糖尿病是一種代謝異常疾病，伴隨著許多的慢性併發症，包含糖尿病神經病變性疼痛。在先前的離體實驗中，我們得知來自海洋的化合物SWV-1具有抗發炎的作用。在本研究中，我們發現椎管給予或口服SWV-1，在鏈脲佐菌素(streptozotocin, STZ)所誘發糖尿病神經病變大鼠表現出鎮痛作用，且相較於ziconotide來說，給予SWV-1沒有產生明顯的副作用。同時，免疫螢光染色分析的結果顯示，SWV-1顯著抑制STZ所誘發的脊髓神經發炎情形。我們進一步證實，給予轉型生長因子乙型受體(transforming growth factor β type I receptor, TGF-β R1)抑制劑後，會減弱SWV-1對STZ大鼠的止痛效果。根據上述結果，我們認為SWV-1具備糖尿病患神經病變性疼痛之治療藥物開發的潛力。

Diabetes mellitus is a metabolic disease that can have long-term complications, including diabetic neuropathy pain. Base on preliminary screening, we had found that a marine-derived compound, SWV-1 has potential in vitro anti-inflammatory effects. In present study, we found that intrathecal or oral SWV-1 produce antinociceptive effects in STZ-induced diabetic neuropathic rats. Moreover, compare with ziconotide, SWV-1 did not produced any obvious adverse effects. Immunohistochemistical analyses also showed that SWV-1 significantly attenuated STZ-induced spinal neuroninflammation. We further demonstrated that administration of TGF-β type I receptor inhibitor attenuate the analgesic effect of SWV-1 in STZ-rats. In conclusion, SWV-1 is a potential candidate compound for drug development to treat neuropathic pain in patients with diabetes.

審定書 ................................................................................................................................i
誌謝 ................................................................................................................................... ii
中文摘要 .......................................................................................................................... iii
英文摘要 .......................................................................................................................... iv
目錄 ...................................................................................................................................v
圖次 ................................................................................................................................ viii
縮寫及中英文對照表 ...................................................................................................... xi
第一章、前言......................................................................................1
糖尿病與神經病變性疼痛......................................................................1
神經病變性疼痛的發生及傳遞................................................................2
神經發炎影響神經病變性疼痛的發展......................................................9
臨床用於治療神經病變性疼痛之藥物.....................................................11
神經病變性疼痛之動物模式..................................................................13
糖尿病神經病變性疼痛的形成及其病理機制...........................................16
海洋天然物的開發及抗發炎作用............................................................17
研究目的............................................................................................18
第二章、實驗材料與方法......................................................................19
實驗動物............................................................................................19
STZ誘發糖尿病大鼠與疼痛行為分析......................................................19
物理性觸覺過敏測試 (mechanical allodynia)...........................................19
丙酮冷覺過敏測試 (acetone cold allodynia)............................................20
平板式熱覺過敏測試 (plantar test、thermal hyperalgesia)........................20
尾部浸泡測試 (tail immersion)...............................................................20
平衡木測試 (narrow beam test)..............................................................22
椎管插管手術(implantation of intrathecal catheter) ..................................22
樣本組織收集及冷凍切片......................................................................22
組織免疫化學螢光染色(immunohistochemistry).......................................23
西方墨點法(western blot)......................................................................24
使用的目標抗體...................................................................................25
實驗動物之分組...................................................................................25
數據分析.............................................................................................27
第三章、實驗結果................................................................................28
STZ誘發大鼠產生高血糖及體重降低情形................................................28
STZ誘發大鼠產生mechanical allodynia, cold allodynia, thermal
hyperalgesia , tail thermal hyperalgesia及行動力下降情形........................28
STZ誘發大鼠脊髓背角之細胞及分子層次的影響.......................................29
STZ誘發大鼠脊髓背角之microglia活化....................................................29
STZ誘發大鼠脊髓背角之astrocytes活化..................................................29
STZ誘發大鼠脊髓背角之p-p38表現量上升................................................29
STZ誘發大鼠脊髓背角之p-mTOR表現量上升...........................................30
STZ誘發大鼠脊髓背角之TGF-β1表現量下降.............................................30
椎管給予SWV-1或ziconotide對STZ誘發mechanical allodynia和行動力的影響.30
利用疼痛行為測試評估椎管給予SWV-1對STZ大鼠之鎮痛作用 .......................31
椎管給予SWV-1抑制STZ誘發之mechanical and cold allodynia......................31
椎管給予SWV-1抑制STZ誘發之tail thermal hyperalgesia..............................32
評估椎管給予SWV-1或gabapentin對STZ大鼠疼痛行為之鎮痛作用.................32
給予SWV-1或gabapentin抑制STZ誘發之mechanical and cold allodynia.........32
給予SWV-1或gabapentin抑制STZ誘發tail thermal hyperalgesia.....................33
椎管給予SWV-1對STZ大鼠脊髓背角細胞及分子的影響.................................34
椎管給予SWV-1抑制STZ誘發脊髓背角microglia的活化情形..........................34
椎管給予SWV-1抑制STZ誘發脊髓背角astrocytes的活化情形........................34
椎管給予SWV-1對於STZ誘發脊髓背角之p-ERK表現量上升的影響.................35
椎管給予SWV-1對於STZ誘發脊髓背角之p-p38表現量上升的影響..................35
椎管給予SWV-1對於STZ誘發脊髓背角之p-mTOR表現量上升的影響..............36
椎管給予SWV-1對於STZ誘發脊髓背角之IL-1β表現量上升的影響...................36
椎管給予SWV-1對於STZ誘發脊髓背角之BDNF表現量上升的影響.................37
椎管給予SWV-1對於STZ誘發脊髓背角之GDNF表現量下降的影響.................37
椎管給予SWV-1對於STZ誘發脊髓背角之TGF-β1表現量下降影響..................37
椎管給予SWV-1對正常大鼠疼痛訊息傳輸的影響.........................................38
椎管給予SWV-1對正常大鼠脊髓抗神經發炎因子TGF-β1表現量的影響...........38
比較口服給予SWV-1或gabapentin對STZ大鼠疼痛行為之鎮痛作用................39
口服SWV-1或gabapentin對STZ誘發mechanical allodynia及tail heat
hyperalgesia的影響..................................................................................39
口服SWV-1或gabapentin可抑制STZ誘發之mechanicaland cold allodynia ......39
口服SWV-1或gabapentin可抑制STZ誘發之tail thermal hyperalgesia..............40
口服SWV-1或gabapentin對STZ大鼠脊髓背角細胞及分子的影響....................41
口服SWV-1可抑制STZ誘發脊髓背角之microglia的活化情形..........................41
口服SWV-1可抑制STZ誘發脊髓背角之astrocytes的活化情形........................41
口服SWV-1對於STZ誘發脊髓背角之IL-1β表現量上升的影響..........................41
口服SWV-1對於STZ誘發脊髓背角之TGF-β1表現量下降的影響......................42
椎管給予TGF-β RI抑制劑對正常大鼠脊髓背角細胞及分子的影響....................42
椎管給予TGF-β RI抑制劑對正常大鼠脊
髓背角microglia的影響 .......................42
椎管給予TGF-β RI抑制劑對正常大鼠脊髓背角astrocytes的影響.....................43
椎管給予TGF-β RI抑制劑對正常大鼠脊髓背角p-mTOR的影響........................43
椎管給予TGF-β RI抑制劑對正常大鼠脊髓背角IL-1β影響................................43
給予TGF-β RI抑制劑對SWV-1減輕STZ大鼠疼痛行為的影響..........................43
TGF-β RI抑制劑對SWV-1減輕STZ誘發之脊髓神經發炎情形的影響................44
TGF-β RI抑制劑對SWV-1減輕STZ大鼠microglia活化情形的影響....................44
TGF-β RI抑制劑對SWV-1減輕STZ大鼠astrocytes活化情形的影響.................45
TGF-β RI抑制劑對SWV-1減輕STZ大鼠IL-1β大量表現的影響.........................45
TGF-β RI抑制劑對SWV-1增加STZ大鼠脊髓TGF-β1表現量的影響..................45
第四章、實驗討論....................................................................................97
建立大鼠DNP模式以評估海洋衍生物的作用................................................97
椎管給予SWV-1、臨床藥物ziconotide及gabapentin於STZ大鼠鎮痛作用之比較 .98
椎管給予SWV-1可減輕STZ大鼠的脊髓背角之神經發炎情形.............................99
背角感覺神經纖維對於疼痛行為的影響........................................................101
口服SWV-1可減輕STZ大鼠的疼痛行為及脊髓背角的神經發炎情形.................102
TGF-β1在神經病變疼痛過程中可能扮演的角色..............................................103
阻斷TGF-β訊號路徑對脊髓神經發炎的影響...................................................105
總結SWV-1抗神經發炎可能之作用機轉........................................................106
未來展望...................................................................................................108
Reference..................................................................................................109
附錄一.......................................................................................................124

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