氧化苯砷 (phenylarsine oxide, PAO) 為一種可穿透細胞膜的三價有機砷化物，哺乳類動物在攝入無機砷化物時大多會在體內再被代謝成PAO，其結構易氧化帶有醯基 (thiol group or sulfhydryl group, R-SH) 或相鄰硫醇基 (vicinal dithiol group, R-(SH)2) 的蛋白質，造成醯基的cross-linkage，形成一個穩定的雙硫鍵環狀結構，導致酵素活性被破壞，進而活化ROS的生成或抑制了胞內各種生化反應之訊息傳導路徑。因此，本研究以whole-cell patch clamp電生理紀錄PAO在胚胎發育早期引導運動神經活性增加的機轉，探討ROS如何透過PAO的誘導而產生，以及其被活化來增加細胞內的氧化壓力之相關訊息傳遞路徑。
經由實驗發現，投予PAO約10至15分鐘後神經自發性傳導物質釋放的頻率明顯增加，此促進作用約30分鐘後會漸漸趨緩，最後神經傳遞物質會被排空，此過程為不可逆。神經細胞釋出神經傳遞物質之能力與神經末梢內鈣離子濃度有直接關係，因此，進一步將胞外溶液置換成不含鈣離子的Ca2+-free medium、加入廣效性鈣離子通道阻斷劑Cd2+ 或膜通透性高的鈣離子螯合劑BAPTA-AM以阻斷胞外鈣離子來源，實驗結果顯示即使在沒有細胞外鈣離子的提供下，PAO仍保有對神經活性的增進作用，表示PAO促進神經傳遞物質釋放所需的鈣離子來源為細胞內鈣離子儲存池所提供。由於細胞內主要由內質網及粒線體來維持鈣離子的恆定，為了釐清PAO的作用與胞內鈣離子儲存池之間的關聯性，針對此兩個胞器膜上調控鈣離子出入的通道投予抑制劑來觀察PAO的促進作用是否會被消除。實驗結果發現在ER/SR Ca2+- ATPase抑制劑 (thapsigargin, TG) 及ryanodine receptor (RyR) 抑制劑 (TMB-8) 的存在下，PAO對神經活性的增強會明顯受到抑制，反之，IP3 receptor抑制劑 (XeC) 對PAO則無抑制作用。另外，粒線體氧化磷酸化耦合劑 (FCCP) 及粒線體膜通透性轉運孔 (mitchondrial permeability transition pore, MPT pore) 抑制劑 (cyclosporin A, CyA) 亦能有效消除PAO的作用，由此推得，無論是內質網或粒線體皆貢獻了一部分的鈣離子來源參與在PAO所誘發的神經傳遞物質釋放情形，其兩者引發的先後順序由TMB-8 + CyA的實驗未能將PAO的作用降至更低可推知，PAO的作用途徑可能由粒線體先啟動釋出鈣離子到細胞質中，再經由Ca2+-induced Ca2+ release (CICR) 的機制使內質網膜上的RyR釋出更多的鈣離子促進神經傳導物質的大量釋放。此外，為了確認PAO造成胞質內鈣離子濃度上升促使神經活性的增強作用是否與ROS的產生有關，加入n-acetylcysteine (NAC) 來增加細胞內的抗氧化分子glutathione與粒線體中的Mn-SOD活性，其幾乎可以完全阻斷PAO對神經活性的影響，然而在catalase清除胞外的H2O2及catalase抑制劑3-AT增加胞內外H2O2的情形下，皆對PAO的作用無影響，顯示PAO可能誘導的ROS主產物非H2O2而是上游的O2˙－，接著即針對會產生O2˙－的氧化酶投予抑制劑，包含NADPH oxidase及xanthine oxidase的抑制劑DPI與allopurinol分別處理之下，仍對PAO無抑制作用，由此推測PAO誘發ROS產生之路徑非經由這些氧化酶的活化而來。除此之外，在thiol-modifying agent (NEM) 和thiol-reducing agent (DTT) 的暴露下，PAO增強神經活性的能力也會喪失，顯示雙硫鍵的形成與PAO的作用有關。粒線體內膜上的電子傳遞鏈 (electron transport chain, ETC) 被認為是胞內ROS的主要發源地，尤其以complex I (NADH dehydrogenase) 和complex III (CoQ-cyt c reductase) 為O2˙－的主來源之一，因此分別利用加入complex I和complex III的抑制劑rotenone與antimycin A來探討PAO作用的可能路徑，實驗結果發現complex III 被抑制的情況下亦可以有效阻斷PAO的促進作用，推測PAO誘導ROS產生的訊息傳遞路徑可能與complex III產生ROS的路徑相似。
綜上實驗結果，可初步推論PAO可能的作用路徑為經由ETC上的complex III產生ROS來誘導MPT pore不可逆性的打開並釋出鈣離子到細胞質中，再經由粒線體釋出的鈣離子透過CICR的機制來活化ryanodine sensitive鈣離子儲存池，使神經末梢內的鈣離子濃度提升，進而促成神經釋放神經傳遞物質的作用。

Phenylarsine oxide (PAO) is a membrane-permeable trivalent arsenic compounds, which interfere the biochemical activity of intracellular enzymes or proteins through reacting specifically with sulfhydryl and vicinal dithiol groups in the protein structure. Although the deleterious effects of arsenic compounds in bioorganisms have been extensively studied, however its role in the synaptogenesis is still obscure. Here we test the role of PAO on the synaptic activity at developing Xenopus neuromuscular synapse by using whole-cell patch clamp recording. Bath application of PAO dose-dependently increases the frequency of spontaneous synaptic currents (SSC frequency) and reaches its maximal effect at 10 μM. The SSC frequency is robustly facilitated in 10~15 minutes after PAO application and then the release of neurotransmitter were abruptly ceased due to the degenerative collapse of the presynaptic motoneuron. Pretreatment of the culture with Ca2+ chelator BAPTA-AM significantly blunted the SSC frequency facilitation induced by PAO, suggesting a rise in Ca2+ in presynaptic motoneuron is a prerequisite. The PAO-induced SSC frequency facilitation is unaffected even that Ca2+ is eliminated from culture medium or addition of pharmacological Ca2+ channel inhibitor cadmium, indicating the influx of extracellular Ca2+ is not needed for the rise of [Ca2+]i. Depletion of endoplasmic reticulum Ca2+ pool with thapsigargin effectively hampered the PAO-induced SSC frequency facilitation. Pretreatment of ryanodine receptor inhibitor TMB-8 but not IP3 receptor inhibitor XeC significantly occluded the increase of SSC frequency elicited by PAO. Furthermore, bath application of the culture with either mitochondria oxidative phosphorylation uncoupler FCCP or mitochondrial permeability transition pore inhibitor cyclosporin A significantly abolished the SSC facilitating effect of PAO. Pretreatment the culture with TMB-8 and cyclosporin A have no addictive effects on the occlusion of PAO-induced SSC frequency facilitation, suggesting a consecutively released Ca2+ from internal store through ryanodine receptor and mitochondria is responsible for PAO-induced SSC frequency facilitation.
The synaptic facilitating effect of PAO is eliminated while incubated with free radical scavenger n-acetylcysteine. Furthermore, treating cultures with complex III of electron transport chain (ETC) inhibitor antimycin A, but not complex I inhibitor rotenone, abolished PAO-induced facilitation of synaptic transmission. PAO elicited no facilitation effects on SSC frequency when pretreatment the culture with either thiol-modifying agent NEM or thiol-reducing agent DTT. Overall, results from our current study provide evidences that reactive oxygen species derived from PAO inhibition on complex III of ETC induce the open of MPT pore in mitochondria, the accompanied Ca2+ leak from mitochondria and Ca2+-induced Ca2+ release from endoplasmic reticulum resulted in a robustly release of neurotransmitter and a destructive damage on the neuron.

目錄 …………………………….………………………….……..…… i
圖目錄 ……………………….………………………………….……. ii
表目錄 ………………………………………………………….……. iii
縮寫表 …………………………………..…………………….……... iv
中文摘要 ..………………..………………………………….....…...... v
Abstract ...…………………………………...………..………........ viii
第 一 章 緒論 …………………………………..…………………. 1
1.1 前言 …………………………………………..……….… 1
1.2 研究目的 ………………………………………………. 18
第 二 章 材料與方法 ………………………………………….… 23
2.1 實驗材料 …………………………..…………………... 23
2.2 實驗方法 ………………………………………………. 26
第 三 章 結果 ………………………………………………….… 31
第 四 章 討論 ………………………………………………….… 56
第 五 章 參考文獻 …………………………………………….… 67
第 六 章 附錄 ………………..…..…………………………….… 79

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