先前的研究已經證實，從軟珊瑚(Cladiella australis)分離的海洋化合物austrasulfone有顯著神經保護作用。而在合成austrasulfone時之中間產物dihydroaustrasulfone alcohol會降低發炎性反應。本研究採用離體和活體方法研究dihydroaustrasulfone alcohol的修飾物1-甲苯磺酰基戊烷-3-酮(1-Tosylpentan-3-One, 1T3O)之神經保護作用。實驗結果顯示1T3O能有效抑制6-羥基多巴胺誘導的激活SH-SY5Y細胞中的p38絲裂原活化蛋白激酶(MAPK)和半胱天冬酶-3，並通過磷酸肌醇3-激酶(PI3K) /蛋白激酶B (Akt)信號增強核因子E2相關因子(Nrf2)和血紅素加氧酶-1 (HO-1)的表達。Hoechst染色和末端脫氧核苷酸轉移酶dUTP缺口末端標記(TUNEL)染色結果顯示1T3O顯著抑制6-OHDA誘導的細胞凋亡。另外，加入Akt或HO-1抑制劑降低了1T3O的保護作用。因此，我們推測1T3O在神經元細胞中的抗凋亡活性是通過調節Akt和HO-1信號途徑傳導。活體實驗則證實，1T3O可以逆轉6-OHDA誘導的斑馬魚運動行為能力下降，同時抑制6-OHDA誘導的腫瘤壞死因子-α (TNF-α)增加。根據我們的實驗結果，我們認為1T3O在6-OHDA攻擊之後在SH-SY5Y細胞中發揮抗凋亡活性，可能通過調節抗氧化信號傳導途徑。因此，該化合物可能是神經退化變性疾病的有希望治療劑。

Previous studies have demonstrated that the marine compound austrasulfone, isolated from the soft coral Cladiella australis, exerts a neuroprotective effect. The intermediate product in the synthesis of austrasulfone, dihydroaustrasulfone alcohol, attenuates inflammatory responses. The present study uses in vitro and in vivo methods to investigate the neuroprotective effects of dihydroaustrasulfone alcohol-modified 1-tosylpentan-3-one (1T3O). Results from in vitro experiments show that 1T3O effectively inhibits 6-hydroxydopamine (6-OHDA)-induced activation of both p38 mitogen-activated protein kinase (MAPK) and caspase-3 in SH-SY5Y cells; and enhances nuclear factor erythroid 2–related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression via phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling. Hoechst staining and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining results reveal that 1T3O significantly inhibits 6-OHDA-induced apoptosis. Moverover, the addition of an Akt or HO-1inhibitor decreases the protective effect of 1T3O. Thus, we hypothesize that the anti-apoptotic activity of 1T3O in neuronal cells is mediated through the regulation of the Akt and HO-1 signaling pathways. In vivo experiments show that 1T3O can reverse 6-OHDA-induced reduction in locomotor behavior ability in zebrafish larvae, and inhibit 6-OHDA-induced tumor necrosis factor-alpha (TNF-α) increase at the same time. According to our in vitro and in vivo results, we consider that 1T3O exerts its anti-apoptotic activities at SH-SY5Y cells after 6-OHDA challenges, probably via the regulation of anti-oxidative signaling pathways. Therefore, this compound may be a promising therapeutic agent for neurodegenerations.

論文審定書 I
致謝 II
中文摘要 III
ABSTRACT IV
目錄 V
圖目錄 VIII
表目錄 IX
中英文對照及縮寫表 X
第壹章、前言 1
神經退化性疾病之病徵及臨床症狀 1
PD病徵 2
PD之臨床徵狀 2
PD診斷及治療 3
臨床PD市場藥物 4
神經發炎於PD之重要性 6
氧化壓力於PD中扮演之角色 8
多巴胺胜合成與分解與氧化壓力之關係 8
Nrf2路徑在抗PD之角色 10
SOD與HO-1在抗氧化路徑達到神經保護之角色 11
絲氨酸/蘇氨酸激酶(serine/threonine kinase)訊息傳遞路徑在PD之角色 13
細胞外訊息因子相關激酶在PD之角色 14
硫胱氨酸蛋白酶(caspase)在PD之角色 15
海洋天然物具備高度開發潛力 16
PD離體模式 18
PD活體模式 19
斑馬魚實驗模式介紹 20
目前斑馬魚PD模式種類 21
本研究動機與目的 22
第貳章、實驗材料與方法 23
細胞培養 24
Alamar blue assay 25
細胞型態觀察 25
細胞氧化壓力分析 25
細胞凋亡分析 27
西方墨點法 28
抗體接合 30
種魚飼養 30
胚胎取得 31
實驗仔魚飼養 31
藥物濃度篩選 31
6-OHDA 誘發斑馬魚仔魚神經退化 31
斑馬魚行動能力測試(locomotor activity) 31
斑馬魚蛋白質分析 32
實驗數據分析 34
第參章、實驗結果 35
第肆章、討論 61
發炎與神經死亡之關聯 61
經由Nrf2/HO-1路徑達到神經保護作用的化合物 62
透過抑制P38及活化ERK路徑保護神經之相關化合物 64
化合物透過PI3K路徑抑制6-OHDA引起SH-SY5Y凋亡之現象 65
利用斑馬魚PD模式分析化合物之神經保護活性 66
化合物在斑馬魚PD模式上之神經保護機轉 67
1T3O神經保護之機轉 69
第伍章、結論 70
第陸章、參考文獻 72
第柒章、附錄 86

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