臺灣博碩士論文加值系統

阿茲海默症 (Alzheimer’s disease， AD) 是一種漸進性且不可逆的神經退化性疾病 (neurodegenerative disease)，也是造成失智症 (Dementia) 最主要的原因之一。阿茲海默症病人除了會表現出記憶能力喪失之臨床症狀外，近來相關研究也指出，在阿茲海默症疾病進展的過程中，除了會造成常見的 β-澱粉樣蛋白斑塊堆積和 tau 蛋白過度磷酸化外，在近期研究中也發現，腦中葡萄糖的代謝及胰島素的訊號傳遞可能產生異常的情形。本研究中，利用鏈佐黴素 (Streptozotocin，STZ) 誘導大鼠成為阿茲海默症動物模式，並探討大鼠腦部葡萄糖代謝以及 tau 蛋白過度磷酸化的改變。在本次實驗中會利用非侵入性的正子造影技術搭配 [18F]FDG 和 [18F]T807 兩種放射性物質來作為造影藥物，分別評估葡萄糖代謝和 tau 蛋白堆積。同時會搭配兩種動物行為測試研究阿茲海默症大鼠認知與記憶力之改變，分別運用放射狀八爪迷宮實驗和開放空間行為測試。結果顯示，經 STZ 藥物誘導之動物記憶力明顯下降，正子造影結果也可發現葡萄糖代謝減少，且 tau 蛋白堆積增加，免疫組織化學染色 (immunohistochemical，IHC) 之結果顯示與造影結果一致。另外我們也選用兩種具神經保護潛力之藥物進行治療研究，分別為右美沙芬 (Dextromethorphan，DM) 和硫酸孕烯醇酮 (Pregnenolone sulfate，PS)，dextromethorphan在臨床運用上為一種便宜、安全且幾乎無副作用的止咳藥物，且先前研究顯示能夠改善被 NMDA 受體所調節造成的神經毒性和缺氧性的神經元損傷， pregnenolone sulfate 是在大鼠和人類的神經組織中最原始且存在最豐富的神經類固醇，早期的研究中已指出 pregnenolone sulfate 在中樞神經系統內具有抗發炎與抑制氧化壓力的功能，從研究結果顯示中也發現兩種藥物均具有神經保護作用，而其中之機制未來可以利用細胞實驗做更進一步之研究。

Alzheimer’s disease (AD) is a progress neurodegenerative disorder that associated with the defects of cognition and memory. Recent studies showed that insulin resistant in the brain may play an important role in the etiopathogenesis of the sporadic AD (sAD). In this study, the SD rat with streptozotocin intracerebroventricular (STZ-icv) treatment was used to be a sAD animal model. The open field test (OFT) and radial arm maze (RAM) behavior test were carried out to evaluate the cognitive and memory deficits in STZ-icv rat. Moreover, the [18F]FDG and [18F]T807 coupled with animal positron emission tomography (animal-PET) were also used to evaluate the status of brain glucose metabolism and the expression of paired helical filament (PHF)-tau protein, respectively. Volumes of interest (VOIs) of brain regions were drawn on PET images and compared between control and STZ-icv rats. We also examined the neuroprotective effects of dextromethorphan (DM) and pregnenolone sulfate (PS) in STZ-icv rat. After the last PET scanning, all the rats were sacrificed for the phosphorylated tau and glucose transporter 3 (GLUT3) immunohistochemical (IHC) staining. The results of OFT and RAM tests showed cognitive and memory deficits in STZ-icv induced sAD rat. The PET images showed that [18F]FDG uptakes was decreased and [18F]-T807 uptake was increased in the rat brains after STZ-icv injection. The STZ-icv rats with DM or PS treatments showed significant uptake changes of [18F]FDG and [18F]T807 in rat brains. Previous studies have shown that DM can be improved caused by NMDA receptors adjusting the neurotoxicity hypoxia and neuronal damage. And pregnenolone sulfate is the most abundant and primitive steroid in the rat and human nerve tissue. Early studies have indicated pregnenolone sulfate has anti-inflammatory and inhibit oxidative stress in the central nervous system. In this study the results showed that both drugs have neuroprotective effects against the STZ-induced neurotoxicity. The results of this study may clarify the toxicity of STZ in the rat brains, and the model may provide a platform for in developing novel therapeutic druds for AD.

正文目錄......................................................Ⅰ
圖目錄........................................................Ⅳ
中文摘要......................................................Ⅶ
英文摘要......................................................Ⅸ
第一章、 序言................................................1
第一節、 阿茲海默症...................................1
第二節、 病理特徵.....................................2
第三節、 阿茲海默症之類型.............................4
第四節、 阿茲海默症動物模式...........................5
一、 動物模式..................................5
二、 鏈佐黴素誘導之機制........................6
第五節、 正子斷層造影.................................8
第六節、 利用 cyclosporine 暫時增加血腦障壁之通透性……10
第七節、 神經保護潛力藥物之介紹.......................11
一、 右美沙芬 (Dextromethorphan，DM) ..........11
二、 硫酸孕烯醇酮 (Pregnenolone sulfate，PS) .....13
第二章、 目的...............................................15
第三章、 材料與方法.........................................16
第一節、 材料........................................16
一、 實驗動物.................................16
二、 藥物.....................................16
第二節、 實驗方法....................................18
一、 實驗組別.................................18
二、 行為測試.................................20
三、 側腦室注射鏈佐黴素引發之阿茲海默症大鼠動物模式.......................................21
四、 小動物正子斷層造影.......................22
五、 藥物給予.................................23
六、 免疫組織化學染色.........................23
第四章、 結果...............................................25
第一節、 鏈佐黴素誘導阿茲海默症大鼠行為測試之改變....25
第二節、 正子斷層造影影像及 [18F]FDG 和 [18F]T807 之標準攝取值........................................25
第三節、 免疫組織化學染色及光學定量..................26
第五章、 討論...............................................57
第一節、 檸檬酸緩衝液對大鼠腦部安全性之探討..........57
第二節、 藥物機制探討................................57
一、 Dextromethorphan..........................58
二、 Pregnenolone sulfate........................59
第三節、 新穎造影藥物 T807 之探討...................60
第六章、 結論..............................................63
第七章、 參考文獻..........................................64

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