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研究生:吳佳霖
研究生(外文):Chia-Lin Wu
論文名稱:腦源神經滋養因子前處理對三硝基丙酸毒性之神經保護機制
論文名稱(外文):Neuroprotective effect of brain-derived neurotrophic factor on mitochondrial dysfunction induced by 3-nitropropionic acid in rat cortical neurons
指導教授:楊定一楊定一引用關係
指導教授(外文):Ding-I Yang
學位類別:碩士
校院名稱:國立陽明大學
系所名稱:腦科學研究所
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:2009
畢業學年度:97
語文別:英文
論文頁數:107
中文關鍵詞:腦源神經滋養因子三硝基丙酸皮質神經細胞
外文關鍵詞:brain-derived neurotrophic factor3-nitropropionic acidcortical neurons
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在許多神經退化性疾病中均觀察到神經元與膠質細胞有粒線體功能缺失的情形,其中包括亨丁頓舞蹈症。三硝基丙酸(以下簡稱3-NP)是一種粒線體抑制劑,被廣泛地運用於模擬亨丁頓舞蹈症的藥物模型中。而近來研究顯示亨丁頓舞蹈症患者的腦部會出現腦源神經滋養因子(以下簡稱BDNF)缺乏。最近我們發現在大鼠胎腦皮質神經細胞中BDNF前處理對3-NP毒性的確具有保護作用,並至少與BDNF所引發之兩條訊息路徑有關。其一,利用西方點墨法發現BDNF促使一氧化碳(NO)增高以及ERK、eNOS和Akt的磷酸化表現,且nNOS、PKG-1、c-Jun、thioredoxin-1/-2、Bcl-xL等蛋白質表現量亦有上升的現象。此外,利用ERK、NOS、PKG、thioredoxin及Bcl-2的抑制劑都會將BDNF的保護作用抑制下來,說明此訊息傳遞路徑可能為“BDNF → NOS/NO → PKG → c-Jun → thioredoxin-1/-2 → Bcl-2/Bcl-xL”。其二,紅血球生成素(以下簡稱EPO)以及在胚胎發育期間扮演重要角色的sonic hedgehog(以下簡稱SHH)在最近研究中也被發現具有神經保護功能。我的實驗結果顯示BDNF可以透過活化SHH而達到神經保護,進一步研究更發現BDNF可能經由活化EPO刺激SHH產生而造成對3-NP神經毒性之保護作用,因此建立一訊息傳遞路徑為 “BDNF → EPO → SHH → 3-NP resistance”。
chapter 1:
Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor that plays a key role in regulation of survival and differentiation in neurons. BDNF deficiency has been linked to Huntington's disease (HD) pathogenesis. 3-Nitropropionic acid (3-NP), an irreversible mitochondrial complex II inhibitor, has been used as a pharmacological model mimicking HD. Recently we have reported that BDNF exerts neuroprotective effects that may involve nitric oxide synthases (NOS), cGMP-dependent protein kinase (PKG), the anti-oxidative thioredoxin, as well as the anti-apoptotic Bcl-2. In this study, we demonstrated that BDNF can enhance endothelial NOS (eNOS) phosphorylation, neuronal NOS (nNOS) expression, extracellular signal-regulated kinase-1/2 (ERK1/2) phosphorylation in primary culture of fetal rat cortical neurons. The ERK1/2 inhibitor PD98059 abolished BDNF-induced increase in nNOS expression. In addition, we also observed Akt phosphoryaltion, as well as expression of PKG-1 and c-Jun expression upon BDNF exposure. In addition, we also detected heightened expression of thioredoxin-1/-2 and Bcl-xL induced by BDNF exposure in the presence of 3-NP. Finally, cGMP/PKG activator 8-Br-cGMP enhanced expression of thioredoxin-1/-2, Bcl-2, Bcl-xL in the presence of 3-NP. In conclusion, results derived from the present study establish a neuroprotective role of BDNF against 3-NP toxicity via multiple signaling pathways.

chapter 2:
We have recently reported that preconditioning of primary rat cortical cultures with brain-derived neurotrophic factor (BDNF) activates expression of sonic hedgehog (SHH), thereby contributing to its neuroprotective effects against metabolic compromise induced by 3-nitropropionic acid (3-NP), an irreversible inhibitor of mitochondrial complex II. In the present study, we further demonstrate that BDNF enhanced the expression of erythropoietin (EPO) at earlier time points than SHH. Furthermore, EPO inducible by BDNF contributes to BDNF induction of SHH based on the observation that BDNF-dependent expression of SHH was attenuated by the soluble EPO receptor (sEPO-R), an EPO inhibitor. Application of recombinant rat EPO (rEPO) was sufficient to induce SHH at both mRNA and protein levels, albeit to a lesser extent as compared to BDNF. Preconditioning of cortical cultures with rEPO and purified human EPO (pEPO) both attenuated 3-NP neurotoxicity in a dose- and time-dependent manner. The sEPO-R also abrogated BDNF- and, as expected, rEPO-mediated neuroprotective effects against 3-NP. More importantly, the rEPO-dependent neuroprotection was abolished by the SHH inhibitor cyclopamine (CPM), but sEPO-R failed to affect SHH neuroprotection despite its inhibitory effect on BDNF action. Overall, our results suggest that “BDNF �_ EPO �_ SHH �_ 3-NP resistance” axis that may together contribute to the observed BDNF effects neutralizing 3-NP toxicity in cortical neurons.
中文摘要.................................................3
目錄.....................................................4
圖表目錄.................................................7
Chapter 1
英文摘要................................................10
Introduction............................................11
Materials and Methods
Primary fetal rat cortical culture..................14
Chemicals...........................................14
NO detection by fluorescence probe..................15
Western blotting....................................15
Cell survival assay by Hoechst staining.............17
Statistical analysis................................17
Results
NO formation, eNOS phosphorylation, and nNOS expression are induced by BDNF exposure............................18
BDNF preconditioning enhances phosphorylation of ERK1/2 and Akt as well as expression of c-Jun and PKG-1 in cortical neurons........................................18
Expression of thioredoxin-1,-2 and Bcl-xL are involved in BDNF-mediated protection.............................20
cGMP was sufficient to induce expression of c-Jun, thioredoxin-1,-2, Bcl-2, and Bcl-xL.....................20
Discussion............................................22
References..............................................25
Chapter 2
英文摘要......................................................58
Introduction............................................59
Materials and Methods
Primary fetal rat cortical culture..................62
Chemicals...........................................62
Real-time RT-PCR....................................63
Western blotting....................................64
Immunocytochemistry by confocal microscope..........65
Cell survival assays by Hoechst staining and PI/Hoechst double staining.........................................66
Statistical analysis................................67
Results
BDNF increases EPO expression in rat cortical neurons.................................................68
BDNF-induced SHH expression is abolished by sEPO-R..68
Exogenous EPO increases expression of SHH mRNA and protein.................................................69
EPO induction is necessary for BDNF-induced neuroprotection.........................................70
EPO alone is sufficient to attenuate 3-NP toxicity..71
Exogenous EPO protects 3-NP cytotoxicity through SHH expression..............................................72
Discussion............................................74
References............................................78
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