Laboratory of Ethnopharmacology, West China School of Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pennsylvania, United States.
J Pharmacol Sci. 2020 Sep;144(1):43-51. doi: 10.1016/j.jphs.2020.07.002. Epub 2020 Jul 3.
Platelet activation is the primary cause of thrombosis. The P2X7 receptor (P2X7R) is a therapeutic target of thrombosis. However, it is still unknown whether P2X7R activation affects platelet thrombus. Our molecular docking results showed that entecavir as a P2X7R antagonist interacted perfectly with the human P2X7R (hP2X7R) in silico simulation studies. Furthermore, our experimental data revealed that entecavir could act as a P2X7R antagonist to exert cytoprotective effects against platelet activation via protecting mitochondrial function, improving lipid peroxidation and increasing antioxidant activity. Correlated with this, entecavir inhibited platelet aggregation, dense-granule secretion, P-selectin expression, integrin activation and Ca increase. In experimental mouse model, entecavir could significantly inhibit arteriovenous thrombosis and prolong the bleeding time. Furthermore, we found that entecavir had no significant effect on prothrombin time (PT), activated partial thrombin time (APTT), thrombin time (TT), fibrinogen (FIB), mean platelet volume (MPV) and platelet counts (PLT). This study demonstrates that entecavir markedly prevents platelet activation and thrombosis through inhibiting P2X7R without affecting coagulation system. Therefore, entecavir may be a potential candidate for treating thrombosis disease.
血小板激活是血栓形成的主要原因。P2X7 受体（P2X7R）是血栓形成的治疗靶点。然而，P2X7R 的激活是否影响血小板血栓形成仍不清楚。我们的分子对接结果表明，恩替卡韦作为 P2X7R 拮抗剂，在计算机模拟研究中与人 P2X7R（hP2X7R）完美相互作用。此外，我们的实验数据表明，恩替卡韦可以作为 P2X7R 拮抗剂，通过保护线粒体功能、改善脂质过氧化和增加抗氧化活性，发挥对血小板激活的细胞保护作用。与此相关的是，恩替卡韦抑制血小板聚集、致密颗粒分泌、P-选择素表达、整合素激活和 Ca 增加。在实验性小鼠模型中，恩替卡韦可显著抑制动静脉血栓形成并延长出血时间。此外，我们发现恩替卡韦对凝血酶原时间（PT）、活化部分凝血活酶时间（APTT）、凝血时间（TT）、纤维蛋白原（FIB）、平均血小板体积（MPV）和血小板计数（PLT）没有显著影响。这项研究表明，恩替卡韦通过抑制 P2X7R 显著预防血小板激活和血栓形成，而不影响凝血系统。因此，恩替卡韦可能是治疗血栓性疾病的潜在候选药物。
