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研究生:游賀培
研究生(外文):He-pei You
論文名稱:中草藥抑制細胞興奮性毒殺以治療第十七型脊髓共濟失調症
論文名稱(外文):Chinese herbal medicine as a new perspective for the treatment of spinocerebellar ataxia type 17 via inhibition of excitotoxicity
指導教授:吳忠信 博士林榮耀 博士
指導教授(外文):Chung-Hsin Wu. Ph.D.Jung-Yaw Lin. Ph.D.
學位類別:碩士
校院名稱:國立臺灣師範大學
系所名稱:生命科學研究所
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:2014
畢業學年度:102
語文別:英文
論文頁數:73
中文關鍵詞:第十七型小腦萎縮症以麩胺酸誘導之興奮性毒殺SH-SY5Y 細胞細胞凋亡
外文關鍵詞:Spinocerebellar ataxia type 17glutamate-induced excitotoxicitySH-SY5Y cellapoptosis
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在神經退化性疾病中過量麩胺酸誘導受器活化與神經細胞損傷具有關聯性,從過去文獻中發現在小腦脊髓萎縮症 (Spinocerebellar ataxia, SCA) 細胞模式中,當活化麩胺酸受器會使得胞外鈣離子大量流入細胞質中,影響粒線體致使其功能損傷,進而誘發細胞凋亡路徑,引發細胞死亡。其中 SCA17 其之發病機制為 TATA 結合蛋白 (TBP) 中多麩醯胺酸 (>42 glutamines) 擴增,無法有效與 DNA 結合,並與轉錄因子蛋白質結合導致轉錄活性受到抑制,細胞內蛋白質異常聚集,產生細胞壓力,最後引發細胞死亡;此外,亦發現鈣離子有大量流入細胞內的情況。本研究的目的篩選出對於神經退化性疾病具有改善作用之中草藥及其成分。實驗以 SH-SY5Y 神經母細胞瘤細胞為細胞模式,篩選各種中草材及其成分對於麩胺酸誘導細胞產生興奮性毒殺是否具有改善作用。以 MTT 和流式細胞儀分析方法,我們發現 NH043-1 有效降低麩胺酸誘導所造成的細胞死亡;從西方墨點法中,觀察 NH043-1 可以降低麩胺酸誘導六小時之後 Bax, Calpain-2 和 SBDPs 的表現量而 Bcl-2 的表現量有上升的趨勢;二十四小時之後cleaved-PARP, cleaved-caspase-3 與 cleaved-caspase-9 的表現量有降低的趨勢。以 CL 冷光偵測儀,觀察 NH043-1 可以有效降低細胞內的自由基含量。利用流式細胞儀檢測粒線體膜電位,發現 NH043-1 可以提升粒線體膜電位。在誘導 nTBP/Q79-EGFP 融合蛋白表現的 SCA17細胞模式上,NH043-1 可以增加細胞的存活率以及 cleaved caspase-9, cleaved caspase-3 與cleaved PARP的表現量有降低的趨勢。在西方墨點法和 Dot-blot 方法,觀察 NH043-1 可以有效降低 TBP 蛋白質的異常聚集。在動物實驗部分使用 8 周大的 SCA17 轉殖基因老鼠從第九週開始注射 NH043-1,從 Rotarod assay 實驗發現在第 16, 18 及 20 周能夠有效延長其在 rotarod 上的時間,在 footprint assay 實驗上也改善步行缺失,並且在實驗小鼠小腦組織內有缺陷的 TBP 蛋白質的異常聚集和cleaved-caspase-3 表現量都有減緩。據以上的結果,NH043-1 可以改善麩胺酸誘導所造成的細胞死亡,具有治療 SCA17 之潛力。



Excessive stimulation of glutamate induces neuronal damage through receptor-mediated excitotoxicity, which is thought to be involved in chronic neurodegenerative disorders. Several studies indicated that calcium influx into the cytoplasm in SCA transgenic cell by activation of glutamate receptors and increased toxic cascades, including the disturbance of mitochondrial function and the enhancement of apoptotic pathway. Spinocerebellar ataxia (SCA) type 17, a neurodegenerative disorder, is caused by polyglutamine (polyQ) expansion (>42 glutamines) in the basal transcription factor TATA binding protein (TBP). The polyQ expansion interferes, increases protein aggregation and results in cell death. It is believed that Chinese herbal medicines (CHMs) prescription might be a new perspective for the treatment of neurodegenerative disorder. Accordingly, we proposed to identify effective compounds of CHMs protecting cells from glutamate-induced excitotoxicity in human neuroblastoma SH-SY5Y cells. We found that NH043-1 protected human neuroblastoma SH-SY5Y cells from cell death induced by glutamate-mediated excitotoxicity, attenuated the production of intracellular reactive oxygen species (ROS), and decreased the expression of Calpain-2, SBDPs and Bax/Bcl-2 ratio for 6 h, and the expressions of cleaved-caspase-9, cleaved-caspase-3 and cleaved-PARP for 24 h. NH043-1 also blocked the decrease of mitochondrial membrane potential by MSG. In nTBP/Q79-EGFP cell model, NH043-1 also showed the remarkably protective activity against the neuronal cell death and decreased the expression of cleaved-caspase-9, cleaved-caspase-3, and cleaved-PARP for 24 h. NH043-1 also inhibited the protein aggregation. In SCA17 animal model, NH043-1-treatment SCA17 mice performed better than Saline-treatment SCA17 mice on an accelerating rota-rod and footprint experiments in 5 months. NH043-1 attenuated expression of TBP protein aggregation and cleaved-caspase-3 in cerebella of SCA17 mice. The results suggest that NH043-1 could be a potential medicine in the treatment of neurodegenerative disorders (SCA17) through inhibition of glutamate-induced apoptosis via mitochondria pathway.
目錄
目錄 I
中文摘要 IV
Abstract VI
Figure lists VIII
1. Introduction 1
2. Research aims 8
3. Material and methods 9
3.1 Materials 9
3.2 Cell culture 10
3.3 MTT assay 10
3.4 Flow cytometric measurement of apoptotic cells 12
3.5 Western blotting 13
3.6 Measuring reactive oxygen species (ROS) activity in vitro by Chemiluminescence (CL) 19
3.7 Measuring mitochondrial membrane potential by flow cytometry 19
3.8 Dot-blot filter retardation assay 20
3.9 Animal model 22
3.9.1 Motor behavioral assessment 22
3.9.2 Footprint patterns analysis 23
3.9.3 Western blot analysis of aggregated TBP and cleaved caspase-3 protein in the cerebellum of tested mice 24
4. Results 26
4.1 NH043-1 effectively protects SH-SY5Y cells against MSG-induced excitotoxicity 26
4.2 NH043-1 attenuates the apoptosis of SH-SY5Y cells induced by MSG 27
4.3 NH043-1 decreases the expressions of Calpain-2 and SBDPs in SH-SY5Y cells treated with MSG 28
4.4 NH043-1 decreases the expressions of Bax, but increased Bcl-2 in SH-SY5Y cells treated with MSG 29
4.5 NH043-1 inhibits the expressions of caspase family proteins mediated by MSG 30
4.6 NH043-1 inhibits the intracellular ROS induced by MSG 31
4.7 NH043-1 blocks the decrease of mitochondrial membrane potential (MMP) mediated by MSG 32
4.8 NH043-1 effectively increases cell viability against Dox-induced nTBP/Q79-EGFP cells 32
4.9 NH043-1 inhibits the expression of caspase family protein mediated by Dox-induced nTBP/Q79-EGFP cells 33
4.10 Effect of NH043-1 on polyQ protein aggregation by Dox-induced nTBP/Q36-EGFP and nTBP/Q79-EGFP cells 34
4.11 NH043-1 ameliorates the neurological behavior of SCA17 transgenic mice 35
4.12 NH043-1 attenuates polyQ protein aggregation and cleaved-caspase-3 protein in cerebella of SCA17 transgenic mice 36
5. Discussion 37
6. References 42
7. Figures 56
8. Table 72
9. Supplementary figure 73

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