Lu Wan-Jung, Li Jiun-Yi, Shih Tzenge-Lien, Chen Ray-Jade, Chen Ting-Yu, Kao Wei-Ting, Liu Jen-Wei, Wang Hsueh-Hsiao, Peng Hsien-Yu, Lin Kuan-Hung
Department of Optometry, MacKay Medical College, New Taipei City, Taiwan.
Traditional Herbal Medicine Research Center, Taipei Medical University Hospital, Taipei, Taiwan.
Front Pharmacol. 2025 Jun 24;16:1541255. doi: 10.3389/fphar.2025.1541255. eCollection 2025.
Bleeding is the inherent adverse effect of antiplatelet drugs that has limited their use in the prevention of secondary heart attack and stroke. Thus, finding a novel antiplatelet drug with antithrombotic activities while preserving hemostatic function remains a crucial issue. Here, we screened naphthalimide derivatives that we previously synthesized and identified a novel derivative compound , which has a more potent antithrombotic effect and has no effect on bleeding cessation. This study is aimed to determine the antiplatelet mechanism of compound and further test whether compound is a safer and more potent antithrombotic agent.
Platelet aggregation, flow cytometry and immunoblotting were used to determine the antiplatelet effect of compound . The study of thrombus formation of mesenteric venules in mice was used to evaluate the antithrombotic effect of compound .
Compound selectively inhibited collagen-mediated platelet aggregation and markedly prevented thrombus formation without bleeding tendency. Compound also inhibited glycoprotein VI (GPVI) downstream signaling, such as Fyn and Lyn, phospholipase C gamma 2, protein kinase C. Moreover, a surface plasmon resonance assay indicated that compound may directly bind to GPVI, thereby interrupting the interaction of collagen and GPVI. Compound also effectively attenuates collagen-induced granule release, calcium mobilization, and GPIIbIIIa activation.
These findings indicate that compound can selectively inhibit GPVI, eventually suppressing platelet activation and thrombus formation while preserving hemostasis. Compound is a GPVI antagonist and safe antiplatelet agent. Compound also has therapeutic potential for treating cardiovascular diseases.
出血是抗血小板药物固有的不良反应，这限制了它们在预防二次心脏病发作和中风中的应用。因此，找到一种具有抗血栓活性同时保留止血功能的新型抗血小板药物仍然是一个关键问题。在此，我们筛选了我们之前合成的萘酰亚胺衍生物，并鉴定出一种新型衍生物化合物，其具有更强的抗血栓作用且对止血无影响。本研究旨在确定该化合物的抗血小板机制，并进一步测试该化合物是否为一种更安全、更有效的抗血栓药物。
采用血小板聚集、流式细胞术和免疫印迹法来确定该化合物的抗血小板作用。利用小鼠肠系膜小静脉血栓形成研究来评估该化合物的抗血栓作用。
该化合物选择性抑制胶原介导的血小板聚集，并显著预防血栓形成且无出血倾向。该化合物还抑制糖蛋白VI（GPVI）下游信号传导，如Fyn和Lyn、磷脂酶Cγ2、蛋白激酶C等。此外，表面等离子体共振分析表明该化合物可能直接与GPVI结合，从而中断胶原与GPVI的相互作用。该化合物还能有效减弱胶原诱导的颗粒释放、钙动员和GPIIbIIIa激活。
这些发现表明该化合物可选择性抑制GPVI，最终在保留止血功能的同时抑制血小板活化和血栓形成。该化合物是一种GPVI拮抗剂和安全的抗血小板药物。该化合物在治疗心血管疾病方面也具有治疗潜力。
