Pharmacological actions of Dieckol on the modulation of platelet
functions and thrombus formation via integrin αIIbβ3 and cAMP signaling
Abstract
Background and purpose: Dieckol is a phlorotannin that can be found in
seaweeds, particularly in Eisenia bicyclis (brown algae) and is known to
have anti-oxidant, anti-inflammatory, and anti-microbial properties. It
also possesses anti-thrombotic and pro-fibrinolytic activities; however,
the mechanistic aspects of anti-platelet and anti-thrombotic activity
are yet to be explored. Experimental approach: We investigated the
pharmacological effects of dieckol on the modulation of platelet
functions using human, rat, and mice models. Inhibitory effects of
dieckol on platelet aggregation were assessed using platelet-rich plasma
and washed platelets, followed by measurement of dense granule
secretions, fibrinogen binding to integrin αIIbβ3, fibronectin adhesion
assay, platelet spreading on immobilized fibrinogen, and clot
retraction. Cyclic nucleotide signaling events were evaluated, such as
cyclic-AMP production followed by vasodilator-stimulated phosphoprotein
(VASP) stimulation. The in vivo anti-thrombotic potential was evaluated
in mice using an acute pulmonary thromboembolism model and tail bleeding
assay. Key Results: Dieckol markedly inhibited platelet aggregation and
granule secretion; furthermore, it down-regulated integrin
αIIbβ3–mediated inside-out and outside-in signaling events, including
platelet adhesion, spreading, and clot retraction, whereas it
upregulated the cAMP–PKA–VASP pathway. Dieckol-treated mice
significantly survived the thrombosis than vehicle-treated mice, without
affecting hemostasis. Histological examinations of lungs revealed
minimum occluded vasculature in dieckol-treated mice. Conclusion and
implications: Taken together, dieckol possesses strong anti-platelet and
anti-thrombotic properties and is a potential therapeutic drug candidate
to treat and prevent platelet-related cardiovascular disorders.