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研究生： 翁啟昌
Weng, Chi-Chang
論文名稱： 以[18F]FP-(+)-DTBZ檢測帕金森氏動物模型之多巴胺神經損傷及相關治療藥物之療效分析
Estimation of The Dopamine Neuron Lesion and The Therapeutic Drug Efficacy on Different Parkinson’s Disease Animal Models with [18F]FP-(+)-DTBZ
指導教授： 許靖涵
Hsu, Ching-Han
口試委員: 魏孝萍
Wey, Shiaw-Pyng
蕭穎聰
Hsiao, Ing-Tsung
林昆儒
Lin, Kun-Ju
江耀璋
Chiang, Yao-Chang
學位類別： 博士
Doctor
系所名稱： 原子科學院 - 生醫工程與環境科學系
Department of Biomedical Engineering and Environmental Sciences
論文出版年： 2017
畢業學年度： 105
語文別： 中文
論文頁數： 77
中文關鍵詞： 氟-18-FP-(+)-DTBZ 、正子電腦斷層造影 、帕金森氏病 、厚朴酚 、1-甲基-4-苯基-1,2,3,6-四氫吡啶 、乳胞素 、體內法自動輻射曝光顯影實驗
外文關鍵詞： F-18-FP-(+)-DTBZ, positron emission tomography, Parkinson’s disease, magnolol, MPTP, lactacystin, ex vivo autoradiography
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    • 本論文為研究氟-18-FP-(+)-DTBZ結合正子電腦斷層造影於不同帕金森氏病動物模型上之應用。本研究共分為兩個部分，第一個部分之實驗以氟-18-FP-(+)-DTBZ 正子電腦斷層造影影像結果評估厚朴酚(Magnolol)於常見之MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) 動物模型上，是否對其已受損之多巴胺神經元具治療效果。第二個部分的實驗則是使用氟-18-FP-(+)-DTBZ 正子電腦斷層造影活體造影方式，確認以Lactacystin抑制UPS (ubiquitin proteasome system) 系統作為帕金森氏病動物模型的可行性。第一部分實驗結果發現，氟-18-FP-(+)-DTBZ造影結果清楚顯示動物經厚朴酚治療後，可有效緩解因MPTP所造成多巴胺神經元之損傷，證實氟-18-FP-(+)-DTBZ 正子電腦斷層造影可以運用於評估新的帕金森氏病治療藥物之療效。第二部分實驗之氟-18-FP-(+)-DTBZ PET 影像結果，不但確認顱內注射Lactacystin 在動物前側腦束 (medial forebrain bundle; MFB) 以抑制 UPS系統功能後，可以清楚觀察到多巴胺神經元之損傷，並可藉由氟-18-FP-(+)-DTBZ PET 測量動物在不同時間點及劑量之Lactacystin處理過後，該動物多巴胺神經元功能的損傷程度，更進一步確認氟-18-FP-(+)-DTBZ 正子電腦斷層造影可應用於評估新的帕金森氏病動物模型之特性評估。

    This thesis reported two studies utilizing F-18-FP-(+)-DTBZ, a radiotracer targeting vesicular monoamine transporter type 2 (VMAT2) and positron emission tomography (PET) on neurotoxin-induced Parkinson’s disease (PD) animal models. The first study was to evaluate the therapeutic efficacy of Magnolol on MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine) animal model using F-18-FP-(+)-DTBZ PET imaging method. The second study was to verify the suitability of a rat model of PD induced by intracranial administration of Lactacystin via medial forebrain bundle (MFB), an ubiquitin proteasome system (UPS) inhibitor, using F-18-FP-(+)-DTBZ PET imaging approach.
    The results of the first study clearly revealed that Magnolol can partially restore the dopaminergic neuron loss induced by MPTP. The results of the second study demonstrated that F-18-FP-(+)-DTBZ PET imaging not only can clearly show the lesion of dopaminergic neuron induced by Lactacystin to the MFB, but also can be used to monitor the different lesion level with various doses of lactacystin and different time after treatment.

    目錄 指導教授推薦書 口試委員審定書 中文摘要………………………………………………………………i Abstract………………………………………………………………iii 誌謝……………………………………………………………………iv 目錄……………………………………………………………………vi 圖目錄…………………………………………………………………x 表目錄…………………………………………………………………xii 第一章 緒論……………………………………………………………1 1.1 帕金森氏病……………………………………………………1 1.2 帕金森氏病的核醫學診斷……………………………………2 1.3 帕金森氏病的小動物模型………………………………5 1.4 帕金森氏病治療藥物……………………………………7 1.5 厚朴酚 (Magnolol)……………………………………………7 1.6 Lactacystin帕金森氏病動物模型………………………8 1.7 論文主旨………………………………………………………9 第二章 材料及方法……………………………………………………10 2.1.1 實驗動物及實驗設計………………………………………10 2.1.2 MPTP 動物處理及Magnolol治療…………………………10 2.1.3 氟-18-FP-(+)-DTBZ製備…...………………………………11 2.1.4 小鼠氟-18-FP-(+)-DTBZ正子電腦斷層造影…………11 2.1.5 小鼠氟-18-FP-(+)-DTBZ正子電腦斷層造影影像分析……12 2.1.6 MPTP及厚朴酚處理後之小鼠氟-18-FP-(+)-DTBZ 離體自動輻射顯影分析（ex vivo autoradiography; ARG）…………………13 2.1.7 MPTP及厚朴酚處理後之小鼠腦組織切片免疫組織染色………………………………………………………………15 2.2.1 實驗動物及實驗設計………………………………………17 2.2.2 Lactacystin顱內注射動物準備………………………………17 2.2.3 氟-18-FP-(+)-DTBZ於健康大鼠上之動態正子電腦斷層造影…………………………………………………………………19 2.2.4 大鼠腦部氟-18-FP-(+)-DTBZ動態正子斷層影像分析………………………………………………………………….20 2.2.5 Lactacystin處理之動物腦部氟-18-FP-(+)-DTBZ分布評估…………………………………………………………………20 2.2.6 Lactacystin處理大鼠氟-18-FP-(+)-DTBZ正子電腦斷層造影.......................................................................................................22 2.2.7 Lactacystin處理大鼠氟-18-FP-(+)-DTBZ正子電腦斷層造影之影像分析………………………………………………………...22 2.2.8 Lactacystin處理之大鼠氟-18-FP-(+)-DTBZ 離體自動輻射顯影分析…………………………………………………………23 2.2.9 Lactacystin處理大鼠之腦組織切片免疫組織染色…………23 2.2.10 實驗數據分析……………………………………………24 第三章 實驗結果………………………………………………………25 3.1.1小鼠氟-18-FP-(+)-DTBZ正子電腦斷層造影………25 3.1.2 MPTP 及厚朴酚處理後之小鼠氟-18-FP-(+)-DTBZ離體自動輻射顯影 (ex vivo autoradiography; ARG) 分析……….………28 3.1.3 MPTP 及厚朴酚處理後之小鼠腦組織切片免疫組織染色 ………………………………………………………………….29 3.2.1 健康大鼠腦部氟-18-FP-(+)-DTBZ 動態正子斷層造影…………………………………………………………………...32 3.2.2 Lactacystin 處理大鼠腦部氟-18-FP-(+)-DTBZ ……………33 3.2.3 Lactacystin 處理之大鼠氟-18-FP-(+)-DTBZ正子電腦斷層造影…………………………………………………………………...34 3.2.4 Lactacystin 處理大鼠氟-18-FP-(+)-DTBZ 離體自動輻射顯影 (ex vivo autoradiography; ARG) 分析….……………………...36 3.2.5 Lactacystin處理大鼠之腦組織切片免疫組織染色…………38 第四章 討論……………………………………………………………39 4.1.1小鼠氟-18-FP-(+)-DTBZ正子電腦斷層造影.………………39 4.1.2 MPTP 及厚朴酚處理後之小鼠氟-18-FP-(+)-DTBZ 離體自動輻射顯影分析…...………………………………………………41 4.1.3 MPTP 及厚朴酚處理後之小鼠腦組織切片免疫組織染色…………………………………………………………………42 4.2.1 Lactacystin 處理之大鼠腦部氟-18-FP-(+)-DTBZ 分布…43 4.2.2 Lactacystin 處理之實驗動物氟-18-FP-(+)-DTBZ 正子電腦斷層造影…………………………………………………………...44 4.2.3 Lactacystin 處理之大鼠氟-18-FP-(+)-DTBZ 離體自動輻射顯影分析……………………………………………...……………45 4.2.4 Lactacystin 處理大鼠之腦組織切片免疫組織染色………46 第五章 結論與未來展望………………………………………………49 參考文獻……………………………………………………..…………51 附錄

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