跳到主要內容

臺灣博碩士論文加值系統

(18.97.14.87) 您好!臺灣時間:2024/12/04 01:19
字體大小: 字級放大   字級縮小   預設字形  
回查詢結果 :::

詳目顯示

我願授權國圖
: 
twitterline
研究生:余曉青
研究生(外文):Hsiao-Ching Yu
論文名稱:YC-1的神經保護作用機轉之探討
論文名稱(外文):Studies on the neuroprotective effect of YC-1
指導教授:符文美符文美引用關係
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:藥理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:70
中文關鍵詞:神經保護巴金森氏症
外文關鍵詞:YC-1MPP+6-OHDASH-SY5YPKG
相關次數:
  • 被引用被引用:0
  • 點閱點閱:180
  • 評分評分:
  • 下載下載:0
  • 收藏至我的研究室書目清單書目收藏:1
巴金森氏症是現今最常見的神經退化性疾病之一,在目前的醫療只能治標不能治本,並且對於其致病機轉仍然不清楚的情況下,研發新的治療藥物並研究致病原因是非常必要的。
我們發現YC-1可以減少SH-SY5Y受到MPP+和6-OHDA的損害,SH-SY5Y是神經母細胞瘤的細胞株,具有多巴胺神經的特徵,對MPP+和6-OHDA具有敏感性,而YC-1可以增加sGC對NO的感受性,是一個sGC 活化劑,早先被發現具有抗血小板凝集和使血管平滑肌放鬆的功能,之後又陸續有報告指出它在其他疾病模式下也有不同的效果。
YC-1可以抑制MPP+或6-OHDA造成SH-SY5Y細胞凋亡達50%以上,並且可以抑制MPP+或6-OHDA造成的Bcl-2 減少, PARP 斷裂, 以及procaspase-3 活化;我們認為YC-1並非藉由NO/cGMP/PKG訊息路徑達到神經保護的作用,因為給予NOS抑制劑(L-NAME, 7-NI),sGC抑制劑(ODQ),PKG抑制劑(KT 5823, RP-8-Br-PET-cGMPS)都不能有效抑制YC-1的作用;而且直接給予cGMP類似物(8-Br-cGMP)並無法減少MPP+和6-OHDA造成的細胞毒性,所以YC-1在這樣的實驗模式裡應該是透過其他路徑達到其神經保護的作用;此外,我們發現PKG抑制劑(KT 5823)可以保護SH-SY5Y細胞,降低MPP+或6-OHDA造成的細胞毒性,因此,我們認為PKG也許參與在MPP+或6-OHDA的毒性機轉當中,或者KT 5823有其他的作用標的。
綜合以上實驗結果,我們認為YC-1可以減少神經細胞受到MPP+或6-OHDA的傷害,有潛力發展成治療巴金森氏症的藥物,而它在細胞及動物模式的保護機轉則仍需再進一步探討。
Parkinson’s disease(PD) is one of the most common neurodegeneration diseases in the world and yet lacks a thorough cure. The studies on its pathogenesis as well as the development of new therapies are indispensable. A compound, YC-1, which was first reported to have an anti-platelet function, is found here to be neuroprotective in SH-SY5Y human neuroblastoma cell line. It can protect SH-SY5Y cells from the damage caused by MPP+ or 6-OHDA.
YC-1 inhibited MPP+ or 6-OHDA-induced cell death, which is evaluated by MTT reaction, PI flow cytometry, and DAPI staining. YC-1 also inhibited Bcl-2 degradation, PARP cleavage, and procaspase-3 activation caused by MPP+ or 6-OHDA. As a sGC activator, we then examined whether YC-1 protects SH-SY5Y through NO-cGMP-PKG pathway. However, all inhibitors acting in NO-cGMP-PKG pathway failed to suppress the effect of YC-1. The neuroprotective mechanism of YC-1 needs further investigation.
On the contrary, the cell death induced by MPP+ or 6-OHDA was partially reversed by KT 5823, a PKG inhibitor, suggesting that PKG inhibition may be protective in dopaminergic neuronal cell line exposed to MPP+ or 6-OHDA. On the other hand, KT 5823 may also act on other targets except PKG.
In conclusion, here we demonstrate that YC-1 possesses neuroprotective quality. Although the mechanisms of action of YC-1 in cell line and in animal model are still required to be investigated, YC-1 is likely to be a potential compound to treat PD patients.
縮寫表…………………………………………………………………1
英文摘要………………………………………………………………3
中文摘要………………………………………………………………4
緒論……………………………………………………………………6
實驗材料及方法………………………………………………………19
結果……………………………………………………………………24
討論……………………………………………………………………51
結論……………………………………………………………………61
參考文獻………………………………………………………………62
Altar CA, Boylan CB, Jackson C, Hershenson S, Miller J, Wiegand SJ, Lindsay RM and Hyman C (1992) Brain-derived neurotrophic factor augments rotational behavior and nigrostriatal dopamine turnover in vivo. Proc Natl Acad Sci U S A 89(23):11347-11351.

Andrew R, Watson DG, Best SA, Midgley JM, Wenlong H and Petty RK (1993) The determination of hydroxydopamines and other trace amines in the urine of parkinsonian patients and normal controls. Neurochem Res 18(11):1175-1177.

Ashkenazi A and Dixit VM (1998) Death receptors: signaling and modulation. Science 281(5381):1305-1308.

Barger SW, Fiscus RR, Ruth P, Hofmann F and Mattson MP (1995) Role of cyclic GMP in the regulation of neuronal calcium and survival by secreted forms of beta-amyloid precursor. J Neurochem 64(5):2087-2096.

Blum D, Torch S, Lambeng N, Nissou M, Benabid AL, Sadoul R and Verna JM (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(2):135-172.

Bove J, Prou D, Perier C and Przedborski S (2005) Toxin-induced models of Parkinson''s disease. NeuroRx 2(3):484-494.

Bruchelt G, Schraufstatter IU, Niethammer D and Cochrane CG (1991) Ascorbic acid enhances the effects of 6-hydroxydopamine and H2O2 on iron-dependent DNA strand breaks and related processes in the neuroblastoma cell line SK-N-SH. Cancer Res 51(22):6066-6072.

Canals S, Casarejos MJ, de Bernardo S, Rodriguez-Martin E and Mena MA (2001) Glutathione depletion switches nitric oxide neurotrophic effects to cell death in midbrain cultures: implications for Parkinson''s disease. J Neurochem 79(6):1183-1195.

Cardone MH, Roy N, Stennicke HR, Salvesen GS, Franke TF, Stanbridge E, Frisch S and Reed JC (1998) Regulation of cell death protease caspase-9 by phosphorylation. Science 282(5392):1318-1321.

Chien WL, Liang KC, Teng CM, Kuo SC, Lee FY and Fu WM (2003) Enhancement of long-term potentiation by a potent nitric oxide-guanylyl cyclase activator, 3-(5-hydroxymethyl-2-furyl) -1-benzyl-indazole. Mol Pharmacol 63(6):1322-1328.

Chien WL, Liang KC, Teng CM, Kuo SC, Lee FY and Fu WM (2005) Enhancement of learning behaviour by a potent nitric oxide-guanylate cyclase activator YC-1. Eur J Neurosci 21(6):1679-1688.

Choi WS, Canzoniero LM, Sensi SL, O''Malley KL, Gwag BJ, Sohn S, Kim JE, Oh TH, Lee EB and Oh YJ (1999) Characterization of MPP(+)-induced cell death in a dopaminergic neuronal cell line: role of macromolecule synthesis, cytosolic calcium, caspase, and Bcl-2-related proteins. Exp Neurol 159(1):274-282.

Chun YS, Yeo EJ, Choi E, Teng CM, Bae JM, Kim MS and Park JW (2001) Inhibitory effect of YC-1 on the hypoxic induction of erythropoietin and vascular endothelial growth factor in Hep3B cells. Biochem Pharmacol 61(8):947-954.

Chun YS, Yeo EJ, and Park JW (2004) Versatile pharmacological actions of YC-1:anti-platelet to anticancer. Cancer Lett. 207(1):1-7.

Cohen G and Heikkila RE (1974) The generation of hydrogen peroxide, superoxide radical, and hydroxyl radical by 6-hydroxydopamine, dialuric acid, and related cytotoxic agents. J Biol Chem 249(8):2447-2452.

Curtius HC, Wolfensberger M, Steinmann B, Redweik U and Siegfried J (1974) Mass fragmentography of dopamine and 6-hydroxydopamine. Application to the determination of dopamine in human brain biopsies from the caudate nucleus. J Chromatogr 99(0):529-540.
Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y and Greenberg ME (1997) Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell 91(2):231-241.

Dauer W and Przedborski S (2003) Parkinson''s disease: mechanisms and models. Neuron 39(6):889-909.

Davis GC, Williams AC, Markey SP, Ebert MH, Caine ED, Reichert CM and Kopin IJ (1979) Chronic Parkinsonism secondary to intravenous injection of meperidine analogues. Psychiatry Res 1(3):249-254.

Desole MS, Esposito G, Fresu L, Migheli R, Enrico P, Miele M, De Natale G and Miele E (1993) Correlation between 1-methyl-4-phenylpyridinium ion (MPP+) levels, ascorbic acid oxidation and glutathione levels in the striatal synaptosomes of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated rat. Neurosci Lett 161(2):121-123.

Dexter DT, Wells FR, Lees AJ, Agid F, Agid Y, Jenner P and Marsden CD (1989) Increased nigral iron content and alterations in other metal ions occurring in brain in Parkinson''s disease. J Neurochem 52(6):1830-1836.

Fadeel B, Orrenius S and Zhivotovsky B (1999) Apoptosis in human disease: a new skin for the old ceremony? Biochem Biophys Res Commun 266(3):699-717.

Fahn S and Cohen G (1992) The oxidant stress hypothesis in Parkinson''s disease: evidence supporting it. Ann Neurol 32(6):804-812.

Farinelli SE, Park DS and Greene LA (1996) Nitric oxide delays the death of trophic factor-deprived PC12 cells and sympathetic neurons by a cGMP-mediated mechanism. J Neurosci 16(7):2325-2334.

Fiscus RR (2002) Involvement of cyclic GMP and protein kinase G in the regulation of apoptosis and survival in neural cells. Neurosignals 11(4):175-190.

Fiscus RR, Tu AW and Chew SB (2001) Natriuretic peptides inhibit apoptosis and prolong the survival of serum-deprived PC12 cells. Neuroreport 12(2):185-189.

Friebe A and Koesling D (1998) Mechanism of YC-1-induced activation of soluble guanylyl cyclase. Mol Pharmacol 53(1):123-127.

Friebe A and Koesling D (2003) Regulation of nitric oxide-sensitive guanylyl cyclase. Circ Res 93(2):96-105.

Garthwaite G, Goodwin DA, Neale S, Riddall D and Garthwaite J (2002) Soluble guanylyl cyclase activator YC-1 protects white matter axons from nitric oxide toxicity and metabolic stress, probably through Na(+) channel inhibition. Mol Pharmacol 61(1):97-104.

Glinka YY and Youdim MB (1995) Inhibition of mitochondrial complexes I and IV by 6-hydroxydopamine. Eur J Pharmacol 292(3-4):329-332.

Golbe LI (1991) Young-onset Parkinson''s disease: a clinical review. Neurology 41(2 ( Pt 1)):168-173.

Hail N, Jr., Carter BZ, Konopleva M and Andreeff M (2006) Apoptosis effector mechanisms: A requiem performed in different keys. Apoptosis in press.

Hengartner MO (2000) The biochemistry of apoptosis. Nature 407(6805):770-776.

Hughes AJ, Daniel SE, Blankson S and Lees AJ (1993) A clinicopathologic study of 100 cases of Parkinson''s disease. Arch Neurol 50(2):140-148.

Hwang TL, Hung HW, Kao SH, Teng CM, Wu CC and Cheng SJ (2003) Soluble guanylyl cyclase activator YC-1 inhibits human neutrophil functions through a cGMP-independent but cAMP-dependent pathway. Mol Pharmacol 64(6):1419-1427.

Javitch JA and Snyder SH (1984) Uptake of MPP(+) by dopamine neurons explains selectivity of parkinsonism-inducing neurotoxin, MPTP. Eur J Pharmacol 106(2):455-456.

Jin K, Mao XO, Zhu Y and Greenberg DA (2002) MEK and ERK protect hypoxic cortical neurons via phosphorylation of Bad. J Neurochem 80(1):119-125.

Johnson DE (2000) Noncaspase proteases in apoptosis. Leukemia 14(9):1695-1703.

Ko FN, Wu CC, Kuo SC, Lee FY and Teng CM (1994) YC-1, a novel activator of platelet guanylate cyclase. Blood 84(12):4226-4233.

Kroemer G and Reed JC (2000) Mitochondrial control of cell death. Nat Med 6(5):513-519.

Kumar R, Agarwal AK and Seth PK (1995) Free radical-generated neurotoxicity of 6-hydroxydopamine. J Neurochem 64 (4) : 1703-1707.

Langston JW, Ballard P, Tetrud JW and Irwin I (1983) Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219(4587):979-980.

Lee HJ, Bach JH, Chae HS, Lee SH, Joo WS, Choi SH, Kim KY, Lee WB and Kim SS (2004) Mitogen-activated protein kinase/extracellular signal-regulated kinase attenuates 3-hydroxykynurenine-induced neuronal cell death. J Neurochem 88(3):647-656.

Li Y, Maher P and Schubert D (1997) Requirement for cGMP in nerve cell death caused by glutathione depletion. J Cell Biol 139(5):1317-1324.

Liu L, Li H, Underwood T, Lloyd M, David M, Sperl G, Pamukcu R and Thompson WJ (2001) Cyclic GMP-dependent protein kinase activation and induction by exisulind and CP461 in colon tumor cells. J Pharmacol Exp Ther 299(2):583-592.

Loweth AC, Williams GT, Scarpello JH and Morgan NG (1997) Evidence for the involvement of cGMP and protein kinase G in nitric oxide-induced apoptosis in the pancreatic B-cell line, HIT-T15. FEBS Lett 400(3):285-288.

Luthman J, Fredriksson A, Sundstrom E, Jonsson G and Archer T (1989) Selective lesion of central dopamine or noradrenaline neuron systems in the neonatal rat: motor behavior and monoamine alterations at adult stage. Behav Brain Res 33(3):267-277.

Majno G and Joris I (1995) Apoptosis, oncosis, and necrosis. An overview of cell death. Am J Pathol 146(1):3-15.

Mizuno Y, Suzuki K, Sone N and Saitoh T (1987) Inhibition of ATP synthesis by 1-methyl-4-phenylpyridinium ion (MPP+) in isolated mitochondria from mouse brains. Neurosci Lett 81(1-2):204-208.

Montoliu C, Llansola M, Kosenko E, Corbalan R and Felipo V (1999) Role of cyclic GMP in glutamate neurotoxicity in primary cultures of cerebellar neurons. Neuropharmacology 38(12):1883-1891.

Nicklas WJ, Vyas I and Heikkila RE (1985) Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1 -methyl-4-pheny l-1,2,5,6 - tetrahydropyridine. Life Sci 36(26):2503-2508.

Nicotra A and Parvez SH (2000) Cell death induced by MPTP, a substrate for monoamine oxidase B. Toxicology 153(1-3):157-166.

Ochu EE, Rothwell NJ and Waters CM (1998) Caspases mediate 6-hydroxydopamine-induced apoptosis but not necrosis in PC12 cells. J Neurochem 70(6):2637-2640.

Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM and Donner DB (1999) NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature 401(6748):82-85.

Pollman MJ, Yamada T, Horiuchi M and Gibbons GH (1996) Vasoactive substances regulate vascular smooth muscle cell apoptosis. Countervailing influences of nitric oxide and angiotensin II. Circ Res 79(4):748-756.

Porter CC, Totaro JA and Stone CA (1963) Effect of 6-hydroxydopamine and some other compounds on the concentration of norepinephrine in the hearts of mice. J Pharmacol Exp Ther 140:308-316.

Przedborski S and Ischiropoulos H (2005) Reactive oxygen and nitrogen species: weapons of neuronal destruction in models of Parkinson''s disease. Antioxid Redox Signal 7(5-6):685-693.

Przedborski S, Jackson-Lewis V, Yokoyama R, Shibata T, Dawson VL and Dawson TM (1996) Role of neuronal nitric oxide in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity. Proc Natl Acad Sci U S A 93(10):4565-4571.

Reed JC, Jurgensmeier JM and Matsuyama S (1998) Bcl-2 family proteins and mitochondria. Biochim Biophys Acta 1366(1-2):127-137.

Saner A and Thoenen H (1971) Model experiments on the molecular mechanism of action of 6-hydroxydopamine. Mol Pharmacol 7(2):147-154.

Schober A (2004) Classic toxin-induced animal models of Parkinson''s disease: 6-OHDA and MPTP. Cell Tissue Res 318(1):215-224.

Senoh S, Witkop B (1959) Non-enzymatic conversions of dopamine to norepinephrine and trihydroxyphenetylamines. J Am Chem Soc 81:6222–6231

Senoh S, Creveling CR, Udenfriend S, Witkop B (1959) Chemical, enzymatic, and metabolic studies on the mechanism of oxidation of dopamine. J Am Chem Soc 81:6236–6240

Seyfried J, Soldner F, Kunz WS, Schulz JB, Klockgether T, Kovar KA and Wullner U (2000) Effect of 1-methyl-4-phenylpyridinium on glutathione in rat pheochromocytoma PC 12 cells. Neurochem Int 36(6):489-497.

Sofic E, Lange KW, Jellinger K and Riederer P (1992) Reduced and oxidized glutathione in the substantia nigra of patients with Parkinson''s disease. Neurosci Lett 142(2):128-130.

Soldner F, Weller M, Haid S, Beinroth S, Miller SW, Wullner U, Davis RE, Dichgans J, Klockgether T and Schulz JB (1999) MPP+ inhibits proliferation of PC12 cells by a p21(WAF1/Cip1)-dependent pathway and induces cell death in cells lacking p21(WAF1/Cip1). Exp Cell Res 250(1):75-85.

Spina MB, Squinto SP, Miller J, Lindsay RM and Hyman C (1992) Brain-derived neurotrophic factor protects dopamine neurons against 6-hydroxydopamine and N-methyl-4-phenylpyridinium ion toxicity: involvement of the glutathione system. J Neurochem 59(1):99-106.

Suenobu N, Shichiri M, Iwashina M, Marumo F and Hirata Y (1999) Natriuretic peptides and nitric oxide induce endothelial apoptosis via a cGMP-dependent mechanism. Arterioscler Thromb Vasc Biol 19(1):140-146.

Teng CM, Wu CC, Ko FN, Lee FY and Kuo SC (1997) YC-1, a nitric oxide-independent activator of soluble guanylate cyclase, inhibits platelet-rich thrombosis in mice. Eur J Pharmacol 320(2-3):161-166.

Tsujimoto Y (2003) Cell death regulation by the Bcl-2 protein family in the mitochondria. J Cell Physiol 195(2):158-167.

von Coelln R, Kugler S, Bahr M, Weller M, Dichgans J and Schulz JB (2001) Rescue from death but not from functional impairment: caspase inhibition protects dopaminergic cells against 6-hydroxydopamine-induced apoptosis but not against the loss of their terminals. J Neurochem 77(1):263-273.

Wang JP, Chang LC, Huang LJ and Kuo SC (2001) Inhibition of extracellular Ca(2+) entry by YC-1, an activator of soluble guanylyl cyclase, through a cyclic GMP-independent pathway in rat neutrophils. Biochem Pharmacol 62(6):679-684.

Wegener JW and Nawrath H (1997) Differential effects of isoliquiritigenin and YC-1 in rat aortic smooth muscle. Eur J Pharmacol 323(1):89-91.

Woodgate A, MacGibbon G, Walton M and Dragunow M (1999) The toxicity of 6-hydroxydopamine on PC12 and P19 cells. Brain Res Mol Brain Res 69(1):84-92.

Wu CF, Bishopric NH and Pratt RE (1997) Atrial natriuretic peptide induces apoptosis in neonatal rat cardiac myocytes. J Biol Chem 272(23):14860-14866.

Wyllie AH, Kerr JF and Currie AR (1980) Cell death: the significance of apoptosis. Int Rev Cytol 68:251-306.

Yasuhara S, Zhu Y, Matsui T, Tipirneni N, Yasuhara Y, Kaneki M, Rosenzweig A and Martyn JA (2003) Comparison of comet assay, electron microscopy, and flow cytometry for detection of apoptosis. J Histochem Cytochem 51(7):873-885.

Zoratti M and Szabo I (1995) The mitochondrial permeability transition. Biochim Biophys Acta 1241(2):139-176.
QRCODE
 
 
 
 
 
                                                                                                                                                                                                                                                                                                                                                                                                               
第一頁 上一頁 下一頁 最後一頁 top