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研究生:張為君
研究生(外文):Chang wei chun
論文名稱:各類神經保護製劑對甲基安非他命誘發神經凋亡作用之研究
論文名稱(外文):The effects of neuroprotective agents on methamphetamine-induced apoptosis
指導教授:萬芳榮萬芳榮引用關係
指導教授(外文):Wan fang jung
學位類別:碩士
校院名稱:國防醫學院
系所名稱:海底醫學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
論文出版年:2006
畢業學年度:94
語文別:中文
論文頁數:108
中文關鍵詞:甲基安非他命細胞凋亡神經細胞
外文關鍵詞:methamphetamineapoptosisneuron culture
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甲基安非他命 (Methamphetamine) 為一個常見的濫用藥物,被發現對神經系統具有毒性,其神經傷害的機轉較為複雜,目前正陸續被釐清中。目前確定,甲基安非他命傷害的機轉包括造成粒線體及內質網的氧化壓力增加,並藉由csapase依存或非caspase依存路徑的一連串活化造成細胞凋亡。本論文利用培養大白鼠皮質神經細胞並給予甲基安非他命的傷害模式,來篩選我們認為對甲基安非他命可能具有神經保護功能,且臨床上容易使用的六個藥物(維他命E、VPA、鋰鹽、LC、FK506及bilobalide)進行篩選,並探討及比較其保護機轉間的差異與功效。實驗結果顯示,給予甲基安非他命6小時可造成細胞內的自由基釋放,給予24小時會粒腺體膜電位下降,給予48小時則會造成初級大腦皮質細胞之細胞凋亡。在神經保護製劑篩選方面,我們發現前處理維他命E及VPA可保護甲基安非他命導致大白鼠皮質神經細胞的細胞凋亡,以及抑制細胞內的自由基增加;此外,VPA及高濃度之維他命E能回復細胞粒線體膜電位。而前處理鋰鹽並不能保護甲基安非他命導致大白鼠皮質神經細胞的細胞凋亡;前處理FK506能抑制甲基安非他命造成的大白鼠皮質神經細胞的細胞凋亡,及粒線體膜電位的下降,但它並不能降低甲基安非他命所造成的細胞自由基增加;LC與bilobalide雖能抑制甲基安非他命造成的大白鼠皮質神經細胞的細胞凋亡及細胞自由基的增加,但對於粒線體膜電位的下降並不能顯著回復。綜合以上,在大腦皮質神經細胞給予甲基安非他命造成細胞損傷的模式中,維他命E、 VPA、FK506與LC雖然對細胞的保護機轉略為不同,但都顯示能保護甲基安非他命造成的細胞凋亡,而bilobalide及鋰鹽對大腦皮質神經細胞受甲基安非他命造成的神經細胞損傷無保護作用。在大腦皮質細胞受到甲基安非他命造成的細胞凋亡傷害機轉中,粒線體功能的維持與抑制細胞凋亡似乎有重要關聯,而與清除甲基安非他命造成之自由基釋放似乎較關聯較間接。
Methamphetamine (METH) is a popular drug of abuse with the neurotoxic mechanisms that are complicated and remains to be studied. We have used METH to cause cortical neuron apoptosis model, and then investigated the neuroprotective effects of six potential neuroprotective agents including vitamine E (vit E), valproic acid (VPA), LiCl, L-Carnitine(LC), FK506 and bilobolide.
According to our findings, the METH caused the intercellular ROS release (6 hours), decreased the mitochondrial membrane potential (24 hours), and caused cortical neuron culture apoptosis (48 hours). We further showed that vit E and VPA can prevent cell apoptosis and ROS release induced by METH. Besides, vit E and high dose of VPA can prevent the decrease of mitochondrial membrane potential induced by METH. The cell apoptosis induced by METH can not be prevented by LiCl. FK506, which is a calcineurin inhibitor, prevented the METH-induced cell apoptosis and mitochondrial membrane potential decreasing. However, FK506 can not prevent ROS increasing induced by METH. LC and bilobolide can prevent call apoptosis and ROS increasing induced by METH, but can not recover the mitochondrial membrane potential changed by METH.
In summary, the neuroprotective mechanisms of those drugs are different. Our studies showed that vit E, VPA, FK506, LC and bilobolide can protect METH-induced neurotoxicity.
目錄
                 頁次
目錄………………………………………………………………………I
圖次………………………………………………………………………II
中文摘要…………………………………………………………………III
英文摘要…………………………………………………………………V
第一章 緒言…………………………………………………………..1
第二章 研究目的…………………………………………………….27
第三章 方法與材料………………………………………………….28
第四章 結果………………………………………………………….36
第五章 討論………………………………………………………….55
第六章 結論………………………………………………………….66
第七章 參考文獻…………………………………………………….98
第七章、參考文獻

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