中文摘要
(Abstract in Chinese)

癲癇是一種腦中神經元不自主放電的慢性疾病，其臨床特徵係不斷自發性的重覆發作。目前在臨床上大約有65-70％的癲癇患者，可以利用現有的抗癲癇藥物進行良好控制。然而約有25-30％對於目前抗癲癇藥物是無效的，此類的癲癇病人被統稱為「頑固型癲癇」病人。然而截至目前為止，對於頑固型癲癇發生的過程、原因及分子機制尚未清楚。因此詳盡地了解頑固型癲癇發生的原因及機制是目前在癲癇研究領域中一個相當重要且急待解決的課題。在近年來的臨床研究觀察中發現，頑固型癲癇病人在以外科手術的方法進行病兆區域切除治療時，其病兆區域的組織中通常會含有大量的第一型單純疱疹病毒DNA表現，因此推測第一型單純疱疹病毒感染與頑固型癲癇的發生過程可能有某種程度的相關性，然而其相關性為何則仍然未知。為了證明第一型單純疱疹病毒感染與頑固型癲癇的相關性，我們擬以長期性腦組織切片培養系統來進行研究模式的建立，並利用電氣生理學、組織免疫染色及組織切片觀察來進行研究。由電氣生理學胞內與胞外記錄法所得到的結果中發現，第一型單純疱疹病毒感染後可以成功地在海馬迴組織切片中誘發出癲癇放電的體外模式。第一型單純疱疹病毒感染後對於海馬迴CA3區域的興奮性神經訊息傳遞並未產生明顯的影響，而是會改變CA3神經元本身細胞膜的特性及興奮度，包括靜止膜電位產生去極化、細胞膜阻抗增加以及後過極化振幅下降。除此之外，GABAB所媒介的抑制性神經傳遞作用也會受到抑制。除以電氣生理學確認第一型單純疱疹病毒造成癲癇發作之機制外，我們也利用免疫組織化學法、結晶紫染色法與Timm氏染色法分別確認第一型單純疱疹病毒在切片組織上之分佈情形、感染後會使細胞型態之變化情形及苔狀纖維重新分佈生長的現象。另一方面，我們也發現在第一型單純疱疹病毒感染七天後，無法以電氣生理學紀錄法記錄到神經元的活性表現。此現象可能與第一型單純疱疹病毒不斷大量複製並毒殺神經元所致，因此採用抗病毒藥物acyclovir 20 mM來前處理抑制病毒進行複製。結果發現，所記錄到的細胞活性會趨向於穩定狀態且也能夠記錄到感染七天的神經元活性表現。另外以蘇木素-伊紅染色法也確認第一型單純疱疹病毒感染後會使神經元受損。從電氣生理學以及組織病理學的結果可以知道在腦組織切片培養系統中感染第一型單純疱疹病毒後，會藉由改變細胞膜本身的興奮性與GABAB抑制作用造成神經元過度興奮而誘發癲癇的發作；另外，其複製過量也會對神經元造成不可逆地傷害而導致神經元的死亡。

英文摘要
(Abstract in English)

Epilepsy is a chronic disorder characterized by recurrent self-limited seizures with excessive discharges throughout localized or generalized groups of neurons in the brain. Recurrent seizures, if frequent, interfere with the patients’ ability to perform day-to-day activities; however, judicious use of antiepileptic medications allows about 65-70% of epileptic patients to be seizure-free. It means that about 25-30% of epileptic patients can’t be cured by classical antiepileptic drugs. This type of drug-resistant epilepsy is called “intractable epilepsy”. However, the consequences and the underlying mechanisms of the generation of intractable epilepsy remain unclear. Recently, clinical observations have described the detection of herpes simplex virus (HSV) in the brain in patients who presented with intractable seizures. It is therefore hypothesized that seizure activity in a subset of epilepsy cases is caused by persistent HSV infection in the seizure foci. To elucidate the role of HSV infection in the development of chronic seizure disorders and the possible epileptogenic mechanisms, we have developed an in vitro organotypic slice culture model of epileptic seizures induced by persistent HSV type 1 (HSV-1) infection and use electrophysiological recordings and immunohitochemistry techniques. Intracellular and extracellular recordings revealed that HSV-1 infection may successfully induce epileptiform discharge pattern on the slice culture in the CA3 region. The postinfected CA3 pyramidal cells exhibited a more depolarizing resting membrane potential concomitanted with an increase in the membrane input resistance, and had an reduction in the amplitude of afterhyperpolarization amplitude and a marked decrease in the GABAB-mediated inhibition. In contrast, the excitatory synaptic transmission in the hippocampal CA3 region did not significantly change. Besides electrophysiological recordings, we also checked HSV-1 distribution, neuron morphological change, and mossy fiber sprouting on cultured slices using immunohistochemistry, Nissl stain, and Timm stain respectively. Accidently, we found that the hippocampal CA3 neurons didn’t present neuronal activities after 7 days HSV-1 infection. We suggested that it may be due to the global neuronal death after chronic HSV-1 infection. In final set of experiment, we cultured the slices in the presence of acyclovir (20 mM) to inhibit HSV-1 replication and found that most CA3 neurons recorded by intracellular recording tended to present stable phenotype. These findings confirmed the hypothesis that HSV-1 continuous replication may cause cell damage. This hypothesis was also confirmed by hematoxylin-eosin staining method. Judging from the characteristics of the electrophysiological correlates, and neuropathology, this chronic slice model has points of resemblance with recent interpretation of the HSV hypothesis for limbic seizures that caused from change of neuron membrane properties and decreased GABAB inhibitory effect, and it may be used to investigate the pathogenesis and therapeutic strategies of human pharmacoresistant epilepsy. Furthermore, HSV-1 infection may injure neurons and eventually lead to neuronal death.

目 錄
頁碼
中文摘要 4-6
英文摘要 7-9
縮寫檢索表 10-13
緒論 14-55
材料與方法 56-70
病毒株與細胞株 57
病毒計量 57-59
組織切片培養 59
感染病毒 60
電氣生理學紀錄法 60-63
抗病毒藥物acyclovir對神經元活性表現的影響 63-64
組織切片染色法 64-68
統計方法 68
藥品購得 68-70
結果 71-88
討論 89-101
圖表 102-140
參考文獻 141-160
自述 161

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