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研究生:蔡宜玲
研究生(外文):Yi-Ling Tsai
論文名稱:N-乙醯基半胱氨酸減輕甲苯引起之行為異常
論文名稱(外文):N-acetylcysteine attenuatestoluene-induced behavioral dysfunction
指導教授:陳慧諴
指導教授(外文):Chen Hwei-Hsien
學位類別:碩士
校院名稱:慈濟大學
系所名稱:藥理暨毒理學研究所
學門:醫藥衛生學門
學類:藥學學類
論文種類:學術論文
畢業學年度:97
語文別:中文
論文頁數:78
中文關鍵詞:甲苯N-乙醯基半胱氨酸
外文關鍵詞:tolueneN-acetylcysteineNAC
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吸食甲苯會出現類似給予非競爭性NMDA受體拮抗劑phencyclidine(PCP)
及ketamine的異常行為,例如:認知功能損傷、社交退縮、運動協調性失常等。
甲苯經由抑制N-methyl-D-aspartate(NMDA)受體,改變大腦內Glutamate system,
進而造成行為異常。N-acetylcysteine(NAC)是cysteine之前趨藥。NAC經由活
化cystine-glutamate antiporters(Xc- transporters)及突觸前mGluR2,降低急性給
予非競爭性NMDA拮抗劑PCP引起大腦突觸間glutamate增加,進而改善PCP誘發
之異常行為。本研究的目的為評估NAC是否可改善急性及亞慢性給予甲苯所引
起的行為異常:社交行為、新物體探索及運動協調性,並探討其機轉。結果發現,
NAC 100 mg/kg可以改善急性甲苯引起之社交退縮、學習認知功能受損及運動協
調性失常。合併給予或後給NAC 100 mg/kg 14天,對於亞慢性甲苯引起之社交退
縮及學習記憶功能受損也有改善效果。給予Xc - t r a n s p o r t e r s 抑制劑
(S)-4-carboxyphenylglycine及mGluR2拮抗劑LY341495都會抑制NAC的保護效
果。為了確認mGluR2在N-acetylcysteine保護效果中的重要性,我們也利用mGluR2
作用劑LY379268觀察其對於急性甲苯作用的影響,結果發現,LY379268可以改
善急性甲苯引起之學習記憶功能受損及運動協調性失常。此外,NAC也誘發
glutathione的合成,利用 -glutamyl-cysteine synthetase 抑制劑L-(S)-buthionin
sulfoximine,抑制glutathione合成,也抑制了NAC保護效果。由以上結果可得知,
N A C對於急性甲苯引起異常行為的保護效果,除了藉由活化X c -
transporters-mGluR2 pathway,glutathione可能也參與其中。NAC為臨床上已使用
多年且安全性高的藥品。所以我們建議NAC可用於當為臨床治療急性甲苯中毒
之治療藥物, 也可改善亞慢性甲苯誘發之行為異常。
Toluene abuse results in behavioral dysfunction including cognitive
impairment, social deficit, and ataxia. These effects are similar to the
behavioral signs of noncompetitive NMDA receptor antagonists, such as
phencyclidine (PCP) and ketamine. Toluene inhibits N-methyl-D-aspartate
(NMDA) receptors, alters glutamate system in brain and produces behavioral
dysfunction. N-acetylcysteine (NAC), a prodrug of cystine, blunts the
PCP-evelated extracellular glutamate levels in the prefrontal cortex via
activation of cystine-glutamate antiporters (Xc- transporters)represent and
improved PCP-induced behavioral dysfunction. The purpose of this study is to
examine whether NAC can attenuate acute and subchronic toluene-induced
behavioral responses, social interaction, novel object recognition test and
rotarod test, and to reveal its mechanisms. In the present study, NAC (100
mg/kg) attenuated acute toluene-induced social interaction deficits, cognitive
impairments and motor incoordination. The effects of cotreatment and
subsequent treatment of NAC 14 days attenuated subchronic toluene-induced
social interaction deficits and cognitive impairments. The capacity of NAC to
reverse acute toluene-induced abnormal behaviors was blocked by the Xc-
transporters inhibitor (S)-4-carboxyphenylglycine or the mGluR2 antagonist
LY341495. In order to confirm that mGluR2 plays a modulatory role in the
reversal of toluene-induced behavioral dysfunction by NAC, we examined
whether the mGluR2 agonist LY379268 can affect acute toluene-induced
abnormal behaviors. LY379268 attenuated acute toluene-induced cognition
impairments and ataxia. In addition, NAC enhanced GSH synthesis,
administration of -glutamyl-cysteine synthetase inhibitior, L-(S)-buthionin
sulfoximine, which diminishes GSH synthesis. The capacity of the protective
effects of NAC on the toluene-induced abnormal behaviors were blocked by
L-(S)-buthionin sulfoximine. These results indicate that the protective effects
of NAC on acute toluene-induced abnormal behaviors via activation of
cystine-glutamate antiporter-mGluR2 pathway and GSH. NAC is safely used in
clinical application for many years. These findings suggest that NAC has
potential to act as an antidote for acute and subchronic toluene-induced
behavioral dysfinction.
圖目錄 ------------------------------------------------------------------------------ 2
中文摘要 --------------------------------------------------------------------------- 4
英文摘要 --------------------------------------------------------------------------- 5
壹、 背景介紹 ---------------------------------------------------------------- 6
貳、 實驗假說 --------------------------------------------------------------- 14
參、 實驗材料 --------------------------------------------------------------- 15
肆、 實驗方法及設計 ------------------------------------------------------ 17
伍、 實驗數據分析------------------------------------------------------------ 25
陸、 實驗結果 --------------------------------------------------------------- 26
柒、 討論 --------------------------------------------------------------------- 39
捌、 結論 --------------------------------------------------------------------- 44
玖、 圖 --------------------------------------------------------------------- 45
壹拾、 參考文獻 --------------------------------------------------------------- 68
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