Abstract
Background and PurposeThe discovery that flavonoids are capable of inhibiting platelet function has led to their investigation as potential antithrombotic agents. However, despite the range of studies on the antiplatelet properties of flavonoids, little is known about the mechanisms by which flavonoids inhibit platelet function. In this study, we aimed to explore the pharmacological effects of a polymethoxy flavonoid, nobiletin, in the modulation of platelet function.Experimental ApproachThe ability of nobiletin to modulate platelet function was explored by using a range of in vitro and in vivo experimental approaches. Aggregation, dense granule secretion and spreading assays were performed using washed platelets. Fibrinogen binding, α-granule secretion and calcium mobilization assays were performed using platelet-rich plasma and whole blood was used in impedance aggregometry and thrombus formation experiments. The effect of nobiletin in vivo was assessed by measuring tail bleeding time using C57BL/6 mice.Key ResultsNobiletin was shown to suppress a range of well-established activatory mechanisms, including platelet aggregation, granule secretion, integrin modulation, calcium mobilization and thrombus formation. Nobiletin extended bleeding time in mice and reduced the phosphorylation of PKB (Akt) and PLCγ2 within the collagen receptor (glycoprotein VI)-stimulated pathway, in addition to increasing the levels of cGMP and phosphorylation of vasodilator-stimulated phosphoprotein, a protein whose activity is associated with inhibitory cyclic nucleotide signalling.Conclusions and ImplicationsThis study provides insight into the underlying molecular mechanisms through which nobiletin modulates haemostasis and thrombus formation. Therefore, nobiletin may represent a potential antithrombotic agent of dietary origins.
Highlights
Platelet activation is initiated upon binding of various ligand molecules to their cognate cell surface receptors, which trigger intracellular signalling cascades that lead to shape change, release of granule contents, thromboxane A2 (TXA2) synthesis and release and thrombus formation (Gibbins, 2004)
We reported that tangeretin inhibits platelet function and thrombus formation via elevation of cGMP and inhibition of PI3K signalling (Vaiyapuri et al, 2013)
We demonstrated that nobiletin is a potent inhibitor of platelet function that acts through similar effects on platelet function, and established these mechanisms as common modes of action which flavonoids may share in order to modulate the function of these cells
Summary
Platelet activation is initiated upon binding of various ligand molecules to their cognate cell surface receptors, which trigger intracellular signalling cascades that lead to shape change, release of granule contents, thromboxane A2 (TXA2) synthesis and release and thrombus formation (Gibbins, 2004). Dietary flavonoids have been shown to inhibit platelet function, reduce lipid levels and maintain vascular integrity, which may underpin a reduced risk of cardiovascular diseases. The complex nature of the mechanism of action of plant flavonoids on the cardiovascular system including platelets has initiated research to better understand the basis of the relationship between these dietary components and cardiovascular health in order to develop more effective strategies to prevent or treat thrombotic diseases (Wright et al, 2012). We aimed to explore the pharmacological effects of a polymethoxy flavonoid, nobiletin, in the modulation of platelet function. Fibrinogen binding, α-granule secretion and calcium mobilization assays were performed using platelet-rich plasma and whole blood was used in impedance aggregometry and thrombus formation experiments. The effect of nobiletin in vivo was assessed by measuring tail bleeding time using C57BL/6 mice
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