類薑黃素在大鼠動物模式中對氣球擴張損傷所誘導的頸動脈血管內膜新生之抑制機轉

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Title:	類薑黃素在大鼠動物模式中對氣球擴張損傷所誘導的頸動脈血管內膜新生之抑制機轉 The inbihitory mechanisms of curcuminoid on balloon injury-induced neointima formation in the carotid artery at rat model
Authors:	周家如;Chou, Chia-Ju
Contributors:	藥學系碩士班
Keywords:	動脈粥狀硬化症;經皮穿腔冠狀動脈血管成形術;血管再阻塞;類薑黃素;atherosclerosis;Percutaneous coronary angioplasty;restenosis;curcuminoid
Date:	2012-01-20
Issue Date:	2012-08-31 16:40:08 (UTC+8)
Publisher:	中國醫藥大學
Abstract:	?前言? 　　氣球擴張術經常應用於治療冠狀動脈粥狀硬化疾病所引起之血管阻塞。然而，大約有 30 %~50 % 曾經接受過氣球擴張術治療的病患，於半年內會有血管再阻塞（restenosis）的不良情況發生，成為氣球擴張術這項手術的最大缺點。在長久以來的研究推論，造成再阻塞的病理機制，是血管結構在遭受氣球擴張術的破壞以後，會誘導血管平滑肌細胞（VSMC）的增生和轉移作用，進而產生內膜新生（neointima），造成血管再阻塞的主要原因。　　類薑黃素是萃取自屬薑科薑黃屬薑黃之地下根莖的天然物，,包含三種主要有效成分：70~76% 的Curcumin（Cur）、10~18% 的Demethoxycurcumin（DMC）以及8% 的Bisdemethoxycurcumin（BDMC）。在先前的研究指出，薑黃素具有抗細胞增生、細胞轉移、抗氧化、抗發炎等作用。 ?目的? 　　本篇論文的研究目的在於：探討類薑黃素Curcuminoid中主要的三種成分：Curcumin、Demethoxycurcumin及Bisdemethoxycurcumin，分別應用在大鼠的頸動脈模式中，對於氣球擴張術所造成的血管損傷而誘導的內膜增生之抑制作用。 ?方法? 　　在動物實驗(in vivo)當中，Curcumin、Demethoxycurcumin、Bisdemethoxycurcumin分別以Pluronic Gel之給藥途徑投予SD大鼠以氣球擴張術破壞之頸動脈區域，並於術後 14 天犧牲，再以H&E staining、IHC staining及Western Bloting分析其術後內膜新生及相關蛋白之變化。另外，為了瞭解不同途徑下，Curcumin、Demethoxycurcumin、Bisdemethoxycurcumin對於內膜新生之抑制程度，因此又以腹腔注射途徑給予接受氣球擴張術之SD大鼠，並同樣以H&E staining分析結果。 ?結果? 　　以Pluronic Gel之給藥途徑投予時，經由H&E staining結果可得知， Curcumin和Demethoxycurcumin對於內膜之厚度及內膜/中膜之比例的抑制效果較為明顯，Bisdemethoxycurcumin則否；經由IHC staining及Western Bloting結果可得知，Demethoxycurcumin對於相關蛋白表現較具抑制效果。 ?結論? 　　經由本論文之實驗結果顯示，類薑黃素中之Curcumin和Demethoxycurcumin較具有抑制細胞增殖的機制，故對預防冠狀動脈氣球擴張術後所以起之再阻塞深具潛力，且對藥物塗層支架之研發具價值。 ?Introduction? 　　Percutaneous coronary angioplasty (PTCA) is the most common therapeutic approach for atherosclerosis. However, there are still 30-50% of patients suffered from restenosis. The pathological mechanism of restenosis by ballon injury is primarily attributed to excessive proliferation of vascular smooth muscle cells (VSMC). 　　Curcuminoid were isolated from underground rhizomes of Curcuma longa L. (Zingiberaceae), contains of 70-76% Curcumin（Cur）, 10~18% Demethoxycurcumin（DMC）and 8% Bisdemethoxycurcumin（BDMC）. Previous reports suggested that Curcumin is an effective antiproliferative, antimigratory, antioxidant, and anti-inflammatory agent. ?Aim? 　　We aimed to investigate the differential effects of these Curcuminoid on balloon injury-induced neointimal formation, and will explore tier molecular mechanisms. ?Methead? 　　In an in vivo study, Curcumin, Demethoxycurcumin and Bisdemethoxycurcumin with high dose ( 20 mg/mL) and low dose ( 10 mg/mL) pluronic gel treat on the balloon-injured areas in Sprague-Dawley rats, and sacrifice after 14 days. After that, analysis the ratio of neointima/media ratio with H&E staining ,and analysis the effect of protein wtih IHC staining and Western Bloting. In addition, in order to understand the effects of Curcumin, Demethoxycurcumin and Bisdemethoxycurcumin during different ways, we use Intraperitoneal injection to treat on the balloon-injury areas in Sprague-Dawley rats, and analysis the ratio of neointima/media ratio with H&E staining, too. ?Result? 　　In H&E staining, we observe that Curcumin and Demethoxycurcumin demonstrates more inhibition in the thickness of neointimal, also neointima/media ratio during pluronic gel; in IHC staining and Western Bloting, we observe that Demethoxycurcumin demonstrates more inhibition in the thickness of interrelated protein. ?Conclusion? 　　These observations provide a mechanism of Curcumin and Demethoxycurcumin in attenuating cell proliferation, thus as a potential intervention for restenosis.
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