Repurposing an old drug for a new use: glybenclamide exerts antiplatelet activity by interacting with the thromboxane A2 receptor

Abstract

Aim: To investigate the potential antagonistic activity of the antidiabetic agent glybenclamide for the human platelet thromboxane A 2 receptor (abbreviated as TPR). Methods: Platelets were obtained from healthy donors. Aggregation studies were performed in a model 700 aggregometry system. Radioactivity was counted in a Beckman LS 6000 liquid scintillation counter and calcium imaging was performed using an LS50B PerkinElmer Fluorescence Spectrometer. Results: It was found that glybenclamide: 1) inhibited aggregation induced by the TPR agonist U46619 (IC 50 =2.3±0.31 µmol/L) and by the thromboxane A 2 precursor arachidonic acid (IC 50 =2.6±0.24 µmol/L); 2) displaced SQ29,548 from its binding sites on platelets; 3) lacked any detectable effects on aggregation stimulated by ADP, or the thrombin receptor activating-peptide 4; 4) blocked calcium mobilization induced by U46619, but not by ADP; and 5) failed to raise cAMP levels. Conclusion:The findings indicate that glybenclamide exerts inhibitory effects on platelets by interacting with TPR. Thus, glybenclamide or a rationally designed derivative has the potential to serve as an antithrombotic agent.

Licochalcones extracted from Glycyrrhiza inflata inhibit platelet aggregation accompanied by inhibition of COX-1 activity

“…Hence, we assume that licochalcones did not inhibit the thrombin-induced aggregation efficiently ( Fig 2 ). In addition, licochalcone A did not block the ADP-induced platelet aggregation ( S1 Fig ) as it has been shown that the ADP-induced platelet aggregation does not require COX activity [ 23 , 24 ]. On the other hand, platelet aggregation by collagen requires COX activity, we and another group showed that NSAIDs such as aspirin and indomethacin completely blocked the platelet aggregation by collagen [ 16 , 22 ].…”

Thromboxane A2Receptor

“…Finally, and most recently, published work has confirmed in vitro that glybenclamide exerts TPR-specific inhibition of platelet aggregation, as it abrogated the response to AA and U46619, while having no effect on aggregation mediated by ADP and TRAP4. 129 These findings were later confirmed under ex vivo platelet aggregation experimental settings, and using an in vivo mouse model of thrombosis. 130…”

“…27 This suggests that Arg 60 is a key amino acid for G q recognition. 30 Furthermore, it has been shown that Glu 129 and Arg 130 , which comprise part of the biologically important Glu-Arg-Tyr (ie, ERY) motif within iL2, are also important for G q coupling. 43 Thus, given the limitations of mutational and truncation studies, at present controversy remains regarding the participation of the various intracellular TPR domains in G-protein coupling.…”

Thyroxine therapy ameliorates serum levels of eicosanoids in Chinese subclinical hypothyroidism patients

“…Hence, the increased ratio of 11-dehydroTXB2/6-Keto PGF1a in hypothyroid patients may represent a shift toward vasoconstriction. Numerous studies have shown that many eicosanoids play key roles in the development of atherosclerosis and are new biomarkers and drug therapy targets [20][21][22][23] . Therefore, whether the eicosanoid profile in SH patients is abnormal and associated with susceptibility to cardiovascular, cerebrovascular and other serious diseases and whether L-T4 replacement therapy (LTR) can affect the eicosanoid profile need to be studied further.…”