白藜蘆醇促進前列腺素抗血小板作用之機轉探討

POTENTIATION OF ANTIPLATELET EFFECT OF PROSTAGLANDINS BY RESVERATROL

吳重儀(Chung-I Wu)

指導教授 ： 吳志中 ； 吳永昌

高雄醫學大學/藥學院/天然藥物研究所碩士班/碩士(2006年)

摘要

在過去的文獻曾報導，長期飲用紅酒能夠有效的降低心血管疾病的好發率。白藜蘆醇(Resveratrol，3,4’,5-trihydroxystilbene)是一種存在自然界的多酚類抗氧化劑，而被認為是紅酒中的生物活性成分。然而，白藜蘆醇是一種弱效的抗血小板藥物，並且長期飲用紅酒血漿中含有白藜蘆醇的濃度並不高，這與在體外試驗中，需要較高濃度白藜蘆醇才能達到抗血小板凝集的作用，並不相符。前列腺素E1和 I2存在於人體內不同的組織與體液中，對血小板的活化具有抑制作用，而我們在血小板凝集試驗中，發現到白藜蘆醇能增強前列腺素抑制血小板凝集的作用。更進一步的研究，我們分別使用螢光免疫分析法及鈣離子的螢光染劑fura-2/AM探測血小板內環狀核?˙臚庤t離子的濃度變化，發現到白藜蘆醇不會增強前列腺素E1對於環狀核?˙藹t量與細胞內鈣離子移動的作用，但使用西方點墨法分析血小板內蛋白質的變化時，可發現到白藜蘆醇會增強前列腺素E1對於PKC活化與蛋白中酪氨酸磷酸化的抑制作用。總結，白藜蘆醇能增強前列腺素E1抗血小板凝集的作用，可能是經由這兩個路徑所達成。

關鍵字

白藜蘆醇 ； 促進 ； 前列腺素 ； 抗血小板 ； 機轉 ； 協同

並列摘要

It has been shown that chronic consumption of red wine improves to decrease risk of cardiovascular diseases. Resveratrol (3,4’,5-trihydroxystilbene), a natural polyphenol antioxidant, was suggested to be the biologically active ingredient of red wine. However, resveratrol is a weak antiplatelet agent, and discrepancy between a low concentration in plasma and much higher one necessary to inhibit platelet aggregation in in vitro experiments casts doubt on the physiological relevance of in vitro effects. PGE1 and PGI2 are found in different body tissues and body fluids. In this study, we found the inhibitory effects of prostaglandins were potentiated by resveratrol in platelet aggregation test. In the further study, we found resveratrol didn’t potentiate the effects of PGE1 both on cyclic nucleotide levels analyzed by enzyme immunoassay and on intracellular calcium mobilization analyzed with fura-2/AM fluorescence dye. In contrast, the combination of resveratrol and PGE1 resulted in greater inhibition of both PKC activation and protein tyrosine phosphorylation analyzed by western blot with individual specific antibodies. Therefore, the potentiation of antiplatelet effect of PGE1 by resveratrol might be through these two pathways.

並列關鍵字

POTENTIATION ； ANTIPLATELET ； PROSTAGLANDINS ； RESVERATROL ； PGE1 ； PGI2 ； SYNERGISM ； MECHANISM

參考文獻

Altman, R., Scazziota, A., Rouvier, J., and Cacchione, R. (1986). Synergistic actions of PAF-acether and sodium arachidonate in human platelet aggregation. 1. Studies in normal human platelet rich plasma. Thromb Res 43, 103-111.

Andrews, R. K., and Berndt, M. C. (2004). Platelet physiology and thrombosis. Thromb Res 114, 447-453.

Armstrong, R. A., Jones, R. L., and Wilson, N. H. (1985). Mechanism of the inhibition of platelet aggregation produced by prostaglandin F2 alpha. Prostaglandins 29, 601-610.

Arya, M., Anvari, B., Romo, G. M., Cruz, M. A., Dong, J. F., McIntire, L. V., Moake, J. L., and Lopez, J. A. (2002). Ultralarge multimers of von Willebrand factor form spontaneous high-strength bonds with the platelet glycoprotein Ib-IX complex: studies using optical tweezers. Blood 99, 3971-3977.

Ashby, J., Tinwell, H., Pennie, W., Brooks, A. N., Lefevre, P. A., Beresford, N., and Sumpter, J. P. (1999). Partial and weak oestrogenicity of the red wine constituent resveratrol: consideration of its superagonist activity in MCF-7 cells and its suggested cardiovascular protective effects. J Appl Toxicol 19, 39-45.