在近年來已從海洋生物中發現到數種顯著具有抗發炎活性潛力之代謝物，而在現今中亦有不少海洋天然物在進行臨床上的試驗。本研究係從軟珊瑚Sinularia querciformis 中分離到一種西柏烷類海洋天然物11-epi-sinulariolide acetate (Ya-s 11)。在先前的酯多醣(lipopolysaccharide, LPS)刺激老鼠巨噬細胞產生發炎反應的模式裡確認11-epi-sinulariolide acetate 具有顯著的抑制誘發型一氧化氮合成酶與第二型環氧化酶之蛋白質的表現。而過去許多研究報告證實，發炎反應在類風濕性關節炎的疾病發展過程中佔有重要的角色，同時此疾病影響世界近1%的人口。因此，我們運用佐劑誘發大白鼠類風性關節炎的疾病模式，探討天然物11-epi-sinulariolide acetate 的在活體動物中是否同樣具有抗發炎作用。類風濕性關節炎的誘發是在大白鼠尾巴基部注射100 μl 的Freund’s incomplete adjuvant，其中含有熱殺死的結核菌Mycobacterium butyricum。並在誘發後第7 天起到第28天間，每隔一天採用背部皮下注射方式給予天然物3 mg/kg 和9 mg/kg 兩種劑量組別，並共給予十次下作為治療。從實驗結果顯示，11-epi-sinularolide acetate 可顯著抑制佐劑誘發類風性關節炎所造成的腳踝腫脹及關節炎的發生。而在進一步在組織切片分析下，我們發現11-epi-sinulariolide acetate 可改善類風濕性關節炎所造成的組織病理上的特徵。我們總結11-epi-sinulariolide acetate 可減少前驅發炎性反應蛋白質的表現，在活體上具治療類風濕性關節炎之作用，在未來可能發展成有效治療類風濕性關節炎的藥物。

In recent years, a significant number of metabolites with potent anti-inflammatory properties have been discovered in marine organisms, and several of these compounds are now under clinical trials. We have isolated 11-epi-sinulariolide acetate (Ya-s 11), a Diterpene-type compound from the soft coral Sinularia querciformis. Preliminary screening revealed that in lipopolysaccharide (LPS)-stimulated murine macrophages, 11-epi-sinulariolide acetate significantly inhibited the expression of proinflammatory proteins, nitric oxide synthetase, and cyclooxygenase-2. It is known that inflammation plays a critical role in the development of rheumatoid arthritis (RA), which affects about 1% of the world population. In the present study, we examined the therapeutic effect of 11-epi-sinulariolide acetate on adjuvant-induced RA in rats. RA was induced by injecting 100 μl of heat-killed Mycobacterium butyricum in Freund’s incomplete adjuvant in the base of the tail of female Lewis rats. After adjuvant injection from day 7 to 28, the rats were subcutaneously injected with 3 or 9 mg/kg 11-epi-sinulariolide acetate once every 2 days. Animal experiments have shown that 11-epi-sinulariolide acetate significantly inhibits adjuvant-induced ankle edema and arthritis. Moreover, using histological analysis, we had found that 11-epi-sinularolide acetate also improved the histopathologic features of RA. We concluded that 11-epi-sinulariolide acetate attenuated the expression of proinflammatory proteins and the disease progression in the RA model. Hence, 11-epi-sinularolide acetate may serve as a useful therapeutic agent for the treatment of RA.

中文摘要.........................................................IV
英文摘要..........................................................V
第一章、前言.................................................1
第二章、實驗方法與程序..........................13
第三章、實驗結果.......................................25
第四章、實驗討論.......................................57
第五章、參考文獻.......................................66

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