脊髓損傷的病理過程涉及原發性傷害與繼發性傷害，大多數研究專注於了解繼發性傷害的病理過程，以及減少脊髓損傷後大量細胞的損失。而繼發性傷害病理過程的特點，包括發炎性反應、活性氧化物(reactive oxygen species)或自由基(free radical)的產生，和神經元的凋亡反應。脊髓損傷後所誘導產生的活性氧化物及自由基會引發氧化傷害(oxidatives damage)，並且促進神經性發炎反應的生成。在本研究中，我們將試驗海洋化合物WY8作用在大白鼠脊髓損傷模式中對於抗發炎反應與抗氧化傷害的功效。脊髓損傷動物模式是將母大白鼠胸椎利用美國紐約大學脊髓損傷撞擊器(NYU impactor)生成創傷性脊髓損傷。而藥物給予方式，分別在椎管內給予WY8(10 μg)七次於大鼠脊髓損傷後，以及腹腔注射臨床藥物甲基培尼皮質醇(methylprenisolone)30 mg/kg一次。實驗結果發現其椎管內給予WY8對於脊髓損傷大鼠具有保留剩餘未損傷白質區域，以及減少受傷區域的擴大，並且顯著提升後肢運動功能。也利用免疫螢光染色分析，其WY8具有顯著減少脊髓損傷所誘導生成的過氧化物自由基(superoxide radical)，也包括降低其生成過氧化物自由基的酵素NADPH氧化酶(NADPH oxidase)和衍生的氨基酪胺酸(nitrotyrosine)的表現。同時我們也發現WY8具有降低發炎因子的表現，如誘導型一氧化氮合成酶(inducible nitric oxide synthase)、細胞間黏附因子-1(intercellular adhesion molecule-1)、白細胞介素-1β(interleukin-1β)和腫瘤壞死因子(tumor necrosis factor-α)。根據上述的結果，我們認為WY8具有脊髓損傷之治療藥物開發的潛力。

The pathophysiology of spinal cord injury(SCI)involves primary and secondary mechanisms of injury, most research however has focused on understanding the pathophysiology of the secondary damage processes and reducing the amount of delayed cell loss following SCI. The pathophysiological hallmarks of secondary injury processes include the inflammatory response, reactive oxygen species or free radical generated, and neuron apoptosis. SCI-induced reactive oxygen species(ROS)generated were elicits oxidative damage, and promoted the inflammatory response. In present study we examined the anti-inflammatory response and anti-oxidative damage effects of WY8 in rat SCI model. The spinal cord contusion injury was induced in thoracic spinal cord of in female Wistar rats by NYU impactor. The saline, WY8(10 μg), and methylprednisolone(MP; a standard SCI agent 30 mg/kg)was administered by intrathecal injection for 7 days and intraperitoneal once after SCI respectively. We found that intrathecal injection WY8 were keep the spared white matter area, reduced the lesion area, and significantly upregulation locomotor function after SCI. Immunohistochemistical analyses showed that WY8 were significantly attenuated SCI-induced superoxide (O2-), including generating enzyme NADPH oxidase (NOX2), byproduct of NO-O2- nitrotyrosine (NT), and inflammatory mediators such as inducible nitric oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), interleukin-1beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) expression. In conclusion, WY8 is a potential candidate compound for drug development to treat SCI.

目錄
審定書..............................................................i
誌謝................................................................ii
中文摘要.............................................................iii
Abstract.............................................................iv
目錄.................................................................v
圖次................................................................xiii
縮寫表..............................................................xv
第一章、前言..........................................................1
1.1 脊髓損傷背景.................................................1
1.2 脊髓之構造...................................................3
1.3 脊髓損傷之致病過程...........................................9
1.4 脊髓損傷所誘導之發炎反應....................................10
1.5 神經膠質細胞在脊髓損傷上扮演的角色..........................11
1.6 MAPK路徑在神經膠質細胞扮演的角色..........................15
1.7 神經性發炎反應在脊髓損傷之角色..............................17
1.8 神經膠質疤痕的形成..........................................18
1.9 脊髓損傷誘導細胞凋亡........................................19
1.10 脊髓損傷誘導氧化壓力所導致的氧化傷害........................20
1.11 脊髓損傷誘導的自由基影響....................................22
1.12 現今臨床治療脊髓損傷藥物(類固醇:Methylprednisolone)...........23
1.13 現今治療脊髓損傷藥物開發主要策略............................26
1.13.1 抗氧化劑與自由基消除劑..............................26
1.13.2 鴉片受體拮抗劑......................................26
1.13.3 神經節糖咁..........................................27
1.13.4 甲釋素及類似物......................................28
1.13.5 NMDA受體拮抗劑....................................28
1.13.6 鈣離子拮抗劑........................................29
1.13.7 花生四烯酸抑制劑....................................30
1.13.8 生長因子............................................30
1.13.9 類固醇-Lazaroids......................................30
1.14 海洋在藥物開發上的優勢......................................31
1.15 脊髓損傷之動物實驗模式......................................32
1.16 研究動機與目的..............................................35
第二章、實驗方法與材料...............................................36
2.1 實驗動物....................................................36
2.2 椎管插管手術................................................36
2.3 大白鼠脊髓損傷手術..........................................37
2.4 後肢運動行為功能分數評估....................................37
2.5 脊髓組織收集及冷凍切片......................................40
2.6 組織病理學..................................................41
2.7 脊髓面積定量................................................41
2.8 運動神經元的定量............................................42
2.9 組織免疫化學螢光染色(immunohistochemistry)....................43
2.10 末端脫氧核苷酸轉移酶脫氧尿苷三磷酸切口標記染色法(terminal deoxynucleotidyl transferase dUTP nick end labeling stain).................44
2.11 過氧化物自由基(superoxide radical)的檢測........................44
2.12 免疫化學螢光染色定量........................................45
2.13 使用的目標抗體..............................................46
2.14 動物實驗設計及分組..........................................46
2.15 預先於椎管內給予WY8在脊髓損傷大白鼠之運動行為能力觀察......47
2.16 預先於椎管內給予WY8在脊髓損傷大白鼠細胞層面分子之影響......47
2.17 椎管內給予WY8在脊髓損傷大白鼠之運動行為能力觀察............47
2.18 椎管內給予WY8在脊髓損傷大白鼠細胞層面分子之影響............48
2.19 統計分析....................................................48
第三章、實驗結果.....................................................49
3.1 預先於椎管內給予WY8對於脊髓損傷大白鼠之影..................49
3.1.1 實驗流程............................................49
3.1.2 WY8對於脊髓損傷大鼠後肢運動功能之影響..............49
3.1.3 WY8對於脊髓損傷大鼠傷口與髓鞘組織之影響............50
3.1.4 WY8對於脊髓損傷後運動神經元存活之影響..............50
3.1.5 WY8對於脊髓損傷誘發神經軸突之影響..................51
3.1.6 WY8對於脊髓損傷誘發神經元凋亡之影響................51
3.1.7 WY8對於脊髓損傷後腹角運動神經元存活之影響..........51
3.1.8 WY8對於脊髓損傷後微膠細胞之型態變化................52
3.1.9 WY8對於脊髓損傷誘發OX42上升之影響................52
3.1.10 WY8對於脊髓損傷後星狀細胞之型態變化................53
3.1.11 WY8對於脊髓損傷誘發GFAP上升之影響................53
3.1.12 WY8對於脊髓損傷後誘發arg-1免疫螢光活性影響.........53
3.1.13 WY8對於脊髓損傷後誘發NOX2免疫螢光活性影響........54
3.1.14 WY8對於脊髓損傷後誘發NT免疫螢光活性影響...........54
3.1.15 WY8對於脊髓損傷後誘發ICAM-1免疫螢光活性影響......54
3.1.16 WY8對於脊髓損傷後誘發TNF-免疫螢光活性影響........55
3.1.17 WY8對於脊髓損傷後誘發iNOS免疫螢光活性影響.........55
3.2 脊髓損傷後椎管給予WY8對於脊髓損傷大鼠之影響................56
3.2.1 WY8對於脊髓損傷後大鼠之後肢運動功能評估............56
3.2.2 WY8對於脊髓損傷大鼠傷口與髓鞘組織之影響............57
3.2.3 WY8對於脊髓損傷後運動神經元存活之影響..............57
3.2.4 WY8對於脊髓損傷誘發神經軸突之影響..................58
3.2.5 WY8對於脊髓損傷後誘發過氧化物自由基之影響..........58
3.2.6 WY8對於脊髓損傷後運動神經元凋亡之影響..............59
3.2.7 WY8對於脊髓損傷後腹角運動神經元存活之影響..........59
3.2.8 WY8對於脊髓損傷後誘發微膠細胞之型態變化............60
3.2.9 WY8對於脊髓損傷後誘發OX42上升之影響..............60
3.2.10 WY8對於脊髓損傷後誘發星狀細胞之型態變化............60
3.2.11 WY8對於脊髓損傷後誘發GFAP上升之影響..............61
3.2.12 脊髓損傷後誘發p-JNK表現之影響.......................61
3.2.13 WY8對於脊髓損傷後所誘發p-JNK免疫螢光活性之影響....62
3.2.14 脊髓損傷後誘發p-ERK表現之影響......................62
3.2.15 WY8對於脊髓損傷後所誘發p-ERK免疫螢光活性之影響....63
3.2.16 脊髓損傷後誘發p-p38表現之影響.......................63
3.2.17 WY8對於脊髓損傷後所誘發p-p38免疫螢光活性之影響.....63
3.2.18 脊髓損傷後誘發arg-1表現之影響........................64
3.2.19 WY8對於脊髓損傷後所誘發arg-1免疫螢光活性之影響.....64
3.2.20 脊髓損傷後誘發NOX2表現之影響.......................65
3.2.21 WY8對於脊髓損傷後所誘發NOX2免疫螢光活性之影響....65
3.2.22 脊髓損傷後誘發NT表現之影響.........................66
3.2.23 WY8對於脊髓損傷後所誘發NT免疫螢光活性之影響.......66
3.2.24 脊髓損傷後誘發ICAM-1表現之影響.....................67
3.2.25 WY8對於脊髓損傷後所誘發ICAM-1免疫螢光活性之影響..67
3.2.26 脊髓損傷後誘發TNF-表現之影響......................68
3.2.27 WY8對於脊髓損傷後所誘發TNF-免疫螢光活性之影響....68
3.2.28 脊髓損傷後誘發IL-1表現之影響.......................68
3.2.29 WY8對於脊髓損傷後所誘發IL-1免疫螢光活性之影響.....69
3.2.30 脊髓損傷後誘發iNOS表現之影響.......................69
3.2.31 WY8對於脊髓損傷後所誘發iNOS免疫螢光活性之影響.....70
第四章、討論........................................................120
4.1 WY8於脊髓損傷大鼠後肢運動行為能力和組織病理學的影響.......120
4.1.1 WY8對於後肢行為運動功能與組織面積的影響...........121
4.1.2 WY8對於運動神經元及神經軸突的影響.................122
4.2 WY8對於脊髓損傷造成微膠細胞活化的影響.....................123
4.3 WY8對於脊髓損傷造成星狀細胞活化的影響.....................124
4.4 WY8對於脊髓損傷大鼠MAPK的影響...........................125
4.5 WY8對於脊髓損傷大鼠氧化壓力(oxidative stress)的影響..........127
4.5.1 WY8對於O2*ˉ的影響.................................127
4.5.2 WY8對於NOX2的影響...............................128
4.5.3 WY8對於ONOO-的影響..............................128
4.6 WY8對於脊髓損傷大鼠神經性發炎反應的影響...................130
4.6.1 WY8對於ICAM-1的影響.............................130
4.6.2 WY8對於促發炎細胞因子TNF-與IL-1的影響..........131
4.6.3 WY8對於iNOS的影響................................131
4.7 WY8對於脊髓損傷誘發神經細胞凋亡的影響.....................132
4.8 WY8於脊髓損傷後神經保護之機轉.............................133
第五章、未來展望....................................................135
第六章、參考文獻....................................................136
 
圖次
圖1-1、脊髓損傷的成因.................................................1
圖1-2-1、(A)脊椎側面圖、(B)脊椎前視圖...................................4
圖1-2-2、脊髓神經連結到人體結構圖......................................5
圖1-2-3、脊髓之橫切面構造..............................................7
圖1-4、脊髓損傷之影響週期.............................................11
圖1-5-1、微膠細胞表型(phenotype)活化路徑及功能.........................14
圖1-5-2、微膠細胞M2之表型(phenotype)介紹..............................14
圖1-6、MAPK路徑示意圖..............................................17
圖1-11、peroxynitrite與微膠細胞之關聯...................................23
圖1-15-1、NYU impactor(脊髓損傷撞擊器) ................................33
圖1-15-2、電腦評估脊髓損傷後標準化的高度、速度與時間...................33
圖2-7、脊髓面積定量示意圖............................................42
圖2-8、(A)腹角運動神經元型態示意圖、(B)脊髓lamina區域分布圖............43
圖2-12、免疫螢光活性定量示意圖.......................................45
圖3-1-1、預先於椎管內給予WY8對於脊髓損傷大白鼠之影響................71
圖3-1-2、WY8對於脊髓損傷大鼠後肢運動功能之影響......................72
圖3-1-3、WY8對於脊髓損傷大鼠傷口與髓鞘組織之影響....................73
圖3-1-4、WY8對於脊髓損傷後運動神經元存活之影響......................74
圖3-1-5、WY8對於脊髓損傷誘發神經軸突之影響..........................75
圖3-1-6、WY8對於脊髓損傷誘發神經元凋亡之影響........................76
圖3-1-7、WY8對於脊髓損傷後運動神經元存活之影響......................77
圖3-1-8、WY8對於脊髓損傷後微膠細胞之型態變化........................78
圖3-1-9、WY8對於脊髓損傷誘發OX42上升之影響.........................79
圖3-1-10 、WY8對於脊髓損傷後星狀細胞之型態變化.......................80
圖3-1-11、WY8對於脊髓損傷誘發GFAP上升之影響........................81
圖3-1-12、WY8對於脊髓損傷後誘發arg-1免疫螢光活性影響.................82
圖3-1-13、WY8對於脊髓損傷後誘發NOX2免疫螢光活性影響...............83
圖3-1-14、WY8對於脊髓損傷後誘發NT免疫螢光活性影響..................84
圖3-1-15、WY8對於脊髓損傷後誘發ICAM-1免疫螢光活性影響..............85
圖3-1-16、WY8對於脊髓損傷後誘發TNF-免疫螢光活性影響...............86
圖3-1-17、WY8對於脊髓損傷後誘發iNOS免疫螢光活性影響................87
圖3-2、脊髓損傷後椎管給予WY8對於脊髓損傷大鼠之影響..................88
圖3-2-1、WY8對於脊髓損傷後大鼠之後肢運動功能評估....................89
圖3-2-2、WY8對於脊髓損傷大鼠傷口與髓鞘組織之影響....................90
圖3-2-3、WY8對於脊髓損傷後運動神經元存活之影響......................91
圖3-2-4、WY8對於脊髓損傷誘發神經軸突之影響..........................92
圖3-2-5、WY8對於脊髓損傷後誘發過氧化物自由基之影響..................93
圖3-2-6、WY8對於脊髓損傷後誘發神經元凋亡之影響......................94
圖3-2-7、WY8對於脊髓損傷後誘發腹角運動神經元存活之影響..............95
圖3-2-8、WY8對於脊髓損傷後誘發微膠細胞之型態變化....................96
圖3-2-9、WY8對於脊髓損傷後誘發OX42上升之影響.......................97
圖3-2-10、WY8對於脊髓損傷後誘發星狀細胞之型態變化...................98
圖3-2-11、對於脊髓損傷後誘發GFAP上升之影響..........................99
圖3-2-12、脊髓損傷後誘發p-JNK表現之影響.............................100
圖3-2-13、WY8對於脊髓損傷後所誘發p-JNK免疫螢光活性之影響..........101
圖3-2-14、脊髓損傷後誘發p-ERK表現之影響.............................102
圖3-2-15、WY8對於脊髓損傷後所誘發p-ERK免疫螢光活性之影響..........103
圖3-2-16、脊髓損傷後誘發p-p38表現之影響..............................104
圖3-2-17、WY8對於脊髓損傷後所誘發p-p38免疫螢光活性之影響...........105
圖3-2-18、脊髓損傷後誘發arg-1表現之影響..............................106
圖3-2-19、WY8對於脊髓損傷後所誘發arg-1免疫螢光活性之影響............107
圖3-2-20、脊髓損傷後誘發NOX2表現之影響.............................108
圖3-2-21、WY8對於脊髓損傷後所誘發NOX2免疫螢光活性之影響..........109
圖3-2-22、脊髓損傷後誘發NT表現之影響................................110
圖3-2-23、WY8對於脊髓損傷後所誘發NT免疫螢光活性之影響.............111
圖3-2-24、脊髓損傷後誘發ICAM-1表現之影響...........................112
圖3-2-25、WY8對於脊髓損傷後所誘發ICAM-1免疫螢光活性之影響.........113
圖3-2-26、脊髓損傷後誘發TNF-表現之影響.............................114
圖3-2-27、WY8對於脊髓損傷後所誘發TNF-免疫螢光活性之影響..........115
圖3-2-28、脊髓損傷後誘發IL-1表現之影響..............................116
圖3-2-29、WY8對於脊髓損傷後所誘發IL-1免疫螢光活性之影響...........117
圖3-2-30、脊髓損傷後誘發iNOS表現之影響..............................118
圖3-2-31、WY8對於脊髓損傷後所誘發iNOS免疫螢光活性之影響...........119

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