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研究生: 楊佩寧
Yang, Pei-Ning
論文名稱: 針對帕金森氏症探討神經性發炎致病機制與具有淺力的治療策略
Parkinson’s disease: investigation of pathogenic mechanism and therapeutic strategy of neuroinflammation
指導教授: 李桂楨
Lee, Guey-Jen
學位類別: 碩士
Master
系所名稱: 生命科學系
Department of Life Science
論文出版年: 2020
畢業學年度: 108
語文別: 中文
論文頁數: 96
中文關鍵詞: 帕金森氏症神經炎症發炎體BV-2微膠細胞α-突觸核蛋白BE(2)-M17細胞治療策略
英文關鍵詞: Parkinson’s disease, Neuroinflammation, Inflammasome, BV-2 microglia, α-Synuclein, BE(2)-M17 cell model, Therapeutics
DOI URL: http://doi.org/10.6345/NTNU202001600
論文種類: 學術論文
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  • 帕金森氏症(Parkinson’s disease)為一種漸進性神經退化疾病,在全球60歲以上的族群中約有1%的人患有此疾病。臨床上,大多數患者顯示出黑質緻密部中多巴胺能神經元的缺失和α-突觸核蛋白(α-Synuclein)的存在,引起運動遲緩、靜息性震顫、僵硬和體位不穩等主要症狀。α-突觸核蛋白本質上是一種非結構化蛋白質,易形成不溶性原纖維和聚集體。最近研究顯示,大腦中的微膠細胞(Microglia)介導的免疫反應積極促進了PD的發病機制,而細胞外α-突觸核蛋白促進了微膠細胞的發炎反應。本研究首先利用原核生物生產的帶有His標籤的α-突觸核蛋白,在37°C下連續搖動三天後,形成α-突觸核蛋白原纖維。用α-突觸核蛋白原纖維刺激小鼠BV-2微膠細胞20小時後,觀察到一氧化氮(NO)和Iba-1的產量增加,且激活的微膠細胞伸長且突起延長。接著利用α-突觸核蛋白原纖維激活BV-2,檢測七種化合物的抗發炎性,包括C12-HSL、3-oxo-C12-HSL (兩種N-酰基高絲氨酸內酯)、7-Chlorokynurenic acid (7-Cl-KYNA,一非競爭型NMDA受體拮抗劑)、4-Chlorokynurenine (4-Cl-KYN,一穿透腦的7-Cl-KYNA前驅藥)、LM-031、LM-021 (兩種查爾酮-香豆素衍生物)和NC009-1 (一種吲哚化合物)等,藉檢測上述化合物前處理的BV-2培養液中NO以及M1 (IL-1β、IL-6、TNF-α)和M2 (IL-4、IL-10、TGF-β)細胞激素的水平,來評估化合物的抗炎潛能。NO和細胞激素ELISA分析結果顯示,α-突觸核蛋白原纖維誘導發炎的BV-2細胞培養液中,NO、IL-1β、IL-6和TNF-α的表達增加,而LM-021和NC009-1預處理可有效降低了上述促炎介質的表達和釋放。為進一步檢查LM-021和NC009-1對帕金森氏症的治療潛力,本研究建立視黃酸(Retinoic acid)誘導神經分化、誘導表達A53T α-突觸核蛋白-GFP及α-突觸核蛋白原纖維依存的神經細胞瘤BE(2)-M17細胞。上述細胞前處理LM-021和NC009-1後,誘導A53T α-突觸核蛋白-GFP表現並加入α-突觸核蛋白原纖維,六天後評估LM-021和NC009-1促進神經突生長情形,並藉點轉漬法來評估抑制α-突觸核蛋白聚集形成的抗炎潛能。結果顯示NC009-1可以促進神經突生長及抑制α-突觸核蛋白聚集,LM-021改善神經突生長雖然未達顯著性,但可抑制α-突觸核蛋白聚集。這項研究提供了新的應用觀點,以有益於α-突觸核蛋白刺激的帕金森氏症神經炎症的藥物開發。

    Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder that is estimated to affect approximately 1% of the population older than 60 years of age. Clinically, most patients present with the cardinal symptoms of bradykinesia, resting tremor, rigidity and postural instability that are induced by the loss of dopaminergic neurons in substantia nigra compacta and the presence of α-synuclein containing Lewy bodies. α-Synuclein is an intrinsically unstructured protein prone to forming insoluble fibrils and aggregates. Recently, it is becoming evident that microglia-mediated immune responses in the brain actively contribute to the pathogenesis of PD and extracellular α-synuclein increases the production of pro-inflammatory mediators in microglia. In this study, prokaryotic-derived His-tagged α-synuclein was incubated at 37°C with continuous shaking for 3 days to form α-synuclein fibrils. After stimulation of mouse BV-2 microglial cells with the preformed α-synuclein fibrils for 20 h, increased production of nitric oxide (NO) and induction of brown adipocytes 1 (Iba-1) was observed and the activated microglia became elongated with extended processes. In the present study, seven compounds including C12-HSL, 3-oxo-C12-HSL (two N-Acyl homoserine lactones), 7-chlorokynurenic acid (a noncompetitive NMDA receptor antagonist), 4-chlorokynurenine (a brain-penetrant prodrug of 7-chlorokynurenic acid), LM-031, LM-021 (two in-house chalcone-coumarin derivatives), and NC009-1 (an indole compound) were tested for the anti-inflammatory effects on α-synuclein-induced inflammation. The anti-inflammatory potentials of these compounds were assessed by examination of NO as well as M1 (IL-1β, IL-6, TNF-α) and M2 (IL-4, IL-10, TGF-β) cytokine levels in cultured medium collected from α-synuclein-activated BV-2 cells with or without compound pretreatment. NO and cytokine ELISA assays revealed increased expression of NO, IL-1β, IL-6 and TNF-α in α-synuclein-inflamed BV-2 cells, and LM-021 and NC009-1 pretreatment effectively reduced the expression and release of these pro-inflammatory mediators. To examine the therapeutic potential of LM-021 and NC009-1 in PD, retinoic acid (a metabolite of vitamin A) differentiated human neuroblastoma BE(2)-M17 cells with inducible A53T α-synuclein-GFP expression and α-synuclein fibril-dependent aggregate formation were established. After LM-021 and NC009-1 pretreatment, A53T α-synuclein-GFP induction and α-synuclein fibrils addition for 6 days, neurite outgrowth promotion and α-synuclein aggregate inhibition (by dot blot) were evaluated. The results demonstrated that NC009-1 promoted neurite outgrowth and inhibited α-synuclein aggregation. Although improvement of neurite growth was not significant, LM-021 inhibited α-synuclein aggregation. The study offers new viewpoints of application to benefit drug development for α-synuclein-stimulated neuroinflammation in PD.

    致謝 i 摘要 iii 目錄 vii 圖目錄 ix 第一章 緒論 1 第一節 帕金森氏症 1 一、帕金森氏症 1 二、病理學 1 三、臨床症狀 4 第二節 α-突觸核蛋白 5 一、生理功能與蛋白結構 5 二、α-突觸核蛋白突變與神經性發炎 6 第三節 神經性發炎 8 一、微膠細胞(Microglia) 8 二、M1/M2細胞激素 9 三、發炎體(Inflammasome) 10 四、神經性發炎與帕金森氏症 11 第四節 待測化合物 12 一、C12-HSL、3-oxo-C12-HSL 12 二、4-Cl-KYN、7-Cl-KYNA 13 三、LM-031、LM-021 14 四、NC009-1 14 第二章 研究架構與動機 16 第三章 研究材料與方法 17 第一節 材料 17 一、化合物 17 二、化學藥品 17 三、抗體 22 四、細胞及培養液 23 第二節 方法 23 一、化合物的里賓斯基五規則、極性表面積及血腦屏障通透性預測 23 二、DPPH自由基清除能力測定 24 三、α-突觸核蛋白纖維製備及化合物抑制原纖維形成分析 24 (一) α-突觸核蛋白誘導表現 24 (二) α-突觸核蛋白純化 25 (三) α-突觸核蛋白原纖維製備 25 (四)化合物抑制原纖維形成分析 26 四、細胞培養及繼代 26 五、細胞毒性測試 27 六、α-突觸核蛋白原纖維活化BV-2微膠細胞及化合物之抗炎性檢測 28 (一)實驗流程 28 (二) NO測試 29 (三)酵素連結免疫吸附分析法 29 (四)西方墨點法分析 29 七、BE(2)-M17細胞多巴胺神經分化檢測 30 八、建立Tet-On SNCA-GFP BE(2)-M17細胞模式 32 (一)篩選細胞群落 32 (二)檢測表現量 33 (三)即時聚合酶連鎖反應定量 33 九、A53T SNCA-GFP BE(2)-M17細胞及化合物之神經保護性測試 34 (一)誘導GFP螢光表現 34 (二)前處理化合物於A53T SNCA-GFP BE(2)-M17細胞的神經突生長分析 35 (三)前處理化合物於A53T SNCA-GFP BE(2)-M17細胞的點轉漬法分析 35 十、統計分析 36 第四章 結果 37 一、化合物溶解度及生物利用性預測 37 二、化合物自由基清除效力分析 38 三、α-突觸核蛋白原纖維製備及化合物抑制α-突觸核蛋白聚集分析 38 四、化合物的細胞毒性分析 39 五、α-突觸核蛋白原纖維活化的BV-2細胞模式的化合物抗發炎分析 40 六、BV-2細胞模式的化合物抗發炎作用 42 七、BE(2)-M17細胞的多巴胺神經分化 43 八、野生型及A53T突變型α-突觸核蛋白-GFP之BE(2)-M17細胞株的建立 45 九、化合物對A53T SNCA-GFP BE(2)-M17細胞神經突生長和α-突觸核蛋白-GFP融合蛋白聚集分析 46 第五章 討論 50 參考文獻 59 附錄圖表 74

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