近年來，斑馬魚已被指出為一相當具有潛力之模式動物，可以被運用於探討人類相關疾病或藥物活性分析上。其中，帕金森氏症(Parkinson’s disease)由於人口老化趨勢日益增加導致患病人口眾多，嚴重危害患者及其家庭之生活品質，但目前此疾病之治療卻僅止於臨床病徵上的治療。因此，開發新藥物治療帕金森氏症為刻不容緩之重要課題。目前研究已有許多帕金森氏症之實驗動物模式以供藥物之篩選和機轉之探討，如大白鼠、靈長類等，上述兩者雖較接近人類，但均有實驗之限制因素，如飼養條件較高，生物體積大而使所需天然藥物量大才可進行分析。因此，本計劃可利用斑馬魚體積小則所需藥物劑量低，低成本，且同樣具有發育完整之神經系統之特性，配合於細胞中所使用致病劑6-羥基多巴胺(6-hydroxydopamine, 6-OHDA)之學理依據，將斑馬魚胚胎浸泡於6-OHDA 中，透過分析斑馬魚之行動能力測試(locomotor activity)，以期建立活體帕金森氏症動物模式。並利用聚合酶連鎖反應(polymerase chain reaction)分析 parkin 和 PINK1 和免疫組織化學螢光染色(immunohistochemistry)分析tyrosine hydroxylase(TH)，探討這些分子在6-OHDA 引起斑馬魚帕金森氏症之分子機轉。實驗結果發現在給予6-OHDA 後，斑馬魚的運動能力明顯的降低，並且在腦部可以觀察到相仿哺乳類TH 表現量下降的情形。另外，parkin 和PINK1 兩者的訊息核糖核酸也會在給予6-OHDA 之後有表現量下降的情況。結合上述成果，我們認為此模組可以應用於快速活體篩選具治療帕金森氏症活性之天然物。

Recently, the zebrafish has been considered an important animal model that can be used to investigate human diseases and drug development. Parkinson’s disease (PD), an
important neurodegenerative disorder, is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra and movement defects, including bradykinesia, tremor, and postural imbalance. However, current treatments for PD are limited and mainly improve only the clinical symptoms of the disease. Thus, a neurodegenerative rat model has been widely used for a long while to search for a new treatment for PD. However, the use of rats as an animal model has certain limitations such as breeding, efficiency, and high dosage. Recently, researchers indicated that neurotoxins such as rotenone, 6-hydroxydopamine (6-OHDA), and paraquat can induce Parkinson’s-like symptoms in zebrafish, and this may be a useful PD model because of the complete development of the zebrafish nervous system, low costs, and low dosage. In this study, we treated zebrafish with 6-OHDA and analyzed their locomotor activity to establish an in vivo animal model of PD. Then, we analyzed the mRNA expression of parkin and PINK1 by reverse transcription–polymerase chain reaction (RT-PCR).Moreover, we observed tyrosine hydroxylase (TH) expression by immunohistochemical (IHC) staining to confirm if this can be used as a PD model. Finally, we found that
treatment with 6-OHDA significantly reduced TH expression. We observed a similar declining trend in the case of mammals. Likewise, parkin and PINK1 mRNA expressions were also decreased after treatment with 6-OHDA. In summary, our study provides a feasible in vivo Parkinson’s model, and a small volume of drugs or compounds can be screened using this model.

論文審定書…………………………………………………………...…i
誌謝…………………………………..……………………………….…ii
中文摘要………………………………...………………………………iii
英文摘要…………………………………….………………..…………iv
目錄…….………………………………………………………..………v
圖次……..……………..…………………………….………..…....……vi
表次………………………………………………….……………..……vii
第壹章：前言……………………........……………..…………….……1
第貳章：實驗材料與方法…………………………..……...………..…9
第参章：實驗結果…….………………………………………..………15
第肆章：討論………………………………..………………….………43
參考文獻 …...…………………………………………….....………….51

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