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研究生:林怡倩
研究生(外文):Yi-Chien Lin
論文名稱:UgoninK與furopyrazole衍生物分別對H2O2誘導SH-SY5Y神經細胞及C2ceramide誘導初級皮質神經細胞凋亡之保護作用
論文名稱(外文):Neuroprotective effects of ugonin K and furopyrazole derivatives on hydrogen peroxide-induced apoptosis in human neuroblastoma SH-SY5Y cells and C2 ceramide-induced apoptosis in primary cortical neurons
指導教授:陳勝智陳勝智引用關係簡伯武簡伯武引用關係
指導教授(外文):Sheng-Chih ChenPo-Wu Gean
學位類別:博士
校院名稱:中國醫藥大學
系所名稱:藥物化學研究所博士班
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:中文
論文頁數:116
中文關鍵詞:神經細胞保護細胞凋亡
外文關鍵詞:Neuroprotectiveapoptosis
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氧化壓力(oxidative stress)所誘導的神經細胞死亡與老化和多種神經退化性疾病相關,例如:帕金森氏症(Parkinson’s disease)和阿茲海默症(Alzheimer’s disease)。分離自釘地蜈蚣(學名Helminthostachys zeylanica (L) Hook )的成分ugonin K屬於類黃酮,在本所其他研究證實有抗氧化活性,而本研究證實ugonin K對H2O2誘導SH-SY5Y細胞凋亡具有保護作用。利用H2O2誘導SH-SY5Y神經細胞死亡,24小時後以MTT分析細胞存活率。Hoechst 33258染色證實H2O2誘導SH-SY5Y細胞凋亡。除此之外,H2O2增加caspase-3片段17-KDa表現,而ugonin K可使caspase-3段裂片段表現降低。在誘導細胞凋亡前給予ugonin K可減少細胞凋亡的現象,呈現劑量依存性的關係,成功的保護細胞免於受H2O2所誘導的細胞凋亡。ugonin K的神經保護作用會被ERK和PI3K抑制劑所阻斷,而不會被JNK和p38 MAPK抑制劑所影響。利用西方墨點法分析,顯示ugonin K有增加ERK和AKT的磷酸化活化。這結果顯示ugonin K保護H2O2誘導SH-SY5Y神經細胞凋亡是經由ERK和PI3K/AKT的神經保護路徑。因此ugonin K所提供的神經保護不僅是它的抗氧化活性也與作用在活化細胞生存和細胞增值的訊息傳遞有關。
由於在很多急性或慢性神經退化性疾病中,發現有ceramide在神經細胞中的累積。在我們的研究證實furopyrazole衍生物對C2 ceramide誘導初級皮質神經細胞凋亡具有保護作用。在12個furopyrazole 衍生物中以carbinol衍生物(化合物CLC-107, CLC-507, CLC-604和CLC-609)對C2 ceramide誘導初級皮質神經細胞死亡的保護效果最為顯著。carbinol forms中,CLC-107、CLC-507雖有保護作用,但保護效果弱於CLC-604和CLC-609。Hoechst 33258染色證實C2 ceramide誘導初級皮質神經細胞凋亡。在誘導細胞凋亡前給予CLC-609可減少細胞凋亡的現象,呈現劑量依存性的關係,成功的保護細胞免於受C2 ceramide所誘導的細胞凋亡。CLC-609的神經保護作用會被ERK抑制劑所阻斷,此結果証實了CLC-609保護C2 ceramide誘導初級皮質神經細胞凋亡可能是經由ERK神經保護路徑。
綜合本論文的研究成果,ugonin K和furopyrazole衍生物可以當作對抗神經退化性疾病的神經保護劑和有效治療劑之藥物設計的重要線索。
Oxidative stress is widely implicated in the neuron cell death that is associated with various neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s disease. Ugonin K, a flavonoid isolated from the rhizomes of Helminthostachys zeylanica (L) Hook, possesses potent antioxidant property. In this study, we investigate the neuroprotective effects of ugonin K on hydrogen peroxide-induced apoptosis in SH-SY5Y cells. Incubation of SH-SY5Y cells with H2O2 for 24 h induced cell death measured with MTT assay. Hoechst 33258 staining confirmed that the reduced cell viability by H2O2 was due to apoptosis. In addition, H2O2 increased the expression of 17-kDa cleaved fragment of caspase-3 which could be reversed by pretreatment with ugonin K. Pretreatment with ugonin K attenuated H2O2-induced cell death in a dose-dependent manner. Neuroprotective effect of ugonin K was abolished by ERK and PI3K inhibitors. Pretreatment with JNK kinase and p38 MAPK inhibitors had no effect on ugonin K-mediated protection against H2O2-induced apoptosis. Western blotting showed that ugonin K increased both ERK1/2 and AKT phosphorylation. These results suggest that ugonin K by activation of ERK1/2 and PI3K/AKT signal pathways protects SH-SY5Y cells from H2O2-induced apoptosis. Therefore, the molecular mechanisms of neuroprotective effects of ugonin K may include not only their antioxidant activities but also their interaction with cell signaling cascades leading to cell survival and cell proliferation.
Ceramide accumulates in neurons during various disorders associated with acute or chronic neurodegeneation. In the present study, we investigate the neuroprotective effects of furopyrazole derivatives on C2 ceramide-induced cell death in primary cortical neurons. Among the 12 furopyrazoles tested, carbinol derivatives (CLC107, CLC-507, CLC-604 and CLC-609) exhibited strong neuroprotective against C2 ceramide-induced cell death. CLC107 and CLC-507 at concentration of 10 μM was also able to inhibit cell death but by far less extent than those of CLC-604 and CLC-609. Hoechst 33258 staining confirmed that the reduced cell viability by C2 ceramid was due to apoptosis. Pretreatment with CLC-609 attenuated C2 ceramide-induced apoptosis in a dose-dependent manner. Neuroprotective effect of CLC-609 was abolished by ERK inhibitors. These results suggest that CLC-609 by activation of ERK1/2 signal pathways protects primary cortical neurons from C2 ceramide-induced apoptosis.
In conclusion, our data demonstrate that ugonin K and furopyrazole derivatives might be an important clue for drug design as neuroprotectants and potential therapeutic agents for against neurodegenerative disease.
目錄……………………………………………………………………I
表目錄…………………………………………………………………IV
圖目錄…………………………………………………………………V
縮寫表…………………………………………………………………VII
中文摘要………………………………………………………………IX
英文摘要………………………………………………………………XI

第一章 緒論………………………………………………………1
第一節 研究背景及動機..………………………………………1
第二節 細胞凋亡與神經系統及其疾病..………………………5
第三節 誘導神經細胞凋亡..…..………………………………11
第四節 神經細胞保護劑…..……………………………………17
第二章 實驗材料和方法…………………………………………23
第一節 實驗材料………………………………………………. 24
第二節 實驗方法………………………………………………. 31
ㄧ、神經細胞培養……………………………………………………31
二、神經細胞存活率的分析…………………………………………34
三、神經細胞凋亡的確認……………………………………………36
四、西方墨點法……………………………………………….39
五、統計分析…………………………………………………………46
第三章 Ugonin K對過氧化氫誘導SH-SY5Y神經細胞凋亡的保護作用47
第一節 Ugonin K對過氧化氫誘導SH-SY5Y神經細胞凋亡的保護作用之
探討…………………………………………………………48
一、過氧化氫誘導SH-SY5Y神經細胞死亡…………………………48
二、Ugonin K對過氧化氫誘導SH-SY5Y細胞死亡之保護作用……49
三、過氧化氫對SH-SY5Y細胞型態之影響…………………………50
四、過氧化氫誘導SH-SY5Y細胞死亡的特徵………………………50
第二節 Ugonin K的作用機轉………………………………………51
一、Ugonin K保護過氧化氫誘導SH-SY5Y細胞凋亡與caspase路徑之
關係……………………………………………………………51
二、Ugonin K保護過氧化氫誘導SH-SY5Y細胞凋亡與ERK路徑之關
係………………………………………………………………54
三、Ugonin K保護過氧化氫誘導SH-SY5Y細胞凋亡與PI3K路徑之關
係………………………………………………………………56
四、Ugonin K保護過氧化氫誘導SH-SY5Y細胞凋亡與p38和JNK路徑之
關係……………………………………………………………60
五、討論……………………………………………………………62
第四章 Furopyrazole衍生物對C2 ceramide誘導初級皮質神經細胞
凋亡的保護作用……………………………………………78
第一節 Furopyrazole衍生物對C2 cereamide誘導初級皮質神經細
胞凋亡的保護作用之探討………………………………..79
一、C2 ceramide誘導初級皮質之神經細胞死亡…………………79
二、Furopyrazole衍生物對C2 ceramide誘導初級皮質神經細胞死亡
保護作用之探討…………………………………………………80
三、C2 ceramide對初級皮質神經細胞型態之影響………………82
四、C2 ceramide誘導初級皮質神經細胞死亡的特徵……………82
第二節 CLC-609的作用機轉…………………………………………83
一、CLC-609保護C2 ceramide誘導初級皮質神經細胞凋亡與cGMP-
PKG路徑…………………………………………………………83
二、CLC-609保護C2 ceramide誘導初級皮質神經細胞凋亡與ERK路
徑之關係……………………………………………………….84
三、討論………………………………………………………………85
第五章 結論與未來展望……………………………………………94
參考文獻……………………………………………………………98
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