riederer, P. (1997) Understanding Parkinson's disease. Sci Am. 276, 52-59.
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