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題名 探討雙酚化合物對神經毒素誘發神經毒害及行為異常的預防與治療效用
Investigation of the protective and therapeutic effects of biphenols on neuronal damage and abnormal behavior induced by neurotoxins作者 劉郁潔
Liu, Yu Chieh貢獻者 詹銘煥
Chan, Ming Huan
劉郁潔
Liu, Yu Chieh關鍵詞 雙酚化合物
巴拉圭
過氧化氫
MPTP
認知功能障礙
神經保護作用
biphenol
paraquat
hydrogen peroxide
MPTP
cognitive impairment
neuroprotection日期 2013 上傳時間 1-Oct-2014 13:41:44 (UTC+8) 摘要 雙酚化合物在文獻報導中發現具有抗發炎和抗氧化的能力，因為其親脂性的特性，雙酚化合物可以輕易穿透血腦屏障到中樞神經系統發揮其藥理活性。因此，雙酚化合物被評估可做為潛在預防及治療神經退化性疾病如帕金森氏症的神經保護藥物。本研究目的為探討新合成的雙酚化合物MH101及MH102是否具有神經保護和治療效用，而對抗神經毒素(包含巴拉圭、過氧化氫及MPTP)引起的神經毒害及其誘發的動物行為異常(如: 學習、記憶及運動協調)。研究中應用Oregon-R的果蠅(年齡: 1-2, 7, 20 和 30天)做為檢測模式，果蠅暴露在巴拉圭 (5-20 mM)或過氧化氫(0.3 %-3 %)環境下，並且給予MH101 (0.1-3 μM)。結果顯示MH101未能有效地減緩巴拉圭及過氧化氫所引起果蠅壽命的下降。此外，給予雄性ICR小鼠 (25-30 g) 腹腔注射MPTP (25mg/kg)每天一次連續五天，觀察神經毒素誘發的行為異常和神經毒害。在觀察保護效果的研究中，雄性小鼠在給予MPTP前一小時腹腔注射MH101 (1-3 mg/kg) 或MH102 (0.1-3 mg/kg) 每天一次連續五天，之後單獨給予MH101或MH102治療連續九天。後處理的組別，雄性小鼠在給予MPTP每天一次連續五天後，每天腹腔注射MH101 (1-3 mg/kg) 或MH102 (0.1-3 mg/kg)連續九天。控制組組別，小鼠則給予生理食鹽水(0.9%)及玉米油的混合液。結果顯示，MH101、MH102及MPTP皆不影響小鼠橫桿行走試驗的運動平衡和協調能力。然而，在前處理和後處理MH101或MH102後用新位置辨識能力測試和新物體辨識能力測試觀察MPTP引起的認知缺失，實驗結果顯示MH101及MH102皆恢復短期記憶和長期記憶的認知辨識指標。另外，前處理和後處理MH101或MH102雖有些微恢復紋狀體內MPTP引起多巴胺神經損傷及多巴胺轉運子減少的趨勢，但不顯著。由此推論，雙酚化合物MH101及MH102具有預防及改善神經毒素所引發的認知與學習缺陷，未來可能發展成為神經退化性疾病如帕金森氏症之潛力治療藥物，另針對MH101及MH102在神經損傷及動物行為障礙的恢復和保護藥理機制則需進一步實驗探討。
Biphenols which are the main constituents of the traditional herbs have been found to possess the antiinflammatory and antioxidative properties. Due to the lipophilic activity, biphenols can readily cross the blood brain barrier to exert their pharmacological effects in the central nervous system. Thus, biphenols are proposed to act as the novel neuroprotective agents for treatment of neurodegenerative disorders such as Parkinson’s disease (PD). The aim of the present study was to examine whether the new synthetic biphenolic compounds MH101 and MH102 have the neuroprotective and therapeutic actions against the neurotoxicity and the behavioral impairments (e.g. learning, memory, and motor coordination) induced by neurotoxins including paraquat, hydrogen peroxide, and MPTP in PD-like animal models. The following experiments examined the lifespan of flies from Oregon-R strain of Drosophoila melanogaster (age: 1-2, 7, 20 and 30 days) chronically exposed to paraquat (5-20 mM) or hydrogen peroxide (0.3 %-3 %) under MH101 (0.1-3 μM) treatment. Our results showed that MH101 could not effectively influence the reduced lifespan of the flies induced by paraquat and hydrogen peroxide. Furthermore, male ICR mice (25-30 g) were administrated with MPTP (25 mg/kg, i.p.) once daily for 5 consecutive days to induce neuronal damage and cognitive deficits. For the protective study, male mice were administrated with MH101 (1-3 mg/kg, i.p.) or MH102 (0.1-3 mg/kg, i.p.) 1 hour prior to MPTP injection once daily for 5 days, and followed daily treatment with MH101 or MH102 alone for consecutive 9 days after the final injection of MPTP. For the post-treatment study, male mice were administrated with MPTP (25 mg/kg, i.p.) once daily for 5 consecutive days, and followed by daily treatment of MH101 or MH102 for 9 days. Mice in control group were injected with vehicle (0.9% saline + corn oil). The results showed that MH101, MH102, and MPTP alone did not alter the motor functions of coordination and balance in beam walking test. On the other hand, both pre-treatment and post-treatment of MH101 and MH102 reversed the cognitive dysfunction induced by MPTP detected by novel location recognition test (NLRT) and novel object recognition test (NORT). Data demonstrated that MH101 and MH102 reversed the reduction in recognition index (RI) of short term memory and long term memory in MPTP-induced PD model. However, pre-treatment and post-treatment of MH101 or MH102 slightly recovered MPTP-induced loss of dopamine neurons and dopamine transporter in striatum. Therefore, the results suggest that biphenols including MH101 and MH102 may be the candidates for treatment of neurodegenerative diseases such as PD. In the future, it will need further study to determine the pharmacological mechanism of MH101 and MH102 in protection and restoration of neuronal injury and cognitive impairment.參考文獻 (一) 書籍論文威廉‧蘭斯頓、強‧帕夫瑞曼 原著，譯者:洪蘭，”喚醒冰凍人”，遠流出版社，2005年1月1日出版李時珍原著，”圖解本草綱目”，紫圖圖書，2007年9月三版一刷史世勤、賀昌木主編，”李時珍全集”本草綱目第二十一至三十八卷，湖北教育出版社，2004年一版(二) 期刊文獻Anandhan A, Janakiraman U, Manivasagam T (2012) Theaflavin ameliorates behavioral deficits, biochemical indices and monoamine transporters expression against subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson’s disease. Neuroscience 218:257-267.Aziz SM, Lipke DW, Olson JW, Gillespie MN (1994) Role of ATP and sodium in polyamine transport in bovine pulmonary artery smooth cells. 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國立政治大學
神經科學研究所
100754008
102資料來源 http://thesis.lib.nccu.edu.tw/record/#G0100754008 資料類型 thesis dc.contributor.advisor 詹銘煥 zh_TW dc.contributor.advisor Chan, Ming Huan en_US dc.contributor.author (Authors) 劉郁潔 zh_TW dc.contributor.author (Authors) Liu, Yu Chieh en_US dc.creator (作者) 劉郁潔 zh_TW dc.creator (作者) Liu, Yu Chieh en_US dc.date (日期) 2013 en_US dc.date.accessioned 1-Oct-2014 13:41:44 (UTC+8) - dc.date.available 1-Oct-2014 13:41:44 (UTC+8) - dc.date.issued (上傳時間) 1-Oct-2014 13:41:44 (UTC+8) - dc.identifier (Other Identifiers) G0100754008 en_US dc.identifier.uri (URI) http://nccur.lib.nccu.edu.tw/handle/140.119/70314 - dc.description (描述) 碩士 zh_TW dc.description (描述) 國立政治大學 zh_TW dc.description (描述) 神經科學研究所 zh_TW dc.description (描述) 100754008 zh_TW dc.description (描述) 102 zh_TW dc.description.abstract (摘要) 雙酚化合物在文獻報導中發現具有抗發炎和抗氧化的能力，因為其親脂性的特性，雙酚化合物可以輕易穿透血腦屏障到中樞神經系統發揮其藥理活性。因此，雙酚化合物被評估可做為潛在預防及治療神經退化性疾病如帕金森氏症的神經保護藥物。本研究目的為探討新合成的雙酚化合物MH101及MH102是否具有神經保護和治療效用，而對抗神經毒素(包含巴拉圭、過氧化氫及MPTP)引起的神經毒害及其誘發的動物行為異常(如: 學習、記憶及運動協調)。研究中應用Oregon-R的果蠅(年齡: 1-2, 7, 20 和 30天)做為檢測模式，果蠅暴露在巴拉圭 (5-20 mM)或過氧化氫(0.3 %-3 %)環境下，並且給予MH101 (0.1-3 μM)。結果顯示MH101未能有效地減緩巴拉圭及過氧化氫所引起果蠅壽命的下降。此外，給予雄性ICR小鼠 (25-30 g) 腹腔注射MPTP (25mg/kg)每天一次連續五天，觀察神經毒素誘發的行為異常和神經毒害。在觀察保護效果的研究中，雄性小鼠在給予MPTP前一小時腹腔注射MH101 (1-3 mg/kg) 或MH102 (0.1-3 mg/kg) 每天一次連續五天，之後單獨給予MH101或MH102治療連續九天。後處理的組別，雄性小鼠在給予MPTP每天一次連續五天後，每天腹腔注射MH101 (1-3 mg/kg) 或MH102 (0.1-3 mg/kg)連續九天。控制組組別，小鼠則給予生理食鹽水(0.9%)及玉米油的混合液。結果顯示，MH101、MH102及MPTP皆不影響小鼠橫桿行走試驗的運動平衡和協調能力。然而，在前處理和後處理MH101或MH102後用新位置辨識能力測試和新物體辨識能力測試觀察MPTP引起的認知缺失，實驗結果顯示MH101及MH102皆恢復短期記憶和長期記憶的認知辨識指標。另外，前處理和後處理MH101或MH102雖有些微恢復紋狀體內MPTP引起多巴胺神經損傷及多巴胺轉運子減少的趨勢，但不顯著。由此推論，雙酚化合物MH101及MH102具有預防及改善神經毒素所引發的認知與學習缺陷，未來可能發展成為神經退化性疾病如帕金森氏症之潛力治療藥物，另針對MH101及MH102在神經損傷及動物行為障礙的恢復和保護藥理機制則需進一步實驗探討。 zh_TW dc.description.abstract (摘要) Biphenols which are the main constituents of the traditional herbs have been found to possess the antiinflammatory and antioxidative properties. Due to the lipophilic activity, biphenols can readily cross the blood brain barrier to exert their pharmacological effects in the central nervous system. Thus, biphenols are proposed to act as the novel neuroprotective agents for treatment of neurodegenerative disorders such as Parkinson’s disease (PD). The aim of the present study was to examine whether the new synthetic biphenolic compounds MH101 and MH102 have the neuroprotective and therapeutic actions against the neurotoxicity and the behavioral impairments (e.g. learning, memory, and motor coordination) induced by neurotoxins including paraquat, hydrogen peroxide, and MPTP in PD-like animal models. The following experiments examined the lifespan of flies from Oregon-R strain of Drosophoila melanogaster (age: 1-2, 7, 20 and 30 days) chronically exposed to paraquat (5-20 mM) or hydrogen peroxide (0.3 %-3 %) under MH101 (0.1-3 μM) treatment. Our results showed that MH101 could not effectively influence the reduced lifespan of the flies induced by paraquat and hydrogen peroxide. Furthermore, male ICR mice (25-30 g) were administrated with MPTP (25 mg/kg, i.p.) once daily for 5 consecutive days to induce neuronal damage and cognitive deficits. For the protective study, male mice were administrated with MH101 (1-3 mg/kg, i.p.) or MH102 (0.1-3 mg/kg, i.p.) 1 hour prior to MPTP injection once daily for 5 days, and followed daily treatment with MH101 or MH102 alone for consecutive 9 days after the final injection of MPTP. For the post-treatment study, male mice were administrated with MPTP (25 mg/kg, i.p.) once daily for 5 consecutive days, and followed by daily treatment of MH101 or MH102 for 9 days. Mice in control group were injected with vehicle (0.9% saline + corn oil). The results showed that MH101, MH102, and MPTP alone did not alter the motor functions of coordination and balance in beam walking test. On the other hand, both pre-treatment and post-treatment of MH101 and MH102 reversed the cognitive dysfunction induced by MPTP detected by novel location recognition test (NLRT) and novel object recognition test (NORT). Data demonstrated that MH101 and MH102 reversed the reduction in recognition index (RI) of short term memory and long term memory in MPTP-induced PD model. However, pre-treatment and post-treatment of MH101 or MH102 slightly recovered MPTP-induced loss of dopamine neurons and dopamine transporter in striatum. Therefore, the results suggest that biphenols including MH101 and MH102 may be the candidates for treatment of neurodegenerative diseases such as PD. In the future, it will need further study to determine the pharmacological mechanism of MH101 and MH102 in protection and restoration of neuronal injury and cognitive impairment. en_US dc.description.tableofcontents 中文摘要 IAbstract II目錄 IV圖次 VI縮寫對照表 (abbreviation) VIII第一章 緒論 1第一節 前言 1第二節 厚朴之簡介 2第三節 和厚朴酚之簡介 3第四節 帕金森氏症簡介 6第五節 帕金森氏症的致病機轉與治療 8第六節 引發類帕金森氏症的動物模式 9第七節 研究動機及目的 12第二章 實驗材料與方法 13第一節 實驗動物 13第二節 實驗藥品配置 13第三節 實驗方法 14第四節 實驗流程設計 18第五節 實驗數據分析 21第三章 實驗結果 21第一節 雙酚化合物MH101對巴拉圭引起果蠅生存及死亡之影響 21第二節 雙酚化合物MH101與過氧化氫對果蠅生存及死亡之影響 27第三節 評估雙酚化合物對MPTP引起的小鼠行為異常之療效 37第四節 探討雙酚化合物對MPTP引起的小鼠神經毒害之相關機制 44第四章 討論 51第五章 結論 55第六章 參考文獻 56 zh_TW dc.language.iso en_US - dc.source.uri (資料來源) http://thesis.lib.nccu.edu.tw/record/#G0100754008 en_US dc.subject (關鍵詞) 雙酚化合物 zh_TW dc.subject (關鍵詞) 巴拉圭 zh_TW dc.subject (關鍵詞) 過氧化氫 zh_TW dc.subject (關鍵詞) MPTP zh_TW dc.subject (關鍵詞) 認知功能障礙 zh_TW dc.subject (關鍵詞) 神經保護作用 zh_TW dc.subject (關鍵詞) biphenol en_US dc.subject (關鍵詞) paraquat en_US dc.subject (關鍵詞) hydrogen peroxide en_US dc.subject (關鍵詞) MPTP en_US dc.subject (關鍵詞) cognitive impairment en_US dc.subject (關鍵詞) neuroprotection en_US dc.title (題名) 探討雙酚化合物對神經毒素誘發神經毒害及行為異常的預防與治療效用 zh_TW dc.title (題名) Investigation of the protective and therapeutic effects of biphenols on neuronal damage and abnormal behavior induced by neurotoxins en_US dc.type (資料類型) thesis en dc.relation.reference (參考文獻) (一) 書籍論文威廉‧蘭斯頓、強‧帕夫瑞曼 原著，譯者:洪蘭，”喚醒冰凍人”，遠流出版社，2005年1月1日出版李時珍原著，”圖解本草綱目”，紫圖圖書，2007年9月三版一刷史世勤、賀昌木主編，”李時珍全集”本草綱目第二十一至三十八卷，湖北教育出版社，2004年一版(二) 期刊文獻Anandhan A, Janakiraman U, Manivasagam T (2012) Theaflavin ameliorates behavioral deficits, biochemical indices and monoamine transporters expression against subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinson’s disease. 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