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研究生:林揚奕
研究生(外文):LIN, YANG-YI
論文名稱:探討 3-Methyladenine 於大鼠透過自噬作用機轉防止搖頭丸所產生之血清素神經毒性
論文名稱(外文):The Effects of 3-Methyladenine against 3,4-Methylenedioxy-N-methylamphetamine (MDMA)-induced Serotonergic Neurotoxicity via Autophagy in Rat
指導教授:李宜勳李宜勳引用關係王孟廷
指導教授(外文):Li, I-HsunWang, Meng-Ting
口試委員:李宜勳王孟廷馬國興黃文盛薛晴彥
口試委員(外文):Li, I-HsunWang, Meng-TingMa, Kuo-HsingHuang, Wen-ShengShiue, Chyng-Yann
口試日期:2014-04-28
學位類別:碩士
校院名稱:國防醫學院
系所名稱:藥學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
論文出版年:2014
畢業學年度:102
語文別:中文
論文頁數:65
中文關鍵詞:自噬作用搖頭丸血清素神經毒性
外文關鍵詞:3-MethyladenineMDMASerotonergic NeurotoxicityAutophagy
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3, 4-Methylenedioxymethamphetamine (MDMA) 為青少年經常使用的毒 品,近年來因濫用 MDMA 而送入急診的案例日增,已發現 MDMA 會影響 腦中血清素系統 (serotonin system) ,並且會產生憂鬱、焦慮等精神狀態的 改變。目前有研究指出, MDMA 可透過活性氧化物 (reactive oxygen species; ROS) 的產生,以及誘導 autophagy-related protein 5 (Atg5) 之表現,使細胞 產生過度的自噬作用 (autophagy) ,對細胞造成傷害。然而,MDMA 引發 毒害的機轉仍待探討。 3-Methyladenine (3-MA) 為一自噬作用抑制劑,可藉 由抑制 class III phosphoinositide 3-kinase (class III PI3K) 抑制自噬小體 (autophagosome) 形成,藉此保護神經細胞。
本實驗分為細胞及動物試驗。細胞實驗利用胚胎期第 14 天之血清素神 經細胞分為以下四組: Control 組、 MDMA 1mM 組、 3-MA 1mM 組及 3-MA / MDMA 組,並以免疫螢光染色配合 Tryptophan hydroxylase (TPH) 及 LC3-II (自噬作用相關標誌) 觀察血清素神經細胞的型態學及自噬作用表 現;動物試驗方面,大鼠於實驗進程的第一天 (Day0) 開始打藥,分別以皮 下注射 SAL 或 MDMA (10mg/kg) ,再以腹腔注射給予 DMSO 或 3-MA (15mg/kg) ,連續注射 4 天,每天 2 次,大鼠依給予之藥物分成四組: DMSO/SAL 組 (即為控制組,先於腹腔注射 DMSO 再於皮下注射 SAL) 、 DMSO/MDMA 組、3-MA/SAL 組、 3-MA/MDMA 組。動物試驗藉由 micro-positron emission tomography (micro-PET) 配合 4-[18F]-ADAM (一種專 一性血清素轉運體造影劑) ,探討 3-MA 對於 MDMA 引發大鼠血清素神經毒性之神經保護作用,並秤量大鼠體重觀察食慾之改變、以血中皮質酮 (corticosterone) 分析下視丘-腦垂體-腎上腺軸 (Hypothalamus - Pituitary - Adrenal axis) 之活化情形,最後以強迫游泳試驗 (Forced swimming test) 觀 察 3-MA 對於 MDMA 造成大鼠類憂鬱症狀的改善情形。
實驗結果顯示, MDMA 導致血清素神經元退化,並增加自噬小體的 表現,而併用 3-MA 可明顯減弱 MDMA 的毒性。此外,於 PET 造影中, 4-[18F]-ADAM 的專一性攝取率 (Specific uptake ratios;SURs) 證實了 MDMA 會導致 4-[18F]-ADAM 於各個腦區的攝取量減少,而 3-MA/MDMA 組專一性攝取率的減少程度則小於 MDMA 組。再者, 3-MA/MDMA 組與 MDMA 組相比,可觀察到強迫游泳試驗的靜止時間、血中皮質酮濃度、體 重喪失情形等,都呈現減少的情況。我們的研究結果發現 3-MA 未來或許 可應用於防止 MDMA 引發之神經毒性。
3, 4-Methylenedioxymethamphetamine (MDMA) is one of the most common recreational drugs taken by adolescents. ER (Emergency room) visits due to the abuse of MDMA have increased recently. MDMA has been found to affect brain serotonin system, resulting in depression, anxiety and other mental status changes. Previous studies indicated that MDMA leads to excessive autophagy in cells by generating reactive oxygen species (ROS) and inducing autophagy-related protein 5 (Atg5) expression, and therefore damages the cells. However, the exact mechanisms of MDMA-induced neurotoxicities still need to be investigated. 3-Methyladenine (3-MA) is an autophagy inhibitor that can reduce the formation of autophagosome by inhibiting class III phosphoinositide 3-kinase (class III PI3K).
The experiment was divided into in vitro and in vivo studies. E14 embryonic cells were divided into the following four groups: control group, MDMA 1mM group,3-MA 1mM group and 3-MA / MDMA group. The immunofluorescent staining of tryptophan hydroxylase (TPH) and LC3-II (an autophagy-related markers) were performed to observe the neural morphology and autophagy in the serotonergic neurons derived from E14 embryonic rat brain. In an in vivo study, male Sprague-Dawley rats were co-treated SAL or MDMA (10mg/kg, s.c.) and DMSO or 3-MA (15mg/kg, i.p.) twice a day for 4 consecutive days. Rats divided into four groups according to the drug administration: DMSO / SAL group (i.e., control group, prior to intraperitoneal injection of DMSO and then subcutaneous injection of SAL), DMSO / MDMA group, 3-MA / SAL group, 3-MA / MDMA group. Micro- positron emission tomography (micro-PET) coupled with 4-[18F]-ADAM (a radioligand specific to serotonin transporter) was used to investigate the neuroprotective effect of 3-MA against MDMA-induced serotonergic toxicity. We weighed rats to evaluate changes in appetite, analyzed plasma corticosterone levels to examine the activation of hypothalamus-pituitary-adrenal axis (HPA axis), and performed the forced swimming test (FST) to evaluate depressive-like behaviors resulting from MDMA.
Experimental results showed that MDMA caused degeneration in serotonin neurons and increased expression of autophagosome, and the concomitant use of 3-MA significantly reduced the toxicity of MDMA. Besides, in the PET imaging studies, the SURs data of 4-[18F]-ADAM demonstrate that MDMA could cause the decreased uptake of 4-[18F]-ADAM in various brain regions of rats. The SURs decrement of 3-MA / MDMA group is less than those of MDMA alone group. Furthermore, immobility time of forced swimming tests, plasma corticosterone levels and weight loss were decreased in 3-MA / MDMA group compared to MDMA alone group. These results indicated that MDMA-induced serotonergic toxicity could be protected by 3-MA.
目錄........................................................................................................................I
圖目錄 ...................................................................................................................III
表目錄 .................................................................................................................. V
中文摘要 .............................................................................................................. VI
Abstract ............................................................................................................ VIII
第一章、緒論.........................................................................................................1
第一節、3,4-methylenedioxy-N-methylamphetamine (MDMA).............................1
壹、MDMA 之歷史與流行病學...............................................................................1
貳、MDMA 之藥物動力學......................................................................................1
參、MDMA 導致之症狀 .........................................................................................2
肆、與 MDMA 相關之毒性 .....................................................................................2
伍、MDMA 毒性之機轉 .........................................................................................3
第二節、血清素系統 (Serotonergic system) ..........................................................6
第三節、細胞自噬作用 (autophagy) ......................................................................7
壹、自噬作用定義...................................................................................................7
貳、自噬作用之成因 ............................................................................................. 7
參、自噬作用內部機轉 ..........................................................................................11
第四節、3-Methyladenine(3-MA) ..........................................................................14
壹、3-MA 簡介.......................................................................................................14
貳、3-MA 與 MDMA 之關聯性 ..............................................................................14
第五節、Positron Emission Tomography(PET) ....................................................15
壹、PET 簡介........................................................................................................15
貳、PET 原理........................................................................................................15
參、造影藥物之差異..............................................................................................15
肆、針對血清素系統開發的造影藥物 ....................................................................16
第二章、實驗目的 .................................................................................................18
第三章、材料與方法 .............................................................................................19
第一節、體外細胞實驗之材料方法 ........................................................................19
壹、血清素神經元之初代培養 (Primary culture of serotonergic neurons)..............19
貳、藥物給予初代培養神經細胞.............................................................................20
參、雙重免疫螢光染色 ...........................................................................................20
肆、染色後細胞觀察...............................................................................................20
第二節、動物造影材料方法.....................................................................................21
壹、實驗動物 ..........................................................................................................21
貳、藥物及給藥分組................................................................................................21
參、放射藥物 4-[18F]-ADAM...................................................................................23
肆、動物造影及圈選資料 ........................................................................................23
第三節、動物血中變化及行為學之材料方法 ...........................................................24
壹、LC tandem mass 分析血中糖皮質酮 (Corticosterone)濃度試驗.......................24
貳、動物憂鬱行為測試............................................................................................30
第四章、結果...........................................................................................................32
第一節、血清素神經細胞於免疫螢光染色結果 ........................................................32
第二節、正子斷層造影(PET)觀察大鼠血清素系統之結果 .......................................35
第三節、藥物於大鼠體重之影響 .............................................................................43
第四節、皮質酮濃度分析結果..................................................................................45
第五節、強迫游泳試驗結果......................................................................................47
第五章、討論............................................................................................................51
第一節、3-MA 對於 MDMA 所引發的神經毒性之保護 .............................................51
第二節、3-MA 對 MDMA 所誘導的副作用之改善.....................................................52
第六章、結論............................................................................................................57
第七章、參考文獻 ………………………………………………………………………..58
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