穗花珊瑚醇 (Lemnalol) 是一個來自軟珊瑚Sinularia querciformis所分離出的天然物。在本研究中，我們使用大白鼠後腳掌注射鹿角菜膠 (carrageenan) 所引起水腫 (edema) 及痛覺過敏 (hyperalgesia) 模式，透過熱覺過敏測試 (thermal hyperalgesia test)、腳掌水腫分析 (paw edema assay) 與組織病理檢查等方式，探討穗花珊瑚醇是否在活體模式 (in vivo) 中具有鎮痛及抗發炎作用。同時，我們也利用免疫組織化學染色法 (immunohistochemistry)，探討穗花珊瑚醇對於鹿角菜膠所引起發炎性反應的細胞學機轉。實驗結果顯示，經由周邊 (systemic) 或中樞 (central) 給予穗花珊瑚醇，皆能有效抑制鹿角菜膠所誘發熱覺過敏行為。而肌肉注射穗花珊瑚醇亦可顯著降低腳掌水腫，並改善組織發炎之現象，以及減少嗜中性白血球浸潤 (neutrophil infiltration)。綜合行為和免疫組織化學染色分析的結果，我們認為穗花珊瑚醇的消炎止痛作用是和抑制發炎性相關因子 (inflammatory mediator) 的大量表現有關，包括誘發性ㄧ氧化氮合成酶 (inducible nitric oxidase synthase, iNOS)、病態型環氧化酶 (cyclooxygenase-2, COX-2)、血管內皮生長因子 (vascular endothelial cell growth factor, VEGF)、腫瘤壞死因子α (TNF-α) 及磷酸肌醇磷酸酶 (phosphatase and tensin homologue deleted on chromosome ten, PTEN) 等。
自1962年，利用大白鼠腳掌注射鹿角菜膠所建立之活體發炎性模式，己被廣泛使用在探討發炎機轉及藥物的抗發炎活性等方面。然而，使用大白鼠作為動物模式卻有其相關限制因素，如飼養條件、經濟性、效能問題，以及需要較高藥物劑量等。在近幾年來，許多研究報告已指出，斑馬魚 (Danio rerio) 是一具潛力之動物實驗模式，可以用於藥物活性和疾病相關機轉的研究。在本研究中，我們試圖利用斑馬魚建立一個發炎性動物模式。實驗結果顯示，腹腔 (intraperitoneal, i.p.) 注射鹿角菜膠會誘發斑馬魚死亡，進而導致累積存活率的降低，以及引起斑馬魚腹部明顯腫脹。而腹腔合併給予methylprednisolone則能有效改善鹿角菜膠所引起的死亡及病理現象。在免疫組織化學染色結果發現，腹腔注射鹿角菜膠可以顯著引起誘發性一氧化氮合成酶、熱休克蛋白質25 (heat shock protein 25, Hsp25)、熱休克蛋白質90 (heat shock protein 90, Hsp90)、磷酸肌醇磷酸酶的蛋白質表現量上升，但造成熱休克蛋白質70 (heat shock protein 70, Hsp70) 的蛋白質表現量下降。本研究提供了一個新的活體發炎動物模式，可運用於篩選少量的藥物或化合物。

Lemnalol (8-isopropyl-5-methyl-4-methylene-decahydro-1, 5-cyclo-naphthalen-
3-ol) is a natural compound isolated from the marine soft coral Lemnalia cervicorni. In the present study, we focused to determine whether lemnalol has in vivo antinociceptive and anti-inflammatory effects on carrageenan-induced rat paw edema and the hyperalgesia model using the thermal hyperalgesia test, paw edema assay, and histological examination. Furthermore, we also explored the possible cellular mechanisms of lemnalol on carrageenan-induced inflammatory responses by immunohistochemistry. The present results show that both systemic and central administration of lemnalol significantly inhibits carrageenan-evoked thermal hyperalgesia behavior. Moreover, intramuscular injection of lemnalol also significantly decreases paw edema and improves the inflammatory status of the tissues with reduced neutrophil infiltration. From behavioral and immunohistological observations, we found that lemnalol exerts its anti-inflammatory and analgesic effects on carrageenan-induced inflammatory responses; the cellular mechanisms of these effects involved the inhibition of elevated inflammatory mediators, including inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), vascular endothelial cell growth factor (VEGF), tumor necrosis factor-α (TNF-α), and deletion of phosphatase and tensin homologues on chromosome 10 (PTEN).
Since 1962, the carrageenan-induced rat model of inflammation has been widely used as an animal model to investigate inflammatory mechanisms and anti-inflammatory activity of drugs and has been fully characterized. However, the use of rats as an animal model has certain limitations such as those associated with breeding, economy, efficiency, and higher dosage. Recently, many studies have demonstrated zebrafish (Danio rerio) to be a valuable animal model for the investigation of bioactive compounds and molecular mechanisms of various diseases. In the present study, we attempted to establish an inflammatory animal model in zebrafish. Our research results showed that intraperitoneal (i.p.) administration of carrageenan significantly increased body edema and caused death of zebrafish resulting in a decrease in the cumulative survival rate. These effects were significantly inhibited by i.p. administration of methylprednisolone. Immunohistochemical observations revealed i.p. carrageenan-induced upregulation of iNOS, heat shock protein 25 (Hsp25), heat shock protein 90 (Hsp90), and PTEN; however, heat shock protein 70 (Hsp70) was observed to be downregulated. The present study provides a new in vivo inflammatory model for the screening of small volumes of drugs or compounds.

目錄……………………………………………………………………………………I
圖目錄…………………………………………………………………………………II
摘要……………………………………………………………………………………V
Abstract………………………………………………………………………………VII
第一部分：叢狀穗花軟珊瑚中穗花珊瑚醇對於鹿角菜膠誘發大白鼠腳掌發炎
和痛覺過敏之影響
第壹章、 前言…………………………………………………………………………2
第貳章、 實驗材料與方法……………………………………………………………9
第參章、 實驗結果……………………………………………………………………17
第肆章、 實驗討論……………………………………………………………………39
第二部份：利用斑馬魚建立活體發炎模式
第壹章、 前言…………………………………………………………………………47
第貳章、 實驗材料與方法……………………………………………………………51
第參章、 實驗結果……………………………………………………………………58
第肆章、 實驗討論……………………………………………………………………75
參考文獻………………………………………………………………………………82

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