title: Novel antiplatelet activity of protocatechuic acid through the inhibition of high shear stress-induced platelet aggregation.
abstract: Bleeding is the most common and serious adverse effect of currently available antiplatelet drugs. Many efforts are being made to develop novel antithrombotic agents without bleeding risks. Shear stress-induced platelet aggregation (SIPA), which occurs under abnormally high shear stress, plays a crucial role in the development of arterial thrombotic diseases. Here, we demonstrate that protocatechuic acid (PCA), a bioactive phytochemical from Lonicera (honeysuckle) flowers, selectively and potently inhibits high shear (>10,000 s(-1))-induced platelet aggregation. In isolated human platelets, PCA decreased SIPA and attenuated accompanying platelet activation, including intracellular calcium mobilization, granule secretion, and adhesion receptor expression. The anti-SIPA effect of PCA was mediated through blockade of von Willebrand factor binding to activated glycoprotein Ib, a primary and initial event for the accomplishment of SIPA. Conspicuously, PCA did not inhibit platelet aggregation induced by other endogenous agonists like collagen, thrombin, or ADP that are important in both pathological thrombosis and normal hemostasis. Antithrombotic effects of PCA were confirmed in vivo in a rat arterial thrombosis model, where PCA significantly delayed the arterial occlusion induced by FeCl(3). Of particular note, PCA did not increase bleeding times in a rat tail transection model, whereas conventional antiplatelet drugs, aspirin, and clopidogrel substantially prolonged it. Collectively, these results suggest that PCA may be a novel antiplatelet agent that can prevent thrombosis without increasing bleeding risks.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul, Korea.
authors.forename: Keunyoung
authors.initials: K
authors.lastname: Kim
authors.forename: Ok-Nam
authors.initials: ON
authors.lastname: Bae
authors.forename: Kyung-Min
authors.initials: KM
authors.lastname: Lim
authors.forename: Ji-Yoon
authors.initials: JY
authors.lastname: Noh
authors.forename: Seojin
authors.initials: S
authors.lastname: Kang
authors.forename: Ka Young
authors.initials: KY
authors.lastname: Chung
authors.forename: Jin-Ho
authors.initials: JH
authors.lastname: Chung
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D035264:Flowers / Q000737:chemistry; D006470:Hemorrhage / Q000139:chemically induced; D006801:Humans; D062385:Hydroxybenzoates / Q000009:adverse effects / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D031239:Lonicera / Q000737:chemistry; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D013927:Thrombosis / Q000517:prevention & control; D055815:Young Adult; D014841:von Willebrand Factor / Q000378:metabolism
chemical_list: D062385:Hydroxybenzoates; D010975:Platelet Aggregation Inhibitors; D014841:von Willebrand Factor; C009091:protocatechuic acid