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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 郭鐘金(Chung-Chin Kuo) | |
dc.contributor.author | Yun-Chu Lin | en |
dc.contributor.author | 林芸竹 | zh_TW |
dc.date.accessioned | 2021-07-11T14:59:03Z | - |
dc.date.available | 2023-03-13 | |
dc.date.copyright | 2020-03-13 | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019-12-30 | |
dc.identifier.citation | 彭奕璇 (民國108年)。Lacosamide抑制鈉離子通道之分子機制。臺灣大學生理所碩士論文,台北市。
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(2003) ‘The position of the fourth segment of domain 4 determines status of the inactivation gate in Na+ channels’. The Journal of Neuroscience. 23:4922-4930. Zeng, Z., E.L. Hill-Yardin, D. Williams, T. O’Brien, A. Serelis & C.R. French. (2016) ‘Effect of phenytoin on sodium conductances in rat hippocampal CA1 pyramidal neurons’. Journal of Neurophysiology. 116:1924-1936. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/78475 | - |
dc.description.abstract | 鈉離子通道是負責動作電位起始階段的通道,藉由通道打開後流入細胞的鈉離子使細胞膜電位大於閾值,繼而產生動作電位。此外,處於活化態的鈉離子通道會在數毫秒內進入不活化態,其從不活化態恢復至休息態的時間長短會影響動作電位頻率或放電情形。一些重大的神經性疾病,例如癲癇,往往以不正常的神經節律或放電為其症狀之主要成因,此時鈉離子通道便可能成為一個主要的治療標的,縱使疾病本身並非因鈉離子通道之異常而起。目前幾種抗癲癇藥物,如:carbamazepine, phenytoin及lamotrigine,在過去的研究中,已知其與鈉離子通道的不活化態較休息態更有親和力,且多結合在快速不活化態。而新的一種藥物rufinamide,目前臨床上用於治療Lennox-Gastaut Syndrome(LGS),也能夠降低部分性癲癇的發作頻率。其相關的研究多著重於臨床與動物實驗,較少研究藥物對於鈉離子通道的分子作用機制。因此本篇論文利用小鼠的海馬迴CA1的神經元細胞進行不同的實驗來驗證先前研究所提出的rufinamide對於鈉離子通道的不活化態之親和力較休息態高,並更加著重探討其對於鈉離子通道的不同不活化態之親和力與藥物動力學的比較。我們發現rufinamide對於抑制鈉離子電流具有濃度依賴性與電壓依賴性,不同電壓之下的抑制程度可用一對一藥物結合曲線估算,得到rufinamide對於-70 mV時的鈉離子通道之Kapp值為574 μM,其較休息態時更為親和。也利用在-70 mV控制電壓之下rufinamide對於鈉離子通道之脫離與結合速率相除,得到其親和力為215 μM,其中兩者相當接近,也可以支持一對一藥物結合的假設。而在不同濃度rufinamide對快速不活化曲線實驗中得到的Ki值為294 μM,對於中度不活化曲線實驗中所得到的Ki值為91 μM,這些結果顯示rufinamide可能對於不同的不活化狀態有不同的親和力,故其對鈉離子通道的作用,受去極化電壓與去極化時間很大的影響,我們於是再藉由不同長度之去極化電壓及恢復時間的實驗結果,確認rufinamide對於中度不活化態有更高的親和力。在50 ms -60 mV去極化刺激後不同恢復時間實驗中,得到rufinamide對於鈉離子通道之親和力Ki約為40 μM。Rufinamide所偏好結合的鈉離子狀態與目前臨床上多數的抗癲癇藥並不相同,在更進一步了解rufinamide對鈉離子通道的分子作用機制之後,將有助於臨床上與其他藥物搭配用藥之使用。 | zh_TW |
dc.description.abstract | The sodium channel plays a key role in the genesis of action potentials. After opening upon membrane depolarization, sodium channels quickly enter the fast inactivated state within a few milliseconds. The kinetics of entry into and recovery from fast inactivation are important determinants of the frequency of action potentials or normal discharges. Several prototypical antiepileptic drugs, such as carbamazepine, phenytoin and lamotrigine, have been shown to have a higher affinity to the inactivated state of sodium channel than the resting state. Specifically, these drugs selectively bind to the fast inactivated state of the sodium channel with relatively slow kinetics to have a use-dependent inhibitory effect on neuronal discharges. A new drug, rufinamide, has been shown to have an effect on sodium currents, and is currently prescribed for the patients with Lennox-Gastaut Syndrome (LGS). The researches on rufinamide, however, have been focused on clinical and animal experiments. There are few studies on the molecular mechanism underlying the action of rufinamide on sodium channels. We therefore investigate the pharmacological effect on native sodium currents in mouse hippocampus CA1 neurons. We found that rufinamide has a concentration-dependent and voltage-dependent inhibitory effect on sodium currents. The extent of inhibition under different voltages can be described by one-to-one drug binding curves. The Kapp value of rufinamide for sodium channels at a holding potential of -70 mV is 574 μM, which also signals that the affinity of rufinamide to the inactivated states is higher than resting state. If derived from the ratio between the off and on rates of rufinamide, the Ki is 215 μM. The consistency would lead a further support for the on-to-one binding stoichiometry. On the other hand, The Ki value derived from shift of the fast inactivation curve in different concentration of rufinamide is 294 μM, while the Ki value derived from shift of the intermediate inactivation curve is 91 μM. The discrepancies mediate that rufinamide may have more different affinity toward different inactivated states. We therefore endeavored to accumulate Na+ channels in a specific inactivated state than the other with different voltage and duration of the inactivating pulse. We demonstrated that rufinamide selectively binds to the intermediate inactivated state of sodium channels. The affinity derived from the recovery course from a -60 mV*50 ms depolaration pulse is ~40 μM. The target gating conformation of sodium channels of rufinamide prefers is therefore different from the other Na+ channel-inhibiting anticonvulants. Elucidation of the molecular actions of rufinamide should contribute to more sophisticated clinical use of the drug for the treatment of epileptic seizures. | en |
dc.description.provenance | Made available in DSpace on 2021-07-11T14:59:03Z (GMT). No. of bitstreams: 1 ntu-108-R06441014-1.pdf: 5066177 bytes, checksum: eb65e127f031dc2d5d7c8c3da9fc6ec0 (MD5) Previous issue date: 2019 | en |
dc.description.tableofcontents | 口試委員會審定書.....................................................#
誌謝..................................................................i 摘要..................................................................ii 英文摘要(Abstract).....................................................iv 目錄.................................................................vi 圖目錄..............................................................viii 第一章 導論..........................................................1 1-1.電壓依賴性鈉離子通道之生理功能.......................1 1-2.電壓依賴性鈉離子通道之結構...........................1 1-3.電壓依賴性鈉離子通道之活化態與不活化態...............2 1-4.電壓依賴性鈉離子通道之快速不活化態與慢速不活化態.....5 1-5.電壓依賴性鈉離子通道之相關疾病.......................7 1-6.電壓依賴性鈉離子通道與藥物phenytoin...................7 1-7.電壓依賴性鈉離子通道與藥物rufinamide..................8 第二章 材料與方法...................................................12 2-1.實驗溶液與藥物之製備................................12 2-2.游離神經細胞之製備..................................13 2-3.玻璃電極之製備......................................13 2-4.沖藥管之製備........................................14 2-5.刺激探針與地線之製備................................14 2-6.游離神經細胞之全細胞電生理紀錄......................15 2-7.數據分析............................................16 第三章 結果..........................................................17 3-1.Rufinamide的抑制效果隨著電壓及濃度上升而增加.........17 3-2.Rufinamide會改變鈉離子通道快速不活化曲線的中點並藉其位移量求得rufinamide對快速不活化態的鈉離子通道之親和力..................18 3-3.Rufinamide並不影響鈉離子通道在-80 mV進入快速不活化態的速率但會使更多比例的通道進入不活化態................................20 3-4.Rufinamide會改變鈉離子通道中度不活化曲線的中點並藉其位移量求得rufinamide對中度不活化態的鈉離子通道之親和力..................22 3-5.Rufinamide對於從鈉離子通道的中度不活化態恢復之情形具有濃度依賴性............................................................23 3-6.Rufinamide對於從鈉離子通道的快速及中度不活化態恢復之情形具有濃度依賴性.......................................................24 3-7.Rufinamide會影響在-60 mV時不活化態的鈉離子通道之時程並使更多比例的通道進入不活化態,再藉由從鈉離子通道的中度不活化態恢復之情形求得其親和力.................. ....................................25 3-8.100 μM rufinamide與低濃度或高濃度phenytoin共同使用之藥效有不同效果.................... ......................................28 第四章 討論..........................................................29 4-1.Rufinamide對鈉離子通道之行為模式.....................29 4-2.Rufinamide結合至鈉離子通道的中度不活化態.............30 4-3.Rufinamide對於不同狀態鈉離子通道之親和力.............34 4-4.鈉離子通道的中度不活化態之形成.......................36 4-5.LGS與鈉離子通道中度不活化態之關聯...................37 4-6.Rufinamide與其他抗癲癇藥物臨床之運用.................38 參考文獻.............................................................82 | |
dc.language.iso | zh-TW | |
dc.title | Rufinamide抑制鈉離子通道之分子機制 | zh_TW |
dc.title | The Mechanisms Underlying the Inhibitory Effect of Rufinamide On the Voltage-gated Sodium Channels | en |
dc.type | Thesis | |
dc.date.schoolyear | 108-1 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 蔡明正,黃榮棋,楊雅晴 | |
dc.subject.keyword | 抗癲癇藥物,全細胞紀錄,中度不活化態,親和力,結合速率,雷葛氏症候群, | zh_TW |
dc.subject.keyword | antiepileptic drugs,whole-cell patch,intermediate inactivated state,affinity,on-rate,Lennox-Gastaut Syndrome, | en |
dc.relation.page | 87 | |
dc.identifier.doi | 10.6342/NTU201904435 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2019-12-30 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 生理學研究所 | zh_TW |
顯示於系所單位: | 生理學科所 |
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