有機磷美文松 (mevinphos, Mev) 為台灣常見自殺用的農藥，有機磷中毒病患會出現癲癇與心血管反應低落的病癥。杏仁核 (amygdala, AMG) 為邊緣系統的核區之一，基底外側杏仁核 (basolateral nucleus of amygdala, BLA) 被認為和癲癇調控相關，而中央杏仁核 (cetral nucleus of amygdala, CeA) 被認為參與在行為和情緒反應以及心血管的調控，然而未有詳細的機制探討於有機磷中毒所引起的癲癇和心血管反應低落中杏仁核是否參與。以腦電波觀測腦神經活性及以血壓和心跳變化觀測心血管反應，本實驗欲探討有機磷 Mev 作用於杏仁核是否會誘發癲癇的發生與心血管反應的低落。
利用微量注射 Mev 至以 propofol 維持持續麻醉狀態之大白鼠基底外側杏仁核引起杏仁核、皮質與海馬迴腦電波功率增加，誘發癲癇的產生，但對於動脈壓、心跳、呼吸和動脈壓低頻功\率成份並無顯著影響，且會造成杏仁核中細胞激素 interleukin (IL)-12、 IL-13、 tumor suppressor factor alpha (TNFα)、 interferon gamma ( IFNγ) 蛋白質與 mRNA 含量及環氧合酶活性隨著時間顯著增加。微量注射 Mev 至海馬迴僅誘發較輕微之皮質和海馬迴癲癇狀腦電波活性，無法於杏仁核中誘發腦電波變化。顯示大鼠 Mev 作用於基底外側杏仁核，可參與癲癇的發生並擴散至其他邊緣系統核區及大腦皮質中。腹腔注射可通過血腦屏障之蕈毒鹼接受器拮抗劑 atropine (ATR)、促進 GABA 抑制型神經傳導藥物 midazolam (MDZ)、抗發炎藥物 pentoxifylline (PTX) 和 Lisofylline (LSF) 而非不可通過血腦屏障之蕈毒鹼接受器拮抗劑 atropine methyl nitrate (AMN) 可抑制由 Mev 作用於基底外側杏仁核誘發的癲癇發生並抑制杏仁核中細胞激素的增加。微量注射 ATR、環氧合酶第一亞型抑制劑 naproxen (NPX) 和環氧合酶第二亞型抑制劑 NS398、及 IL-12、 IL-13、 TNFα、 IFNγ 接受器之抗血清而非尼古丁接受器拮抗劑 mecamylamine (MEL) 至基底外側杏仁核，可抑制由 Mev 作用於基底外側杏仁核造成的杏仁核中細胞激素蛋白質含量與環氧合酶活性的增加，並抑制杏仁核中所偵測到的發炎反應及癲癇的發生。然而 Mev 作用於基底外側杏仁核，並未於杏仁核中偵測到 caspase 3活性的增加及 DNA 斷裂的產生，顯示當 Mev 作用於基底外側杏仁核誘發癲癇的過程中並未產生細胞凋亡。
利用微量注射 Mev 至中央杏仁核導致動脈壓及呼吸速率下降，造成心血管反應低落，且會造成動脈壓低頻成分的短暫上升而心跳速率無顯著變化，但對於杏仁核腦電波變化無顯著影響。微量注射 Mev 至中央杏仁核使得杏仁核中caspase 3 活性的增加及 DNA 斷裂的產生，造成細胞凋亡。微量注射 ATR、細胞凋亡抑制劑 NS-3694 而非 MEL 至中央杏仁核可抑制由 Mev 作用於中央杏仁核所產生之心血管反應低落及杏仁核中 caspase 3 活性的增加及 DNA 斷裂的產生。然而於杏仁核中並未偵測到細胞激素蛋白質含量的改變，顯現 Mev 作用於中央杏仁核造成心血管反應低落並非由發炎反應所媒介。
利用靜脈注射 Mev 並未改變杏仁核組織中氧分壓與血流速度，且未於杏仁核中偵測到超氧陰離子之含量變化或超氧陰離子之螢光訊號。微量注射 Mev 至基底外側杏仁核或中央杏仁核中亦無觀測到杏仁核中超氧陰離子含量的變化，顯現超氧陰離子並未參與在 Mev 作用於基底外側杏仁核造成的癲癇或 Mev 作用於中央杏仁核造成的心血管反應低落過程中。
由實驗結果可得知杏仁核參與在有機磷 Mev 中毒大鼠中癲癇的發生與心血管反應低落的調控，此外基底外側杏仁核的發炎反應與中央杏仁核的細胞凋亡將於癲癇發生與心血管反應低落中各自扮演重要的角色。

Mevinphos (Mev) is an orgnophosphate insectide used for suicidal purposes in Taiwan; seizure and cardiovascular depression are commom syptoms observed in organophosphate-poisoned patients. The amygdala (AMG) is part of the limbic system and the basolateral nucleus of AMG (BLA) is one of the most seizure-prone brain structures. The central neucleus of AMG (CeA) is thought to play a central role in behavioral, physiological response and cardiovascular regulation. However, detailed mechanisms in Mev-induced seizure and cardiovascular depression by an action on AMG are lacking. Based on electroencephalographic (EEG) activity to indicate neuronal electrical activity and arterial blood pressure (AP) and heart rate (HR) to indicate cardiovascular responses, the present study investigated whether Mev acts on AMG to elicit seizure or cardiovascular depression.
Microinjection of Mev into BLA of adult male Sprague-Dawley (SD) rats maintained under propofol anesthesia increased EEG activity in AMG, cortex and CA3 of hippocampus leading to seizure initiation; however AP, HR, respiration rate (RR) and the power density of low-frequency (LF) component of AP was not significantly changed. Microinjection of Mev into BLA also time-dependently increased protein level and mRNA of cytokines interleukin (IL)-12, IL-13, tumor suppressor factor alpha (TNFα) and interferon gamma (IFNγ) and cyclooxygenase (COX) activity in AMG. Microinjection of Mev into CA3 induced less seizure activity in cortex and CA3 than that induced by microinjection of Mev into BLA. In addition, microinjection Mev into CA3 did not induce seizure in AMG. These results suggest that Mev acted on BLA to initiate limbic seizures. Intraperitoneal injection of muscarinic receptor antagonist atropine (ATR), which can pass the blood-brain barrier (BBB), activator of GABAergic neurotransmission midazolam (MDZ) or antiinflaamatory agent pentoxifylline (PTX) and Lisofylline (LSF), but not muscarinic receptor antagonist atropine methyl nitrate (AMN), which can not pass BBB, inhibited Mev-induced seizure and increase of cytokines in AMG by an action on BLA. Microinjection of ATR, COX-1 inhibitor naproxen (NPX) or COX-2 inhibitor NS-398, antiserum against receptor of IL-12, IL-13, TNFα or IFNγ, but not nicotinic receptor antagonist mecamylamine (MEL), into BLA inhibited Mev-induced seizure and increase of cytokines and COX activity in AMG by an action on BLA. However, caspase 3 activity and DNA fragmentation at AMG were not changed by microinjection of Mev into BLA.
Microinjection of Mev into CeA induced a decrease in AP and RR leading to cardiovascular depression and an increase of power desity of LF, accompanied with insignificant HR and EEG activity change. Microinjection of Mev into CeA induced the time-dependently increase of caspase 3 activity and DNA fragmentation leading to apoptosis in AMG. Microinjection of ATR or caspase 3-dependent apoptosome inhibitor NS-3694, but not MEL, into CeA inhibited cardiovascular depression and the increase of caspase 3 activity and DNA fragmentation induced by Mev action on CeA. However, the levels of cytokines were not changed by Mev treatment.
Intravenous injection of Mev did not induce changes of partial pressure of oxygen, blood flow and the level of superoxide anion in AMG. In addition, microinjection of Mev into BLA or CeA did not affect the level of superoxide anion in AMG.
These results suggest that AMG mediates the initiation of seizure and cardiovascular depression induced by Mev. Furthermore, inflammation in BLA and apoptosis in CeA individually play an important role in Mev-induced seizure and cardiovascular depression.

論文審定書 i
致謝 iii
中文摘要 v
英文摘要 vii
第一章 緒論 Introduction 1
一、 Mev 中毒之作用機轉與對中樞神經系統和心血管變化之影響 2
二、 基底外側杏仁核與中央杏仁核對於癲癇及心血管之調控 3
三、 乙醯膽鹼系統之蕈毒鹼及尼古丁接受器對於癲癇及心血管之調控 5
四、 發炎反應對於癲癇及心血管之調控 7
五、 細胞凋亡對於癲癇及心血管之調控 9
六、 氧化壓力對於發炎反應與細胞凋亡之調控 11
七、 腦電波頻譜分析 12
八、 動脈壓頻譜分析 13
第二章 研究動機與目的 Motivation and Research Objectives 15
第三章 研究材料與方法 Materials and Methods 19
一、 動物準備 20
二、 動脈壓之血壓、心跳與頻譜分析 20
三、 微量注射或腹腔注射化學物質 21
四、 記錄腦電波及腦電波頻譜分析 22
五、 實驗流程 22
六、 腦部組織切片與 Hemotoxyline and eosin 染色 23
七、 免疫螢光染色 23
八、 動物全身灌流以及組織取樣 23
九、 蛋白質萃取 24
十、 核醣核酸萃取 24
十一、反轉錄聚合酶鏈式反應 24
十二、即時定量聚合酶鏈式反應 24
十三、發炎反應之檢測 25
十四、細胞凋亡之檢測 25
十五、超氧陰離子之檢測 26
十六、統計分析 26
十七、藥品及抗體來源 27
第四章 實驗結果 Results 29
一、 靜脈注射 Mev，觀測 Ctx 與 AMG 之 EEG 改變與心血管反應 30
二、 微量注射 Mev 於 AMG 和 CA3，觀測 EEG 改變與心血管反應 30
三、 於 Mev 中毒大鼠癲癇模式給予 ATR、 AMN 和 MDZ 31
四、 探討 BLA 中 AChR 於 Mev 中毒大鼠癲癇模式所扮演的角色 32
五、 Mev 中毒大鼠癲癇模式下 BLA 中發炎反應與細胞凋亡是否參與 32
六、 探討 BLA 中發炎反應於 Mev 中毒大鼠癲癇模式所扮演的角色 33
七、 探討 CeA 中 AChR 於 Mev 中毒大鼠心血管反應低落所扮演的角色 35
八、 Mev 中毒大鼠心血管反應低落 CeA 中發炎反應與細胞凋亡是否參與 36
九、 探討 CeA 中細胞凋亡於 Mev 中毒大鼠心血管反應低落中所扮演的角色 36
十、 Mev 中毒大鼠癲癇模式下 AMG 中氧化壓力是否參與 37
第五章 討論 Discussion 39
一、 建立 Mev 中毒大鼠癲癇模式 40
二、 BLA 中 mAChR 而非 nAChR 參與 Mev 中毒大鼠癲癇模式與心血管低落反應 41
三、 Mev 中毒誘發大鼠癲癇由 BLA 中發炎反應而非細胞凋亡所媒介 42
四、 Mev 中毒誘發大鼠心血管反應低落由 CeA 中細胞凋亡而非發炎反應所媒介 43
五、 AMG 中氧化壓力於 Mev 中毒大鼠癲癇模式中所扮演的角色 43
第六章 結論 Conclusion 45
第七章 未來展望 Future Prospect 47
參考文獻 References 49

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