氧化壓力是指體內自由基生成量與抗自由基氧化系統失衡現象，因而造成細胞內的氧化傷害，例如脂質過氧化、鈣離子濃度改變、粒線體膜電位下降，甚至細胞凋亡或壞死。近年來，越來越多的實驗與臨床研究顯示氧化壓力與許多神經退化性疾病有關，像是阿茲海默症、巴金森症等。另一方面，顯示癲癇重積症（status epilepticus）發作會造成腦細胞死亡、甚至認知功能缺陷。pilocarpine (PC) 和kainic acid (KA)是目前國際公認較理想誘發動物癲癇模式的化學藥劑。前者是刺激腦內膽鹼受體的物質，後者則是麩胺酸的類似物，二者用來產生人類顳葉癲癇藥物，本論文目的利用上述二種藥物經由體內和體外方式誘發細胞傷害，第一部分探討氧化壓力在PC引致癲癇發作致病機轉以及氧化壓力在癲癇發作所扮演的角色，第二部份探討KA誘發興奮性毒素造成皮質細胞凋亡與壞死之蛋白質表現。臨床研究指出，癲癇患者服用抗癲癇藥物常引發高同半胱氨酸血症(homocysteine, Hcy)，不但增加心血管疾病罹患率，腦也會造成氧化傷害，加重癲癇的症狀。因此第三部份探討Hcy對不同腦區產生氧化傷害狀況，補充葉酸與山藥對其神經保護作用。

首先利用pilocarpine 誘發活體(in vivo)動物癲癇，目的為(1)建立PC誘發癲癇之動物模式(2)評估不同發作程度與氧化壓力之關聯性 (3)探討腦內DNA氧化傷害狀況。結果PC (350 mg/kg)誘導小雞癲癇，發現5隻小雞呈現長時間痙攣(prolonged seizure, PC+ PS），10隻小雞為短暫性且重複性癲癇發作(repeated seizure, PC+ RS)， PC + PS組活性氧（ROS）和丙二醛 (MDA, 脂肪過氧化物）含量顯著比PC + RS組高，腦內抗氧化酵素(超氧化物歧化酶（SOD）、過氧化氫酶（CAT）)活性比PC + RS組低（P<0.05）。神經細胞死亡百分比和單股 DNA含量顯示，PC + PS組均比PC + RS組增加（P<0.01）。此外，粒線體膜電位（MMP）低於PC+RS組，結果證實，發作時間越長粒線體膜的完整性破壞。二者癲癇發作與控制組相比較，腦內抗氧化活性，Gpx活性與GSH含量皆比控制組低，鈣離子濃度顯著高於控制組，其他並無顯著差異。顯示，癲癇發作腦細胞內鈣離子濃度增加，抗氧化物質GSH與Gpx活性降低。結論，發作程度不同，腦內活性氧物質(ROS)、粒線體功能和DNA均扮演重要角色。因此長時間癲癇發作，如癲癇重積症宜補充抗氧化物質以清除ROS，如此才有保護作用。

第二部分以不同劑量KA 誘發腦內氧化壓力探討不同氧化傷害引發細胞死亡--細胞凋亡(apoptosis) 與細胞壞死(necrosis)以及二者蛋白質表現差異。先以利用流式細胞儀分析不同濃度KA與作用時間引發腦內氧化傷害(包括反應性氧化物、胞內鈣離子濃度、粒線體膜電位)以及細胞死亡百分比。結果發現，高濃度KA (>5 uM) 顯著增加腦內皮質細胞內ROS 生成量與細胞死亡。比較作用時間，高濃度KA (>5 uM)且作用達180 分顯著增加腦細胞內ROS、〔Ca+2〕i、造成細胞膜電位(MMP)下降與高細胞死亡百分比，顯示高濃度KA長時間作用引致高度神經傷害。低濃度KA (50 pM 及0.5 pM)腦內ROS、〔Ca+2〕i、高細胞膜電位(MMP )與細胞死亡百分比則顯著比高濃度KA者少，DNA 片段、細胞膜PS外翻(Annexin-V 染色)用來確認低劑量（0.5 pM）KA 作用180 分為細胞凋亡，而高劑量(5 μM ) KA作用180分鐘誘發細胞壞死。進而利用蛋白質體學探討細胞凋亡與壞死二者之蛋白質體表現差異，先以二維凝膠電泳（two-dimensional gel electrophoresis，簡稱2-DE）分離蛋白質混合物，再以tandem 質譜儀（MS/MS）找出二者之蛋白質圖譜差異。細胞凋亡與壞死的組織樣本分別經二維凝膠電泳圖樣、銀染後，每個樣本約可解析出800 個蛋白質點。使用ImageMaster software軟體將這些蛋白質點量化比對後發現，細胞凋亡有4 個蛋白質的量比細胞壞死顯著增加，再將這些蛋白質點取出，並以液相層析串聯式質譜儀鑑定其身分。確定為熱休克蛋白70，3 mercaptopyruvate sulfurtransferase，tubulin-B-5, pyruvate dehydrogenase E1 component subunit beta 和Guanine nucleotide binding protein。結果表明，不同濃度KA誘發興奮性毒性導致細胞凋亡或細胞壞死。細胞凋亡時，這些蛋白質表達顯著增加意謂它們是決定細胞凋亡而不是壞死的一重要因子，為臨床上提供重要的預後與治療之生物摽記。

第三部分利用甲硫胺酸誘發高同半胱胺酸血症(HHcy)，探討不同腦區的氧化傷害以及探討補充葉酸與山藥的神經保護作用。大鼠隨機分為控制組，甲硫胺酸組(Met)組、甲硫胺酸與補充葉酸組(Met+FA)和甲硫胺酸與山藥組(Met+Dios)四組。顯示腹腔注射甲硫胺酸八週其血漿同半胱胺酸濃度和血漿MDA濃度顯著比控制組高 (p<0.01)，即成功導致老鼠高同半胱胺酸血症。 至於腦部方面研究，HHcy腦內二個腦區皮質部與海馬迴內ROS顯著增加，抗氧化酵素catalase (CAT)活性因HHcy作用而增加，腦內超氧歧化酶(SOD)活性增加，可能是因HHcy在腦區形成ROS而促發腦內抗氧化酵素的產生反應性補償作用(compensation)，尤其是腦區中海馬迴的GSH含量顯著比其他腦區低，顯示HHcy對不同腦區的氧化壓力結果不同。補充葉酸和山藥對於血液HHcy與脂質過氧化均有顯著下降，至於腦區方面，葉酸和山藥的神經保護作用不只是顯著減少活性氧的產生，也造成超氧化物歧化酶（SOD）和CAT活性和GSH含量上升，以及顯著恢復腦內GSH含量。結果顯示，HHcy對腦造成氧化壓力，尤其是紋狀體與小腦，當補充葉酸與山藥將有助於降低HHcy所造成腦內的氧化壓力。
我們由體內和體外實驗均證實氧化壓力在腦部扮演極為重要的角色，這些不同氧化壓力指標對未來的臨床醫學提供相關治療策略。

Oxidative stress is an imbalance between radical-generating and antioxidative defensive system (SOD, CAT, Gpx) to cause cell damage triggered lipid peroxidation, calcium disorders, mitochondrial dysfunction, and even cell death. In recent years a growing number of experimental and clinical studies have shown that oxidative stress implicated in the pathophysiology of many neurodegenerative diseases such as Alzheimer's, Parkinson's psychosis. Evidence for epilepticus after seizure onset may result in cells death and cognitive dysfunction. Pilocarpine (PC) and kainic acid (KA) are currently accepted internationally as the ideal chemical agents for the induction of epilepsy in animal models. Pilocarpine stimulates cortical acetylcholine receptors whereas kainic acid has a similar action to glutamic acid. Both substances can be used to induce human temporal lobe epilepsy in animal models. The main aim of the present study is to use these two chemicals to induce cellular injury using both in vivo and in vitro techniques. In the first part of the study, we will investigate the role of oxidative stress in epilepsy. In the second part of the study, we will analyse the proteins produced by exitotoxin induced apoptosis in cortical cells. The effect of different KA concentrations and exposure times on the induction of oxidative stress and cell death will also be assessed. In addition, proteomics will be used to analyze the protein expression profiles in cellular apoptosis as compared to necrosis. Clinical research has found that the use of antiepileptic medication by persons with epilepsy often results in high levels of homocysteine (Hcy). High concentrations of Hcy are not only associated with an increased incidence of cardiovascular disease but can also result in oxidative injury in the brain and worsening of epileptic symptoms. As a result, in the third part of the study we will investigate the relationship between Hcy and different types of cortical oxidative injury. In addition, we will investigate the neuroprotective function of supplementation with Diascorea or folic acid in the presence of high concentrations of Hcy.

The purposes of first part of study include (1) the pilocarpine (PC)-induced animal model of epilepsy is well established. (2) the effects of different level of seizure on oxidative stress was assessed (3) the percentage of oxidative DNA damage was evaluated. First, Taiwan Native Breeder chicks, weighing 150–200 g, day-old, were used as experimental animals. Intraperitoneal injection in chicks with 3 mEq/kg LiCl and 30 min later by 350 mg/kg pilocarpine hydrochloride (PC) induced severe prolonged seizures (PC + PS) and repeated seizures (PC + RS) after 4 h behavioral observations. Results showed that PC + PS group had excessive levels of reactive oxygen species (ROS) and malondialdehyde (MDA) production and lower activities of superoxide dismutase (SOD) and catalase (CAT) compared to the PC + RS group (p < 0.05). Neuronal death and single strand DNA were significantly increased in dissociated brain cells of PC + PS group compared to that in the PC + RS group (p < 0.01). Furthermore, a decrease in mitochondrial membrane potential (MMP) was observed in PC + PS group as compared with that in PC + RS group indicating neuronal mitochondrial dysfunction in PS group not in RS group. ROS, mitochondrial dysfunction and DNA damage played important roles in pathophysiology of the immature brain to prolonged-seizure-induced damage. A manifest result of depleted enzymatic antioxidants (SOD and CAT) was also contributed for the vulnerability of the neonatal brain to prolonged-seizure-induced oxidative damage. The replenishment of SOD and CAT activities might be useful in protecting brain against prolonged-seizure-induced neuronal death.

In the second part of the study, cortical oxidative stress was induced with different concentrations of KA to investigate the different types of cell death (apoptosis and necrosis) that result from oxidative injury. We used flow cytometry to measure the oxidative injury resulting from different concentrations and exposure periods of KA (measured indices included reactive oxygen species, intracellular calcium ion concentration, mitochondrial membrane potential) and to estimate the percentage cell death. We found that high concentrations of KA (>5 uM) resulted in increased ROS in cortical cells and an increased percentage of cell death. Exposure to a higher concentration of KA for 180 minutes resulted in an increase in cortical ROS, [Ca+2] ions and the percentage cell death, and a decrease in mitochondrial membrane potential (MMP%). This demonstrates that prolonged exposure to high concentrations of KA results in a high level of neuronal damage. Exposure to low concentrations of KA (50 pM and 0.5 pM) resulted in lower cortical ROS, [Ca+2] ions and percentage cell death, and higher mitochondrial membrane potential (MMP%) than that of high concentrations of KA. In addition, analysis of DNA fragments and PS on the surface of the cell membrane (Annexin-V dye) confirmed that low concentration (0.5 pM) KA with 180 minutes of exposure can induce neuronal cell apoptosis, and that high concentrations of (5 μM ) KA with 180 minutes of exposure can induce neuronal cell necrosis. Therefore, different levels of oxidative stress result in two types of neuronal cell death: apoptosis and necrosis. We then used comparative proteonomics to investigate differences in protein expression between apoptosis and necrosis. Two-dimensional gel electrophoresis (2-DE) and mass spectrometry demonstrated different protein profiles for the two types of cell death. Apoptotic and necrotic tissue samples were passed separately through 2-DE and after silver staining, each sample produced about 800 protein spots for analysis. We then used ImageMaster software to measure and compare these protein spots and found that 5 proteins were significantly increased. We collected these protein spots from the electrophoresis gel and identified them using liquid chromatography mass spectrometry as heat shock protein 70, 3 mercaptopyruvate sulfurtransferase, tubulin-B-5, pyruvate dehydrogenase E1 component subunit beta and Guanine nucleotide binding protein. Therefore, in this study we have confirmed the proteins directly expressed by free-radical induced cellular apoptosis. These results could provide important markers of cellular apoptosis or neuroprotection.

In the third stage of the study, we used methionine to induce hyperhomocysteinemia (HHcy) and investigate oxidative injury in different brain regions. We also examined the neuroprotective function of supplementation with folate and dioscorea. The rats used in the animal models were randomized into control, methionine (Met), methionine plus folic acid (Met + FA), and methionine plus dioscorea (Met + Dios) groups. HHcy promotes an increase in ROS in the cortex and hippocampus. We found that the activity of four cortical antioxidant enzyme catalases (CAT) increased as a result of HHcy, and that the activity of superoxide dismutase (SOD) increased only in the corpus striatum and cerebellum. It is possible that HHcy produces ROS in the cortex that leads to a type of reactive compensation of increased activity of antioxidant enzymes. The quantity of GSH in the brain was significantly lower than in other cortical regions, demonstrating that HHcy results in different levels of oxidative stress in different cortical regions. Supplementation with folic acid or diascorea resulted in decreased HHcy and the resulting HHcy induced oxidation. The protective action of folic acid not only significantly reduced the production of ROS in the cortex and hippocampus, but also increased the quantity of GSH, CAT activity and SOD produced by HHcy oxidative stress. Dioscorea demonstrated the same protective action against HHcy induced oxidation. Not only did it remove the HHcy induced sensitivity to ROS in the cerebral cortex, it also increased the activity of antioxidant enzymes in the cortex and demonstrated a recovery of GSH levels in the corpus striatum. This indicates that folic acid and dioscorea can reduce the cortical oxidative stress produced by HHcy.

We confirmed that oxidative stress plays a very important role in the brain from in vivo and in vitro experiments. This type of model could be used to further investigate biomarkers that are important in the treatment strategy for clinical application.

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