Myricetin as a promising inhibitor of platelet fibrinogen receptor in humans.

Platelets play a vital role in the formation of dangerous arterial thrombosis. Platelets are activated by adhesive proteins or soluble agonists through their specific receptors. The receptor-mediated signaling pathways lead to common signaling events, which result in shape changes and inside-out signaling, leading fibrinogen binding to glycoprotein IIb/IIIa complex (integrin αβ). This interaction initiates integrin αβ-mediated outside-in signaling, subsequently culminating in granule secretion and aggregation. Myricetin is a flavonoid that occurs in a variety of plants. Although myricetin has been demonstrated to have several bioactive properties, its role in platelet activation has not been extensively studied. The present study demonstrated the ability of myricetin to inhibit platelet aggregation stimulated by collagen, thrombin, and U46619. Myricetin reduced the ATP-release, cytosolic Ca mobilization, and P-selectin expression and the activation of PLCγ2/PKC, PI3K/Akt/GSK3β, and MAPK. Myricetin exerted a direct inhibitory effect on the activation of integrin αβ by disrupting the binding between FITC-PAC-1 and the integrin. Moreover, myricetin suppressed integrin αβ-mediated outside-in signaling, such as integrin β, Src, and Syk phosphorylation on immobilized fibrinogen. In animal studies, myricetin significantly prolonged the occlusion time of thrombotic platelet plug formation in mesenteric microvessels without extending bleeding time. This study concludes that myricetin is a natural integrin αβ inhibitor and a novel antithrombotic agent.