1-甲基-4苯基吡啶離子引發神經毒性之研究; Studies on 1-methyl-4 phenylpyridinium ion –induced neurotoxicity

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题名:	1-甲基-4苯基吡啶離子引發神經毒性之研究;Studies on 1-methyl-4 phenylpyridinium ion –induced neurotoxicity
作者:	廖文玲;Wen-Ling Liao
贡献者:	中國醫藥大學：醫學研究所碩士班
关键词:	1-甲基-4苯基吡;啶離子;帕金森氏症;微小膠細胞;神經細胞;MPP+;Parkinson;microglia;neuron
日期:	2006-07-19
上传时间:	2009-08-13 14:50:48 (UTC+8)
摘要:	帕金森氏症是常見的神經退化性疾病之一。其特徵是大腦內黑質區多巴胺神經細胞漸進式的退化。然而，多巴胺神經細胞的退化機制仍有待釐清。近幾年來，越來越多的文獻探討神經膠細胞在帕金森氏症的致病機轉上所扮演的角色。在帕金森氏症病人腦組織可發現較正常人多量的發炎物質 (pro-inflamatory cytokine)，如介白素-1β (interlukin-1β, IL-1β) 和腫瘤壞死因子(tumor necrosis factor-α, TNF-α)等。而且，有實驗顯示多巴胺神經細胞的退化係經由微小膠細胞的活化來調控，這亦可由在帕金森氏症動物模式中，阻礙微小膠細胞的活化可產生神經保護作用來得到支持。本實驗利用人類neuroblastoma SH-SY5Y細胞與類微小膠細胞THP-1來進行研究。探討MPP+處理單獨培養的神經細胞及與微小膠細胞共同培養的神經細胞兩種模式之作用。此外，我們亦探討抗氧化劑維生素C和維生素E是否在MPP+處理引發的神經毒性以及經由微小膠細胞調控的神經毒性 (microglia-mediated neurotoxicity) 中具有保護的作用。MTT分析結果顯示，神經細胞死亡率隨MPP+處理濃度的增加而上升，而已分化的SH-SY5Y對MPP+的毒性較為不敏感。實驗結果顯示， MPP+的毒性機轉係經由p38的磷酸化，而已分化的SH-SY5Y細胞上有較低量的p38的磷酸化。此外，維生素C或維生素E並無顯著保護神經細胞免於MPP+的毒性。實驗結果亦顯示，相較於單獨 SH-SY5Y培養，24小時MPP+處理於已分化的SH-SY5Y細胞與活化的THP-1細胞共同培養的模式中引起顯著的神經細胞死亡。但48和72小時MPP+處理在單獨或共同培養的模式所引起的細胞死亡率則無統計差異。此外，在共同培養的模式中，維生素C和維生素E處理亦皆沒有保護神經細胞免於MPP+毒性的傷害。我們的結果顯示，微小膠細胞-神經互動也許是作用在短期的效應，並且MPP+及微小膠細胞調控的細胞死亡主要因素皆不是藉由氧化壓力路徑。 Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. It is characterized by a progressive degeneration of dopaminergic neurons in the substantia nigra. The intricate neurotoxic mechanisms underlying dopaminergic neurdegeneration still need to be elucidated. Nowadays, more and more emerging studies connect the pathogenic roles of glial cells in PD. Pro-inflammatory cytokines, such as interlukin (IL)-1β and tumor necrosis factor (TNF)-α were elevated in PD brains. In addition, the microglial activation is demonstrated to mediate the neurodegeneration process in PD. In this current experiment, we took the advantages of co-culture models of human neuroblastoma SH-SY5Y cell line and microglia–like THP-1 cell line; and studies the effect of MPP+ treatment on mono-cultured neurons and co-cultured neurons. In addition, we assessed the potential neuroprotection effects of antioxidants vitamin C and vitamin E on MPP+ and microglia-mediated neurotoxicity. Results from MTT assay showed that MPP+ treatment increased SH-SY5Y cell death in a dose-dependent manner. Differentiated SH-SY5Y cells are less sensitive to MPP+ treatment. Western blot analysis indicated that decreased phosphorylation of p38 is involved in both differentiation of SH-SY5Y and protected cells from MPP+ toxicity. Furthermore, neither vitamin C nor vitamin E effectively protects neurons from MPP+ insults. When compared with the mono-culture neurons, treatment of MPP+ significantly increased cell death in 24 hr in the co-culture group. However, there is no significant difference in cell viabilities between mono-culture and co-culture groups after 48 hr and 72 hr of MPP+ treatment. In addition, in co-culture system, vitamin C and vitamin E administration did not significantly protect neurons from MPP+ insult. Our results suggest that the microglia-neuron interaction might be a short term effect, and that oxidative stress may not be a primary cause of either MPP+-induced or microglia-mediated neurotoxicity in this event.
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