Garcinol acts as a novel integrin α_IIbβ₃ inhibitor in human platelets

Platelet activation plays a central role in arterial thrombosis. Platelets are activated by adhesive proteins (i.e., collagen) or soluble agonists (i.e., thrombin), the respective receptor-specific signaling cause inside-out signaling, leading to the binding of fibrinogen to integrin α_IIbβ₃. This binding triggers outside-in signaling, resulting in platelet aggregation. Garcinol, a polyisoprenylated benzophenone, is extracted from the fruit rind of Garcinia indica. Although garcinol exhibits considerable bioactivities, few studies have investigated the effect of garcinol on platelet activation.

Aggregometry, immunoblotting, flow cytometer, confocal microscopic analysis, fibrin clot retraction, animal studies such as fluorescein-induced platelet plug formation in mesenteric microvessels, acute pulmonary thromboembolism, and tail bleeding time were performed in this study.

This study indicates that garcinol inhibited platelet aggregation stimulated by collagen, thrombin, arachidonic acid, and U46619. Garcinol reduced integrin α_IIbβ₃ inside-out signaling, including ATP release; cytosolic Ca²⁺ mobilization; P-selectin expression; and Syk, PLCγ2/PKC, PI3K/Akt/GSK3β, MAPKs, and NF-κB activation stimulated by collagen. Garcinol directly inhibited integrin α_IIbβ₃ activation by interfering with FITC-PAC-1 and FITC-triflavin by collagen. Additionally, garcinol affected integrin α_IIbβ₃-mediated outside-in signaling, such as decreasing platelet adhesion and the single-platelet spreading area; suppressing integrin β₃, Src, FAK, and Syk phosphorylation on immobilized fibrinogen; and inhibiting thrombin-stimulated fibrin clot retraction. Garcinol substantially reduced mortality caused by pulmonary thromboembolism and prolonged the occlusion time of thrombotic platelet plug formation without extending bleeding time in mice.

This study identified that garcinol, a novel antithrombotic agent, acts as a naturally occurring integrin α_IIbβ₃ inhibitor.