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研究生:曾雅瑋
研究生(外文):Ya-Wei Tzeng
論文名稱:自噬作用參與在神經母細胞瘤SH-SY5Y細胞中低氧預處理對1-甲基-4-苯基吡啶離子毒性之神經保護
論文名稱(外文):Autophagy is involved in the neuroprotection by hypoxic preconditioning of MPP+ -induced neurotoxicity in SH-SY5Y neuroblastoma cells
指導教授:林滿玉
指導教授(外文):Anya Maan-Yuh Lin
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
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:85
中文關鍵詞:自噬作用低氧預處理神經保護
外文關鍵詞:autophagyhypoxiapreconditioningMPP+neuroprotection
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對許多中樞神經退化疾病而言,非致命性之預處理被認為為一有效的神經保護性策略,包括對抗中風及帕金森氏症等。在我的論文中,以具有多巴胺神經特性之神經母細胞瘤SH-SY5Y細胞為材料,探討低氧預處理對誘發帕金森氏症模式藥物1-甲基-4-苯基吡啶離子(1-methyl-4-phenylpyridinium, MPP+)毒性之神經保護機制,並進一步研究細胞自噬作用是否參與在其中。
利用兩種不同低氧濃度處理發現,0.1%低氧處理4-24小時與1%低氧處理48-72小時造成SH-SY5Y細胞明顯之細胞死亡;反之,1%低氧處理在24小時內不會引發細胞毒性。經過1%低氧處理4-24小時之SH-SY5Y細胞,除了抗凋亡蛋白Bcl-2表現量短暫增加,其他壓力蛋白包括heme oxygenase-1、heat shock protein 70、activating transcription factor 4、activating transcription factor 6、C/EBP homologous protein、及X-box binding protein 1表現量並無明顯變化。1%低氧處理短暫地增加自噬相關蛋白LC3-II表現量,低氧處理8小時提高LC3-II 表現程度最高,並引發自噬泡的聚集及低氧誘導因子(Hypoxia-inducible factor-1��, HIF-1���w之表現,而24小時低氧處理LC3-II 表現量下降。利用Bafilomycin A1加入8小時低氧處理,發現低氧引發之LC3-II大量累積,而自噬作用抑制劑3-methyladenine (3MA, 10 mM)則抑制低氧處理之作用。這些研究結果皆顯示,低氧處理短暫地活化細胞自噬作用。
另一方面,探討MPP+之神經毒性,發現MPP+依濃度梯度引發SH-SY5Y細胞死亡,50%致死濃度為2 mM。以該濃度藥物處理細胞24小時會引發凋亡相關蛋白caspase 3的活化、DNA嚴重斷裂,且明顯提高LC3-II 表現,顯示MPP+會引發細胞凋亡和自噬作用。進一步研究低氧預處理對MPP+神經毒性之影響,發現8小時低氧預處理伴隨24小時之回復正常氧壓處理,能對抗MPP+造成之細胞死亡,並降低其活化自噬作用之程度,而減緩MPP+引發之凋亡。在8小時低氧期間給予3MA處理,發現3MA會抑制低氧預處理之神經保護作用,使細胞死亡率增加、LC3-II表現再度上升、caspase 3的活化,且DNA斷裂程度更為嚴重,顯示3MA藉抑制了低氧引發之細胞自噬,而阻斷低氧預處理的保護效果。由以上顯示,低氧預處理的確可以保護MPP+之神經毒性,且自噬作用被證實參與在此低氧預處理之神經保護機制中,因此,研發影響自噬作用之藥物,或許可用於神經退化疾病之治療。
Sub-lethal preconditioning has been proposed as a neuroprotective strategy against several central nervous system (CNS) neurodegenerative diseases including stroke and Parkinsonism. In my thesis, the involvement of autophagy in the protection by hypoxic preconditioning of MPP+ (1-methyl-4-phenylpyridinium)-induced neurotoxicity was studied in SH-SY5Y neuroblastoma cells.
In contrast to 0.1% hypoxia and 1% hypoxia for 48-72h which caused significant cell death, 1% hypoxic treatment for 4-24 h transiently increases Bcl-2 expression and has no effect on cytotoxicity and no significant changes in levels of stress proteins including heme oxygenase-1, heat shock protein 70 as well as endoplasmic reticulum stress-related proteins, including activating transcription factor 4, activating transcription factor 6, C/EBP homologous protein, and X-box binding protein 1. At the same time, microtubule-associated protein 1 light chain-3-II (LC3-II) recruitment was transiently elevated by hypoxic treatment. Maximal LC3-II recruitment and Monodansylcadaverine fluorescent activities were observed after 8-h hypoxia. Furthermore, hypoxia-inducible factor-1�� (HIF-1���w expression was elevated in the nuclear fraction of the 8-h hypoxia-treated SH-SY5Y cells. However, the elevated LC3-II recruitment was diminished after 24 h hypoxic treatment. Bafilomycin A1 enhanced hypoxia-induced LC3-II recruitment; 3-Methyladenine (3MA, 10 mM) efficiently attenuated the elevation in LC3-II recruitment induced by 8-h hypoxia, indicating that hypoxic treatment transiently induced autophagy.
MPP+ concentration-dependently reduced cell viability with an EC50 of 2 mM. MPP+ (2 mM) activated caspase 3 and induced DNA fragmentation in the treated SH-SY5Y cells, suggesting the involvement of apoptosis in MPP+-induced cytotoxicity. At the same time, MPP+-induced elevation in LC3-II was demonstrated in a concentration-dependent manner. A prior 8-h hypoxic treatment followed by 24 renormoxia attenuated MPP+-induced cell death, caspase 3 activation and DNA fragmentation. Furthermore, MPP+-induced LC3-II recruitment was diminished by hypoxic pretreatment. Co-incubation with 3-methyladenine was found to inhibit the protection by hypoxic preconditioning of MPP+-induced cell death and LC3-II recruitment. Interestingly, activation of caspase 3 and DNA fragmentation were more evident after 3MA. Taken together, the data in my thesis suggest that autophagy is transiently activated by hypoxia. In addition, autophagy may be involved in the protection by hypoxic preconditioning of MPP+-induced cytotoxicity, indicating a prosurvival role of autophagy in neuroprotection by hypoxic preconditioning.
目錄 …………………………………………………………………… 1
圖次目錄 ……………………………………………………………… 3
縮寫表………………………………………………………………… 4
英文摘要……………………………………………………………… 6
摘要…………………………………………………………………… 8
緒論……………………………………………………………………10
一、細胞自噬 (Autophagy) ……………………………..........10
1.1 定義與功能……………………………………………………….10
1.2 自噬作用之機制…………………………………………………..10
1.3 細胞自噬之上游訊息……………………………………………..11
1.4細胞自噬的生理角色……………………………………………….11
1.5細胞自噬的病理角色……………………………………………….12
1.5.1 腫瘤…………………………………………………..........12
1.5.2 心衰竭 (heart failure) ………………………...........13
1.5.3 感染性疾病 (infectious disease) ……………………....13
1.5.4 神經相關疾病……………………………..................14
1.5.4.1 腦缺血 (brain ischemia;stroke) …………..........14
1.5.4.2 神經退化疾病………………………....................14
1.6 自噬作用之誘發劑…………………………………......15
1.7 自噬作用之抑制劑..………………………………......15
1.8 自噬作用之檢測方法…16
二、低氧 (Hypoxia)………………………........................................16
2.1 定義與分類…………………………………………………......16
2.2 低氧引發的訊息傳遞:低氧誘導因子(hypoxia-inducible factor-1��)的調控.........................................17
2.3 低氧與氧化壓力之關聯………………………………………....18
2.4 低氧與細胞自噬(autophagy)…………………………………18
2.5 低氧對生物體之影響…………………………………………....19
三、預處理 (preconditioning) ……………………………………20
3.1 緣由及定義………………………………....................20
3.2 預處理的訊息調控………………………………..............20
3.3 低氧預處理(hypoxic preconditioning, HP) ……………….21
3.3.1 定義與特性…………………………………………………21
3.3.2 低氧預處理之保護效果……………………………………...22
3.3.3 低氧預處理的訊息調控…………………………………......22
四、帕金森氏症 (Parkinson’s disease) …………………………23
4.1 病理特徵與成因 …………………………………………………23
4.2 帕金森氏症模式藥物:MPTP之作用機制 ……………………….24
4.3 MPP+引發神經死亡之途徑 ……………………………….25
實驗目的 ………………………………………………………………28
實驗材料與方法 ………………………………………………………29
I. 藥品與試劑 ………………………………………………29
II. 儀器與材料 ………………………………………………31
III. 實驗方法 ………………………………………………….31
實驗結果 ………………………………………………………………37
討論 ………………………………………………………………....42
結論 ………………………………………………………………....47
參考文獻 ……………………………………………………………...48
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