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研究生:許珮琪
研究生(外文):Pei-Chi Hsu
論文名稱:神經毒素MPTP誘發的紋狀體黑質徑路之神經膠細胞反應
論文名稱(外文):MPTP-induced glial activation in the mice nigrostriatal pathway
指導教授:陳淑姿陳淑姿引用關係
指導教授(外文):S. T. Chen
學位類別:碩士
校院名稱:國立成功大學
系所名稱:細胞生物及解剖學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2002
畢業學年度:90
語文別:中文
論文頁數:73
中文關鍵詞:神經退化神經發炎紋狀體黑質徑路神經膠細胞
外文關鍵詞:MPTPneurodegenerationglialneuroinflammationnigrostriatal pathway
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  哺乳類的中樞神經系統缺乏淋巴組織,而且由於血腦障壁隔離了腦實質組織與血液交換的部分,所以一向被認為是免疫作用無法達到的區域。一般相信在週邊免疫系統產生的細胞素不能穿過血腦障壁到達中樞神經組織,因為星狀細胞的終足會包圍著腦部的微血管內皮細胞之外圍。現在卻有相當的資訊顯示許多神經退化疾病跟發炎現象很有關係。神經毒物1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 誘導的帕金森氏症之動物實驗似乎提供了一個良好的模式,可以研究神經發炎現象。一般狀況下,正常的腦組織有特化的機制抑制小膠細胞不要變得太活化,但是在施打MPTP之後可能會誘導細胞素不正常的表現,而改變小膠細胞的活性,對多巴胺神經元產生傷害。根據大腸桿菌突變體M4 E.coli的β-galactosidase活性表現,發現MPTP誘發的神經毒性可以改變血腦障壁的通透性而改變中樞的免疫特性。我們在MPTP注射後不同的時間點分別檢查紋狀體黑質區徑路中,神經膠細胞產生的反應與牽涉其中的細胞素表現。免疫組織染色的結果顯示,紋狀體內的星狀細胞增生(astrogliosis)現象明顯表現在MPTP注射後3到30天,而在1到兩週時增加最高,但是在黑質區卻沒有顯著的改變。黑質區跟紋狀體的小膠細胞增生現象(microgliosis)在藥物注射後15小時就明顯提高,一個月後的表現回復到基準值。然而根據免疫組織染色法的實驗結果顯示,原發炎因子IL-1β、免疫致效者TNF-α、免疫調節者IFN-γ這些細胞素在對照組與施打MPTP組之間並沒有明顯可偵測到的表現差異。在膠細胞活化的期間以西方墨點法也偵測不到細胞素的表現,因此,雖然神經毒素MPTP可以引起紋狀體黑質徑路的神經膠細胞活化,研究發生在中樞神經的免疫反應時,還要考慮到動物的年齡跟神經細胞受到傷害的程度。
  The central nervous system (CNS) of the mammal is considered to be an immunologically privileged site because it lacks lymphatic drainage, and the brain is separated from the blood compartment by the blood-brain-barrier (BBB). It is generally believed that cytokines produced in the peripheral tissue can’t cross BBB because of the unique features of brain microvascular endothelial cells wrapped by end feet of astrocytes. There is now considerable information implicating many inflammatory conditions associated with neurodegeneration. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-administrated animal model of Parkinson’s disease seems to be a good model for studying neuroinflammation. As a rule, the normal brain blocks microglia from becoming too active, but an abnormal elevation of certain cytokines induced by MPTP can overcome the restraint and be quite harmful to dopaminergic neurons. Based on the preliminary data of M4 E.coli tracer with β-galactosidase activity, the vasopermeability of BBB can be changed by MPTP intoxication and then the immune privileged property of CNS can be alterable. We have investigated MPTP-induced glial response and proof of direct involvement of cytokines within short- and long-term neurotoxin damage. After different time courses with MPTP i.p. injection, the immuno- histochemical results show that in the striatum astrogliosis obviously was found from 3 to 30 day, and reached the highest with 1 to 2 weeks postinjury, while there is no significant change in the substantia nigra. Microgliosis in the substantia nigra and the striatum appeared as soon as 15hr after MPTP injection, then returned to the basal level about 1 month postinjury. However, the expressions of proinflammatory factor IL-1β, immune effector TNF-α, and immune modulator IFN-γ showed no significant difference between control and MPTP-injection groups as revealed by immunohistochemistry. The western blotting results of the expression of these cytokines were also unable to detect during glial activation. Thus, although glial activation can be induced by MPTP intoxication, the inflammatory features are considered to be associated with animal age and the extent of neuronal death.
中文摘要 1
英文摘要 2
目錄 4
圖表目錄 5
符號及縮寫 6

第一章 文獻回顧 7
 (一) 帕金森氏症(Parkinson’s disease) 7
 (二) MPTP神經毒性的作用機制 8
 (三) MPTP誘發之神經免疫作用 10
第二章 實驗材料與方法 15
 第一節 實驗動物與切片製作 15
 第二節 一般染色及免疫組織化學染色(Immunohistochemistry) 18
 第三節 以M4作為追蹤劑偵測血腦障壁的通透性 22
 第四節 西方轉漬墨點法(Western blot) 23
第三章 實驗結果 25
 第一節 施打MPTP造成的含多巴胺神經反應 25
 第二節 MPTP對血腦障壁通透性的影響 25
 第三節 星狀細胞免疫染色性的表現 26
 第四節 小膠細胞之免疫反應的染色結果 26
 第五節 偵測細胞素表現 27
 第六節 其他細胞素或免疫分子的反應性 30
第四章 討論 31
 神經退化 31
 血腦障壁通透性的改變 32
 星狀細胞的活化與改變 33
 小膠細胞活性與Mac-1(CD11b)之免疫化學反應 35
 並未偵測到預期中的免疫特徵 35
 有關免疫組織染色法在細胞上的應用 37
第五章 結論 39
參考文獻 40

附錄一 圖表 45
附錄二 藥品與抗體 63
附錄三 試劑配方 65
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