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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林君榮 | |
dc.contributor.author | Ying Tai | en |
dc.contributor.author | 戴瑩 | zh_TW |
dc.date.accessioned | 2021-06-15T03:57:34Z | - |
dc.date.available | 2010-09-13 | |
dc.date.copyright | 2010-09-13 | |
dc.date.issued | 2010 | |
dc.date.submitted | 2010-06-10 | |
dc.identifier.citation | Bachi S. P. (1992) Trace dosage of neurotoxins MPTP and MPP+ may affect brain dopamine in vivo. Life Sci 51, 389-396.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/44893 | - |
dc.description.abstract | 攝入1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) 會增加其具毒性之代謝物1-methyl-4- phenylpyridinium (MPP+) 於大腦的量,並進而選擇性的對多巴胺神經產生毒性,使得腦中多巴胺濃度降低,造成類似巴金森氏症的症狀。Amantadine在臨床上可用於治療巴金森氏症,但其機制尚未完全清楚。已知amantadine為有機陽離子轉運蛋白 (organic cation transporters,OCTs) 的受質。本研究目的於探討amantadine對於MPTP在血腦屏障穿透與MPTP引發之多巴胺毒性的影響,同時,本研究也探討腦血管內皮細胞上OCTs的表現和分布位置,以及OCTs在腦血管內皮細胞攝取MPTP扮演中的角色。
由腦部微透析實驗發現amantadine明顯的降低了大鼠與小鼠之腦透析外液中MPTP與MPP+時間對濃度做圖的曲線下面積;同樣地,相較於只給予MPTP的組別,amantadine明顯增加了小鼠腦部紋狀體中多巴胺與多巴胺代謝物濃度。小動物正子掃描之實驗結果顯示MPTP在小鼠腦中所引起的多巴胺毒性可被amantadine改善。在本研究中使用共軛焦顯微鏡和西方墨點法兩種實驗方式探討有機陽離子轉運蛋白OCT1與OCT2在腦血管內皮細胞上分布的位置,發現OCT1與OCT2主要分布在細胞膜的luminal側,並且在OCT1/OCT2基因靜默後腦血管內皮細胞攝取MPTP減少。 總結以上的實驗結果,我們發現amantadine可減少MPTP通過血腦屏障以及MPTP在囓齒類中引起的多巴胺毒性,並且OCT1與OCT2對MPTP通過血腦屏障扮演重要的角色。 | zh_TW |
dc.description.abstract | Exposure to the chemical 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) can lead to the presence of its toxic metabolite, 1-methyl-4-phenylpyridinium (MPP+), in the brain, which induces a selective destruction of dopaminergic nigrostriatal neurons and the occurance of Parkinson’s disease. Amantadine is used in the treatment of Parkinson’s disease. However, its mechanism is not fully understood. Amantadine is known to be as substrate of organic cation transporters (OCTs). The purpose of this study was to evaluate the effects of amantadine on blood-brain barrier (BBB) transport of MPTP, and on MPTP-induced dopaminergic toxicity. Also, the expression and cellular localization of OCTs were investigated. The role of OCTs on MPTP uptake was studied in brain microvessel endothelial cells (BMECs).
The results of in vivo brain microdialysis showed that amantadine significantly reduced the area under the time-concentration curves of MPTP and MPP+ in brain extracellular fluid in rats and mice. Likewise, amantadine increased the level of dopamine and dopamine metabolites in brain striatum of mice, compared with mice recieving MPTP only. PET scan showed amantadine ameliorated MPTP-induced dopaminergic toxicity in the brain of mice. The confocal and Western blot analyses showed that OCT1 and OCT2 were mainly expressed on the luminal side of BMECs and adult rat brain endothelial cells (ARBECs). Cellular uptake of MPTP was decreased with OCT1/OCT2 silencing in BMECs and ARBECs. In conclusion, amantadine reduces the BBB transfer of MPTP and MPTP-induced dopaminergic toxicity in rodents, and OCT1 and OCT2 are important for MPTP transfer across the BBB. | en |
dc.description.provenance | Made available in DSpace on 2021-06-15T03:57:34Z (GMT). No. of bitstreams: 1 ntu-99-R97423013-1.pdf: 1091968 bytes, checksum: 26963a3da395d94f102e97247ca28bcc (MD5) Previous issue date: 2010 | en |
dc.description.tableofcontents | 目錄
Abstract…………………………………………………………………………………i 中文摘要……………………………………………………………………………...iii 目錄…………………………………………………………………………………...iv 圖目錄……………………………………………………………………………….viii 表目錄………………………………………………………………………………...ix 第1章 文獻回顧……………………………………………………………………1 1.1 巴金森氏症 (Parkinson’s disease,PD)……………………………………1 1.2 MPTP與MPP+ (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 1-methyl-4-phenyl-pyridinium)…………………………………………….2 1.3 血腦屏障 (Blood-brain barrier,BBB)……………………………………3 1.4 有機陽離子轉運蛋白 (Organic cation transporters,OCTs)…………… 4 1.5 Amantadine…………………………………………………………………7 第2章 研究目的……………………………………………………………………9 第3章 實驗材料…………………………………………………………………..10 3.1. Adult Rat Brain Endothelial Cells (ARBECs) 細胞培養………………...10 3.1.1 試劑…………………………………………………………………..10 3.1.2 材料與設備…………………………………………………………..10 3.2. Human Brain Microvessel Endothelial Cells (Human BMECs) 細胞培養.................................................................................................................11 3.2.1. 試劑…………………………………………………………………..11 3.2.2. 材料與設備…………………………………………………………..11 3.3. 分離大鼠與小鼠腦血管內皮細胞……………………………………….11 3.3.1. 試劑…………………………………………………………………..11 3.4. Rats and mice Brain Microvessel Endothelial Cells (Rats and mice BMECs) 培養……………………………………………………………………….12 3.4.1. 試劑…………………………………………………………………..12 3.5. 免疫螢光染色…………………………………………………………….12 3.5.1. 試劑…………………………………………………………………..12 3.5.2. 一級抗體……………………………………………………………..12 3.5.3. 二級抗體……………………………………………………………..13 3.6. 分離細胞膜luminal與abluminal (Isolation of luminal and abluminal plasma membrane vesicles)……………………………………………….13 3.6.1. 試劑…………………………………………………………………..13 3.7. OCT1/OCT2基因靜默 (OCT1/OCT2 silencing)………………………...13 3.7.1. 試劑…………………………………………………………………..13 3.8. 細胞蛋白萃取 (Cell lysate extraction)…………………………………...15 3.8.1. 試劑…………………………………………………………………..15 3.9. MPTP在BMECs與ARBECs細胞攝取量研究 (uptake study)……….15 3.9.1. 試劑…………………………………………………………………..15 3.10. 蛋白質濃度測定 (Bio-Rad DC protein assay)…………………………...16 3.10.1. 材料與設備……………………………………………………..16 3.11. 西方墨點法 (Western Blot)………………………………………………16 3.11.1. 試劑……………………………………………………………..16 3.11.2. 一級抗體………………………………………………………..17 3.11.3. 二級抗體………………………………………………………..17 3.12. 微透析試驗 (Microdialysis)……………………………………………...17 3.12.1. 實驗動物………………………………………………………..17 3.12.2. 試劑……………………………………………………………..17 3.13. 小鼠紋狀體多巴胺與其代謝物之分析………………………………….18 3.13.1. 試劑……………………………………………………………..17 3.14. 高效能液相層析試驗…………………………………………………….18 3.14.1. 試劑……………………………………………………………..18 3.15. 小動物正子掃描 (Small animal Positron Emission Tomography)………19 3.15.1. 實驗動物………………………………………………………..19 3.15.2. 試劑……………………………………………………………..19 第4章 實驗方法…………………………………………………………………..20 4.1. Adult Rat Brain Endothelial Cells (ARBECs) 細胞培養………………...20 4.2. Human Brain Microvessel Endothelial Cells (Human BMECs) 細胞培養………………………………………………………………………….20 4.3. 分離大鼠與小鼠腦血管內皮細胞……………………………………….21 4.4. Rats and mice Brain Microvessel Endothelial Cells (Rats and mice BMECs) 培養……………………………………………………………………….21 4.5. 免疫螢光染色…………………………………………………………….22 4.6. 分離細胞膜luminal與abluminal (Isolation of luminal and abluminal plasma membrane vesicles)……………………………………………….23 4.7. OCT1/OCT2基因靜默 (OCT1/OCT2 silencing)………………………...23 4.8. 細胞蛋白萃取 (Cell lysate extraction)…………………………………...24 4.9. MPTP在BMECs與ARBECs細胞攝取量研究 (uptake study)…………24 4.10. 蛋白質濃度測定 (Bio-Rad DC protein assay)…………………………...25 4.10.1. 藥物攝取實驗之蛋白質濃度測定……………………………..25 4.10.2. 細胞蛋白之蛋白質濃度測定…………………………………..25 4.11. 西方墨點法 (Western Blot)………………………………………………26 4.12. OCT1/OCT2在血腦屏障通透量之研究…………………………………26 4.12.1. 大腦微透析探針製備方法……………………………………..26 4.12.2. 探針回收率 (Recovery) 體外試驗……………………………27 4.12.3. 大鼠與小鼠立體定位手術……………………………………..28 4.12.4. 大腦微透析系統體內試驗……………………………………..28 4.12.5. 高效能液相層析法與螢光偵測法……………………………..29 4.13. 小鼠紋狀體多巴胺與其代謝物之分析….………………………………29 4.13.1. MPTP與amantadine給藥………………………………………29 4.13.2. 高效能液相層析法與電化學偵測法…………………………..30 4.13.3. 小動物正子掃描………………………………………………..30 4.14. 數據分析………………………………………………………………….31 第5章 實驗結果……………………………………………………………………32 5.1 OCT1與OCT2於BMECs與ARBECs細胞分布情形之研究…………….32 5.1.1 免疫螢光染色……………………………………………………..32 5.1.2 西方墨點法………………………………………………………..32 5.2 BMECs與ARBECs細胞進行OCT1/OCT2基因靜默後之MPTP攝取….32 5.3 Amantadine對於腦中紋狀體MPTP/MPP+通透量變化之研究…………..33 5.4 Amantadine對於MPTP引發多巴胺毒性變化之研究……………………34 5.4.1 MPTP毒性對紋狀體中多巴胺與其代謝物濃度影響之探討…...34 5.4.2 MPTP毒性對紋狀體破壞程度之研究…………………………...34 第6章 結果討論……………………………………………………………………40 第7章 結論…………………………………………………………………………44 第8章 參考文獻…………………………………………………………………..45 第9章 附錄………………………………………………………………………..52 | |
dc.language.iso | zh-TW | |
dc.title | 第一型及第二型有機陽離子轉運蛋白在大腦微血管內皮細胞的分布位置以及其與MPTP所造成紋狀體毒性關係之研究 | zh_TW |
dc.title | Cellular localization of the organic cation transporters, OCT1 and OCT2, in brain microvessel endothelial cells and its implication for MPTP-induced dopaminergic toxicity | en |
dc.type | Thesis | |
dc.date.schoolyear | 98-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 胡幼圃,劉宏輝,陳儀莊 | |
dc.subject.keyword | 有機陽離子轉運蛋白,MPTP,amantadine, | zh_TW |
dc.subject.keyword | organic cation transporters (OCTs),MPTP,amantadine, | en |
dc.relation.page | 53 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2010-06-10 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 藥學研究所 | zh_TW |
顯示於系所單位: | 藥學系 |
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