Please use this identifier to cite or link to this item: http://hdl.handle.net/11455/22396
標題: 腦缺血誘發之神經性傷害及腦組織保護機轉之探討
Neurodegenerative and brain protective mechanisms induced by cerebral ischemia
作者: 林琦鑫
Lin, Chi-Hsin
關鍵字: cerebral ischemia;腦缺血;apoptosis;neurotrophic factors;細胞凋亡;神經滋養因子
出版社: 生命科學系所
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摘要: 
中文摘要
中風,又稱為腦缺血,是一種嚴重的血管性疾病,除對病人造成生理及心理雙重性的傷害外,更高居國人十大死因的第二位。本論文因此首先利用一個體外缺血的研究模式,針對缺血所導致的神經細胞凋亡的分子機轉做探討,特別著重分析粒線體相關凋亡路徑的活化是否扮演關鍵性角色。此外,我對受傷害之缺血星芒狀細胞和神經細胞的釋出液的保護效益及其背後的作用機轉亦有進一步的評估及探討。研究結果顯示體外缺血對老鼠之神經細胞明顯造成傷害,此傷害隨缺血時間之增長而加劇。雖然粒線體膜電位差並沒有明顯下降之趨勢,但粒線體內cytochrome c之釋出及caspase-9和caspase-3蛋白之相繼被活化,均顯示神經細胞內經由粒線體路徑所導致的細胞凋亡明顯在缺血時被誘發。我們同時發現Bax自細胞質轉移至粒線體膜上的現象可能和cytochrome c之釋出有關,是啟動粒線體相關凋亡路徑的重要調控蛋白。而furosemide (Bax轉移抑制劑) 及ZVAD-fmk (凋亡蛋白抑制劑) 皆對缺血神經細胞之存活具顯著保護性的實驗結果更進一步驗證上述之想法。在此,也同時顯示furosemide及ZVAD-fmk在未來對抗腦中風的治療上有其臨床潛力。
除了體外缺血研究模式外,論文中亦以結紮S.D.鼠右側中大腦動脈及雙側頸動脈的動物模式進一步評估缺血星芒狀細胞及神經細胞釋出液對不同缺血腦細胞(微膠細胞、星芒狀細胞及神經細胞)是否具保護效益。結果顯示缺血所誘發之星芒狀細胞及神經細胞釋出液對周遭三種不同缺血腦細胞均有明顯的保護性;其保護性是透過星芒狀細胞和神經細胞釋出之TGF β1、GDNF和NT-3所致。對於缺血微膠細胞的保護是透過TGF β1和NT-3,缺血星芒狀細胞所受到的保護和GDNF有關,而缺血神經細胞所受到的保護則和NT-3有關。結果亦顯示細胞釋出液中的生長因子必須和不同腦細胞表面表現之特定受體作用,才能達到保護該細胞之作用。更進一步確認不論是星芒狀細胞和神經細胞釋出液對缺血星芒狀細胞和神經細胞之保護均需仰賴ERK路徑的活化,對缺血微膠細胞之保護則可能經由其他訊號傳遞路徑的參與。
另外,進一步評估不同缺血腦細胞釋出液及三種不同的生長因子對缺血鼠之腦組織是否具有保護性時發現三種不同缺血腦細胞釋出液、TGF β1、GDNF和NT-3皆具有明顯降低缺血鼠腦水腫的功效,其中又以神經細胞釋出液的保護效果最佳。此外, furosmide (Bax inhibitor)、ZVAD-fmk (caspase inhibitor)及ERK activator對缺血腦組織之保護亦值得進一步評估及探討。總體而言,此研究結果使我們對缺血時神經細胞的死亡路徑及不同腦細胞間的相互影響及作用機轉有進一步的認識。同時亦提供一個可靠的┌體外及體內┘缺血研究模式,有助於缺血藥物之篩選及評估。兩者均有助於日後腦中風疾病之治療或預防。

Abstract
Stroke (also called cerebral ischemia) is a blood vessel-related disease often leads to sever physiological and functional defects in patients in accompany with high mortality rate. In this thesis, molecular mechanisms underneath ischemia-induced neuronal death were first investigated, particularly focused on the involvement of mitochondria-mediated apoptotic pathway. In addition, a protective role of ischemic astrocytes and neurons were also evaluated in both in vitro and in vivo study, also focusing on the possible involvements of growth factors and related signaling molecules. Results showed that in vitro ischemia significantly damaged neurons in a time- and mitochondria-dependent manner. In response to in vitro ischemia, the amounts of Bax, cytochrome c, caspase-9 and -3 significantly increased in the cytoplasm of ischemic neurons. Although reduction of mitochondrial membrane potential was not observed in the ischemic neurons, increased translocation of Bax to mitochondria was significantly promoted. Furosemide (a Bax blocker), ZVAD-fmk (caspase inhibitor), but not cyclosporine A (a MPT pore blocker), were further proven to elevate the survival of the ischemic neurons. These results indicate in vitro ischemia-induced neuronal apoptosis is mainly triggered by Bax-regulated mitochondrial alteration and caspase activation, which eventually leads to increased apoptosis. Blocking of Bax and/or caspase activity therefore have their respective potentials in protecting neurons from ischemic damage.
As for the protective role of the ischemic astrocytes and neurons, results for the first time demonstrate that despite their injury suffering from the in vitro ischemia, ischemic astrocytes and neurons both can protect other brain cell types from ischemic insults. The same set of growth factors (TGF β1, GDNF, and NT-3) was released from both astrocytes and neurons after in vitro ischemic challenge. Through these growth factors, supernatants (derived from ischemic astrocytes and neurons, respectively)-mediated protection of the ischemic microglia was TGF β1 and NT-3 dependent, of ischemic astrocytes was GDNF dependent, and of ischemic neurons was NT-3 dependent. These results suggest that ischemic brain cell-derived protection of various brain targets depends on not only types of growth factors being released from the effector cells but also types (amount also) of growth factor receptors present on the target brain cells. I further demonstrate that both supernatants-derived protections are not only growth factor-dependent, activation of ERK signaling also plays a critical role in mediating these protections.
To further confirm the protective efficacy of both astrocyte- and neuron-derived supernatants, an in vivo ischemic animal model was developed by occluding right side of middle cerebral artery (MCAO) plus bilateral common carotid artery (CCAO) for 90 min followed by reperfusion for 24 h. Through this model, astrocyte-, neuron-, and microglia-derived supernatants, TGF β1, GDNF, and NT-3 given at the end of occlusion prior to reperfusion were all proven to be therapeutical and useful in significantly reducing the infarct volume of the ischemic brains.
In overall, results from the thesis not only strengthen our knowledge about cerebral ischemia but also provide valuable information for future design of a therapeutic regimen in control of cerebral ischemia. Furosemide (Bax blocker), ZVAD-fmk (caspase inhibitor), TGF β1, GDNF, NT-3, and ERK activator, all appear to be therapeutically valuable and worth to be further investigated in both animal model and clinical trials.
URI: http://hdl.handle.net/11455/22396
其他識別: U0005-2408200614560300
Appears in Collections:生命科學系所

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