Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, 309 E. Second Street, Pomona, CA 91766, USA.
Eur J Pharmacol. 2010 Dec 15;649(1-3):249-54. doi: 10.1016/j.ejphar.2010.09.009. Epub 2010 Sep 19.
While proper platelet function is a vital component of hemostasis, their inappropriate activation contributes to thrombotic disorders. One pathway for platelet activation involves their synthesis of the lipid mediator thromboxane A₂ (TXA₂). Although TXA₂ acts by binding to a seven-transmembrane receptor (i.e., the prostanoid TP receptor) that participates in the genesis of thrombosis, currently, there are no antagonists available for clinical use. Since the only available drug targeting this pathway (aspirin) is associated with inherent limitations/serious side effects, developing prostanoid TP receptor antagonists is clearly warranted. To this end, we have previously employed the "repurposing old drugs for new uses" approach to identify prostanoid TP receptor antagonists and showed that the antidiabetic agent glybenclamide selectively inhibited human platelet prostanoid TP receptors (in vitro). On this basis, we hypothesized that glybenclamide exhibits in vivo antiplatelet potential, and therefore, may protect against thrombosis development. Using murine platelets, it was found that glybenclamide injections: 1) inhibited platelet aggregation induced by the prostanoid TP receptor agonist U46619 and the TXA₂ precursor arachidonic acid, under ex vivo experimental settings, concentration-dependently; 2) lacked any detectable effects on aggregation stimulated by ADP, or the thrombin receptor activating-peptide 4; 3) impaired hemostasis by prolonging tail bleeding time; and 4) delayed the development of occlusive thrombi in a carotid artery injury model. Taken together, these findings indicate that glybenclamide does indeed exert, ex vivo and in vivo, prostanoid TP receptor-dependent inhibitory effects on platelet function. Thus, glybenclamide has the potential to be applied in the management of thromboembolic disorders.
虽然适当的血小板功能是止血的重要组成部分，但它们的异常激活会导致血栓形成障碍。血小板激活的一个途径涉及它们合成脂质介质血栓素 A₂（TXA₂）。尽管 TXA₂ 通过与参与血栓形成的七跨膜受体（即前列腺素 TP 受体）结合起作用，但目前尚无临床可用的拮抗剂。由于靶向该途径的唯一可用药物（阿司匹林）存在固有局限性/严重副作用，因此开发前列腺素 TP 受体拮抗剂是合理的。为此，我们之前采用了“重新利用旧药物用于新用途”的方法来识别前列腺素 TP 受体拮抗剂，并表明抗糖尿病药物格列本脲选择性抑制人血小板前列腺素 TP 受体（体外）。在此基础上，我们假设格列本脲具有体内抗血小板作用，因此可能预防血栓形成。使用鼠血小板，发现格列本脲注射：1）在体外实验条件下，浓度依赖性地抑制由前列腺素 TP 受体激动剂 U46619 和 TXA₂ 前体花生四烯酸诱导的血小板聚集；2）对由 ADP 或凝血酶受体激活肽 4 刺激的聚集没有任何可检测到的影响；3）通过延长尾巴出血时间来破坏止血；4）在颈动脉损伤模型中延迟闭塞性血栓的形成。总之，这些发现表明，格列本脲确实在体外和体内对血小板功能发挥前列腺素 TP 受体依赖性抑制作用。因此，格列本脲有可能应用于血栓栓塞性疾病的治疗。
