Department of Physiology, Faculty of Biological Sciences, Universidad de Concepción, Chile.
Thrombosis Reasearch Center, Department of Clinical Biochemistry and Immunohematology, Faculty of Health Sciences, Chile.
Biomed Pharmacother. 2019 Mar;111:378-385. doi: 10.1016/j.biopha.2018.12.087. Epub 2018 Dec 26.
Cardiovascular diseases are one of the main public health problems, and many of them, their pathophysiology involves alterations in platelet activity. Platelet activation is an essential event that is regulated by the intracellular concentrations of Ca2+ and cAMP. Interestingly, it has been shown that the activation of adenosine A2A receptors increases cAMP levels and produces the inhibition of platelet aggregation, which appears as a potential target for regulation of platelet activity. Therefore, we tried to activate A2A receptors using Indiplon, a drug developed for the treatment of insomnia, and analyze its effect on platelet activity in vitro. Our results indicate that Indiplon is able to interact in silico with the adenosine A2A receptor (ΔG of -73.321 kcal/mol, similar to that obtained with adenosine), which is involved in the regulation of platelet cAMP levels. In functional studies using PRP, a reduction in platelet aggregation induced by ADP was observed in the presence of Indiplon at 500 μM with a percentage of inhibition 70%, where the use of specific inhibitors (ZM241385 and MSX-2) of the A2A receptor also blocked these effects reducing the percentage of inhibition to 41% and 34.1%, respectively. Also, the use of Indiplon produced a decrease in the expression in the membrane of P-selectin. Thus, Indiplon acts as an A2A receptor agonist and whose activation results in inhibition of platelet aggregation and activation, showing a possible cardiovascular protective role.
心血管疾病是主要的公共卫生问题之一，其中许多疾病的病理生理学涉及血小板活性的改变。血小板激活是一个重要的事件，由细胞内 Ca2+和 cAMP 的浓度调节。有趣的是，已经表明，腺苷 A2A 受体的激活增加了 cAMP 水平，并产生了血小板聚集的抑制，这似乎是调节血小板活性的潜在靶点。因此，我们试图使用用于治疗失眠的 Indiplon 激活 A2A 受体，并分析其对体外血小板活性的影响。我们的结果表明，Indiplon 能够在计算机上与腺苷 A2A 受体相互作用（ΔG 为-73.321 kcal/mol，与腺苷获得的值相似），该受体参与血小板 cAMP 水平的调节。在使用 PRP 的功能研究中，在 500 μM 的 Indiplon 存在下观察到 ADP 诱导的血小板聚集减少，抑制率为 70%，其中 A2A 受体的特异性抑制剂（ZM241385 和 MSX-2）的使用也阻断了这些效应，抑制率分别降低至 41%和 34.1%。此外，Indiplon 的使用导致膜上 P-选择素的表达减少。因此，Indiplon 作为 A2A 受体激动剂起作用，其激活导致血小板聚集和激活的抑制，显示出可能的心血管保护作用。
