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研究生:林易瑾
研究生(外文):Yi-Chin Lin
論文名稱:美諾四環素、雷帕黴素和依維莫司在動物癲癇模式與細胞模式的角色
論文名稱(外文):The Roles of Minocycline, Rapamycin, and Everolimus in Kainic acid-induced Seizure
指導教授:李旺祚李旺祚引用關係
指導教授(外文):Wang Tso Li
口試委員:劉昭麟黃憲松
口試日期:2015-07-24
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:腦與心智科學研究所
學門:醫藥衛生學門
學類:其他醫藥衛生學類
論文種類:學術論文
論文出版年:2015
畢業學年度:103
語文別:英文
論文頁數:62
中文關鍵詞:神經發炎反應微膠細胞活化卡英酸依維莫司哺乳動物雷帕黴素靶蛋白癲癇發作
外文關鍵詞:neuroinflammationmicroglia activationkainic acideverolimusmTORseizure
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微膠細胞(microglia)負責腦中神經發炎反應以抵抗外來物或腦部損傷,而神經發炎反應亦關乎某些神經退化疾病和腦部的傷害,例如癲癇即為其一。當腦部有所損傷,微膠細胞活化(microglia activation)會即時促進促發炎因子(pro-inflammatory factor)引起神經發炎反應。哺乳動物雷帕黴素靶蛋白(mammalian target of rapamycin)被證明與微膠細胞活化與後續的發炎反應有關;為了釐清神經發炎反應與癲癇發作之關係與生理機制,我們使用脂多醣(liposaccharide (LPS))引發的發炎模式,使BV2 microglia產生發炎反應。藉即時聚合酶鏈式反應(Quantitative real time polymerase chain reaction)和西方墨點法(western blot)研究發炎相關物質:誘導型一氧化氮合酶(inducible NO synthase (iNOS))、mTOR、NLRP3發炎體與interleukin-1β(IL-1β)的mRNA和蛋白質的在發炎時期的表現變化。美諾四環素(minocycline)和其他兩種mTOR 抑制劑,分別為雷帕黴素(rapamycin)和依維莫司(everolimus),這三種藥有潛力於減緩癲癇發作。在本研究中,LPS所導致iNOS 的mRNA提升與,此三種藥皆可減緩之,因iNOS的提升,細胞內NO升高,此三種藥也都有減緩之作用;此外,everolimus對於降低mTOR的mRNA效果最佳。然而以卡英酸(kainic acid (KA))作為刺激物,導致神經過度興奮而產生之毒性的模式,三種藥的作用效果類似。BV2細胞的蛋白質變化結果也顯示:KA加everolimus或rapamycin,以及LPS加everolimus或minocylcine皆可降低phospho-ERK表現,由此推論三種藥物可經由ERK細胞訊息傳遞路徑來影響發炎反應與神經興奮性毒性之影響,其中又以everolimus效果最佳。
在動物模式,我們使用〖B6.129P-Cx3cr1〗^tm1Litt/J品系之基因轉殖鼠,特色為其microglia在被活化時會發螢光,方便在癲癇發作和神經發炎反應時觀察microglia activation之變化。小鼠在25天大時被注射第一劑KA以導致癲癇,在31天(或38天)大時被注射第二劑,兩劑KA刺激間,每日給予everolimus,定義自注射到發作第三期癲癇行為反應(根據Racine scale分期之 stage Ⅲ seizure)之時間為潛伏期(latency),在38天之癲癇發作潛伏期比第一次延長。推論everolimus藉由抑制神經發炎反應之相關物質,進而抑制microglia activation,因而推論出everolimus在藉由減緩神經發炎反應之路徑以對癲癇發作有影響之潛力。


Microglia is responsible for neuroinflammation, which mediates neurodegenerative disorder and brain injury such as epilepsy. When there is brain injury, chronic microglia activation prompts pro-inflammatory factor to lead to neuroinflammatory response. Furthermore, mammalian target of rapamycin (mTOR) kinase is related to microglia activation and subsequent neuroinflammation. In order to clarify the mechanism of neuroinflammation in seizure, in vitro, we use liposaccharide (LPS) model to induce neuroinflammation in BV2 cell line. By real-time PCR and western blotting methods, we can confirm the transcriptional and translational effect of LPS on the neuroinflammation indicators: mTOR, IL-1β, and inducible nitric oxide synthase (iNOS). Minocycline, and two kinds of mTOR inhibitors, rapamycin as well as everolimus are potential to treat seizure. We find all of these three drugs are able to decrease iNOS mRNA level after LPS stimulation, and everolimus downregulates mTOR mRNA level. The three drugs decrease nitrite production after LPS stimulation. The application of kainic acid lead to similar results. Western blot results show that p-ERK is reduced by KA+everolimus, KA+rapamycin, LPS+everolimus, and LPS+minocycline. We suppose that the drugs affect inflammation and neurotoxicity through ERK pathway, and everolimus has better efficacy than rapamycin and minocycline.
In vivo, we use 〖B6.129P-Cx3cr1〗^tm1Litt/J transgenic mice whose activated microglia show fluorescence to research the roles of neuroinflammation and microglial activation in seizure. We inject kainic acid (KA) twice to induce seizure on postnatal day 25 (P25) and P31(or P38). During the two KA stimulations, everolimus is applied to investigate its role in anti-inflammatory response. We assume these drugs can block microglia activation following KA injection. We suppose that drugs are able to block the activation of inflammation-related molecules to inhibit the microglia activation and neuroinflammation. Taken together, mTOR as the one of the target of anti-epileptic drug treatment may be a potential pharmacological approach to reduce neuroinflammation.


Ⅰ.Introduction…………………………………………………………8
Ⅱ.Method……………………………………………………………12
Ⅲ. Result…………………………………………………………………19
3.1 Effects of treatment drugs on BV2 cell ……………………… 19
3.2 Everolimus efficacy on KA seizure model of mice…………….23

Ⅳ. Dicussion……………………………………………………………..…….…25
4.1 LPS and KA as stimuli and inflammation indicators……………...25
4.2 ERK and Akt pathway involved in everolimus and rapamycin mediated inflammation and neurotoxicity ………….... 29
4.3 Comparison of everolimus, rapamycin and minocycline………….30
4.4 Everolimus efficacy on weakening KA-induced seizure of mice…32
Figure………………………………………………………………..……….……33
Reference……………………………………………………………………...… 56

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