時至今日，臨床對抗帕金森氏症之藥物僅停留在減輕些許臨床症狀的階段，除了服用後均伴隨極多副作用，且相關機制也還有待釐清。本研究中，我們首先發現海洋化合物11-de會增加DJ-1蛋白的表現並活化其下游Akt/PI3K，磷酸CREB (p-CREB)及Nrf2/HO-1路徑。此外，我們亦發現11-de可以回復6-OHDA所造成斑馬魚游行距離的下降。我們也在帕金森氏症大鼠模式中發現11-de可以有效回復6-OHDA造成旋轉行為圈數的上升及獨木橋實驗中秒數的上升。最後我們在大鼠模式及斑馬魚模式中均可看到11-de可有效回復6-OHDA造成TH的下降。接著，我們欲證實一個周邊發炎因子，髓系細胞觸發受體-1 (TREM-1)可能在帕金森氏症亦佔有一席之地。我們發現其拮抗胜肽LP17可以有效回復6-OHDA造成之細胞凋亡情形。其可能之機轉可能透過抗發炎及發炎細胞的自噬作用。此外，我們同樣可以在斑馬魚PD模式中發LP17可以有效抑制6-OHDA造成游行距離的下降。更可在大鼠PD模式中降低6-OHDA造成旋轉行為圈數上升之情形。綜合上述成果，我們發現一個具有神經保護之化合物及拮抗發炎因子在帕金森氏症之效用。

Nowadays, the clinical drugs for PD only limited to relieve the clinical symptoms. Besides, the administration of these drug not only accompanied with severe side effects but also without clear mechanism. Our present results found the marine derived compound, 11-de could up-regulate the DJ-1 protein to further activate its downstream pathway, such as Akt/PI3K, p-CREB, and Nrf2/HO-1 pathway. Our present results showed that 11-de could increase cytosol or mitochondria DJ-1 expression and then activate the downstream Akt/PI3K, p-CREB and Nrf2/HO-1 pathway. Additionally, we found that 11-de could reverse the 6-OHDA-induced increase in the swimming total distance (an indication of locomotor activity) in zebrafish PD. We also revealed that increase of turns of rotation behavior and time in beam induced by 6-OHDA treatment could be reversed by 11-de. Lastly, we showed that the 6-OHDA-induced attenuation on TH expression in zebrafish and rat PD model. Moreover, DJ-1 expression in zebrafish revealed a similar trend in in vitro studies. Finally, we showed a peripheral inflammatory factor, TREM-1 may played an important role in neuroinflammation. Our present results showed that LP17 could significantly rescued the 6-OHDA-induced cell apoptosis through anti-inflammation activity and autophagy procedure. Additionally, we found that LP17 could reverse the 6-OHDA-induced increase in the swimming total distance (an indication of locomotor activity) in zebrafish PD. We also revealed that increase of turns of rotation behavior induced by 6-OHDA treatment could be reversed by LP17. Lastly, we showed that the 6-OHDA-induced attenuation on TH expression in rat PD model.

Table of contents
Table of contents iii
List of Figures v
中文摘要 ix
Abstract xi
General introduction 1
General Materials and methods: 5
Part I: Neuroprotective effect of the marine-derived compound 11-dehydrosinulariolide through DJ-1-related pathway in in vitro and in vivo models of Parkinson’s Disease 10
Introduction 11
Materials & methods 13
Results 18
Figures & Legends 21
Discussion 44
Part II: Investigation of the role and effect of triggering receptor expressed on myeloid cells (TREM-1) in Parkinson’s disease in vivo and in vitro 49
Introduction 50
Materials & methods 53
Results 62
Figures & Legends 65
Discussion 87
Reference 94

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