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研究生:王淑親
研究生(外文):Shu-Chin Wang
論文名稱:沒食子酸減輕大鼠血管性失智之機制探討
論文名稱(外文):Mechanism for gallic acid to alleviate vascular dementia in rats
指導教授:吳瑞碧
指導教授(外文):James Swi-Bea Wu
口試委員:吳明昌廖慧芬沈賜川
口試日期:2014-06-06
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:食品科技研究所
學門:農業科學學門
學類:食品科學類
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:61
中文關鍵詞:血管性失智症腦部缺氧沒食子酸神經保護作用
外文關鍵詞:vascular dementiacerebral ischemiagallic acidneuroprotection
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人口老化,失智症人數近年來急速上升。血管性失智症 (vascular dementia) 是老年失智症主要類別,盛行率僅次於阿茲海默症。其主要成因是腦中風或慢性腦血管病變,造成腦部血液循環不良,導致腦細胞死亡而智力減退。沒食子酸 (gallic acid) 屬於酚酸類,具有抗氧化、抗發炎、抗癌等作用。腦部血管缺氧後再灌流,會產生大量自由基,造成腦部組織再次傷害,因此本研究使用兩血管阻斷再灌流模式 (two-vessel occlusion model of forebrain ischemia; 2-VO) ,進行沒食子酸減輕血管性失智之機制探討。實驗隨機分成六組:假手術組、控制組、餵食阿斯匹靈 (aspirin) 之正控制組、餵食沒食子酸 (gallic acid) 包括低劑量 (10mg/kg)、中劑量 (50mg/kg) 、高劑量 (100mg/kg) 之樣品組三組,餵食五周之後犧牲,分析血清生化數值,餵食沒食子酸 (gallic acid) 大鼠與其他組別在血清電解質無顯著性之差異,及血脂質分析結果,推測餵食沒食子酸不會提高罹患心血管疾病風險,顯示沒食子酸具安全性。以西方點墨法 (western blot) 分析腦部皮質層及海馬迴PI3K-Akt-CREB 路徑的表現量,以釐清沒食子酸是否對神經細胞具有保護作用。結果顯示在皮質層餵食高劑量組之PI3K、p-Akt / Akt表現量高於控制組、且在p-CREB/CREB、表現量則顯著性高於控制組 (p < 0.05) 。 CREB (cAMP response element-binding protein;核內轉錄因子),其磷酸化可激活相關基因的轉錄,發揮抑制細胞凋亡、細胞分化再生、細胞損傷後的修復等作用。
結果亦顯示,在皮質層餵食高劑量組之BDNF表現量顯著高於控制組 (p < 0.05)。 BDNF為重要神經保護因子 (neuroprotective factor) ,可以抵抗興奮毒性之胺基酸(anti-excitatory amino acid)、抑制發炎因子、降低細胞凋亡。根據上述結果,推論沒食子酸可能是經由PI3K-Akt-CREB-BDNF路徑來減輕神經細胞受損之功效。



The increased prevalence of the older generation raises important questions about their physical and mental health. Many older individuals express significant concern about the potential loss of cognitive function and the development of dementia. Vascular dementia (VaD) related to stroke is generally recognized as the second most common cause of dementia after Alzheimer’s disease (AD). Only Gallic acid (3, 4, 5-trihydroxybenzoic acid) and its derivatives are among the major phenolic compounds in plants. The present study investigated the neuroprotective effect of gallic acid using a cerebral ischemic animal model. Wistar rats were fed with normal diet for 1 week, fed with normal diet supplemented with gallic acid in various doses between 10 and 100 mg/kg/day for 5 weeks, and then subjected to a two-vessel occlusion (2VO) operation with 90 min of blood occlusion followed by 48 h of reperfusion. The rats were sacrificed to take the cortex and hippocampus for analyzing the contents of proteins in the PI3k- Akt - CREB signaling pathway by western blotting. The results show that the expressions of cell survival signaling proteins PI3K, Akt and p-CREB/CREB in rats fed with gallic acid were increased compared with the control groups. The expression of p-CREB/CREB, which is a neuron survival signal, significantly increased with the dose of gallic acid at 100mg/kg/day in the feed (p < 0.05). BDNF is an important neuroprotective factor for the alleviation of ischemic brain injury in vivo by its antagonistic function against excitatory amino acids, inflammatory factors and apoptosis. The result showed that the expression of BDNF significantly increased with the dose of gallic acid at 100mg/kg/day in the feed (p < 0.05). These data showed that gallic acid helps neurons in cerebral ischemic rats to survive, probably via the activation of the PI3K-Akt-CREB-BDNF signaling pathway. Our finding support the potential for the use of gallic acid in health food to attenuate neuronal damage in ischemia condition .

目錄
中文摘要 ........................I
Abstract.......................II
目錄..........................IV
圖目錄..........................V
表目錄.........................VI
第一章、 前言...................1
第二章、 文獻回顧...............2
第一節、 血管性失智症 (Vascular dementia).......2
一、 失智症.....................................2
二、 流行病學統計...............................2
三、 病理解剖來分類 (O’Brien et al., 2004).....2
四、 中風後併發失智症...........................4
五、 目前臨床治療方法 (Baskys et al., 2007).....4
第二節、 缺血性腦中風(Ischemic stroke).........10
一、 治療與預防................................10
二、 發炎反應 (Inflammation)...................11
第三節、 缺氧和再灌流 (Ischemia and reperfusion) 13
第四節、 兩血管阻斷再灌流之動物實驗模式.........18
第五節、 腦缺氧狀態下之神經保護機制.............19
第六節、 多酚類與缺血性失智之相關研究...........21
第三章、 研究動機與實驗架構.....................26
第一節、 研究動機與目的.........................26
第二節、 實驗架構...............................27
第四章、 材料與方法.............................28
第一節、 兩血管阻斷再灌流之動物實驗模式.........28
一、 實驗材料...................................28
二、 實驗方法...................................31
第五章、 結果與討論.............................39
第一節、 餵食沒食子酸 (gallic acid) 對兩血管阻斷再灌流之大鼠生理、生化之影響................................39
一、體重 .......................................39
二、電解質平衡狀態..............................39
三、血脂 ........................................40
第二節、 大鼠腦部蛋白質表現量...................42
第六章、 結論...................................54
第七章、 參考文獻...............................55



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