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研究生:顏阡聿
研究生(外文):Yen, Chien-Yu
論文名稱:抗發炎相關化合物 VB-037 及甘草次酸 在帕金森氏症細胞模式上之治療潛力
論文名稱(外文):Therapeutic potential of anti-inflammatory compounds VB-037 and glycyrrhetic acid in Parkinson’s disease cell model
指導教授:李桂楨李桂楨引用關係
指導教授(外文):Lee-Chen, Guey-Jen
學位類別:碩士
校院名稱:國立臺灣師範大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2018
畢業學年度:107
語文別:中文
論文頁數:78
中文關鍵詞:帕金森氏症α-Synuclein神經發炎VB-037甘草次酸
外文關鍵詞:Parkinson’s diseaseα-synucleinneuroinflammationVB-037glycyrrhetic acid
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帕金森氏症為僅次於阿茲海默氏症之第二常見的神經退化性疾 病,主要症狀有手足顫抖、僵硬、動作緩慢、站立不穩等,患者黑質 多巴胺神經元大量減少,並出現包含 α-Synuclein (簡稱 α-Syn)蛋白的 路易氏體。α-Syn 蛋白本質上無特定結構,易形成不溶性的纖維及聚 集。近年研究發現微膠細胞參與的免疫與發炎反應,與帕金森氏症致 病機制相關,且細胞外的 α-Syn 蛋白,會刺激微膠細胞產生前發炎激 素及活性氧化物。為探究 α-Syn 刺激的發炎反應,本研究以大腸桿菌 BL21 表現 His 標籤的 α-Syn 蛋白,並以親和性色層純化之。2 μg/μl 濃度的單體 α-Syn 於 37°C 培養箱搖晃一週後,Thioflavin T 螢光分析 及共軛焦顯微鏡觀察,皆確認了時間依
Parkinson’s disease (PD) is an age-related neurodegenerative disorder that ranks only second behind Alzheimer’s disease in prevalence. PD is characterized by resting tremor, rigidity and bradykinesia, in addition to the loss of dopaminergic (DA) neurons in substantia nigra and the presence of α-synuclein (α-Syn)-containing Lewy bodies. α-Syn is an intrinsically unstructured protein prone to forming insoluble fibrils and aggregates. Recently, it is becoming evident that immune response engaged by microglia actively contributes to the pathogenesis of PD and extracellular α-Syn increases the production of pro-inflammatory mediators in microglia. To examine the capacity of α-Syn to stimulate inflammation, His-tagged α-Syn was expressed in Escherichia coli BL21 and purified by affinity chromatography. Monomeric α-Syn in 2 μg/μl concentration was incubated at 37°C with continuous shaking for a week and a time-dependent fibrillation of α-Syn was confirmed by biochemical thioflavin T fluorescence assay and confocal microscope examination. Increased production of nitric oxide (NO) and Iba1 was observed after addition of α-Syn fibrils and pretreatment with a quinoline compound VB-037 and a pentacyclic triterpenoid glycyrrhetic acid (a metabolite of glycyrrhizin, an active constituent of Chinese herbal medicine Glycyrrhiza inflata and Shaoyao Gancao Tang) suppressed the NO production, Iba1 expression and IL-1β maturation in mouse BV-2 microglia. Mouse inflammation antibody array and western/ELISA/real-time PCR confirmation further revealed increased expression of IL-1α, IL-1β, TNF-α, IFN-γ, GM-CSF, IL-6 and G-CSF in α-Syn-inflamed BV-2 cells and both VB-037 and glycyrrhetic acid pretreatment effectively reduced the expression and release of these pro-inflammatory mediators. To examine the therapeutic potential of anti-inflammatory compounds VB-037 and glycyrrhetic acid in PD, phorbol ester 12-O-tetradecanoylphorbol-13-acetate (TPA) up-regulated tyrosine hydroxylase (TH, DA neuronal marker) and neuronal differentiation in human neuroblastoma SH-SY5Y cells with inducible A53T α-Syn-GFP expression and α-Syn fibril-dependent aggregate formation were established. By ProteoStat stain and western/dot blot examination, VB-037 and glycyrrhetic acid effectively reduced α-Syn aggregation. The study offers new viewpoints of application to benefit drug development for α-Syn-stimulated neuroinflammation in PD.

Keywords: Parkinson’s disease, α-synuclein, neuroinflammation, VB-037, glycyrrhetic acid
目錄 I
圖表次 IV
摘要 V
英文摘要 VII

壹、緒論 1
一、帕金森氏症 1
(一). 帕金森氏症之介紹 1
(二). 帕金森氏症之病理學特徵 1
(三). 帕金森氏症與神經發炎 2
二、α-Syn蛋白 3
(一). 蛋白結構與生理功能 3
(二). 路易士體的形成與神經發炎 4
三、神經發炎反應 5
(一). 微膠細胞(Microglia) 5
(二). 神經發炎反應與帕金森氏症的關聯 6
四、藥物篩檢之方向 8
(一). 中藥脹果甘草、芍藥甘草湯及其或活性成分 8
(二). 化合物AM404、VB-037、甘草次酸 (Glycyrrhetic acid) 10

貳、研究架構與動機 13

參、研究材料與方法 14
一、建構pET-28a(+)-SNCA重組質體 14
二、α-Syn蛋白質誘導表現 14
三、α-Syn蛋白質純化 15
四、Thioflavin T及螢光顯微鏡分析α-Syn纖維形成 15
五、A53T α-Syn-GFP SH-SY5Y細胞建構 15
六、細胞培養與繼代 16
七、細胞毒性測試 17
八、NO含量測試 17
九、西方墨點法分析 18
十、小鼠抗體矩陣測試(Mouse inflammation antibody array) 19
十一、酵素免疫分析法(Enzyme-linked immunosorbent assay, ELISA) 20
十二、即時聚合酶鏈式反應(Real time polymerase chain reaction, RT-PCR) 22
十三、圓點墨點分析法(Dot blot/Filter filtration assay) 23
十四、蛋白聚集測試(ProteoStat® protein aggregation assay) 23
十五、統計分析 24

肆、結果 25
一、製備α-Syn纖維 25
二、建立LPS/α-Syn活化BV-2微膠細胞發炎模式 26
三、待測化合物及中藥的細胞毒性分析 27
四、待測化合物及中藥的細胞發炎保護性分析 27
五、VB-037及甘草次酸抑制BV-2微膠細胞發炎的標的 29
六、α-Syn纖維及VB-037、甘草次酸的SH-SY5Y細胞毒性 31
七、誘導表達A53T α-Syn-GFP之SH-SY5Y細胞株的建立 32
八、A53T α-Syn-GFP SH-SY5Y細胞的聚集分析 32
九、VB-037及甘草次酸抑制A53T α-Syn-GFP聚集的情形 34
十、高通量分析VB-037及甘草次酸抑制A53T α-Syn-GFP SH-SY5Y細胞聚集的情形 34

伍、討論 36

陸、參考資料 43

柒、附錄圖表 59

圖表次
圖一、pET-28a(+)-SNCA-His tag重組質體的建構 59
圖二、SNCA-His融合蛋白的誘導表現 60
圖三、SNCA-His纖維製備 61
圖四、LPS及α-Syn纖維誘導BV-2細胞發炎反應 62
圖五、待測化合物之結構、分子式及分子量 64
圖六、待測化合物及中藥對BV-2細胞之毒性 65
圖七、待測化合物及中藥對BV-2細胞發炎之保護性 66
圖八、小鼠抗體矩陣測試檢測化合物VB-037及甘草次酸對BV-2細胞發炎相關因子的影響 68
圖九、VB-037及甘草次酸影響BV-2細胞發炎相關因子的驗證 70
圖十、VB-037及甘草次酸影響BV-2細胞發炎因子IL-1β、TNF-α、GM-CSF、IL-6、G-CSF的酵素免疫分析 72
圖十一、α-Syn纖維及VB-037、甘草次酸對SH-SY5Y細胞之毒性 74
圖十二、建立誘導表達A53T突變的α-Syn-GFP之SH-SY5Y細胞株 75
圖十三、Tet-On A53T α-Syn-GFP SH-SY5Y細胞的聚集測試及西方點墨法檢測VB-037、甘草次酸抑制聚集形成的情形 76
圖十四、ProteoStat®蛋白質聚集試劑測試VB-037、甘草次酸抑制A53T α-Syn-GFP聚集形成的情形 78
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