Key Lab of New Animal Drug Project, Gansu Province; Key Lab of Veterinary Pharmaceutical Development, Ministry of Agriculture; Lanzhou Institute of Husbandry and Pharmaceutical Science of CAAS, No.335, jiangouyan, qilihe district, Lanzhou 730050, China.
Key Lab of New Animal Drug Project, Gansu Province; Key Lab of Veterinary Pharmaceutical Development, Ministry of Agriculture; Lanzhou Institute of Husbandry and Pharmaceutical Science of CAAS, No.335, jiangouyan, qilihe district, Lanzhou 730050, China.
Eur J Pharmacol. 2019 Jun 5;852:1-13. doi: 10.1016/j.ejphar.2019.02.032. Epub 2019 Feb 21.
Aspirin eugenol ester (AEE) was a promising drug candidate for treating inflammation, pain and fever and preventing cardiovascular diseases with fewer side effects than its precursors. Previous researches indicated that AEE could markedly inhibit agonist-induced platelet aggregation in vitro and ex vivo, however, the anti-platelet aggregation mechanisms of AEE remain to be defined. Here, AEE in vitro effects on agonist-induced granule-secretion, intercellular Ca mobilization and thromboxane A (TXA) generation were examined. Vasodilator-stimulated phosphoprotein (VASP), mitogen-activated protein kinase (MAPK), Akt, Sirt 1 and CD40L expressions were also studied. In agonist-activated platelets in vitro, AEE markedly attenuated granule secretion markers (P-selectin expression and ATP release), intercellular Ca mobilization and thromboxane B (TXB) formation. AEE also attenuated CD40L activation, suppressed extracellular-signal-regulated protein kinase 2 (ERK2), c-Jun N-terminal kinase 1 (JNK1) and Akt phosphorylation, and recovered Sirt1 expression, but the activation of p38, VASP and VASP, and the levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) were not affected by AEE. Overall, this study demonstrates that AEE inhibits agonist-induced platelet aggregation in vitro by regulating PI3K/Akt, MAPK and Sirt 1/CD40L pathways.
阿司匹林丁香酚酯 (AEE) 是一种有前途的药物候选物，可用于治疗炎症、疼痛和发热，并预防心血管疾病，其副作用比其前体少。先前的研究表明，AEE 可以显著抑制体外和体内激动剂诱导的血小板聚集，但 AEE 的抗血小板聚集机制仍有待确定。在这里，研究了 AEE 对激动剂诱导的颗粒分泌、细胞间钙动员和血栓素 A (TXA) 生成的体外影响。还研究了血管扩张刺激磷蛋白 (VASP)、丝裂原激活蛋白激酶 (MAPK)、Akt、Sirt1 和 CD40L 的表达。在体外激动剂激活的血小板中，AEE 明显减弱了颗粒分泌标志物（P-选择素表达和 ATP 释放）、细胞间钙动员和血栓烷 B (TXB) 形成。AEE 还减弱了 CD40L 的激活，抑制了细胞外信号调节蛋白激酶 2 (ERK2)、c-Jun N 末端激酶 1 (JNK1) 和 Akt 的磷酸化，并恢复了 Sirt1 的表达，但 p38、VASP 和 VASP 的激活，以及环腺苷酸 (cAMP) 和环鸟苷酸 (cGMP) 的水平不受 AEE 影响。总的来说，这项研究表明，AEE 通过调节 PI3K/Akt、MAPK 和 Sirt1/CD40L 通路来抑制体外激动剂诱导的血小板聚集。
