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山竺萃取之 xanthone 類衍生物 8-deoxygartanin 和gartanin 於兔子血小板之作用機轉探討
國立陽明大學藥理學研究所
研究生:吳明錫
指導教授:廖志飛;蔡維人
| [ 摘要 ] | ||
| 山竺（Garcinia mangostana L.）為福木科植物（Guttiferae），是東南亞地區常見的植物，其果殼被使用於治療皮膚感染、外傷及緩解腹瀉之生藥。根據文獻報導，山竺果殼中所含之化學成分大多屬於xanthone類化合物，此類化合物已知的生物活性包括抗憂鬱、抗結核、利尿、抗菌、抗病毒、抗白血病、抗腫瘤、抗潰瘍、抗肝毒性、抗過敏、促進支氣管擴張及抗血小板等作用。8-deoxygartanin及gartanin是由山竺果殼中所萃取出來之xanthone類衍生物，具有明顯抑制血小板凝集的能力，但其作用機轉尚未見相關之報導，因此本研究探討其抑制血小板可能之作用機轉。實驗結果顯示8-deoxygartanin與gartanin 具有抑制AA誘導血小板凝集和MDA生成的作用，其IC50分別為15.0+/-1.9，8.9+/-1.5 和 14.2+/-2.5，7.2+/-1.6 microM。並且同時會抑制血小板中TXA2與PGE2的產生。上述因此，8-deoxygartanin和gartanin抑制AA所誘導之血小板凝集之作用機轉可能是經由抑制血小板中cyclooxygenase的活性，使TXA2的生成減少，進而抑制血小板的凝集。另外，實驗結果亦顯示，8-deoxygartanin及gartanin對於U46619、ADP、PAF和AlF4−誘導的血小板凝集也具有抑制作用，其IC50分別為23.8+/-2.4，7.1+/-1.2；11.1 +/-1.9，5.7+/-0.6；11.4+/-3.2，6.7+/-0.8和28.4+/-6.7，3.7+/-0.7 microM，而血小板受PAF活化後的細胞內鈣離子流動，IP3的生成，蛋白質激酶C的轉移及受thapsigargin所誘導之store-mediated calcium entry（SMCE）都會受8-deoxygartanin與gartanin所抑制，但是藥物對血小板中cAMP及cGMP的產生，以及蛋白質激酶C的活性無影響，上述因此認為，8-deoxygartanin和gartanin可能經由抑制PLCβ的活性而降低IP3的產生，使細胞內儲存的鈣離子釋放減少，並減弱SMCE的現象，而藥物同時也會直接抑制SMCE所造成的外鈣內流，最後造成細胞內自由鈣離子濃度降低而抑制PAF所誘導的血小板活化凝集。 | ||
| [ 英文摘要 ] | ||
| Garcinia mangostana L. (Guttiferae) hull has been used as a folk remedy for skin infection, wound and diarrhea healing in Southeast Asia. Previous studies indicated the hulls chiefly contained xanthones that have a great deal of bioactivities such as anti-depressant, anti-tubercular, diuretic, anti-microbial, anti-viral, anti-leukemia, anti-tumor, anti-ulcer, anti -hepatotoxic, anti-allergy, bronchial dilation actions and anti-platelet aggregation. Two xanthone derivatives 8-deoxygartanin and gartanin were purified from the hull of this plant and previous study showed that they could significantly inhibit platelet aggregation with unknown action mechanisms. The present results indicated that these two compounds concentration-dependently inhibited aggregation and MDA formation induced by AA on washed rabbit platelets, with IC50 values of 15.0+/-1.9 , 8.9+/-1.5 and 14.2+/-2.5 , 7.2+/-1.6 microM. They also restrained both TXA2 and PGE2 formation. These results suggest that inhibitory effects of 8-deoxygartanin and gartanin on AA-induced platelet aggregation are related to the decrease of TXA2 synthesis by suppressing platelet cyclooxygenase activity. These two compounds also inhibited U46619-, ADP-, PAF- and AlF4-induced platelet aggregation in a concentration dependent manner with the IC50 values of 23.8+/-2.4 , 7.1+/-1.2 ; 11.1+/-1.9 , 5.7+/-0.6 ; 11.4+/-3.2 , 6.7+/-0.8 and 28.4+/-6.7 , 3.7+/-0.7 microM, respectively. Furthermore these two compounds also inhibited PAF-induced intracellular calcium mobilization, IP3 formation as well as PKC translocation and thapsigargin-induced SMCE in activated platelets, but had no effects on cAMP, cGMP levels and PKC activity. Therefore, the present study demonstrated that 8-deoxygartanin and gartanin inhibited PAF-induced platelet aggregation by attenuating the concentration of intracellular free calcium, which was probably attributed to inhibitory effects of both the PLCβ activity and SMCE. |
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