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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/29935完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳朝峰(Chau-Fong Chen) | |
| dc.contributor.author | Yih-Hao Peng | en |
| dc.contributor.author | 彭逸豪 | zh_TW |
| dc.date.accessioned | 2021-06-13T01:25:53Z | - |
| dc.date.available | 2007-08-08 | |
| dc.date.copyright | 2007-08-08 | |
| dc.date.issued | 2007 | |
| dc.date.submitted | 2007-07-17 | |
| dc.identifier.citation | Adams JM, Cory S. The Bcl-2 protein family: arbiters of cell survival. Science 281:1322-1326,1998.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/29935 | - |
| dc.description.abstract | Simvastatin，為statins類藥物中的一類，其作用為3-hydrixy-3-methylglutaryl Co-enzyme A的競爭型抑制劑。臨床上已廣泛應用於高血中膽固醇的病人。
本實驗的目的為觀察simvastatin是否可以提升大鼠中視網膜中HO-1的表現，並且更重要的是否也可保護視網膜，使其神經節細胞免於遭受缺血/再灌流的傷害。 首先，我們使用雌性之Wistar大鼠，以玻璃體內注射的方法注射simvastatin，如此在24小時後觀察到HO-1的表現呈現劑量依存性。能引發最大量 HO-1表現的為1.6μg，而使用此劑量可使HO-1的表現由藥物注射後6小時候開始增加，並在3天時達到尖峰，因此後續實驗接使用此劑量。 接著，我們再觀察simvastatin是否可以挽救因視網膜缺血/再灌流(I/R)而喪失的神經節細胞。先以5%的Fluorogold由上丘 (superior colliculus) 注射來對視網膜神經節細胞進行標示。視網膜的缺血則是以30號針頭刺入眼球前房，並將針頭連接至一裝有生理食鹽水之儲水袋，將此儲水袋提高至150mmHg，如此維持60分鐘，使前房內壓力高於大鼠之收縮血壓以達到視網膜缺血之目的。之後再使之再灌流不同的時間。大鼠再隨機分為兩組:I/R後3天及7天。在I/R後3天組中，在再灌流後15分鐘內由玻璃體內注射simvastatin或溶劑，結果發現到神經節細胞的存活率由溶劑組的80.32±1.62%提升至 simvastatin組的88.06±2.49% (p=0.038)，而在I/R後7天組中溶劑組及simvastatin組的存活率分別為72.48±4.55%及78.16±2.95%，而兩組之間沒有達到統計上顯著的差異(p=0.297)。 雖然在I/R後3天我們觀察到simvastatin可以增加神經節細胞的存活率，然而我們卻也同時發現到視網膜在單純遭受缺血/再灌流後HO-1即有增加的現象，自6小時侯開始增加並於24小時達到尖峰。更進一步的我們發現到無論在缺血/再灌流的1天或3天後，simvastatin皆無法更進一步的使HO-1的增加有加成的作用。因此我們認為simvastatin可能是經由HO-1以外的路徑達到神經保護的作用。 除了提升HO-1的作用外，我們也觀察視網膜缺血/再灌流後，一種促進細胞凋亡的分子-Bax的變化，發現到Bax的表現在缺血/再灌流後的8至24小時有增加的現象，而在缺血/再灌流後並未發現simvastatin有降低Bax表現的現象。 相反的，我們卻發現到simvastatin可以提升一重要抗細胞凋亡的分子Bcl-2在缺血/再灌流後的表現。 綜合以上，我們認為simvastatin可以在視網膜缺血/再灌流的早期對視網膜神經節細胞扮演ㄧ保護的角色，雖然其真正的作用機轉還未完全明白，但可能是透過HO-1之外的路徑來達成，而Bcl-2表現的提昇有可能是simvastatin造成神經保護的原因之一。 | zh_TW |
| dc.description.abstract | Simvastatin, one of the family of statins, is known as competitive inhibitors of 3-hydroxy-3-methylglutaryl Coenzyme A (HMG-CoA), are widely to treat hypercholesterolemic patients.
The aim of present study is to investigate whether simvastatin can up-regulate HO-1 in the rat retina and protect retina ganglion cells from I/R injury. In using female Wistar rats, Intravitreal injection of simvastatin induces retinal HO-1 protein up-regulation in dose dependent manner after 24h of simvastatin injection, the maximum increase in HO-1 was 1.6 μg, thus 1.6 μg was chosen for further experiment.By using this dose, simvastatin also increase HO-1 in a time dependent manner, start from 6h and peaked at 3 days after treatment. RGCs was labeled by injections 5% Fluorogold (FG) injected into superior colliculus. Retinal ischemia/reperfusion (I/R) was done by high intraocular pressure (HIOP)procedure, The procedure was performed by inserting with a 30-gauge needle connected to a saline reservoir, the reservoir was lifted to a height of 150 mmHg for 60 minutes, and reperfusion was allowed to different duration of time. Animals were further divided into two major groups: 3 days after I/R and 7 days after I/R. For 3 days after ischemia/reperfusion, simvastatin or solvent was administered intravitreally 15 minutes after reperfusion. RGCs survival rate was significantly increased from 80.32±1.62 % (solvent) to 88.06±2.49 % (p=0.038) , For 7days after I/R, simvastatin was administered intravitreally immediately , 2 days and 5 days after ischemia. And RGCs survival rate were 72.48±4.55 % (solvent) and 78.16±2.95%(simvastatin)respectively, but there is no statistical significant between two groups (p=0.297). Although simvastatin promotes RGCs survival 3 days after retinal I/R and promotes HO-1 expression in the retina, however, we also find that HO-1 expression after I/R alone was dramatically increase, start from 6h and peaked at 24h after retinal I/R. However, in Western blot analysis, we find that simvastatin did not further increase HO-1 both 24h and 72h after retinal I/R. Therefore, we suggest that simvastatin may protect RGCs from I/R injury not via HO-1 induction. In the present results, Bax expression was increased from 8h to 24hr after retinalI/R, but simvastatin did not reduce Bax expression 24h after retinal I/R,Interestingly, simvastatin can up-regulate Bcl-2, an important anti-apoptotic molecule in rat retina after I/R. Conclusively, these data shown that simvastatin may play a protective role in early stage of retinal I/R, although the exact mechanisms underlying the neuroprotective effects of simvastatin against retina I/R is not clear, HO-1 induction may be ruled out and our results imply that at least in part,Bcl-2, may be one of the mechanisms in simvastatin – induced neuroprotective effects in retinal I/R injury. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-13T01:25:53Z (GMT). No. of bitstreams: 1 ntu-96-R94441009-1.pdf: 960453 bytes, checksum: 33e86b2bf7e322bd8289ded50d90382a (MD5) Previous issue date: 2007 | en |
| dc.description.tableofcontents | 縮寫表 I
中文摘要 III 英文摘要 IV 一、文獻回顧 1.視網膜 1 1-1 視網膜的解剖構造及其生理功能 1 1-2 視網膜神經節細胞 1 1-3 視網膜的病變 2 1-4視網膜病變的研究模式 2 2.缺血再灌流 2 2-1缺血的定義 2 2-2缺血再灌流之病理生理學 3 3.視網膜缺血再灌流 4 3-1視網膜缺血再灌流之動物模式 4 3-2 視網膜缺血再灌流之病理生理學 5 3-2-1 視網膜缺血時對神經元代謝的影響……………………………………5 3-2-2 視網膜缺血時釋放的神經傳導物質……………………………………6 3-2-3 視網膜缺血時鈣離子的作用……………………………………………7 3-2-4 發炎媒介物在視網膜缺血時所扮演的角色……………………………7 3-2-5 氧化物 (oxidant) 在視網膜缺血再灌流傷害中所扮演的角色……..10 3-2-6 視網膜缺血再灌流後對視網膜神經節細胞的影響…………………..11 4.血基質氧化酶 (Heme oxygenase,HO) 11 4-1 血基質氧化酶之分類及其酵素作用 11 4-2 第一型血基質氧化酶之生理調節作用 12 4-3 第一型血基質氧化酶及其產物之分子調節機制 13 4-4 第一型血基質氧化酶在視網膜中的表現及其對神經節細胞之保護作用…....13 5. 細胞凋亡 (Apoptosis)/Bax/Bcl-2 14 5-1 細胞凋亡 (apoptosis)/Bax/Bcl-2 14 6.辛伐他汀(Simvastatin) 15 6-1 引言 15 6-2 Statin類藥物的作用機轉 16 6-3 Statin類藥物與HO-1的關係 17 6-4 Statin類藥物在各器官受到傷害時所提供的保護 18 6-4-1 Statin類藥物在心臟傷害中所提供的保護 18 6-4-2 Statin類藥物在腎臟傷害中所提供的保護 19 6-4-3 Statin類藥物在中樞神經傷害中所提供的保護 19 6-5 Simvastatin 在視網膜中的作用: 20 二、研究目的 22 三、研究材料與方法 23 1.動物處理 23 1-1實驗動物的準備 23 1-2逆行標記視網膜神經節細胞 23 1-3視網膜缺血再灌流之手術 24 1-4藥物的給予 24 1-4-1 腹腔注射 24 1-4-2 玻璃體內注射 25 1-5 視網膜神經節細胞的計數 25 2視網膜檢體處理 26 2-1 西方墨點分析(Western blotting analysis): 26 2-1-1 西方墨點法的檢體製備 26 2-1-2 西方墨點法分析 27 2-1-3 呈色反應 29 2-2 TUNEL ( Terminal deoxynucleotidyl-tra sferase-mediated dUTP nick end-labeling (TUNEL method) 29 3.資料處理與統計方法 30 四、結果 31 1.Simvastatin對視網膜中HO-1表現的影響 31 2. Simvastatin對於視網膜缺血再灌流3天及7天後對神經節細胞的影響 31 3. 視網膜缺血/再灌流後HO-1的表現 32 4. 玻璃體內注射simvastatin對於缺血/再灌流後HO-1表現的影響: 32 5.給予 HO-1 small interfering RNA (siRNA) 後，simvastatin對於缺血/再灌流後視 網膜神經節細胞數目的影響 33 6.玻璃體內注射HO-1 small interfering RNA (siRNA) 對於simvastatin與視網膜缺 血/再灌流後引發的HO-1的表現的影響 33 7.視網膜缺血/再灌流後Bax表現量的變化 33 8.simvastatin對於視網膜缺血/再灌流後Bax表現量的影響 34 9.玻璃體內注射simvastatin對於視網膜中Bcl-2表現的影響 34 10.視網膜缺血/再灌流後Bcl-2的變化 34 11.玻璃體內注射simvastatin對於缺血/再灌流後視網膜中Bcl-2表現的影響 34 五、討論 36 1. Simvastatin對視網膜中HO-1表現的影響 36 2. Simvastatin對於視網膜缺血再灌流3天及7天後對神經節細胞的影響 37 3. 視網膜缺血/再灌流後HO-1的表現 40 4. 玻璃體內注射simvastatin對於缺血/再灌流後HO-1表現的影響 40 5. 給予 HO-1 siRNA後，simvastatin對於缺血/再灌流後視網膜神經節細胞數目及HO-1表現的影響 41 6. 視網膜缺血/再灌流後Bax表現量的變化 41 7. simvastatin對於視網膜缺血/再灌流後Bax表現量的影響 43 8. 玻璃體內注射simvastatin對於視網膜中Bcl-2表現的影響 43 9. 視網膜缺血/再灌流後Bcl-2表現的變化 44 10. 玻璃體內注射simvastatin對於缺血/再灌流後視網膜中Bcl-2表現的影響 45 六、結論 46 七、圖表 47 圖1:視頂蓋內注射 (intratectal injection) 47 圖2:提高眼壓已造成視網膜缺血/再灌流之手術 48 圖3:玻璃體內注射之方法 49 圖4:視網膜切割與計數方法 50 圖5:以400倍之螢光顯微鏡觀察正常視網膜中心、中間、周邊之神經節細胞代表圖 50 圖6:以腹腔注射simvastatin後不同時間點視網膜中HO-1的表現 51 圖7:以不同劑量之simvastatin進行玻璃體注射24小時後，視網膜HO-1的表現量 52 圖8:玻璃體內注射simvastatin後，視網膜中HO-1在不同時間的表現 53 圖9:視網膜缺血/再灌流後不同時間點HO-1的表現 54 圖10 :視網膜經過60分鐘的缺血後，分別於3天及7天觀察視網膜神經節細胞之 存活率 55 圖11:各組視網膜缺血/再灌24小時後之TUNEL stain 56 圖12:各組視網膜缺血/再灌流後24小時後TUNEL(+)細胞數 57 圖13:HO-1 siRNA對simvastatin與視網膜缺血/再灌流後24小時所產生的HO-1 的表現的影響 58 圖14:視網膜缺血/再灌流後，玻璃體內注射溶劑或simvastatin，再於24小時後觀 察視網膜HO-1的表現量 59 圖15:視網膜缺血/再灌流後，玻璃體注射溶劑或simvastatin，再於3天後觀察視網 膜中HO-1的表現量 60 圖16：視網膜缺血/再灌流後不同時間點視網膜中Bax的變化 61 圖17 :視網膜缺血/再灌流24小時後，simvastatin對於Bax變化的影響 62 圖18 :玻璃體內注射simvastatin後不同時間視網膜中Bcl-2之表現之影響 63 圖19:視網膜缺血/再灌流後不同時間點Bcl-2之表現 64 圖20:缺血再灌流後，玻璃體內注射溶劑或simvastatin，於24小時後視網膜中 Bcl-2的變化 65 八、參考文獻 66 | |
| dc.language.iso | zh-TW | |
| dc.subject | 缺血 | zh_TW |
| dc.subject | 視網膜 | zh_TW |
| dc.subject | 再灌流 | zh_TW |
| dc.subject | 血基質氧化酶 | zh_TW |
| dc.subject | 辛伐他汀 | zh_TW |
| dc.subject | heme oxygenase | en |
| dc.subject | reperfusion | en |
| dc.subject | simvastatin | en |
| dc.subject | retinal | en |
| dc.subject | ischemia | en |
| dc.title | 辛伐他汀對大鼠視網膜缺血/再灌流後神經節細胞的保護作用 | zh_TW |
| dc.title | The protective effects of simvastatin on retinal ganglion cells after ischemia/reperfusion in rats | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 95-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 謝正勇,柯美蘭,呂大文,趙效明 | |
| dc.subject.keyword | 視網膜,缺血,再灌流,血基質氧化酶,辛伐他汀, | zh_TW |
| dc.subject.keyword | retinal,ischemia,reperfusion,heme oxygenase,simvastatin, | en |
| dc.relation.page | 78 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2007-07-18 | |
| 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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