Potent antiplatelet activity of sesamol in an in vitro and in vivo model: pivotal roles of cyclic AMP and p38 mitogen-activated protein kinase.
Sesamol is a potent phenolic antioxidant which possesses antimutagenic, antihepatotoxic and antiaging properties. Platelet activation is relevant to a variety of acute thrombotic events and coronary heart diseases. There have been few studies on the effect of sesamol on platelets. Therefore, the aim of this study was to systematically examine the detailed mechanisms of sesamol in preventing platelet activation in vitro and in vivo. Sesamol (2.5-5 μM) exhibited more potent activity of inhibiting platelet aggregation stimulated by collagen than other agonists. Sesamol inhibited collagen-stimulated platelet activation accompanied by [Ca(2+)](i) mobilization, thromboxane A(2) (TxA(2)) formation, and phospholipase C (PLC)γ2, protein kinase C (PKC) and mitogen-activated protein kinase (MAPK) phosphorylation in washed platelets. Sesamol markedly increased cAMP and cGMP levels, endothelial nitric oxide synthase (eNOS) expression and NO release, as well as vasodilator-stimulated phosphoprotein (VASP) phosphorylation. SQ22536, an inhibitor of adenylate cyclase, markedly reversed the sesamol-mediated inhibitory effects on platelet aggregation and p38 MAPK phosphorylation, and sesamol-mediated stimulatory effects on VASP and eNOS phosphorylation, and NO release. Sesamol also reduced hydroxyl radical (OH(●)) formation in platelets. In an in vivo study, sesamol (5 mg/kg) significantly prolonged platelet plug formation in mice. The most important findings of this study demonstrate for the first time that sesamol possesses potent antiplatelet activity, which may involve activation of the cAMP-eNOS/NO-cGMP pathway, resulting in inhibition of the PLCγ2-PKC-p38 MAPK-TxA(2) cascade, and, finally, inhibition of platelet aggregation. Sesamol treatment may represent a novel approach to lowering the risk of or improving function in thromboembolism-related disorders.
Chang
Chao C
CC
Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei 110, Taiwan.
Lu
Wan J
WJ
Chiang
Cheng W
CW
Jayakumar
Thanasekaran
T
Ong
Eng T
ET
Hsiao
George
G
Fong
Tsorng H
TH
Chou
Duen S
DS
Sheu
Joen R
JR
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D001792:Blood Platelets / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis*; D006152:Cyclic GMP / Q000096:biosynthesis; D006801:Humans; D051379:Mice; D008840:Microfilament Proteins / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology*; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000494:pharmacology*; D000098662:Vasodilator-Stimulated Phosphoprotein
D000975:Antioxidants; D052117:Benzodioxoles; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010636:Phenols; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D000098662:Vasodilator-Stimulated Phosphoprotein; D003094:Collagen; C025583:sesamol; D000242:Cyclic AMP; D052250:Nitric Oxide Synthase Type III; D048051:p38 Mitogen-Activated Protein Kinases; D006152:Cyclic GMP