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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 張芳嘉(Fang-Chia Chang) | |
| dc.contributor.author | Chin-Yu Lu | en |
| dc.contributor.author | 呂瑾瑜 | zh_TW |
| dc.date.accessioned | 2021-06-13T15:21:08Z | - |
| dc.date.available | 2010-07-26 | |
| dc.date.copyright | 2008-07-26 | |
| dc.date.issued | 2008 | |
| dc.date.submitted | 2008-07-22 | |
| dc.identifier.citation | 1. Parkinson J. An essay on the shaking palsy. 1817. J Neuropsychiatry Clin Neurosci 2002;14(2):223-36.
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Ann N Y Acad Sci 2001;933:211-21. 21. Krueger JM, Fang J, Taishi P, Chen Z, Kushikata T, Gardi J. Sleep. A physiologic role for IL-1 beta and TNF-alpha. Ann N Y Acad Sci 1998;856:148-59. 22. Takahashi S, Kapas L, Krueger JM. A tumor necrosis factor (TNF) receptor fragment attenuates TNF-alpha- and muramyl dipeptide-induced sleep and fever in rabbits. J Sleep Res 1996;5(2):106-14. 23. Taishi P, Churchill L, Wang M, et al. TNFalpha siRNA reduces brain TNF and EEG delta wave activity in rats. Brain research 2007;1156:125-32. 24. Kubota T, Kushikata T, Fang J, Krueger JM. Nuclear factor-kappaB inhibitor peptide inhibits spontaneous and interleukin-1beta-induced sleep. Am J Physiol Regul Integr Comp Physiol 2000;279(2):R404-13. 25. Dhawan V, Healy DG, Pal S, Chaudhuri KR. Sleep-related problems of Parkinson's disease. Age Ageing 2006;35(3):220-8. 26. Tandberg E, Larsen JP, Karlsen K. A community-based study of sleep disorders in patients with Parkinson's disease. Mov Disord 1998;13(6):895-9. 27. Garcia-Borreguero D, Larrosa O, Bravo M. Parkinson's disease and sleep. Sleep Med Rev 2003;7(2):115-29. 28. Chen XY, Li J, Qi WQ, Shen SH. Experimental change on dopaminergic neurons in striatum of Parkinson disease rats. Histol Histopathol 2007;22(10):1085-90. 29. Ghosh A, Roy A, Liu X, et al. Selective inhibition of NF-{kappa}B activation prevents dopaminergic neuronal loss in a mouse model of Parkinson's disease. Proc Natl Acad Sci U S A 2007. 30. Salamanca-Gomez F. [Flies and Parkinson disease]. Gac Med Mex 2000;136(3):281-2. 31. Bier E. Antioxidants put Parkinson flies back in the PINK. Proc Natl Acad Sci U S A 2006;103(36):13269-70. 32. Barsoum NJ, Gough AW, Sturgess JM, de la Iglesia FA. Parkinson-like syndrome in nonhuman primates receiving a tetrahydropyridine derivative. Neurotoxicology 1986;7(1):119-26. 33. Pelissier T, Laurido C, Hernandez A, Constandil L, Eschalier A. Biphasic effect of apomorphine on rat nociception and effect of dopamine D2 receptor antagonists. Eur J Pharmacol 2006;546(1-3):40-7. 34. Bonnet AM, Houeto JL. Pathophysiology of Parkinson's disease. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. Biomed Pharmacother 1999;53(3):117-21. 35. Fiedler MA, Wernke-Dollries K, Stark JM. Inhibition of TNF-alpha-induced NF-kappaB activation and IL-8 release in A549 cells with the proteasome inhibitor MG-132. Am J Respir Cell Mol Biol 1998;19(2):259-68. 36. Sun F, Anantharam V, Zhang D, Latchoumycandane C, Kanthasamy A, Kanthasamy AG. Proteasome inhibitor MG-132 induces dopaminergic degeneration in cell culture and animal models. Neurotoxicology 2006;27(5):807-15. 37. Goldbaum O, Vollmer G, Richter-Landsberg C. Proteasome inhibition by MG-132 induces apoptotic cell death and mitochondrial dysfunction in cultured rat brain oligodendrocytes but not in astrocytes. Glia 2006;53(8):891-901. 38. 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IL-1 is a mediator of increases in slow-wave sleep induced by CRH receptor blockade. Am J Physiol Regul Integr Comp Physiol 2000;279(3):R793-802. 44. Hernandez-Gutierrez S, Garcia-Pelaez I, Zentella-Dehesa A, et al. NF-kappaB signaling blockade by Bay 11-7085 during early cardiac morphogenesis induces alterations of the outflow tract in chicken heart. Apoptosis 2006;11(7):1101-9. 45. Mignot E, Taheri S, Nishino S. Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders. Nat Neurosci 2002;5 Suppl:1071-5. 46. Ongini E, Bonizzoni E, Ferri N, Milani S, Trampus M. Differential effects of dopamine D-1 and D-2 receptor antagonist antipsychotics on sleep-wake patterns in the rat. J Pharmacol Exp Ther 1993;266(2):726-31. 47. Monti JM, Jantos H, Fernandez M. Effects of the selective dopamine D-2 receptor agonist, quinpirole on sleep and wakefulness in the rat. Eur J Pharmacol 1989;169(1):61-6. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/37197 | - |
| dc.description.abstract | 帕金森氏症 (Parkinson’s Disease, PD) 於1817年由英國的帕金森醫師發表的病例報告之後，世人開始注意到這些患者。在許多人投入帕金森的研究之後，針對帕金森症患者的大腦進行種種實驗，發現患者腦中紋狀體 (striatum) 的多巴胺含量顯著少於正常人，進一步分析則發現，多巴胺減少是由於患者黑質 (substantia nigra, SN) 所存活分泌多巴胺的神經元大量減少，並由此結果得知帕金森患者所出現的眾多症狀皆起因於此。
本研究關心的重點在帕金森患者所產生的睡眠症狀上，這個部分較不為一般人所重視，有許多症狀產生的機轉仍待研究人員進一步了解。我們試著將藥物直接施打於大鼠大腦黑質處，阻斷黑質附近ubiquitin-proteasome system之功能，造成被ubiquitin結合的蛋白質無法經由proteasome分解而大量堆積於位在黑質的多巴胺神經元，而使微膠細胞 (microglia cell) 活化，造成多巴胺神經活性衰退，大鼠上產生類似PD患者的睡眠障礙症狀，並藉由此模式來探討PD患者睡眠產生改變的機轉是否經過微膠細胞活化所釋放之細胞素 (cytokine) 而造成。 MG-132 (proteasome inhibitor) 施打之後，apomorphine (多巴胺的作用劑) 的測試的確能觀察到大鼠原地轉圈的數目在給予後有增加的現象，證明多巴胺神經元的確有減少釋出多巴胺的情形，並且能產生大鼠的運動障礙。我們分析大鼠EEG的變化，發現MG-132施打後一週，大鼠的睡眠便產生了在活動期睡眠增加，但在睡眠期之睡眠有減少的變化，這與PD患者所產生的睡眠障礙相當類似。此變化經由tumor necrosis factor receptor fragment (TNFRF) 、或是nuclear factor-kappa B (NF-κB) inhibitor的施打，都能令其回復至與控制組接近的睡眠量，而interlukin-1 receptor antagonist (IL-1ra) 對MG-132所造成的增加在大鼠活動期睡眠現象卻無法產生顯著的抑制作用。理論上MG-132的施予能造成大鼠腦中IL-1β及TNF-α在特定幾個影響睡眠的腦區中含量增加，實際上MG-132的確使中腦及下視丘TNF-α的表現量增加，NF-κB的表現也因為MG-132的施打，可看到紋狀體 (striatum) 所偵測到NF-κB有明顯增加活化的情形，而IL-1β的表現在MG-132給予之後並沒有看到顯著的增加。由此可推論，MG-132所導致的睡眠失調，是經過TNF-α-NF-κB這條路徑的改變所造成，而非IL-1β。 | zh_TW |
| dc.description.abstract | For patients with the Parkinson’s disease (PD), the degeneration of dopaminergic neurons causes the decrease of dopamine release from the substantia nigra pars compecta (SNpc) to the striatum. It is also found that the PD patient’s brain has inclusion bodies of α-synuclein in this area. These inclusion bodies can lead to activate mitochondrial and to subsequently release cytokines, such as tumor necrosis factor – alpha (TNF-α) and interlukin-1beta (IL-1β), which affect the PD patient’s sleep. We herein used a proteasome inhibitor, MG-132, to inhibit the function of proteasome, which caused the loss of dopaminergic neurons in SNpc, and subsequently changed the sleep architecture in rats. The total amount of NREMS was significantly increased, and the of wakefulness was decreased during the dark-period at the 7th day after MG-132 treatment. We administered tumor necrosis factor receptor fragment (TNFRF) and interlukin-1 receptor antagonist (IL-1ra), to elucidate the involvement of TNF-α and IL-1β in MG-132-induced sleep alteration. The MG-132-induced sleep alteration was reversed after giving those blockers of cytokines. We employed BAY11-7085 and SN50, the nuclear factor-kappa B (NF-κB) inhibitors, to verify the involvement of NF-κB activation. Out results indicated that NF-κB inhibitor also blocked MG-132-induced sleep disturbance. The expression of TNF-α was increase after MG-132 administration, but there has no alteration on IL-1β expression. The activation of NF-κB at the striatum was significantly increased after injection of the MG-132. In this study, we demonstrated that TNF-NF-κB pathway is involved in the mechanism of sleep disturbance in rats with MG-132-induced parkinsonism. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T15:21:08Z (GMT). No. of bitstreams: 1 ntu-97-R95629014-1.pdf: 3975520 bytes, checksum: ace5c15fa6b727d3b135e46ab3e5ebf1 (MD5) Previous issue date: 2008 | en |
| dc.description.tableofcontents | 中文摘要 …………………………………………………… i
英文摘要 …………………………………………………… ii 1. 背景介紹及研究目的 ……………………………………… 1 1.1 研究歷史 ……………………………………… 1 1.2 症狀 ……………………………………… 1 1.3 多巴胺神經路徑 ……………………………………… 1 1.4 運動路徑 ……………………………………… 2 1.5 病因 ……………………………………… 3 1.6 帕金森氏症與細胞素 ……………………………………… 4 1.7 細胞素與睡眠 ……………………………………… 5 1.8 帕金森氏症的睡眠研究 ……………………………………… 6 1.9 動物模式 ……………………………………… 6 1.10 研究目的 ……………………………………… 7 2. 材料與方法 ……………………………………… 12 2.1 實驗材料 ……………………………………… 12 2.1.1 實驗動物 ……………………………………… 12 2.1.2 實驗用藥 ……………………………………… 12 2.2 實驗方法 ……………………………………… 13 2.2.1 EEG ……………………………………… 13 2.2.2 EEG資料分析 ……………………………………… 14 2.2.3 Apomorphine Locomotion Test ……………………… 14 2.2.4 總活動時間 ……………………………………… 15 2.2.5 組織學 ………………………………………. 15 2.2.5.1 Tyrosine Hydroxylase Stain (TH-Stain) …………. 15 2.2.5.2 Transmission Electron Microscope (TEM) ……… 16 2.2.6 Enzyme Linked Immunesorbent Assay (ELISA) ……… 17 2.2.7 NoShiftTM Transcription Factor Assay ………………… 17 2.2.8 統計學分析 ……………………………………… 18 3. 結果 ……………………………………… 21 3.1 帕金森氏症的動物模式 ……………………………………… 21 3.1.1.1 睡眠上的變化 ……………………………………… 21 3.1.1.2 對運動的影響 ……………………………………… 21 3.1.1.2.1 Locomotion Test …………………………… 21 3.1.1.2.2 Total moving time …………………………… 21 3.2 睡眠結構 ……………………………………… 22 3.2.1 TNFRF ……………………………………… 22 3.2.2 IL-1ra ……………………………………… 22 3.2.3 BAY11-7085 ……………………………………… 22 3.3 睡眠品質 ……………………………………… 22 3.4 組織學檢驗 ……………………………………… 23 3.4.1 Tyrosine Hydroxylase Stain (TH-Stain) …………… 23 3.4.2 Transmission Electron Microscope (TEM) …………… 23 3.5 細胞素的表現及轉錄因子活化情形 ……………………… 23 3.5.1 TNF-α and IL-1β ELISA …………………………… 23 3.5.2 NoShiftTM Transcription Factor Assay ………………… 23 4. 討論 ……………………………………… 38 4.1 MG-132的帕金森氏症動物模式 …………………………… 38 4.2細胞素在此模式中對睡眠的作用 …………………………… 41 4.3運動症狀的部分 ……………………………………… 42 5. 結論 ……………………………………… 44 6. 參考文獻 ……………………………………… 45 7. 作者小傳 ……………………………………… 53 貳、 圖目錄 Fig. 1.1正常與帕金森症腦中Nigrastriatal 徑路的變化 …………… 8 Fig. 1.2 Rotenone及MPTP造成多巴胺神經元死亡示意圖 …………… 9 Fig. 1.3腦中各項因子與睡眠的關係圖 …………………………… 10 Fig. 1.4 MG-132大鼠PD模式影響細胞素分泌之機制 …………… 11 Fig. 2.1大鼠顯微注射及EEG手術各物品放置位置示意圖 ……… 19 Fig. 2.2 BAY11-7085組EEG記錄時程 …………………………… 19 Fig. 2.3 TNFRF及IL-1ra組EEG記錄時程 ……………………… 20 Fig. 3.1 TNFRF對MG-132的PD大鼠dark-period睡眠的作用 … 24 Fig. 3.2 TNFRF組中MG-132施打後第七天，大鼠之睡眠變化 … 25 Fig. 3.3 BAY11-7085組中MG-132施打後第七天，大鼠之睡眠變化 26 Fig. 3.4 IL-1ra組MG-132施打後第七天，大鼠dark-period睡眠變化 27 Fig. 3.5 TNFRF對MG-132的PD大鼠light-period睡眠的作用 … 28 Fig. 3.6 IL-1ra對MG-132的PD大鼠dark-period睡眠的作用 … 29 Fig 3.7 BAY11-7085對MG-132的PD大鼠dark-period睡眠的作用 30 Fig. 3.8 BAY11-7085對MG-132的PD大鼠light-period睡眠的作用 31 Fig. 3.9 MG-132施打後第七天各腦區TNF-α表現情形 …………… 32 Fig. 3.10 MG-132施打後第七天各腦區IL-1β表現情形 …………… 32 Fig. 3.11 MG-132施打後第七天各腦區NF-κB活化情形 …………… 33 Fig. 3.12 Tyrosine hydroxylase stain (TH-Stain) ……………………… 36 Fig. 3.13 Transmission Electron Microscope …………………………… 37 參、 表目錄 Tab. 2.1 睡眠狀態判定表 ……………………………………… 20 Tab. 3.1 BAY11-7085對大鼠slow wave activity (SWA) 的影響 … 33 Tab. 3.2 IL-1ra對MG-132之PD大鼠睡眠結構的影響 …………… 34 Tab. 3.3 BAY11-7085對MG-132之PD大鼠睡眠結構的影響 … 35 | |
| dc.language.iso | zh-TW | |
| dc.subject | ubiquitin-proteasome system | zh_TW |
| dc.subject | 腦波圖 | zh_TW |
| dc.subject | MG-132 | zh_TW |
| dc.subject | 睡眠 | zh_TW |
| dc.subject | 細胞素 | zh_TW |
| dc.subject | NF-κB | zh_TW |
| dc.subject | 帕金森氏症 | zh_TW |
| dc.subject | electroencephalograph (EEG) | en |
| dc.subject | ubiquitin-proteasome system | en |
| dc.subject | MG-132 | en |
| dc.subject | NF-κB | en |
| dc.subject | cytokines | en |
| dc.subject | sleep | en |
| dc.title | 以大鼠模式探討帕金森症患者睡眠失常之機轉 | zh_TW |
| dc.title | The sleep Disturbance in Rats with Parkinsonism | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 96-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 詹東榮(Tong-Rong Jan),林中天(Chung-Tien Lin),徐崇堯(Chung-Yao Hsu) | |
| dc.subject.keyword | 帕金森氏症,腦波圖,睡眠,細胞素,NF-κB,MG-132,ubiquitin-proteasome system, | zh_TW |
| dc.subject.keyword | electroencephalograph (EEG),sleep,cytokines,NF-κB,MG-132,ubiquitin-proteasome system, | en |
| dc.relation.page | 51 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2008-07-23 | |
| dc.contributor.author-college | 生物資源暨農學院 | zh_TW |
| dc.contributor.author-dept | 獸醫學研究所 | zh_TW |
| 顯示於系所單位： | 獸醫學系 | |
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