玄參萃取物對抗低氧誘發之毒性在微膠細胞的保護效果

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題名:	玄參萃取物對抗低氧誘發之毒性在微膠細胞的保護效果 The Protective Effects of Radix Scrophulariae Extracts against Hypoxia-induced Toxicity on Microglial Cells
作者:	洪意雯 Hong, Yi-Wen
貢獻者:	藥學系(碩博士班) 許秀蘊孫瑞昇
關鍵詞:	低氧;微膠細胞;抗發炎反應 anti-inflammation;hypoxia;microglia
日期:	2014-06-26
上傳時間:	2019-09-24 12:01:49 (UTC+8)
摘要:	在低氧狀態下微膠細胞會活化並釋放神經發炎物質，過多的神經發炎物質會導致神經細胞的死亡且會加速神經退化性疾病的產生，因此如何有效預防微膠細胞的神經發炎反應成為研究的一大目標。近幾年中藥玄參的活性成分哈巴俄苷(harpagoside)已被發現具有抗發炎功能，但其機制尚未有完整透徹之研究，故本研究想要探討預先給予harpagoside再以低氧刺激微膠細胞是否具有抑制神經發炎反應的作用。本研究選用初生二至三天大的ICR小鼠的微膠細胞做實驗。細胞活性分析確定不同濃度harpagoside對微膠細胞無細胞毒性後，再觀察神經發炎物質的表現量並探討其機轉。實驗發現微膠細胞在三小時低氧(1% O2)刺激下會大量生成TNF-α、IL-1β、iNOS、COX-2、IL-6、NO六種神經發炎物質，但若在低氧刺激前先預先給予harpagoside，此六種神經發炎物質的表現量會受到抑制。另外，本研究進一步探討此機轉和NF-κB路徑是否有關，NF-κB是神經發炎反應過程中重要的轉錄因子，實驗發現在低氧刺激前先預先給予harpagoside會使微膠細胞細胞質內IκB-α蛋白表現量增加和細胞核內p65蛋白表現量降低，此結果表示harpagoside可以抑制微膠細胞內NF-κB路徑的活化。最後本研究探討微膠細胞的HIF-1α蛋白表現情況，HIF-1α可調節細胞適應不同氧分壓環境，是細胞在低氧狀態所產生的轉錄因子。近年研究指出HIF-1α可參與發炎反應，但HIF-1α調控發炎反應的機轉仍未清楚，實驗發現在低氧刺激前先預先給予harpagoside會使微膠細胞細胞質和細胞核內HIF-1α蛋白表現量降低。微膠細胞的神經發炎反應是引發神經退化性疾病的關鍵過程，而綜合本研究實驗結果發現低氧狀態下harpagoside會透過調控NF-κB和HIF-1α而抑制微膠細胞神經發炎物質的分泌，使神經發炎反應受到控制，此結果顯示harpagoside在神經退化性疾病的預防及治療上具有發展之潛力。 Hypoxia could lead to microglia activation and toxic inflammatory mediators’ overproduction. Those inflammatory molecules could amplify the neuroinflammatory process and exacerbate neuronal injury. Therefore, the aim of the study was to find out whether harpagoside, the active compound of Scrophularia ningpoensis Hemsl., could reduce microglia inflammation and neurotoxicity.In this study, primary microglia cultured from neonatal ICR mice and microglia was activated by exposure to hypoxia (1% O2 for 3h). MTT assay showed that different concentrations of harpagoside on microglia had no cytotoxicity. Besides, we found that harpagoside could suppress the TNF-α, IL-1β, iNOS, COX-2 and IL-6 mRNA expression and lower microglia nitric oxide production. In addition, the anti-inflammatory mechanism of harpagoside might be associated with the transcription factor nuclear factor kappa B (NF-κB) signaling pathway. Harpagoside could decrease IκB-α protein phosphorylation and inhibit p65 protein translocation from the cytosol to the nucleus. The results suggested that harpagoside could suppress NF-κB activation. What’s more, we also explored the hypoxia inducible factor-1α (HIF-1α) protein expression. HIF-1α is one of the principal transcription factors regulated by hypoxia and harpagoside could reduce the HIF-1α generation. Anti-inflammatory therapy has been studied as potential treatment of neurodegenerative disease. The above experimental data indicated that harpagoside was not toxic to microglia and could reduce microglia inflammatory mediators’ overproduction. However, the mechanisms of harpagoside have not been completely understood and the facts need to be validated by further studies both in vitro and in vivo. In conclusion, harpagoside could be an effective regulator of microglia inflammatory and a potential therapeutic target in neurodegenerative diseases.
描述:	碩士指導教授-許秀蘊共同指導教授-孫瑞昇委員-蔡東湖委員-林淑娟委員-李仁愛
資料類型:	thesis
顯示於類別:	[藥學系] 博碩士論文

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