臺灣博碩士論文加值系統

巴金森氏症(Parkinson’s disease)是一種好發於老年人的慢性、進行性神經退化性疾病(neurodegenerative disorder)。此病的主要特徵是位在中腦黑質部緻密區(substantia nigra pars compacta)內，含有黑色素(melanin-pigmented)的多巴胺神經元(dopaminergic neurons)大量退化死亡，因而造成紋狀體(striatum)的多巴胺(dopamine)含量嚴重缺乏。目前一些研究結果顯示巴金森氏症病因仍未明，但已有很多證據顯示氧化壓力在此疾病過程扮演重要角色，例如在巴金森氏症之病人屍體發現在黑質內的鐵比正常人增加。在巴金森氏症早期由於試圖代償損失的多巴胺神經元而增加多巴胺的轉換率，導致產生過多的過氧化氫，正常生理情況下，過氧化氫會由glutathione peroxidase進一步代謝成穩定的水分子。然而，當glutathione系統受損時，則促使過氧化氫累積。 由於鐵離子可以催化多巴胺的自體氧化作用，同時經由Fenton reaction與過氧化氫作用形成高活性氫氧游離基。而麩胺酸(Glutamate)及NMDA也能增加活體內及試管外自由基的產生，因此一方面我們尋找能衰減或阻斷鐵及多巴胺氫氧游離基的形成，另一方面我們假設鐵也可能借著經由活化興奮性胺基酸(excitatory amino acid)受體，產生氫氧游離基。以大白鼠紋狀體灌流鐵(FeSO4.7H2O 200μM)或多巴胺(100μM)合併水楊酸之微透析，觀察氫氧游離基及興奮性胺基酸的產生，並給予不同的前處理藥物。結果發現apomorphine, PBN及NAC能衰減或阻斷鐵灌流大白鼠紋狀體形成氫氧游離基，而MK-801, CPP, NBQX及Mepacrine也能阻斷或衰減鐵灌流大白鼠紋狀體形成氫氧游離基，Deferoxamine可以更增加氫氧游離基的形成，卻不見原本鐵造成興奮性胺基酸增加的現象，另外以FeCl3 800μM也可以增加四到六倍氫氧游離基的形成，也不見興奮性胺基酸的增加，所以在本實驗的模式中，鐵產生的氫氧游離基大多是經由興奮性胺基酸途徑而來，少部份經由Fenton反應而來的。
在大白鼠紋狀體灌流多巴胺(100μM)形成氫氧游離基的實驗中，apomorphine及MK-801能有效的阻斷氫氧游離基的形成。 Tc-99m TRODAT-1應用在6-OHDA建立的類巴金森氏症動物模式，以autoradiography 測Tc-99m標幟TRODAT-1代表多巴胺轉運子的量和經由HPLC-ECD所得多巴胺的量，在紋狀體因6-OHDA減少的量(90%對97%)相近，然而Tc-99m TRODAT-1及autoradiography是較簡便且快速的方法。
綜合來說，在機轉上，我們提出鐵在大白鼠紋狀體也可以經由興奮性胺基酸途徑形成氫氧游離基。在處置上，apomorphine, PBN, NAC, NMDA及non-NMDA受體拮抗劑，及mepacrine皆能減緩鐵灌流大白鼠紋狀體氫氧游離基的形成；而apomorphine及MK-801也可以阻斷多巴胺在大白鼠紋狀體氫氧游離基的形成。在診斷上，Tc-99m TRODAT-1顯示紋狀體多巴胺轉運子的量與HPLC-ECD所得多巴胺的量相近，在評估動物多巴胺轉運子的功能，Tc-99m TRODAT-1是極具潛力的造影製劑。

Parkinson’s disease (PD) is a slowly progressive neurodegenerative disorder commonly observed in the elder. PD is characterized by the primary degeneration of the melanin-pigmented dopaminergic neurons of the substantia nigra pars compacta with striatal dopamine deficiency. The pathogenesis of PD remains unclear. However, evidence have shown that oxidative stress may play an important role in the pathogenic process of PD. For example, increased dopamine turnover in the early stages of PD in an attempt to compensate for dopaminergic neuronal loss may generate excessive H2O2, which would normally be inactivated by glutathione in a reaction catalyzed by glutathione peroxidase to form harmless metabolites (H2O and O2). By contrast, impaired glutathione system may lead to H2O2 accumulation. It is well-known that iron catalyze the auto-oxidation reaction of dopamine and form the highly reactive hydroxyl radical through the Fenton reaction with H2O2. In addition, elevated free radical generation has been demonstrated by glutamate and NMDA both in vitro and in vivo. In this study, we attempted to attenuate or block the generation of iron and hydroxyl radical. Also, we examined whether iron-induced excitatory amino acid (EAA) efflux with the partial hydroxyl radical formation of iron is mediated by the activation of NMDA receptor. Striatal perfusion of FeSO4.7H2O (200μM) or dopamine (100μM) with sodium salicylate microdialysis was performed in Sprague-Dawley rats and various pre-treatments were given to observe the formation of hydroxyl radical and EAA. Our results show that the formation of iron perfusion-induced hydroxyl radical in rat striatum is attenuated or blocked by apomorphine, PBN and NAC. The same phenomenon is also showed with MK-801, CPP, NBQX and Mepacrine treatments. Deferoxamine is found to increase the formation of hydroxyl radical. However, the iron-induced EAA increase is not observed. In addition, treatment of 800μM FeCl3 significantly increases the formation of hydroxyl radical up to 4- to 6-fold whereas increase of EAA is also absent. Therefore, it is concluded that, in this study, iron-induced hydroxyl radical is mainly generated through the EAA pathway whereas the rest may come from the Fenton reaction.
In the study of hydroxyl radical formation caused by dopamine (100μM) perfusion in rat striatum, it is found that apomorphine and MK-801 can effectively block the formation of hydroxyl radical. In the animal model of PD initiated by 6-OHDA, the level of Tc-99m TRODAT-1 in the striatum representing the level of dopamine transporter is close to the level of dopamine measured by HPLC-ECD (90% vs. 97%). However, measurement of Tc-99m TRODAT-1 with autoradiography is much more convenient and less time-consuming than HPLC-ECD.
To sum up, we proposed that hydroxyl radical formation in rat striatum may be generated through the EAA pathway. Apomorphine, PBN, NAC, NMDA and non-NMDA receptor antagonist, and mepacrine can all attenuate the iron-induced hydroxyl radical formation in rat striatum. Apomorphine and MK-801 may also block the dopamine-induced hydroxyl radical formation. The use of Tc-99m TRODAT-1 demonstrates that the level of striatal dopamine transporter is very close to the level of dopamine measured by HPLC-ECD. Therefore, Tc-99m TRODAT-1 appears to be an imaging agent with high potential to evaluate the function of animal dopamine transporter.

目錄
頁次
目錄………………………………………………………………………I
『圖』目錄………………………………………………………………III
中文摘要…………………………………………………………………VI
英文摘要………………………………………………………………….IX
第一章 緒言……………………………………………………………… 1
第二章 觀察鐵灌流紋狀體及黑質產生氫氧游離基及腦組織脂質過氧化情形…………………………………………………………… 9
第一節 緒言…………………………………………………………..9
第二節 材料與方法………………………………………………... 20
第三節 結果…………………………………………………………26
第四節 討論…………………………………………………………30
第三章 鐵之氧化壓力與一氧化氮的相關性………………………48
第一節 緒言…………………………………………………………48
第二節 材料與方法…………………………………………………54
第三節 結果…………………………………………………………56
第四節 討論…………………………………………………………58
第四章 鐵之氧化壓力與興奮性胺基酸之興奮性毒性的相關性……………………………………………………………66
第一節 緒言…………………………………………………………66
第二節 材料與方法…………………………………………………71
第三節 結果…………………………………………………………73
第四節 討論…………………………………………………………76
第五章 多巴胺氧化作用與氫氧游離基之形成….…………….…92
第一節 緒言…………………………………………………………92
第二節 材料與方法…………………………………………………98
第三節 結果…………………………………………………………99
第四節 討論………………………………………………………..101
第六章 巴金森氏症之動物模式及Tc-99m TRODAT-1診斷之應用…117
第一節 緒言………………………………………………………..117
第二節 材料與方法………………………………………………..123
第三節 結果………………………………………………………..126
第四節 討論………………………………………………………..128
第七章 總結………………………………………………………….…136
參考文獻………………………………………………………………...138

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