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研究生:蔡秀玲
研究生(外文):Hsiu-LingTsai
論文名稱:氧化壓力在癲癇發作、興奮性毒性和同半胱胺酸血症之研究
論文名稱(外文):Studies on the oxidative stress in epileptic seizures, excitotoxicity and homocysteinemia
指導教授:張素瓊張素瓊引用關係
指導教授(外文):Sue-Joan Chang
學位類別:博士
校院名稱:國立成功大學
系所名稱:生命科學系碩博士班
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2012
畢業學年度:100
語文別:中文
論文頁數:146
中文關鍵詞:癲癇發作氧化壓力神經毒害細胞凋亡細胞壞死同半胱胺酸山藥
外文關鍵詞:epilepsyseizureoxidative stressneurotoxicityapoptosisnecrosishomocysteinemiadioscorea
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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.

謝誌-----------------------------------------------------------------------------------------Ⅰ
中文摘要------------------------------------------------------------------------------------II
英文摘要------------------------------------------------------------------------------------V
目次------------------------------------------------------------------------------------------X
表目錄--------------------------------------------------------------------------------------XIV
圖目錄--------------------------------------------------------------------------------------XV
導論-------------------------------------------------------------------------------------------1
第一部份 pilocarpine誘發動物癲癇與氧化壓力之研究---------------------------2
第一章 緒論---------------------------------------------------------------------------------3
第二章 文獻探討---------------------------------------------------------------------------5
一、 癲癇(epilepsy) --------------------------------------------------------------------5
二、 興奮性與癲癇生成(excitability and epileptogenesis) ----------------------6
三 、引致癲癇的動物模式(animal models of epilepsy)-------------- -----------8
四 、氧化壓力(oxidative stress) -----------------------------------------------------11
第三章材料與實驗方法------------------------------------------------------------------16
一、 化學藥劑--------------------------------------------------------------------------16
二、 儀器----------------------------------------------------------------------------- --17
三、實驗方法-------------------------------------------------------------------------- -18
(一) 引致動物癲癇實驗------------------------------------------------------------ -18
(二) 癲癇腦內抗氧化酵素之測定------------------------------------------------- 19
(三) 癲癇腦內氧化壓力之測定-----------------------------------------------------22
1. 活性氧(reactive oxygen species)物質之測定--------------------------------22
2. 丙二醛(malondialdehyde, MDA)含量之測定-------------------------------23
(四) 腦細胞功能檢測--------------------------------------------------------------24
1. 粒線體膜電位(mitochondrial membrane potential, MMP) -----------------24
2. 細胞內鈣離子濃度(intracellular calcium concentrateon) --------------------24
3. 細胞死亡率(necrosis) --------------------------------------------------------------25
4. 染色體結構完整性檢測:單/雙股DNA------------------------------------------26
(五) 統計分析----------------------------------------------------------------------------26
第四章實驗結果------------------------------------------------------------------------------27
第五章討論------------------------------------------------------------------------------------31
第二部份 kainic acid引致氧化壓力與神經細胞死亡之研究-----------------------39
第一章 緒論----------------------------------------------------------------------------------40
第二章 文獻探討----------------------------------------------------------------------------42
一、麩胺酸(glutamate) ------------------------------------------------------------------42
二、興奮性毒素(excitotoxicity) -------------------------------------------------------42
三、NMDA受體與興奮性毒素(NMDA receptors and excitotoxicity) ----------43
四、AMPA/KA受體與興奮性毒性(AMPA/KA receptors and excitotoxicity)-44
五、海人草酸與氧化壓力(kainic acid and oxidative stress)—體內研究--------45
六、海人草酸與氧化壓力(kainic acid and oxidative stress)—體外研究--------46
七、細胞死亡(cell death) ---------------------------------------------------------------46
八、細胞凋亡與海人草酸(apoptosis and kainic acid )------------------------------47
第三章 材料與實驗方法-------------------------------------------------------------------48
一、化學藥劑------------------------------------------------------------------------------48
二、儀器------------------------------------------------------------------------------------50
三、實驗方法------------------------------------------------------------------------------51
(一) 初級皮質細胞培養-----------------------------------------------------------51
(二) 海人草酸處理-----------------------------------------------------------------52
(三) 分離腦細胞氧化壓力之測定-----------------------------------------------52
1. 活性氧含量測定------------------------------------------------------------------52
2. 粒線體膜電位測定---------------------------------------------------------------53
3. 細胞內鈣離子濃度測定---------------------------------------------------------53
4. 細胞壞死測定---------------------------------------------------------------------54
(四) 細胞凋亡檢測-----------------------------------------------------------------55
1. DNA片段分析--------------------------------------------------------------------55
2. Annexin-V分析-------------------------------------------------------------------55
(五) 蛋白質表現分析--------------------------------------------------------------56
1. 第一維等電點聚焦法(First-Dimension Isoelectric focusing,IEF) --------56
2 第二維SDS 凝膠電泳(Second-dimension ; SDS-PAGE) ------------------57
3 銀染(silver stain)---------------------------------------------------------------57
4 二維凝膠電泳影像處理與分析-------------------------------------------------58
(六) 統計分析--------------------------------------------------------------------------60
第四章實驗結果-------------------------------------------------------------------------------61
第五章討論-------------------------------------------------------------------------------------64
第六章結論-------------------------------------------------------------------------------------68
第三部份 homocysteine 誘發腦部氧化壓力與傷害----------------------------------78
第一章 緒論-----------------------------------------------------------------------------------79
第二章 文獻探討-----------------------------------------------------------------------------81
一、同半胱胺酸(homocysteine) --------------------------------------------------------81
二、同半胱胺酸與腦(homocysteine and brain) --------------------------------------81
三、同半胱胺酸與氧化壓力(homocysteine and oxidative stress) -----------------82
四、同半胱胺酸與癲癇發作(homocysteine and epilepsy) --------------------------83
第三章 材料與實驗方法--------------------------------------------------------------------85
一、化學藥劑-------------------------------------------------------------------------------85
二、儀器-------------------------------------------------------------------------------------87
三、實驗方法-------------------------------------------------------------------------------88
(一) 血液氧化壓力測定---------------------------------------------------------------89
1. 血漿製備---------------------------------------------------------------------------89
2. 血漿同半胱胺酸濃度測定------------------------------------------------------89
3. 血漿丙二醛濃度測定------------------------------------------------------------90
(二) 氧化壓力測定---------------------------------------------------------------------90
1. 組織均質液之製備-----------------------------------------------------------------90
2. 組織同半胱胺酸濃度測定--------------------------------------------------------90
3. 組織丙二醛濃度測定--------------------------------------------------------------91
4. 組織活性氧 (reactive oxygen species) 物質之測定-------------------------91
5. 超氧歧化酵素 (Superoxide dismutase, SOD) 活性測定--------------------92
6. 催化酶 (Catalase, CAT) 活性測定----------------------------------------------92
7. 麩胱甘肽(Glutathione, GSH)含量測定------------------------------------------93
8. 氧化態麩胱甘肽(Glutathione Disulfide, GSSG)含量測定------------------93
9. 蛋白質含量測定-------------------------------------------------------------------94
10. 統計分析---------------------------------------------------------------------------94
第四章實驗結果-------------------------------------------------------------------------------96
第五章討論-----------------------------------------------------------------------------------101
第六章結論---------------------------------------------------------------------------------104總結--------------------------------------------------------------------------------------------113
參考文獻--------------------------------------------------------------------------------------114
附錄 論文發表簡述表----------------------------------------------------------------------144

參考文獻
第一部分
1.Aebi H. Catalase in vitro. In: Methods in enzymology. New York: Academic Press; pp 121–6. 1984
2.Albowitz B., Konig P and Kuhnt U. Spatiotemporal distribution of intracellular calcium transients during epileptiform activity in guinea pig hippocampal slices. J. Neurophysiol. 77: 491-501. 1997
3.Allen RG. Oxygen-reactive species and antioxidant responses during development: the metabolic paradox of cellular differentiation. Proc. Soci. Exp. Bio. & Med. 196: 117-29. 1991
4.Annegers J. The epidemiology of epilepsy. In: Wyllie, E. (Ed.), The Treatment of Epilepsy. Lea and Febiger, Philadelphia, pp. 157-64. 1993
5.Annunziato L, Amoroso S, Pannaccione A, Cataldi M, Pignataro G, D'Alessio A, Sirabella R, Secondo A, Sibaud L, Di Renzo GF. Apoptosis induced in neuronal cells by oxidative stress: role played by caspases and intracellular calcium ions. Toxicol Lett. 139(2-3): 25-33. 2003
6.Batini C, Teillet M-A, Naquet R, Le Douarin NM. Brain chimeras in birds: application to the study of a genetic form of reflex epilepsy. Trends Neurosci 19:246 –52. 1996
7.Baulac S, Gourfinkel-An I, Picard F, et al. A second locus for familial generalized epilepsy with febrile plus maps to chromosome 2q21–q33. Am J Hum Genet 65:1078–85. 1999
8.Beck H, Steffens R, Elger CE, Heinemann U. Voltage-dependent Ca2+ currents in epilepsy. Epilepsy Res 32: 321–32. 1998
9.Beghi E. Overview of studies to prevent posttraumatic epilepsy. Epilepsia. 44 Suppl 10:21-6. 2003
10.Ben-Ari Y, Tremblay E, Riche D, et al: Electrographic, clinical and pathological alterations following systemic administration of kainic acid, bicuculline or pentetrazole: metabolic mapping using the deoxyglucose method with special reference to the pathology of epilepsy. Neuroscience 6:1361-1391, 1981
11.Berridge MJ, Bootman MD, Lipp P. Calcium—a life and death signal. Nature 395: 645–648. 1998
12.Biervert C, Schroeder BC, Kubisch C, et al. A potassium channel mutation in neonatal human epilepsy. Science 279: 403–06. 1998
13.BindokasVP, LeeCC, ColmersWF, MillerRJ. Changes in mitochondrial function resulting from synaptic activity in the rat hippocampal silice. J. neurochem. 18: 4570-4587. 1998
14.Brini M, Pinton P, King MP, Davidson M, Schon EA, Rizzuto R. A calcium signaling defect in the pathogenesis of a mitochondrial DNA inherited oxidative phosphorylation deficiency. Nat Med. 5: 951-4. 1999
15.Bruce AJ and Baudry M. Oxygen free radicals in rat limbic structures after kainite-induced seizures. Free Radical Biol Med 18: 993-1002. 1995
16.Cavalheiro EA, Riche DA, Le Gal La Salle G: Long-term effects of intrahippocampal kainic acid injection in rats: a method for inducing spontaneous recurrent seizures. Electroenceph clin Neurophysiol 53:581-589, 1982
17.Chen Z-F, Schottler F, Bertram E, Gall CM, Anzivino MJ, Lee KS. Distribution and initiation of seizure activity in a rat brain with subcortical band heterotopia. Epilepsia 41:493–501.2000
18.Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhover C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet 68: 1327–32. 2001
19.Clifford DB, Olney JW, Maniotis A, Collins RC, Zorumski C.F. The functional anatomy and pathology of lithium-pilocarpine and high-dose pilocarpine seizures, Neuroscience, 23 :953–968. 1987
20.Dailey JW, Reigel CE, Mishra PK, Jobe PC. Neurobiology of seizure predisposition in the genetically epilepsy-prone rat. Epilepsy Res 3:3–17. 1989
21.Dawson TM, Dawson VL., 2003. Molecular pathways of neurodegeneration in Parkinson's disease. Science. 31;302(5646), 819-22.
22.Delgado-Escueta A V; Wilson W A; Olsen R W; Porter RJ. New waves of research in the epilepsies: crossing into the third millennium. Adv. Neurol. 79:3 –58. 1999
23.Dizdaroglu M. Oxidative damage to DNA in mammalian chromatin. Mutat Res. 275:331-42. 1992
24.Dube C, Chen K, Eghbal-Ahmadi M, Brunson K, Soltesz I, Baram TZ. Prolonged febrile seizures in the immature rat model enhance hippocampal excitability long term. Ann Neurol 47:336–44. 2000
25.Dufour F, Koning E, Nehlig A. Basal levels of metabolic activity are elevated in Genetic Absence Epilepsy Rats from Strasbourg (GAERS): measurement of regional activity of cytochrome oxidase and lactate dehydrogenase by histochemistry. Exp Neurol. 182: 346-52. 2003
26.Duncan JS. Seizure-induced neuronal injury: human data. Neurology. 59:S15-20. 2002
27.Evenson DP, Darzynkiewicz Z, Melamed MR. Relation of mammalian sperm chromatin heterogeneity to fertility. Science 240: 1131-1133. 1980
28.Farrell MA, DeRosa MJ, Curran JG, et al. Neuropathologic findings in cortical resections (including hemispherectomies) performed for the treatment of intractable childhood epilepsy. Acta Neuropathol 83:246 –59. 1992
29.Fletcher CF, Lutz CM, O’Sullivan TN, et al. Absence epilepsy in tottering mutant mice is associated with calcium channel defects. Cell 87:607–17. 1996
30.Frankel E N. Recent advances in lipid oxidation. J. Sci. Food Agric. 54:495–511. 1991
31.Gambardella A, Annesi G, De Fusco M, et al. A new locus for autosomal dominant nocturnal frontal lobe epilepsy maps to chromosome 1. Neurology 55: 1467–71. 2000
32.GrifÆths T, Evans M. C, Meldrum B S, Intracellular calcium accumulation in rat hippocampus during seizures induced by bicuculline or l-allylglycine. Neuroscience 10: 385-395. 1983
33.Hatherill JR, Till GO, Ward PA.Mechanisms of oxidant-induced changes in erythrocytes. Agents Actions. 32:351-8. 1991
34.Hauser WA, Kurland LT. The epidemiology of epilepsy in Rochester, Minnesota, 1935 through 1967. Epilepsia. 16(1):1-66. 1975
35.Hirose S, Okada M, Kaneko S, Mitsudome A. Are some idiopathic epilepsies disorders of ion channels?: a working hypothesis. Epilepsy Res. 41: 191—204. 2000
36.Honchar MP, Olney JW, Sherman WR. Systemic cholinergic agents induce seizures and brain damage in lithium-treated rats. Science 220:323–5. 1983
37.Jasper HH, Kershman J. Electroencephalography. Prog Neurol Psychiatry. 1:372-97. 1946
38.Jerrett SA, Jefferson D and Mengel CE. Seizure, H2O2 and lipid peroxidase in brain during exposure to oxygen during high pressure. Aerospace Med 44: 40-44. 1973
39.Jordan J, Cena V, Prehn JH. Mitochondrial control of neuron death and its role in neurodegenerative disorders. J Physiol Biochem. 59(2): 129-41. 2003
40.Kawanishi S, Inoue S, Oikawa S, Yamashita N, Toyokuni S, Kawanishi M, Nishino K. Oxidative DNA damage in cultured cells and rat lungs by carcinogenic nickel compounds. Free Radic Biol Med. 31(1):108-16. 2001
41.Kawanishi, S., Hiraku, Y. and Oikawa, S. Mechanism of guanine-specific DNA damage by oxidative stress and its role in carcinogenesis and aging. Mutat. Res. 488: 65-76. 2001
42.Killam KF, Killam EF, Naquet R. An animal model of light sensitive epilepsy. Electroencephalogr Clin Neurophysiol 22:497–513. 1967
43.Kotloski R, Lynch M, Lauersdorf S, Sutula T. Repeated brief seizures induce progressive hippocampal neuron loss and memory deficits. Prog Brain Res. 135:95-110. 2002
44.Kovacs R, Schuchmann S, Gabriel S, Kann O, Kardos J, Heinemann U. Free radical-mediated cell damage after experimental status epilepticus in hippocampal slice cultures. J Neurophysiol Dec.88(6): 2909-18.2002
45.Lee KS, Schottler F, Collins JL, et al. A genetic animal model of human neocortical heterotopia associated with seizures. J. Neurosci 17:6236–42. 1997
46.Letts VA, Felix R, Biddlecome GH, et al. The mouse stargazer gene encodes a neuronal Ca21 channel gamma subunit. Nat Gen 19:340 –7. 1998
47.Liang, L.P., Ho, Y.S and Patel, M. Mitochondrial superoxide production in kainite-induced hippocampal damage. Neuroscience. 101: 563-570. 2000
48.Lipicky RJ, Gilbert DL, Stillman IM.Diphenylhydantoin inhibition of sodium conductance in squid giant axon. Proc Natl Acad Sci USA 69: 1758–60. 1972
49.Lombardo AJ, Kuzniecky R, Powers RE, Brown GB. Altered brain sodium channel transcript levels in human epilepsy. Mol Brain Res 35: 84–90. 1996
50.Marin J, Encabo A, Briones A, Garcia-Cohen EC, Alonso MJ. Mechanisms involved in the cellular calcium homeostasis in vascular smooth muscle: calcium pumps. Life Sci. 64: 279–303. 1999
51.Marklund S, Marklund. GInvolvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Eur J Biochem. 47(3):469-474.1974
52.Matsumoto H, Ajmone-Marsan C. Cortical cellular phenomena in experimental epilepsy. Interictal manifestations. Exp Neurol 9: 286–304. 1964
53.Minta A, Kao JP, Tsien RY. Fluorescent indicators for cytosolic calcium based on rhodamine and fluorescein chromophores. J Bio Chem 264: 8171-8178. 1989
54.Morrell F, Whisler WW, Hoeppner TH, et al. Electrophysiology of heterotopic gray matter in “double cortex syndrome. Epilepsia 33:76. 1992
55.Moshé SL, Albala BJ. Kindling in developing rats: persistence of seizures into adulthood. Brain Res. 256:67-71. 1982
56.Nadler JV, Perry BW, Cotman CW: Intraventricular kainic acid preferentially destroys hippocampal pyramidal cells. Nature 271:676-677. 1978
57.Nadler JV. kainic acid as a tool for the study of temporal lobe epilepsy. Life Sciences 29:2031-2042. 1981
58.Nakayama J, Hamano K, Iwaski N, et al. Significant evidence for linkage of febrile seizures to chromosome 5q14–q15. Hum Mol Genet 9:87–91. 2000
59.Naritoku DK, Mecozzi LB, Aiello MT, Faingold CL. Repetition of audiogenic seizures in genetically epilepsy-prone rats induces cortical epileptiform activity and additional seizure behaviors. Exp Neurol 115:317–24. 1992
60.Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 95:351–8. 1979
61.Olney JW, Fuller T, De Gubareff T: Acute dendrotoxic changes in the hippocampus of kainate treated rats. Brain Res 176:91-100, 1979
62.Olney JW, Rhee V, Lan Ho.Kainic acid: a powerful neurotoxic analogue of glutamate. Brain Res 77:507-512. 1974
63.Paglia DE, Valentine WN.Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase.J Lab Clin 70(1):158-169.1967
64.Phillips HA, Scheffer IE, Berkovic SF, Hollway GE, Sutherland GR, Mulley JC. Localization of a gene for autosomal dominant nocturnal frontal lobe epilepsy to chromosome 20q13.2. Nat Genet 10: 117–18. 1995
65.Pohlmann-Eden B, Gass A, Peters CN, Wennberg R, Blumcke I. Evolution of MRI changes and development of bilateral hippocampal sclerosis during long lasting generalised status epilepticus. J Neurol Neurosurg Psychiatry. 75(6):898-900. 2004
66.Rizzuto R, Bernardi P, Pozzan T. Mitochondria as all-round players of the calcium game. J. Physiol. 529 : 37–47. 2000
67.Rottenberg H, Wu SL. Quantitative assay by flow cytometry mitochondrial membrane potential in intact cells. Biochim Biophys Acta 1404: 393-404. 1998
68.Schon EA. Mitochondria. In: DiMauro, S., Wallace, D.C. (Eds.),242, 1427–1430. Mitochondrial DNA in Human Pathology. Raven Press, New York, pp.1–7. 1993.
69.Schuchmann S, Buchheim.K, Meierkord H, Heinemann U. A relati energe failure is associated with low Mg+2 but not with 4-amoinopridine induced seizure-like events in entorhinal cortex. J. Neurophysio. 81,:399-402.1999
70.Seidenberg M, Beck N, Geisser M, Giordani B, Sackellares JC, Berent S, Dreifuss FE, Boll TJ Academic achievement of children with epilepsy. Epilepsia. 27(6):753-9. 1986
71.Sian J, Dexter D T, Lees A J, Daniel S, Agid Y, Javoy-Agid F. Alterations in glutathione levels in Parkinson’s disease and other neurodegenerative disorders affecting basal ganglia. Annals of Neurology 36: 348-355. 1994
72.Sies H, Stahl W, Sundquist AR. Antioxidant functions of vitamines. Vitamins E and C, beta-carotene, and other carotenoids. Annals of the New York Acaderny of sciences 669:7-20. 1992
73.Singh R and Pathak DN. Lipid peroxidation and glutathione reductase, superoxide dismutase, catalase, and glucose-6-phosphate dehydrogenase activities in FeCl3 –induced epileptogenic foci in the rat brain. Epilepsia 31: 15-26.1990
74.Siow RCM, Aato H, Mann G E. Heme oxygenase-carbon monoxide signalling pathway in atherosclerosis: anti-atherogenic actions of bilirubin and carbon monoxide? Cardiovasc. Res. 41: 385-394. 1999
75.Sperk G, Lassmann H, Baran H, et al: Kainic acid induced seizures: Neurochemical and histopathological changes. Neuroscience 10:1301-1315, 1983
76.Straub H, Köhling R, Frieler A, Grigat M, Speckmann EJ. Contribution of L-type calcium channel to epileptiform activity in hippocampal and neocortical slices of guinea-pigs. Neuroscience 95: 63–72. 2000
77.Sutula T, He XX, Cavazos J, Scott G. Synaptic reorganization in the hippocampus induced by abnormal functional activity. Science 239: 1147–50. 1988
78.Takahashi K, Calpain substrate specifity. In: Melgren, R.L., Gunter, T.E., Buntinas, L., Sparagna, G.C., Gunter, K.K., 1998. The Ca2+ transport mechanisms of mitochondria and Ca2+ uptake from physiological -type Ca2+ transients. Biochim. Biophys. Acta 1366: 5–15. 1990
79.Tanaka T, Kaijima M, Daita G, et al: Electroclinical features of kainic acid-induced status epilepticus in freely moving cats. Microinjection into the dorsal hippocampus. Electroenceph clin Neurophysiol 54:288-300, 1982
80.Toth Z, Yan X-X, Haftoglou S, Ribak CE, Baram TZ. Seizureinduced neuronal injury: vulnerability to febrile seizures in an immature rat model. J Neurosci 18:4285–94. 1998
81.Turski WA, Cavalheiro EA, Schwarz M, Czuczwar SJ, Kleinrok Z, Turski L. Limbic seizures produced by pilocarpine in rats: behavioural, electroencephalographic and neuropathological study. Behav. Brain Res. 9: 315-335. 1983
82.Van den Pol AN, Obrietan K, Belousov A. Glutamate hyperexcitability and seizure-like activity throughout the brain and spinal cod upon relief from chronic glutamate receptor blockade in culture. Neuroscience. 74: 653-674. 1996
83.Wallace RH, Scheffer IE, Barnett S, et al. Neuronal sodium-channel a1-subunit mutations in generalized epilepsy with febrile seizures plus. Am J Hum Genet 68:859–65. 2001
84.Wallace RH, Wang DW, Singh R, et al. Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel 1 subunit gene SCN1B. Nat Genet 19: 366–70. 1998
85.Walsh CA. Genetic malformations of the human cerebral cortex. Neuron 23:19 –29. 1999
86.Wieshmann UC, Woermann FG, Lemieux L, Free SL, Bartlett PA, Smith SJ, Duncan JS, Stevens JM, Shorvon SD. Development of hippocampal atrophy: a serial magnetic resonance imaging study in a patient who developed epilepsy after generalized status epilepticus. Epilepsia. 38:1238-41. 1997
87.Wilson WD, Wang YH, Krishnamoorthy CR, Smith JC. Intercalators as probes of DNA conformation: propidium binding to alternating and non-alternating polymers containing guanine. Chemico-Biol Interactions 58: 41-56. 1986

第二部分
1.Alberdi E, Sánchez-Gómez MV, Torre I, Domercq M, Pérez-Samartín A, Pérez-Cerdá F, Matute C. Activation of kainate receptors sensitizes oligodendrocytes to complement attack. J Neurosci.26(12):3220-8. 2006
2.Ames BN, Shigenaga MK, Hagen TM. Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci 90:7915–7922. 1993
3.Ankarcrona M, Dypbukt JM, Bonfoco E, et al. Glutamateinduced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function. Neuron 15: 961–973. 1995
4.Armstrong JN, Plumier JC, Robertson HA, Currie RW. The inducible 70,000 molecular/weight heat shock protein is expressed in the degenerating dentate hilus and piriform cortex after systemic administration of kainic acid in the rat. Neuroscience 74:685–693. 1996
5.Ashwood, T.J., Lancaster, B. and Wheal, H.V., lntracellular electrophysiology of CA1 pyramidal neurones in slices of the kainic acid lesioned hippocampus. Exp Brain Res. 62:189-198. 1986
6.Bala’zs R, Jorgensen OS, Hack N. NMDA promotes the survival of cerebellar granule cells in culture. Neuroscience 27: 437–451. 1988
7.Beal, M. F. Mitochondria take center stage in aging and neurodegeneration. Ann. Neurol. 58: 495–505. 2005
8.Berdichevsky E, Muñoz C, Riveros N, Cartier L, Orrego F. Neuropathological changes in the rat brain cortex in vitro: effects of kainic acid and of ion substitutions. Brain Res. 423:213-20. 1987
9.Brewer GJ, Cotman CW. NMDA receptor regulation of neuronal morphology in cultured hippocampal neurons. Neurosci Lett 99:268-273. 1989
10.Bromme HJ and Holtz J: Apoptosis in the heart: when and why? Mol Cell Biochem 164: 261-275, 1996
11.Burnashev N, Monyer H, Seeburg PH, Sakmann B. Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit. Neuron 8: 189-198. 1992
12.Choi DW. Calcium: still center-stage in hypoxic-ischemic neuronal death. Trends Neurosci 18:58–60. 1995
13.Choi DW, Maulucci-Gedde M, Kriegstein AR. Glutamate neurotoxicity in cortical cell cultures. J Neurosci 7:357-368. 1987
14.Choi DW. Calcium-mediated neurotoxicity: relationship to specific channel t ypes and role in ischemic damage. Trends Neurosci 11:465–469. 1988
15.Choi DW. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634. 1988
16.Clavien PA, Rudiger HA, Selzner M. Mechanism of hepatocyte death after ischemia: apoptosis versus necrosis. Int J Oncol 17: 869-879. 2000
17.Collins RJ, Harmon BV, Gobe´ GC, Kerr JF. Internucleosomal DNA cleavage should not be the sole criterion for identifying apoptosis. Int J Radiat Biol 61:451–453. 1992
18.Coyle JT, Puttfarcken P. Oxidative stress, glutamate and neurodegenerative disorders. Science 262:689–694. 1993
19.Darnay BG and Aggarwal BB. Early events in TNF signaling:a story of associations and dissociations. J Leukoc Biol 61: 559-566. 1997
20.Demand J, Alberti S, Patterson C, Höhfeld J. Cooperation of a ubiquitin domain protein and an E3 ubiquitin ligase during chaperone/proteasome coupling. Curr Biol 11:1569–1577. 2001
21.Ditcher M. and Ayala G. Cellular mechanisms of epilepsy: a status report. Science 237 :157-164. (1987)
22.Dong Z, Saikumar P, Weinberg JM Venkatachalam MA. Internucleosomal DNA cleavage triggered by plasma membrane damage during necrotic cell death. Involvement of serine but not cysteine proteases. Am J Path 151:1205–1213. 1997
23.Eguchi Y, Shimizu S, Tsujimoto Y. Intracellular ATP levels determine cell death fate by apoptosis or necrosis. Cancer Res 57:1835–1840. 1997
24.Eiserich JP, Hristova M, Cross CE, Jones AD, Freeman BA,Halliwell B van der Vliet A. Formation of nitric oxidederived inflammatory oxidants by myeloperoxidase in neutrophils.Nature 391: 393-397. 1998
25.Formigli L, Papucci L, Tani A, Schiavone N, Tempestini A, Orlandini GE, Capaccioli S, Orlandini SZ. Aponecrosis: morphological and biochemical exploration of a syncretic process of cell death sharing apoptosis and necrosis. J Cell Physiol 182:41–49. 2000
26.Geiger JRP, Melcher T, Koh D-S, Sakmann B, Seeburg PH, Jonas P, Monyer H. Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA recepors in principal neurons and interneurons in rat CNS. Neuron 15: 193–204. 1995
27.Gerner C, Frohwein U, Gotzmann J, Bayer E, Gelbmann D, Bursch W, Schulte-Hermann R. The fas-induced apoptosis analyzed by high throughput proteome analysis. J Biol Chem 275:39018–39026. 2000
28.Hara MR , Snyder SH.Cell signaling and neuronal death. Annu Rev Pharmacol Toxicol 47:117–141. 2007
29.Hernández-Fonseca K, Cárdenas-Rodríguez N, Pedraza-Chaverri J, Massieu L. Calcium-dependent production of reactive oxygen species is involved in neuronal damage induced during glycolysis inhibition in cultured hippocampal neurons. J Neurosci Res 86:1768–1780. 2008
30.Heyninck K and Beyaert R. Crosstalk between NF-kappaBactivating and apoptosis-inducing proteins of the TNF-receptor complex. Mol Cell Biol Res Commun 4: 259-265, 2001
31.Hollmann M, Heinemann S. Cloned glutamate receptors. Annu Rev Neurosci 17:31–108. 1994
32.Hyun D-H, Lee M, Hattori N, Kubo S-I, Mizuno Y, Halliwell B, Jenner P. Effect of wild-type or mutant parkin on oxidative damage, nitric oxide, antioxidant defenses and the proteasome. J Biol Chem277:28572–28577. 2002
33.Ireland CM, Pittman SM. Tubulin alterations in taxol-induced apoptosis parallel those observed with other drugs. Biochem Pharmacol 49:1491–1499. 1995
34.Jäättelä M. Overexpression of major heat shock protein 70 inhibits tumour necrosis factor-induced activation of phospholipase A2. J Immunol 151:4286–4296. 1993
35.Jakobsen B, Zimmer J Modulation of AMPA excitotoxicity in hippocampal slice cultures. NeuroReport 16: 3593–7. 2001
36.Jenner P. Oxidative stress in Parkinson's disease. Ann Neurol 53 :S26–S36. 2003
37.Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory sharesimilar mechanisms? Trends Neurosci26(12): 696-705. 2003
38.Jiang X and Wang X Cytochrome c-mediated apoptosis. Annu Rev Biochem 73:87–106. 2004
39.Kalb RG. Regulation of motor neuron dendrite growth by NMDA receptor activation. Development 120:3063–3071. 1994
40.Komuro H, Rakic P. Modulation of neuronal migration by NMDA receptors. Science 260:95–97. 1993
41.Lee JM, Grabb MC, Zipfel GJ, Choi DW. Brain tissue responses to ischemia. J Clin Invest 106:723-731. 2000
42.Lucas D. R. and Newhouse J. P. The toxic effect of sodium L-glutamate on the inner layers of the retina. Arch. Ophthalmol. 58: 133–201. 1957
43.Marı´a Victoria Sa´nchez-Go´mez, Elena Alberdi, Gaskon Ibarretxe, Iratxe Torre, and Carlos Matute Caspase-Dependent and Caspase-Independent Oligodendrocyte Death Mediated by AMPA and Kainate Receptors The Journal of Neuroscience. 23:9519 –9528. 2003•
44.Martín-Romero FJ, Ortíz-de-Galisteo JR, Lara-Laranjeira J, Domínguez-Arroyo JA, González-Carrera E, Alvarez IS. Store-operated calcium entry in human oocytes and sensitivity to oxidative stress. Biol Reprod78:307–315. 2008
45.Maru E, Kanda M, Ashida H. Functional and morphological changes in the hippocampal neuronal circuits associated with epileptic seizures. Epilepsia. 43 Suppl 9: 44-9. 2002
46.McCaslin, Smith TG Quisqualate, high calcium concentration and zero chloride prevent kainate-induced toxicity of cerebellar granule cells. Eur J Pharmacol 152: 341–346. 1988
47.Milatovic D, Gupta RC, Dettbarn WD. Involvement of nitric oxide in kainic acid-induced excitotoxicity in rat brain. Brain Res. 957(2): 330-7. 2002
48.Milatovic D, Zivin M, Gupta RC, Dettbarn WD. Alterations in cytochrome c oxidase activity and energy metabolites in response to kainic acid-induced status epilepticus. Brain Res. 912(1): 67-78. 2001
49.Miller E. Apoptosis measurement by annexin v staining. Methods Mol Med 88:191–202. 2004
50.Minta A, Kao JP, Tsien RY. Fluorescent indicators for cytosolic calcium based on rhodamine and fluorescein chromophores. J Bio Chem 264: 8171-8178, 1989
51.Moloney MG. Excitatory amino acids. Nat. Pro. Rep.15:205-219. 1998
52.Mori, H. and Mishina, M. Neurotransmitter receptors VIII, structure and function of the NMDA receptor channel. Neuropharmacology. 34:1219-1237. 1995
53.Murphy BM, Engel T, Paucard A, Hatazaki S, Mouri G, Tanaka K, Tuffy LP, Jimenez-Mateos EM, Woods I, Dunleavy M, Bonner HP, Meller R, Simon RP, Strasser A, Prehn JH, Henshall DC. Contrasting patterns of Bim induction and neuroprotection in Bim-deficient mice between hippocampus and neocortex after status epilepticus. Cell Death Differ. 17(3):459-68. 2010
54.Nagahara N, Katayama A. Post-translational regulation of mercaptopyruvate sulfurtransferase via a low redox potential cysteine-sulfenate in the maintenance of redox homeostasis. J Biol Chem 280:34569–34576. 2005
55.Nuijtinck RRH, Baker RE, Ter Gast E, Struik ML, Mud MT. Glutamate dependent dendritic outgrowth in developing neuronal networks of rat hippocampal cells in vitro. Int J Dev Neurosci 15:55–60. 1997
56.Olney JW, Wozniak DF, Farber NB. Excitotoxic neurodegeneration in Alzheimer disease. New hypothesis and new therapeutic strategies. Arch Neurol 54:1234–1240. 1997
57.Olney JW. Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science164:719–721. 1969
58.Parks TN, Artman LD, Alasti N, Nemeth EF. Modulation of N-methyl-D-aspartate receptor-mediated increase in cytosolic calcium in cultured rat cerebellar granule cells. Brain research 552:13–22. 1991
59.Patel MN. Oxidative stress, mitochondrial dysfunction, and epilepsy. Free Radic Res. 36(11): 1139-46. 2002
60.Pellegrini F, Budman DR. Review: tubulin function, action of antitubulin d rugs, and new drug development. Cancer Invest 23:264–273. 2005
61.Phelps, S., Mitchell, J. and Wheal, H., Changes to synaptic ultrastructure in field CA1 of the rat hippocampus following intracerebroventricular injection of kainic acid, Neuroscience, 40 :687-699.1991
62.Platt SR. The role of glutamate in central nervous system health and disease--a review. Vet. J. 173 (2): 278–86. 2007
63.Rajdev S, Sharp FR. Stress proteins as molecular markers of neurotoxicity. Toxicol. Pathol 28:105–112. 2000
64.Robinson BH, MacMillan H, Petrova-Benedict R, Sherwood WG. Variable clinical presentation in patients with defective E1 component of pyruvate dehydrogenase complex. J Pediatr111:525–553. 1987
65.Robinson MB, Coyle JT. Glutamate and related acidic excitatory neurotransmitters: from basic science to clinical application. Faseb J 1:446–455. 1987
66.Rossi DJ, Oshima T, Attwell D. Glutamate release in severe brain ischaemia is mainly by reversed uptake. Nature 403:316-321. 2000
67.Rothman SM, Olney JW. Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann Neurol 19:105–111. 1986
68.Rottenberg H, Wu SL. Quantitative assay by flow cytometry mitochondrial membrane potential in intact cells. Biochim Biophys Acta 1404: 393-404. 1998
69.Routbort MJ, Bausch SB, McNamara JO.Seizures, cell death a nd mossy fiber sprouting in kainic acid-treated organotypic hippocampal cultures. Neuroscience 94:755-765. 1999
70.S.G. Carriedo, S.L. Sensi, H.Z. Yin, J.H. Weiss AMPA exposures induce mitochondrial Ca2+ overload and ROS generation in spinal motor neurons in vitro J. Neurosci. 20: 240–250.2000
71.Schinder AF, Olson EC, Spitzer NC, Montal M. Mitochondrial dysfunction is a primary event in glutamate neurotoxicity. J Neurosci 16:6125–6133. 1996
72.Shih YH, Wu SL, Chiou WF, Ku HH, Ko TL, Fu YS. Protective effects of tetramethylpyrazine on kainate-induced excitotoxicity in hippocampal culture. Neuroreport 13:515–519. 2002
73.Skulachev VP. Mitochondria in the programmed death phenomena; a principle of biology: it is better to die than to be wrong IUBMB Life 49:365–373. 2000
74.Strater J and Moller P: Expression and function of death receptors and their natural ligands in the intestine. Ann NY Acad Sci 915: 162-170, 2000
75.Strauss KI, Marini AM. Cyclooxygenase-2 inhibition protects cultured cerebellar granule neurons from glutamate-mediated cell death. J Neurotrauma.19(5):627-38. 2002
76.Tanaka S, K Sako T Tanaka, I Nishihara,Y Yonemasu. Uncoupling of local blood flow and metabolism in the hippocampal CA3 in kainic acid-induced limbic seizure status. Neurosci. 36: 339-348. 1990
77.Tanaka, T., S. Tanaka, T. Fujita, K. Takano, H. Fukkuda, K. Sako, and Y. Yonemasu. Experimental complex partial seizures induced by a microinjection of kainic acid into limbic structures. Prog. Neurobiol. 38: 317-334. 1992
78.Tang L, Reiter R, Li Z, Ortiz GG, Yu BP, Garcia J.J. Melatonin reduces the increase in 8-hydroxy-deoxyguanosine levels in the brain and liver of kainic acidtreated rats. Mol. Cell. Biochem. 178: 299–303. 1998
79.Tremblay, E., L. Nitecka, M. L. Berger, and Y. Ben-Ari. Maturation of kainic acid seizure-brain damage syndrome in the rat. I. Clinical, electrographic and metabolic observations. Neuroscience. 13: 1051-1072. 1984
80.Trump BF, Berezesky IK, Chang SH and Phelps PC: The pathways of cell death: oncosis, apoptosis, and necrosis. Toxicol Pathol 25: 82-88. 1997
81.Tymianski M. Cytosolic calcium concentrations and cell death in vitro, in: B.K. Siesjo, T. Wieloch (ed) Advances in Neurology:Cellular and Molecular Mechanisms of Ischemic Brain DamageLippincott-Raven, Philadelphia pp 85–105. 1996
82.Van Reyk DM, King NJC, Dinaure MC, Hunt NH. The intracellular oxidation of 2’7’-dichlorofluorescin in murine T lymphocytes. Free Radic Biol Med 30: 82-88. 2001
83.Vaupel P and Hockel M: Blood supply, oxygenation status and metabolic micromilieu of breast cancers: characterization and therapeutic relevance. Hepatology 33: 1555-1557. 2001
84.Vrooman L, Jhamandas K, Boegman RJ, Beninger RJ. Picolinic acid modulates kainic acid-evoked glutamate release from the striatum in vitro. Brain Res. 627(2):193-8. 1993
85.Wang HG, Pathan N, Ethell IM, Krajewski S, Yamaguchi Y, Shibasaki F, McKeon F, Bobo T, Franke TF, and Reed JC Ca2-induced apoptosis through calcineurin dephosphorylation of BAD. Science 284:339–343. 1999
86.Watkins JC. L-glutamate as a central neurotransmitter: Looking back. Biochem Soc T 28:297–310. 2000
87.White RJ, Reynolds IJ. Mitochondrial depolarization in glutamate-stimulated neurons: an early signal specific to excitotoxin exposure. J Neurosci 16:5688-5697. 1996
88.Wilson MT, Keith CH. Glutamate modulation of dendrite outgrowth: alterations in the distribution of dendritic microtubules. J Neurosci Res 52:599-611. 1998
89.Wilson WD, Wang YH, Krishnamoorthy CR, Smith JC. Intercalators as probes of DNA conformation: propidium binding to alternating and non-alternating polymers containing guanine. Chemico-Biol Interactions 58: 41-56. 1986
90.Yamamoto HA, Mohanan PV. Ganglioside GT1B and melatonin inhibit brain mitochondrial DNA damage and seizures induced by kainic acid in mice. Brain Res. 964:100-6. 2003
91.Zhu X, Raina AK, Lee HG, Casadesus G, Smith MA, Perry G. Oxidative stress signalling in Alzheimer's disease. Brain Res 1000:32–39. 2004

第三部分
1.Arpino C, Brescianini S, Robert E, et al. Tetatogenic effects of antiepileptic drugs: use of an International Database on Malformations and Drug Exposure (MADRE). Epilepsia 41:1436-43. 2000
2.Asmis R, Wang Y, Xu L, Kisgati M, Begley JG, Mieyal JJ. A novel thiol oxidation-based mechanism for adriamycin-induced cell injury in human macrophages. FASEB J 19: 1866–1868. 2005
3.Bramswing S, Kerksiek A, Sudhop T, Luers C, Bergman KV,Berthold HK. Carbamazepine increases atherogenic lipoproteins:mechanism of action in male adults. Heart Circ Physiol 282:704-16. 2002
4.Cai BZ, Gong DM, Liu Y, Pan ZW, Xu CQ, Bai YL, Qiao GF, Lu YJ, Yang BF. Hmocysteine inhibits potassium channels in human atrial myocytes. Clin Exp Pharmacol Physiol 34: 851-855. 2007
5.Chang SJ, Lee YC, Liu SY, Chang TW. Chinese yam (Dioscorea alata cv. Tainung No. 2) feeding exhibited antioxidative effects in hyperhomocysteinemia rats. Journal of Agricultural and Food Chemistry 52:1720-1725. 2004
6.Clarke R. Homocysteine and cardiovascular disease. Overview. J Cardiovasc Risk. 5(4):213-215. 1998
7.Crawley HF, While D. The diet and body weight of British teenage smokers at 16-17 years. Eur J Clin Nutr. 49:904-914. 1995
8.De Franchis R, Sperandeo MP, Sebastio G, Andria G. Clinical aspects of cystathionine ¯-synthase: How wide is the spectrum? Eur. J. Pediatr. 157(Suppl. 2):S67–S70. 1998
9.De Lorgeril M, Salen P. Selenium and antioxidant defenses as major mediators in the development of chronic heart failure. Heart Fail Rev. 11:13–17. 2006
10.Durand P, Lussier-Cacan S, Blache D. Acute methionine load-induced hyperhomocysteinemia enhances platelet aggregation, thromboxane biosynthesis, and macrophage-derived tissue factor activity in rats. FASEB. 11: 1157-1168. 1997
11.Dutta S, Chatterjee A, Sinha S, Chattopadhyay A, Mukhopadhyay K. Correlation between cystathionine beta synthase gene polymorphisms, plasma homocysteine and idiopathic mental retardation in Indian individuals from Kolkata. Neurosci Lett. 453(3):214-8. 2009
12.Farombi, E.O., Nwankwo, J.O., Emerole, G.O. Modulation of carbon tetrachloride-induced lipid peroxidation and xenobiotic-metabolizing enzymes in rats fed browned yam flour diet. The African Journal of Medical Sciences 29:127-132. 2000
13.Fowler, B. Disorders of homocysteine metabolism. J. Inher. Metab. Dis. 20:270–285. 1997
14.Gao J, Xue A. Study on the oxidative injury of ECV304 cell induced by homocysteine. Wei Sheng Yan Jiu 32: 20–21. 2003
15.Gorgone G, Caccamo D, Pisani LR, Curro` M, Parisi G, Oteri G, et al. Hyperhomocysteinemia in patients with epilepsy: Does it play a role in the pathogenesis of brain atrophy? A preliminary report. Epilepsia, 50(Suppl 1):33–36. 2009
16.Halliwell, B. Free radicals, proteins and DNA: Oxidative damage versus redox regulation. Biochem. Soc.Trans. 24:1023–1027. 1996
17.Halliwell, B., and Gutteridge, J.M.C. Oxygen radicals and nervous system. Trends Neurosci. 8:22–26. 1985
18.Ho PI, Ortiz D, Rogers E, Shea TB. Multiple aspects of homocysteine neurotoxicity: glutamate excitotoxicity, kinase hyperactivation and DNA damage. J Neurosci Res. 70(5):694-702. 2002
19.Hogg N. The effect of cyst(e)ine on the auto-oxidation of homocysteine. Free Rad. Biol. Med. 27:28–33.1999
20.Honer WG, Beach TG, Hu L, Berry K, Dorovini-Zis K, Moore G R. et al. Hippocampal synaptic pathology in patients with temporal lobe epilepsy. Acta Neuropathologica, 87: 202-210. 1994
21.Hota SK, Barhwal K, Singh SB, Ilavazhagan G. Differential temporal response of hippocampus, cortex and cerebellum to hypobaric hypoxia: a biochemical approach. Neurochemistry International 51: 384-390. 2007
22.Jakubowski H. Molecular basis of homocysteine toxicity in humans. Cell Mol Life Sci 61:470-487. 2004
23.Karolczak K, Olas B. Mechanism action of homocysteine and its thiolactone in haemostasis system. Physiol Res 58:623-633. 2009
24.Kilic G, Sciancalepore M, Cherubini E. Single-channel currents of NMDA type activated by L- and D-homocysteic acid in cerebellar granule cells in culture. Neurosci Lett. 141:231-235. 1992
25.KimWK, and Pae YS. Involvement of N-methyl-D-aspartate receptor and free radical in homocysteinemediated toxicity on rat cerebellar granule cells in culture. Neurosci Lett. 216:117–120. 1996
26.Kraus JP. Biochemistry and molecular genetics of cystathionine -synthase deficiency. Eur. J. Pediatr. 157(Suppl. 2):S50–S53. 1998
27.Kruman II, Kumaravel TS, Lohani A, Pedersen WA, Cutler RG, Kruman Y, Haughey N, Lee J, Evans M, Mattson MP.Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease. J Neurosci. 22(5):1752-62. 2002
28.Kruman II., Culmsee C, Chan SL, Kruman Y, Guo Z, Penix L, and Mattson MP. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci. 20: 6920–6926. 2000
29.Lee ME, Wang H. Homocysteine and hypomethylation: a novel link to vascular disease. Trends Cardiovasc Med. 9: 49-54. 1999
30.Leret ML, San Millán JA, Fabre E, Gredilla R, Barja G. Deprenyl protects from MPTP-induced Parkinson-like syndrome and glutathione oxidation in rat striatum. Toxicology 170:165-171. 2002
31.Levrand S, Pacher P, Pesse B, Rolli J, Feihl F, Waeber B, Liaudet L. Homocysteine induces cell death in H9C2 cardiomyocytes through the generation of peroxynitrite. Biochem Biophys Res Commun 359: 445–450. 2007
32.Li S, Li X, Rozanski GJ. 2003. Regulation of glutathione in cardiac myocytes. J Mol Cell Cardiol 35: 1145–1152.
33.Liao JK, Shin WS, LeeWY, Clark SL. Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem. 270:319-324. 1995
34.Lipton SA, Kim WK, Choi YB, Kumar S, D'Emilia DM, Rayudu PV, Arnelle DR, Stamler JS. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci USA. 94(11):5923-5928. 1997
35.Lipton S A, Kim WK, Choi YB, Kumar S, D'Emilia DM, Rayudu PV, Arnelle DR, Stamler JS. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci. 94: 5923-5928. 1997
36.Loring DW, Meador KJ. Cognitive side effects of antiepileptic drugs in children. Neurology 62:872-7. 2004
37.Marangos PJ, Loftus T, Wiesner J, Lowe T, Rossi E, Browne CE, et al. Adenosinergic modulation of homocysteineinduced seizures in mice. Epilepsia, 31: 239–246. 1990
38.Mares P, Folbergrova, J, Langmeier M, Haugvicova´ R, Kubova´ H. Convulsant action of D, L-homocysteic acid and its stereoisomers in immature rats. Epilepsia. 38:767-776. 1997
39.Mathern GW, Kuhlman PA, Mendoza D, Pretorius JK. Human fascia dentata anatomy and hippocampal neuron densities differ depending on the epileptic syndrome and age at first seizure. J Neuropathology and Experimental Neurology. 56:199-212. 1997
40.Mosharov E, Cranford MR, Banerjee R. 2000. The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes. Biochemistry 39: 13005–13011.
41.Mudd S H, Skovby F, Levy HL, Pettigrew KD, Wilcken B, Pyeritz RE, et al. The natural history of homocystinuria due to cystathionine beta-synthase deficiency. American Journal of Human Genetics. 37: 1–31. 1985
42.Musavi S, Kakkar P. Effect of diazepam treatment and its withdrawal on pro/antioxidative processes in rat brain. Molecular and Cellular Biochemistry 245: 51-56. 2003
43.Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Analytical Biochemistry. 95: 351-358. 1979
44.Parnetti L, Bottiglieri T, Lowenthal D. Role of homocysteine in age-related vascular and non-vascular diseases. Aging. 9(4):241-57. 1997
45.Pei TX, Xu CQ, Li B, Zhang ZR, Gao XX, Yu J, Li HZ, Yang BF. Protective effect of quercetin against adriamycin-induced cardiotoxicity and its mechanism in mice. Yao Xue Xue Bao 42:1029–1033. 2007
46.Perez-de-Arce K, Foncea R, Leighton F. Reactive oxygen species mediates homocysteine-induced mitochondrial biogenesis in human endothelial cells: modulation by antioxidants. Biochem Biophys Res Commun 338:1103–1109. 2005
47.Perla-Kajan J, Twardowski T, Jakubowski H. Mechanisms of homocysteine toxicity in humans. Amino Acids 32:561–572. 2007
48.Perna AF, Ingrosso D, Satta E, Romano M, Cimmino A, Galletti P, Zappia V, De Santo NG. Metabolic consequences of hyperhomocysteinemia in uremia. Am J Kidney Dis. 38: S85-S90. 2001.
49.Rajeswari A. Curcumin protects mouse brain from oxidative stress caused by 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine. European Review for Medical and Pharmacological Sciences 10:157-161. 2006
50.Raposo B, Rodriguez C, Martinez–Gonzales J, Badimon L. Highlevels of homocysteine inhibit lysyl oxidase (LOX) and downregulateLOX expression in vascular endothelial cells. Atheroscl 177: 1–8. 2004
51.Ravaglia G, Forti P, Maioli F, Scali RC, Saccheitti L, Talerico T, Mantovani V, Bianchin M. Homocysteine and cognitive performance in healthy elderly subjects. Arch Gerontol Geriatr (9):349-57. 2004
52.Reznick AZ, and Packer L. In (G. Poli, E. Albano, and M.U. Dianzani, eds.), Free radicals: From Basic Science to Medicine, Birkh¨auser, Basel, pp. 425–437. 1993
53.Rosenquist TH, Ratashak SA, Selhub J. Homocysteine induces congenital defects of the heart and neural tube: effect of folic acid. Proc Natl Acad Sci. 93:15227–15232. 1996
54.SantaCruz KS, Yazlovitskaya E, Collins J, Johnson J, DeCarli C. Regional NAD(P)H:quinone oxidoreductase activity in Alzheimer’s disease. Neurobiology of Aging 25: 63-69. 2004
55.Schneider JA, Tangney CC, Morris MC. Folic acid and cognition in older persons. Expert Opinion on Drug Safety 5: 511-512. 2006
56.Schwaninger M, Ringleb P, Winter R, Kohl B, Fiehn W, Rieser P A, et al. Elevated plasma concentrations of homocysteine in antiepileptic drug treatment. Epilepsia. 40: 345–350. 1999.
57.Selhub J, Bagley LC, Miller J, Rosenberg IH. B vitamins, homocysteine, and neurocognitivte function in the elderly. Am J Clin Nutr. 71: 614S-620S. 2000
58.Sly, and D. Valle, eds. The Metabolic and Molecular Bases of Inherited Disease. 8th edn., McGraw-Hill, New York, pp. 1279–1327.
59.Tanaka K, Yoshioka M, Miyazaki I, Fujita N, Ogawa N. GPI1046 prevents dopaminergic dysfunction by activating glutathione system in the mouse striatum. Neuroscience Letters 321: 45-48. 2002
60.Tchantchou F, Graves M, Ortiz D, Rogers E, Shea TB. Dietary supplementation with 3-deaza adenosine, Nacetyl cysteine, and S-adenosyl methionine provide neuroprotection against multiple consequences of vitamin deficiency and oxidative challenge: relevance to age-related neurodegeneration. Neuromolecular Medicine 6:93-103. 2004
61.Thomas B, Saravananm KS, Mohanakumar KP. In vitro and in vivo evidences that antioxidant action contributes to the neuroprotective effects of the neuronal nitric oxide synthase and monoamine oxidase-B inhibitor, 7-nitroindazole. Neurochemistry International 52: 990-1001. 2008
62.Troen AM. The central nervous system in animal modelsofhyperhomocysteinemia. Prog Neuropsychopharmacol Biol Psychiatry29:1140-1151. 2005
63.Trolin CG, Löfberg C, Trolin G, Oreland L. Brain ATP:L-methionine S-adenosyltransferase (MAT), Sadenosylmethionine (SAM) and S-adenosylhomocysteine (SAH): regional distribution and age-related changes. European Neuropsychopharmacology 4: 469-477. 1994
64.Ventura P, Panini R, Verlato C, Scarpetta G, Salvioli G. Peroxidation indices and total antioxidant capacity in plasma during hyperhomocysteinemia induced by methionine oral loading. Metabolism 49(2):225-8. 2000
65.Verhoef P, Kok FJ, Kruyssen DA, Schouten EG, Witteman JC, Grobbee DE, Ueland PM, Refsum H. Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 17: 989-995. 1997
66.Verrotti A, Pascarella R, Trotta D, Giuva T, Morgese G, Chiarelli F. Hyperhomocysteinemia in children treated with sodium valproate and carbamazepine. Epilepsy Research. 41:253–257.2000
67.Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med. 338(15):1042-1050.1998
68.Welch GN, Upchurch GR, Loscalzo J. Homocysteine, oxidative stress, and vascular disease. Hosp Pract. 32:81-92. 1997
69.Whalley LJ, Starr JM, Deary I.J. Diet and dementia. The Journal of the British Menopause Society 10: 113-117. 2004
70.Yilmazer-Hanke D M, Wolf HK, Schramm J, Elger CE,Wiestler OD, Blu¨mcke I. Subregional pathology of the amygdala complex and entorhinal region in surgical specimens from patients with pharmacoresistant temporal lobe epilepsy. Journal of Neuropathology and Experimental Neurology. 59: 907-920. 2000
71.Yoshioka M, Tanaka K, Miyazaki I, Fujita N, Higashi Y, Asanuma M, Ogawa N. The dopamine agonist cabergoline provides neuroprotection by activation of the glutathione system and scavenging free radicals. Neuroscience Research 43: 259-267. 2002
72.Zhang R, Ma J, Xia M, Zhu H, Ling W. Mildhyperhomocysteinemia induced by feeding rats diets rich in methionine or deficient in folate promotes early atherosclerotic inflammatory processes. Journal of Nutrition 134: 825-830. 2004


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