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研究生:吳軍滬
研究生(外文):Wu, Chunhu
論文名稱:7,8-Dihydroxyflavone 磷酸化TrkB受器調控下游 PI3K/Akt 途徑對實驗性腦創傷神經保護作用之探討
論文名稱(外文):7,8-Dihydroxyflavone, a TrkB Receptor Agonist, Protects Against Experimental Traumatic Brain Injury via Activation of the PI3K/Akt Signaling Pathway
指導教授:陳思甫蔡旻倩蔡旻倩引用關係
指導教授(外文):Chen, szufuTsai, Minchien
口試委員:林惠卿徐松錕洪泰和蔡旻倩陳思甫
口試委員(外文):LIN, HuichingShyue, SongkunHung, TaihoTsai, MinchienChen, szufu
口試日期:2012-05-25
學位類別:碩士
校院名稱:國防醫學院
系所名稱:生理學研究所
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:2012
畢業學年度:100
語文別:中文
論文頁數:95
中文關鍵詞:腦創傷類黃酮腦源神經因子受器細胞凋亡
外文關鍵詞:Traumatic brain injury7,8-DihydroxyflavoneTrkB Receptorapoptosis
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經外力撞擊腦部引起腦創傷,此傷害不僅直接破壞腦組織造成神經細胞死亡,亦啟動許多細胞分子機制而引發腦部續發性傷害;其中計畫性凋亡為造成續發性傷害的主要機制之一。腦中神經滋養因子受器(tropomyosin-related kinase receptor, TrkB) 經神經滋養因子 (brain-derived neurotrophic factor, BDNF) 磷酸化,可調控下游訊息傳遞途徑,具促細胞存活能力;亦有研究指出 TrkB 磷酸化後會活化轉錄因子而增加 BDNF 表現量,進一步幫助細胞存活。然活化 TrkB 對於腦創傷後神經保護作用及其機轉尚待探討。本篇研究使用 7,8-Dihydroxyflavone (DHF) 做為 TrkB 促效劑,利用小鼠控制性腦皮質撞擊誘發腦創傷動物模式與利用初代小鼠皮質神經元細胞培養造成延展性損傷誘發神經細胞死亡模式,探討腦創傷後磷酸化TrkB之神經保護功能及其相關細胞分子機制。動物實驗結果發現,給與 DHF 的小鼠能持續改善運動及神經功能的表現;降低腦組織的損傷程度、腦水腫、神經死亡數量與細胞凋亡比例。而此保護作用可能與 TrkB 磷酸化程度增加有關。分子機制上發現,給與 DHF 的小鼠改善其凋亡訊號 cleaved caspase-3 表現量與增加Bcl-2/Bax ratio;並增加下游 Akt 在 Ser 473 和 Thr 308 兩個位置的磷酸化程度以及 BDNF 的表現量;但不影響下游 Erk 磷酸化程度。經腦室注射給予 LY294002 抑制 PI3K/Akt 途徑後,削弱原本 DHF 改善腦組織損傷的效果。細胞實驗結果發現,給與 DHF 能改善細胞存活程度、降低 cleaved caspase-3 與增加 Bcl-2/Bax ratio。此研究結果顯示活化 TrkB 能直接保護神經元細胞,於腦創傷模式中具神經保護角色,可做為治療腦創傷的另一思考策略。
Traumatic brain injury (TBI) induces secondary biochemical changes thatresult in subsequent tissue damage and neurological deficits. Previousstudies have shown that brain-derived neurotrophic factor (BDNF)activation of tropomyosin-related kinase receptor B (TrkB) and itsdownstream of PI3K/Akt and MAPK signaling pathways is critical inneuronal survival. TrkB phosphorylation has also been reported toincrease BDNF expression through the CREB signaling pathway. However, the neuroprotective effects of TrkB activation on TBI are still unknown. In this study, we used 7,8-dihydroxyflavone (DHF), amimicking-BDNF TrkB agonist to investigate the neuroprotective effectsof TrkB phosphorylation following mouse TBI in vivo andstretch-induced neuronal injury in vitro. Our results showed that DHF 20mg/kg improved behavior performances and attenuated contusion volumes up to post-injury day 28. DHF also attenuated brain edema, reduced the number of apoptotic cells and degenerating neurons at day 4. These changes were associated with a significant decrease of cleaved caspase-3. Moreover, DHF increased phosphorylation of TrkB, phosphorylation of Akt on Ser 473 and Thr 308, Bcl-2/Bax ratio, and BDNF levels at day 4. However, there was no difference in phosphorylation of Erk between the DHF and vehiclegroups. Pre-injury injection of LY294002, a PI3K/Akt inhibitor abolishedthe DHF-mediated protective effect on tissue damage. In the in vitroexperiment, DHF group ameliorated stretch -induced cell viability loss,reduced the cleaved caspase-3 level and increased the Bcl-2/Bax ratio.These results showed that the activation of TrkB signaling could be apotential neuroprotective strategy in TBI.
目錄
誌謝 2
目錄 3
表目錄 6
圖目錄 6
中文摘要 8
英文摘要 10
第一章 緒論 12
第一節 腦創傷的成因及重要性 12
第二節 腦創傷的病理機轉 12
 腦水腫 13
 發炎反應 14
 神經興奮性毒性反應 14
第三節 凋亡相關訊號在腦中扮演的角色 16
 Caspases家族蛋白 17
 Bcl-2家族蛋白 18
第四節 神經滋養因子受器Trk receptor 19
第五節 神經滋養因子受器訊號傳遞途徑 22
 PI3K/Akt 訊號傳遞途徑 23
 MAPK訊號傳遞途徑 24
第六節 腦源神經滋養因子BDNF 25
第七節 7,8-Dihydroxyflavone 26
第八節 實驗目的 27
第二章 材料與方法 29
第一節 實驗動物與初代細胞 (animals and primary cortical neuron cultures) 29
第二節 實驗設計 (experimental design) 30
第三節 腦創傷動物模式 (TBI animal model) 31
腦創傷動物實驗分組 31
腦創傷實驗手術流程 31
第四節 腦室注射手術 (intracerebraventricularly, injection) 32
 腦室注射手術動物實驗分組 32
 腦室注射手術流程 32
第五節 動物實驗藥物給予 (drugs) 33
 7,8-Dihydroxyflavone 33
 LY294002 33
第六節 小鼠大腦皮質初代神經細胞培養 (primary cortical neuron culture).34
第七節 細胞延展性損傷 (cell stretch injury) 35
 細胞實驗分組 35
 延展性損傷實驗流程 35
第八節 細胞實驗藥物給予 (drugs) 36
 7,8-Dihydroxyflavone 36
第九節 肝腎功能測定 (metabolic characteristics) 36
第十節 腦創傷術後行為評估 (behavior analysis) 37
跑步機 (rotorad) 37
獨木橋 (beam walking) 37
第十一節 綜合性神經功能評分量表 ( modified neurological severity score) 38
第十二節 細胞檢測 (cell analysis) 39
 細胞存活檢測 - MTT assay 39
 細胞死亡檢測 - LDH assay 39
第十三節 腦組織灌流 ( perfusion ) 與冷凍切片 ( cryosection ) 40
第十四節 組織染色 (immunohistochemical staining) 41
Cresyl violet staining 41
Fluoro-jade B staining 42
TUNEL staining 42
Immunofluorescent staining 43
第十五節 腦水腫分析 (brain water content analysis) 44
第十六節 組織分析與計算 (histology analysis and quantification) 45
第十七節 細胞染色 (immunofluorescent staining) 46
第十八節 西方墨點法 (western blotting) 47
 腦組織的蛋白質萃取 (tissue protein extraction) 47
 細胞的蛋白質萃取 (cell protein extraction) 47
 蛋白質定量 (protein quantification) 48
 配製loading sample 48
 電泳 (Running) 48
 轉漬 (transferring) 49
 Blocking & 抗體 49
第十九節 Enzyme-linked immunosorbent assay 49
第二十節 試劑 ( buffers ) 51
第二十一節 抗體 ( antibodies ) 52
第二十二節 量化與統計 (quantification and analysis) 53
第三章 結果 54
第一節 動物腦創傷後 TrkB 受器磷酸化程度 54
第二節 給予 DHF 對生理參數的影響 54
第三節 給予 DHF 對運動功能的影響 55
第四節 給予 DHF 對腦組織損傷程度的影響 59
第五節 給予 DHF 對腦水腫程度的影響 60
第六節 給予 DHF 對細胞死亡程度的影響 60
第七節 給予DHF對細胞凋亡和TrkB磷酸化後相關訊號途徑的影響 62
第八節 磷酸化對BDNF表現量的影響 64
第九節 給予 LY294002 抑制PI3K/Akt 途徑的影響 65
第十節 磷酸化 TrkB 在不同細胞型態上的表現 66
第十一節 給予 DHF 對神經細胞存活程度的影響 66
第十二節 給予 DHF 抑制神經細胞凋亡的影響 68
第四章 討論 69
第五章 結論 72
參考文獻 73
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