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博碩士論文 etd-0308116-093841 詳細資訊
Title page for etd-0308116-093841
論文名稱
Title
第一型血紅素氧化酶在珊瑚衍生物對於神經病變之止痛作用的角色
The role of heme oxygenase-1 in the antinociceptive effects of coral-derived compounds in neuropathy
系所名稱
Department
畢業學年期
Year, semester
語文別
Language
學位類別
Degree
頁數
Number of pages
159
研究生
Author
指導教授
Advisor
召集委員
Convenor
口試委員
Advisory Committee
口試日期
Date of Exam
2016-01-26
繳交日期
Date of Submission
2016-04-08
關鍵字
Keywords
神經病變性疼痛、坐骨神經結紮、神經發炎、活性氧物質、第一型血紅素氧化酶
heme oxygenase-1 (HO-1), neuropathic pain, chronic constriction injury, neuroinflammation, reactive oxygen species (ROS)
統計
Statistics
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The thesis/dissertation has been browsed 5801 times, has been downloaded 0 times.
中文摘要
近年來,天然海洋化合物已被認為是具有潛力可開發成新的抗發炎藥物,其被報導出具有廣泛的生物效應,包括抗發炎,抗神經發炎和神經保護等作用。經由初步篩選發現,分離自台灣軟珊瑚的NRPG4-3和NRPG07具有抗發炎活性,因此,我們利用坐骨神經慢性壓迫(chronic constriction injury, CCI)所誘發的神經病變性疼痛大鼠模式,測試NRPG4-3和NRPG07對於神經病變性疼痛的消炎止痛效果。結果顯示,椎管給予NRPG4-3和NRPG07於神經病變的大鼠所誘發之thermal hyperalgesia和mechanical allodynia具有抑制疼痛之效果,且呈劑量依賴效應,此外,亦可抑制因CCI所誘發的脊髓神經發炎現象。而給予HO-1 inhibitor (ZnPP)後在免疫螢光染色中發現,經由NRPG4-3和NRPG07所抑制的astrocyte, microglia, neuroninflammation 和reactive oxygen species (ROS)效果明顯降低。綜合以上結果得知,NRPG4-3和NRPG07是具有相當大的潛力被做為開發神經病變性疼痛的候選藥物。
Abstract
Recently, natural marine compounds have been considered as having potential for use in the development of novel anti-inflammatory drugs. They have been reported to have a broad spectrum of biological effects, including anti-inflammatory, anti-neuroinflammatory, and neuroprotective effects. Through preliminary screening, we previously found that marine-derived compounds, NRPG4-3 and NRPG07, isolated from Taiwanese soft coral, have anti-inflammatory effects. In the present study, to characterize the potential anti-nociceptive properties of NRPG4-3 and NRPG07, we evaluated NRPG4-3 and NRPG07 in a rat model of chronic constriction injury (CCI), a well-established model of neuropathic pain. We found that NRPG4-3 and NRPG07 significantly inhibit the neuropathic symptoms of thermal hyperalgesia and mechanical allodynia in a dose-dependent manner. Moreover, they also attenuated CCI-induced spinal neuroinflammation. Finally, we confirmed that administration of HO-1 inhibitor (ZnPP) attenuated the analgesic effect of NRPG4-3 and NRPG07 in rats with CCI. However, immunohistochemical analyses showed that NRPG4-3 and NRPG07 significantly inhibited CCI-induced activation of microglia, astrocytes, neuroinflammation, and reactive oxygen species (ROS) in the dorsal horn of the spinal cord. In conclusion, NRPG4-3 and NRPG07 are potential candidate compounds for the development of drugs to treat neuropathic pain.
目次 Table of Contents
論文審定書......................................................................i
誌謝...............................................................................ii
中文摘要........................................................................iii
Abstract.........................................................................iv
目錄...............................................................................v
表目錄...........................................................................xii
中英文對照及縮寫表.......................................................xiii
前言................................................................................1
神經病變性疼痛(neuropathic pain)之新藥開發的急迫性.........1
神經病變性疼痛之臨床藥物的市場現狀與不足......................2
海洋天然物開發潛力與應用................................................8
神經病變性疼痛之致病機制...............................................11
Glia在神經病變性疼痛之重要角色......................................14
中樞神經發炎性反應對神經病變性疼痛的關鍵影響...............15
坐骨神經慢性壓迫誘發神經病變性疼痛的介紹......................24
研究目的..........................................................................27
實驗方法與材料................................................................28
實驗動物..........................................................................28
椎管插管手術(implantation of intrathecal catheter) ...............28
坐骨神經結紮誘發神經病變性疼痛模式................................28
疼痛行為評估....................................................................29
脊髓樣本組織收集與冷凍切片.............................................30
組織免疫化學螢光染色(immunohistochemistry)....................30
實驗動物設計與分組..........................................................32
數據分析..........................................................................34
結果.................................................................................36
討論 118
NRPG4-3與NRPG07與臨床藥物於CCI大鼠鎮痛作用之比較..118
椎管給予NRPG4-3與NRPG07於CCI大鼠之脊髓背角之細胞
及分子層次的影響............................................................120
HO-1在神經病變性疼痛過程中可能扮演的角色....................123
阻斷HO-1訊息路徑對脊髓背角神經發炎之影響....................124
NRPG4-3、NRPG07抗氧化、抗神經發炎可能作用機轉........125
NRPG4-3及NRPG07在神經病變性疼痛上作用之機制............127
未來展望...........................................................................128
參考文獻...........................................................................129
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