請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/33232
標題: | YC-1的神經保護作用機轉之探討 Studies on the neuroprotective effect of YC-1 |
作者: | Hsiao-Ching Yu 余曉青 |
指導教授: | 符文美 |
關鍵字: | 神經保護,巴金森氏症, YC-1,MPP+,6-OHDA,SH-SY5Y,PKG, |
出版年 : | 2006 |
學位: | 碩士 |
摘要: | 巴金森氏症是現今最常見的神經退化性疾病之一,在目前的醫療只能治標不能治本,並且對於其致病機轉仍然不清楚的情況下,研發新的治療藥物並研究致病原因是非常必要的。
我們發現YC-1可以減少SH-SY5Y受到MPP+和6-OHDA的損害,SH-SY5Y是神經母細胞瘤的細胞株,具有多巴胺神經的特徵,對MPP+和6-OHDA具有敏感性,而YC-1可以增加sGC對NO的感受性,是一個sGC 活化劑,早先被發現具有抗血小板凝集和使血管平滑肌放鬆的功能,之後又陸續有報告指出它在其他疾病模式下也有不同的效果。 YC-1可以抑制MPP+或6-OHDA造成SH-SY5Y細胞凋亡達50%以上,並且可以抑制MPP+或6-OHDA造成的Bcl-2 減少, PARP 斷裂, 以及procaspase-3 活化;我們認為YC-1並非藉由NO/cGMP/PKG訊息路徑達到神經保護的作用,因為給予NOS抑制劑(L-NAME, 7-NI),sGC抑制劑(ODQ),PKG抑制劑(KT 5823, RP-8-Br-PET-cGMPS)都不能有效抑制YC-1的作用;而且直接給予cGMP類似物(8-Br-cGMP)並無法減少MPP+和6-OHDA造成的細胞毒性,所以YC-1在這樣的實驗模式裡應該是透過其他路徑達到其神經保護的作用;此外,我們發現PKG抑制劑(KT 5823)可以保護SH-SY5Y細胞,降低MPP+或6-OHDA造成的細胞毒性,因此,我們認為PKG也許參與在MPP+或6-OHDA的毒性機轉當中,或者KT 5823有其他的作用標的。 綜合以上實驗結果,我們認為YC-1可以減少神經細胞受到MPP+或6-OHDA的傷害,有潛力發展成治療巴金森氏症的藥物,而它在細胞及動物模式的保護機轉則仍需再進一步探討。 Parkinson’s disease(PD) is one of the most common neurodegeneration diseases in the world and yet lacks a thorough cure. The studies on its pathogenesis as well as the development of new therapies are indispensable. A compound, YC-1, which was first reported to have an anti-platelet function, is found here to be neuroprotective in SH-SY5Y human neuroblastoma cell line. It can protect SH-SY5Y cells from the damage caused by MPP+ or 6-OHDA. YC-1 inhibited MPP+ or 6-OHDA-induced cell death, which is evaluated by MTT reaction, PI flow cytometry, and DAPI staining. YC-1 also inhibited Bcl-2 degradation, PARP cleavage, and procaspase-3 activation caused by MPP+ or 6-OHDA. As a sGC activator, we then examined whether YC-1 protects SH-SY5Y through NO-cGMP-PKG pathway. However, all inhibitors acting in NO-cGMP-PKG pathway failed to suppress the effect of YC-1. The neuroprotective mechanism of YC-1 needs further investigation. On the contrary, the cell death induced by MPP+ or 6-OHDA was partially reversed by KT 5823, a PKG inhibitor, suggesting that PKG inhibition may be protective in dopaminergic neuronal cell line exposed to MPP+ or 6-OHDA. On the other hand, KT 5823 may also act on other targets except PKG. In conclusion, here we demonstrate that YC-1 possesses neuroprotective quality. Although the mechanisms of action of YC-1 in cell line and in animal model are still required to be investigated, YC-1 is likely to be a potential compound to treat PD patients. |
URI: | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/33232 |
全文授權: | 有償授權 |
顯示於系所單位: | 藥理學科所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-95-1.pdf 目前未授權公開取用 | 2.4 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。