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研究生:吳佩蓉
研究生(外文):Pei-jung Wu
論文名稱(外文):Postinsult Administration of Cortistatin Attenuates Brain Damage and Facilitates Neurological Recovery in A Rat Ischemia/Reperfusion Brain Injury Model
指導教授:王家儀王家儀引用關係劉亞平劉亞平引用關係
學位類別:碩士
校院名稱:國防醫學院
系所名稱:生理學研究所
學門:醫藥衛生學門
學類:醫學學類
論文種類:學術論文
畢業學年度:99
語文別:中文
論文頁數:107
外文關鍵詞:Oxidative stressischemia/reperfusioncortistatinautophagystrokeHO-1
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Cortistatin (CST) 是一種神經胜肽,1998年H. Braun等學者利用注射kainic acid (KA) 誘導大鼠腦部產生癲癇的動物模式,發現CST-14可保護腦部免於KA 誘導產生癲癇所帶來的神經傷害。而腦缺血/再灌流刺激亦導致神經組織產生病理變化,在血管梗塞的主要灌流區,由於細胞迅速壞死產生所謂的「缺血核心區」,在此周圍的「缺血緩衝區」,因可獲得部份側枝血流循環供應養分,使得該區域的神經細胞可生存數小時至數天之久。本實驗的動物中風模式,是以顱內微注射血管內皮素-1 (400 pmol) 至大鼠右中大腦動脈周圍,並輔以右側頸總動脈結紮以製造一個局部腦缺血的情況,該動物模式也確實造成局部腦血流降低至基礎值之20%~25%,再灌流後48小時亦產生穩定的腦部梗塞範圍。我們藉此動物模式來探討外給一個CST-14是否能保護腦組織免於腦缺血/再灌流所帶來的腦部傷害以對於神經行為恢復能力的影響。我們的實驗結果發現,腦缺血/再灌流後30分鐘以腹腔注射投與CST-14 (250 μg/kg),能降低 48小時後腦部梗塞體積。且在三種不同的運動行為功能測試中:肢體不對稱擺動測試評估 (EBST)、神經學缺失分數評估 (mNSS) 和前肢觸覺黏附測試 (TART),發現CST-14可以改善由於腦缺血/再灌流所導致的大鼠運動行為功能缺失,而 CST-14 的投與也降低血腦障壁 (BBB) 的損傷及腦部水腫的現象,此外更降低因缺血再灌流後,由自由基造成之脂質過氧化。由以上實驗結果初步判斷,在腦缺血/再灌流的動物模式中,CST-14的投與可提供神經保護作用。因此我們在腦缺血/再灌流之後的不同時間點將老鼠犧牲,進一步探討CST-14的神經保護機轉。以西方點墨實驗研究HO-1於缺血緩衝區中的表現,發現HO-1蛋白質表現在腦缺血/再灌流刺激下會大量增加,且持續到48小時,而藉由CST-14的投與可顯著減少HO-1的表現量。另外,細胞發炎相關酵素iNOS之蛋白質和發炎相關因子IL-6、IL-1β、TNF-α之mRNA表現量則是在腦缺血/再灌流後大量增加,而CST-14的投予可顯著降低iNOS和發炎相關因子的表現量。另一方面,iNOS產生的NO可以和氫氧化自由基結合形成peroxynitrite,而peroxynitrite會攻擊細胞膜造成脂質過氧化產物MDA;透過測量缺血緩衝區內MDA含量發現CST-14可降低因腦缺血/再灌流刺激所誘導的脂質過氧化情形。在細胞自噬相關蛋白方面,LC3 II和Beclin-1蛋白質表現量在腦缺血/再灌流之後都有明顯增加,而CST-14投予後可減少其表現,此實驗顯示CST-14可以避免細胞自噬現象過度表現而使細胞死亡。綜合以上結果,於腦缺血/再灌流後,投予CST-14可降低腦部梗塞體積、改善運動功能缺失、減緩BBB的損傷及脂質過氧化情形,其原因可能為降低HO-1的過度表現和降低細胞過度自噬現象所導致。
Cortistatin (CST) is a neuropeptide with homology to somatostatin. It binds to somatostatin receptors and has a variety biological effect including anti-inflammatory and neuroprotection. We previously found that the gene expression of endogenous CST was was increased up 33.7 fold in the brain at 24 hrs after ischemia/reperfusion (I/R). In this study we further investigated whether administration of CST-14 could protect brain tissue from I/R injury. Adult SD rats underwent 40 min of middle cerebral artery ischemia then reperfusion. Rats received CST-14 (250mg/kg, i.p.) at 0.5, 1, 2, 3 hrs after I/R. We found that infarct volume, measured by 2, 3, 5-triphenyltetrazolium chloride staining at 48 hrs after I/R, was significantly reduced by CST-14 injected at 0.5, 1 and 2, but not 3 hrs, after I/R. The functional outcome was evaluated by neurological deficit scores, elevated body swing test and tactile adhesive removal test. CST-14 administration at 0.5, 1 and 2 hrs, but not 3 hrs, after I/R improved functional outcome. The integrity of blood brain barrier (BBB) was evaluated by extravasation of Evans blue and the brain edema was measured by brain tissue dry-wet weight. CST-14 administraion also improved BBB leakage at 24 hrs and reduced brain edema at 48 hrs after I/R. Lipid peroxidation, as measured by levels of malondialdehyde (MDA), showed time-dependent increases after I/R, but was reduced by post-administration of CST-14. Our data suggest that post-treatment of CST-14 alleviates I/R injury in the brain including decreases of proinflammatory cytokines (IL-6, IL-1β、TNF-α), antioxidative capacities, BBB leakage. Finally, our data indicated that CST-14 attenuated the over-expression of HO-1, LC3 and Beclin-1. It may be involved in neuroprotective effect of CST-14.
目錄
Abstract III
縮寫表 V
第一章、 緒論 1
第一節 腦中風簡介及其相關研究 1
第二節 顱內微注射血管內皮素-1 (endothelin-1, ET-1) 誘發大鼠腦缺血/再灌流之動物模式 11
第三節 Cortistatin (CST) 之藥理作用 13
第二章、實驗材料與研究方法 15
第一節 實驗動物 15
第二節 顱內微量注射內皮素-1 (Endothelin-1, ET-1) 誘發腦缺血/再灌流之動物模式 15
第三節 神經保護藥物之投與 16
第四節 實驗設計 16
第五節 缺血緩衝區 (penumbra) 腦血流之測定 17
第六節 腦組織切片 17
第七節 腦切片染色(TTC staining)及腦部梗塞區域體積計算 17
第八節 Fluoro-Jade B staining 觀察神經退化情形 18
第九節 Cresyl violet staining 觀察神經細胞存活情形 18
第十節 雙重免疫螢光染色法 (Double-immunofluorescence) 19
第十一節 動物行為評估 20
第十二節 腦部組織之收集 22
第十三節 腦組織秤重觀察腦水腫情形 22
第十四節 以伊凡氏藍染劑 (Evans blue dye) 測試血腦障壁通透性 23
第十五節 腦組織中丙二醛 (malondialdehyde, MDA) 之測定 24
第十六節 蛋白質之萃取 25
第十七節 蛋白質濃度之測定 26
第十八節 蛋白質膠體電泳分析 (sodium dodecyl sulfate polyacrylamide gel electrophoresis, SDS-PAGE) 27
第十九節 西方點墨法 (Western blot) 30
第二十節 腦組織中核醣核酸 (ribonucleic acid, RNA) 之萃取 31
第二十二節 即時定量聚合酶連鎖反應 (real time polymerase chain reaction) 33
第二十三節 統計分析 33
第二十四節 實驗藥品與試劑 34
第三章、實驗結果 37
第一節 顱內注射血管內皮素-1 (Endothelin-1, ET-1) 誘發大鼠腦缺血/再灌流造成腦梗塞之動物中風模式 37
第二節 內生性CST在腦缺血/再灌流刺激後之影響 37
第三節 腹腔給予CST-14 (250 μg/kg) 對大鼠腦缺血/再灌流後腦損傷之改善情形 37
第三節 CST-14 改善腦缺血/再灌流後大鼠運動協調能力 39
第四節 缺血緩衝區組織中CST-14對血腦障壁通透性 (Blood brain barrier, BBB) 與腦水腫之影響 41
第五節 CST-14 改善腦缺血/再灌流所誘發的氧化壓力 43
第六節 腦缺血/再灌流刺激後發炎相關因子基因之影響 44
第七節 CST-14降低壓力反應蛋白質HO-1之過度表現 44
第八節 壓力反應蛋白質HO-1之表現型態 45
第九節 CST-14 減少腦缺血/再灌流所導致的Autophagy-like cell death 45
第四章、討論 47
第一節 本研究所使用之腦缺血/再灌流動物模式之運動行為缺損時程與其他動物模式一致 47
第二節 CST-14對I/R造成神經損傷的保護作用之相關探討 48
第五章、結論 55
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