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請用此 Handle URI 來引用此文件: http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/34241
完整後設資料紀錄
DC 欄位值語言
dc.contributor.advisor彭福佐
dc.contributor.authorHsiao-Ping Weien
dc.contributor.author魏小屏zh_TW
dc.date.accessioned2021-06-13T05:59:32Z-
dc.date.available2011-08-03
dc.date.copyright2006-08-03
dc.date.issued2006
dc.date.submitted2006-06-27
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dc.identifier.urihttp://tdr.lib.ntu.edu.tw/jspui/handle/123456789/34241-
dc.description.abstractKetamine 為一快速作用、非巴比妥類藥物及解離性(dissociative)之麻醉劑,主要用途為手術麻醉或短暫之診斷使用。Ketamine俗稱K仔、Special K或K等,服用低劑量會很快地產生幻覺,而服用較高劑量常會產生瀕臨死亡的經驗。其作用機轉可能是作用在中樞神經系統之蕈毒乙醯膽鹼受體(muscarinic receptor)、鴉片類受體(opioid receptor)及興奮性氨基酸類之N-methyl-D-aspartate(NMDA)受體。先前研究指出ketamine處理均會誘發成鼠腦部之神經毒性反應及細胞凋亡。近年來在老鼠腦細胞初級培養實驗亦發現,ketamine處理後其細胞凋亡途徑可能和NMDA receptor代償性增加、GSK-3及caspase 3的活化有關。研究ketamine對於腦部成長及繁殖快速老鼠是一個有利之實驗模式,然而ketamine對人類神經毒性上尚未確知。因而本實驗乃採用了人類膠母神經瘤細胞株(GBM cells)為材料,其目的在探討ketamine對GBM cells引起細胞凋亡途徑及其機轉。
本文以下列所述之研究方法來探討:(1)以MTT test,LDH 釋放,DAPI 染色,PI 染色及annexinV/PI 雙染測試ketamine之細胞毒性;(2)藉由Greiss Reaction 測量NO之釋放量;(3)藉由流式細胞儀偵測ROS;(4)以西方點墨法分析NR1(NMDA receptor subunit 1)、iNOS、TNFα、Bax、IkBα、NFkB、caspase 8、caspase 3、caspase 9、p38、ERK 及JNK之蛋白質含量;(5)對GBM 細胞處理ketamine 及共同處理JNK 抑制劑(SP600125)、ERK 抑制劑(PD98059)、p38 抑制劑 (SB203580)、IkBα抑制劑(lactacystin)、NFkB 抑制劑(PTDC)、 caspase 8 抑制劑(z-IETD-fmk)及caspase 3 抑制劑(z-DEVD-fmk)之作用來視其細胞存活率。
實驗結果顯示:LDH 釋放量無明顯變化、經DAPI 染色後發現染色質有縮濃的現象、annexin V(+)的螢光強度及細胞數目增加,由此可知,細胞死亡很可能是經由細胞凋亡所形成。另一方面,ketamine 可增加NO 及ROS 的釋放量且有時間及劑量之效應,NO 的增加是經由iNOS所導致。由西方點墨法分析結果顯示NMDA receptor 中NR1subunit 的蛋白質表現量增加,因此,ketamine 之神經毒性經由NMDA receptor 代償性增加引起細胞凋亡。而另實驗證據顯示,ketamine 可誘導IkBa衰退而活化NFkB,並伴隨TNFα、caspase 8 及caspase 3、MAP kinase 蛋白質蛋白質活化,然而對Bax 無過度表現及casepase 9 無活化現象,可知ketamine 引起細胞死亡是經外在路徑而不是經內在路徑對mitochondria所引起的細胞凋亡。另外,實驗給予IkBα,NFkB,caspase 8,caspase 3,MAP kinase 抑制劑後,確認IkBα,NFkB,caspase 8,caspase 3,MAPkinase 均有參與ketamine 誘導細胞凋亡之途徑。
本研究證實ketamine 會經由活化NMDA receptor 之NR1 subunit 而引起發炎前趨物質如NO 及ROS 之大量釋放。進一步,ketamine 亦經由活化caspase 8、 caspase 3 及MAPK 之訊息傳導路徑而導致細胞凋亡的發生。
zh_TW
dc.description.abstractKetamine is a rapid-acting, non-barbiturate and dissociative anesthetic to provide anesthesia for short diagnostic and surgical procedures. Street names for ketamine include Kit Kat, Special K, or just “K”. Psychedelic effects are produced quickly by low doses of the drug, although larger doses are frequently used in an attempt to produce “near-death” experiences. The possible mechanism of action is ketamine appears to interact with CNS muscarinic acetylcholine-receptors, opiate-receptors and one of these excitatory amino acid neurotransmitters receptors, specifically the N-methyl-D-aspartate (NMDA) receptor. Previous studies have shown that ketamine induced a neurotoxic response and apoptosis. Recent in vitro studies have shown that a compensatory upregulation of the NMDA receptor and activation of GSK-3 and caspase 3 is involved in ketamine-induced apoptosis in rat cortical neurons. The rat model used takes advantage of the period of greatest growth and proliferation of the brain in this species, however its applicability to human neurotoxicology remains problematic. Therefore, the aim of the study is to elucidate the pathway and mechanism of apoptosis following the ketamine treatment in human glioblastoma cells.
The methods used are as following: (1) Determination of cytotoxicity of ketamine with MTT test, LDH release, DAPI staining, PI staining and annexinV/PI double staining; (2) Determination of NO through the Greiss Reaction; (3) ROS is detected by flowcytometry. (4) Western blot analysis for NR1 (NMDA receptor subunit 1), iNOS, TNFα, IkBα, NFkB, caspase 8, caspase 3, caspase 9, Bax, MAP kinase; (5) We examined the cell viability of ketamine or co-incubated with JNK inhibitor (SP600125), ERK inhibitor (PD98059), p38 inhibitor (SB203580), IkBα inhibitor (lactacystin), NFkB inhibitor (PTDC), caspase 8 inhibitor (z-IETD-fmk) and caspase 3 (z-DEVD-fmk) inhibitor in human gliablastoma cells.
The first set of experiments established the validity of ketamine induced cell death is through apoptotic pathway resulted from no difference of LDH release, chromatin condensation exist after DAPI staining, fluroscent intensity and cell number increased of annexin V(+). Ketamine stimulation in that NO and ROS all increased dose and time dependently in response to ketamine stimulation and that iNOS expression accounted for the increase in NO production. Western analysis showed that neurotoxic concentrations of ketamine increased NMDA receptor subunit 1 protein levels, suggesting that ketamine-induced apoptosis is associated with a compensatory upregulation of the NMDA receptor. Other exisiting evidence also indicates that ketamine can active NFkB via the degradation of IkBα.
Moreover, TNFα, caspase 8, caspase 3 and MAP kinase activation was accompanied by the ketamine-induced apoptosis. Resulting from Bax did not overexpress and caspase 9 inactivated, the validity of ketamine induced cell death is through extrinsic apoptotic pathway without through intrinsic mitochondria pathway. In experiments, employing IkBα, NFkB, caspase 8, caspase 3, the MAP kinase inhibitor, we also confirm that they are involved.
The current study demonstrated that ketamine treatment can release in proinflammatory factors such as NO and ROS via activate NR1 subunit of NMDA receptor. Furthermore, Ketamine-induced apoptosis maybe via
activate the signal transduction pathway involving caspase 8, caspase 3 and the MAPK pathways.
en
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Previous issue date: 2006
en
dc.description.tableofcontents圖表目錄……………………………………………………………II
中文摘要……………………………………………………………V
英文摘要……………………………………………………………VIII
縮寫表………………………………………………………………X
第一章 緒論……………………………………………………………1
第二章 實驗材料與方法………………………………………………22
第三章 實驗結果………………………………………………………38
第四章 討論……………………………………………………………44
第五章 參考文獻………………………………………………………57
附圖 ……………………………………………………………………79
dc.language.isozh-TW
dc.title高劑量K他命誘導人類多型性神經膠母細胞瘤
細胞株細胞死亡之訊息傳遞途徑
zh_TW
dc.titleThe signal transduction pathways of high dose of
ketamine induced cell death in human gliablastoma
multiforme cells
en
dc.typeThesis
dc.date.schoolyear94-2
dc.description.degree碩士
dc.contributor.oralexamcommittee林國隆,呂鋒洲,郭宗禮,郭明良
dc.subject.keywordK他命,細胞凋亡,氧化壓力,有絲分裂因數活化蛋白質,zh_TW
dc.subject.keywordKetamine,apoptosis,oxidative stress,MAP kinases,en
dc.relation.page113
dc.rights.note有償授權
dc.date.accepted2006-06-27
dc.contributor.author-college醫學院zh_TW
dc.contributor.author-dept毒理學研究所zh_TW
顯示於系所單位:毒理學研究所

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