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研究生:林紘正
研究生(外文):Hung-Cheng Lin
論文名稱:黃芩苷元活化Akt及低氧誘導因子活性之神經保護作用研究
論文名稱(外文):Study of baicalein neuroprotection via enhancement of Akt and hypoxia-inducible factor-1α activities in cortical neurons
指導教授:李怡萱李怡萱引用關係
學位類別:碩士
校院名稱:臺北醫學大學
系所名稱:醫學研究所
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:2007
畢業學年度:95
語文別:英文
論文頁數:63
中文關鍵詞:黃芩苷神經低氧誘導因子-1α
外文關鍵詞:baicaleinneuroprotectionAkthypoxia-inducible factor-1αcortical neurons
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  民國94及95年,連續兩年腦血管疾病與事故傷害分居十大主要死因之第二與第五名;而中樞神經因腦血管疾病或事故傷害受損後,興奮性胺基酸麩胺酸(glutamate)將大量釋放,繼而更進一步造成續發性的神經損傷。本實驗室曾發表中藥黃芩(Scutellaria baicalensis Georg)萃取物:Baicalein於興奮性胺基酸麩胺酸造成之神經興奮毒性中具有神經保護效果(neuroprotection);然而,其分子機制仍待探討。本論文主旨即研究所提供神經保護功能之分子機制。實驗以成長17至18天大白鼠(Sprague Dawley, SD)胚胎之大腦皮質神經元(cerebral cortical neurons)體外培養至神經成熟後為研究系統。給予麩胺酸及N-methyl-D-aspartate (NMDA)模擬神經損傷。Baicalein、麩胺酸及N-methyl-D-aspartate (NMDA) 共同投予下,確實能夠降低麩胺酸與NMDA所增加之乳酸脫氫酵素釋放[lactate dehydrogenase (LDH) release assay; 細胞死亡程度測試]。於細胞訊息傳遞中,被磷酸化的Akt,能活化其下游之促進細胞存活因子(例:HIF-1α)而引導細胞趨向存活。而不論是否有神經損傷的情況下,都能提高Akt之磷酸化 (phosphorylation);推測其進而穩定hypoxia inducible factor-1 alpha (HIF-1α)且使HIF-1α成為更具有進核(nuclear translocation)能力之轉錄因子(transcription factor)。我們進而發現baicalein能提高以HIF-1α為轉錄因子的HRE (Hypoxyia Responsive Elements) 驅動之reporter基因表現。染色質免疫沈澱(Chromatin Immunoprecipitation)實驗進一步證實了baicalein 能夠促使HIF-1α結合至erythropoietin (EPO)與 vascular endothelial growth factor (VEGF) 驅動子(promoter)基因序列上的HRE;而根據此結果,進行反轉錄聚合酵素鏈鎖反應(reverse transcriptase PCR) 證實baicalein會增加HIF-1α所調控之細胞保護基因(EPO及VEGF)的mRNA表現。而EPO也於其他報導中呈現神經細胞保護效果。由於baicalein引發這些神經保護基因表現需要8-12小時,我們進一步證實了其神經保護作用必須以在興奮性胺基酸引發神經損傷前8-12小時投予才會有效,且此保護性可被PI3K inhibitor所抑制。總結上述,本論文進一步闡明了baicalein神經保護作用的分子機制之ㄧ,即可能來自於其能夠活化Akt及HIF-1α,進而引發神經保護基因EPO之表現。
Glutamate-induced excitotoxicity is believed be involved in several neurodegenerative diseases, including stroke, brain/head injury, Alzheimer''s disease and Parkinson''s disease. Our previous study has demonstrated that baicalein, one of the flavonoids extracted from Scutellaria baicalensis Georgi, protects primary cortical neurons from glutamate/NMDA induced cell death. In this study, we further revealed that baicalein treatment enhanced phosphatidylinositol 3-kinase (PI3K)-mediated Akt phosphorylation, which is known to mediate survival signal in cells under detrimental insults. Furthermore, 24 h baicalein treatment dose-dependently increased the expression of luciferase reporter gene driven by human erythropoietin gene promoter that contains hypoxia-responsive element (HRE) for the binding of hypoxia-inducible factor 1α (HIF-1α); and this increase was reversed by PI3K inhibitor LY294002. Furthermore, the nuclear HIF-1α was increased by baicalein after 30 min and 60 min treatment, but this effect was not reversed by PI3K inhibitor. Chromatin immunoprecipitation (ChIP) shows that HIF-1α binds to HRE on erythropoietin (EPO) and vascular endothelial growth factor (VEGF) enhancer. In this regard, baicalein was found increasing of the EPO and VEGF gene expression by RT-PCR analysis. Consequently, the mitochondrial dysfunction resulted from glutamate and NMDA was significantly reversed baicalein pretreatment (12 or 8 hour), and this reversion was blocked by PI3K inhibitor. In conclusion, our results suggest that baicalein may activate Akt and HIF-1α, and might in turn give rise to more HIF-1α available for transactivating neuroprotective genes, EPO and VEGF, expression.
CHAPTER I INTRODUCTION 1
I.1 JEKYLL AND HYDE ROLE OF GLUTAMATE AND NMDA 1
I.1.1 The Signaling Pathway of Glutamate 1
I.1.2 Glutamate and Neurodegenerative Diseases 2
I.2 BAICALEIN 6
I.2.1 Baicalein and Neuroprotection 6
I.3 CELL SURVIVAL SIGNALING 7
I.3.1 PI3K/Akt pathway 8
I.3.2 ERK/MAP Kinases Pathway 9
I.4 HYPOXIA INDUCIBLE FACTOR 1Α (HIF-1Α) 10
I.4.1 How dose hypoxia induce HIF-1α? 10
I.4.2 Genes Regulated by HIF-1α 11
I.5 RATIONALE AND AIMS 13
CHAPTER II EXPERIMENTAL PROCEDURE 14
II.1 CHEMICALS 14
II.2 METHODS 15
II.2.1 Primary culture of cortical neurons 15
II.2.2 Quantitative assay of neuronal cell death and survival 15
II.2.3 Transfection of HRE/Luc constructs and Dual-Luciferase Assays in Cultured Cortical Neurons 16
II.2.4 Western Blot Analysis 17
II.2.5 Semi-Quantitative and Quantitative RT-PCR 18
II.2.6 Chromatin Immunoprecipitation (ChIP) Assay 19
II.2.7 Statistic analysis 19
CHAPTER III RESULTS 21
III.1 MANIFESTATION OF NEUROPROTECTION 21
III.2 BAICALEIN INCREASES PHOSPHORYLATION OF AKT THROUGH PI3K IN RAT CORTICAL NEURON 22
III.3 BAICALEIN ENHANCES HRE DRIVEN LUCIFERASE ACTIVITY 22
III.4 PI3K INHIBITOR, LY294002, SUPPRESSES BAICALEIN INDUCTION OF HRE-DRIVEN LUCIFERASE ACTIVITY 23
III.5 BAICALEIN CAN INDUCE HIF-1Α ACCUMULATION 24
III.6 TRANSLOCATION OF HIF-1Α FROM CYTOPLASM TO NUCLEUS FOLLOWING THE BAICALEIN TREATMENT 24
III.7 CHROMATIN IMMUNOPRECIPITATION WAS PERFORMED TO DEMONSTRATE THE HIF-1Α BINDS TO THE ENHANCER OF EPO PROMOTER. 25
III.8 BAICALEIN ENHANCED HYPOXIA-INDUCIBLE GENES ERYTHROPOIETIN AND VASCULAR ENDOTHELIAL GROWTH FACTOR 26
III.9 PRETREATED BAICALEIN PERFORMED THE ABILITY AGAINST MITOCHONDRIAL DYSFUNCTION. 27
CHAPTER IV DISCUSSION 29
CHAPTER V CONCLUSION AND PERSPECTIVE 33
CHAPTER VI TABLES AND FIGURES 34
CHAPTER VII REFERENCES 49
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