Antiplatelet Activity of Carnosic Acid, a Phenolic Diterpene from Rosmarinus officinalis

Abstract

Carnosic acid is a major phenolic diterpene derived from Rosmarinus officinalis and has been reported to have antioxidant, antibacterial, anticancer, antiobese and photoprotective activities. This study investigated the antiplatelet activity of carnosic acid. Carnosic acid significantly inhibited collagen-, arachidonic acid-, U46619- and thrombin-induced washed rabbit platelet aggregation in a concentration-dependent manner, with IC₅₀ values of 39 ± 0.3, 34 ± 1.8, 29 ± 0.8 and 48 ± 2.9 μM, respectively, while it failed to inhibit PMA- (a direct PKC activator) and ADP-induced platelet aggregation. In agreement with its antiplatelet activity, carnosic acid blocked collagen-, arachidonic acid-, U46619- and thrombin-mediated cytosolic calcium mobilization. Accordingly, serotonin secretion and arachidonic acid liberation were also inhibited in a similar concentration-dependent manner. However, in contrast to the inhibition of arachidonic acid-induced platelet aggregation, carnosic acid had no effect on the formation of arachidonic acid-mediated thromboxane A₂ and prostaglandin D₂, thus indicating that carnosic acid has no effect on the cyclooxygenase and thromboxane A₂ synthase activity. Overall, these results suggest that the antiplatelet activity of carnosic acid is mediated by the inhibition of cytosolic calcium mobilization and that carnosic acid has the potential of being developed as a novel antiplatelet agent.

Rosmarinus officinalis - Lamiaceae - carnosic acid - calcium mobilization - antiplatelet activity

References

• 1 Majid A, Delanty N, Kantor J. Antiplatelet agents for secondary prevention of ischemic stroke.  Ann Pharmacother. 2001;  35 1241-7
• 2 Jackson S P, Nesbitt W S, Kulkarni S. Signaling events underlying thrombus formation.  J Thromb Haemost. 2003;  1 1602-12
• 3 Jackson S P, Schoenwaelder S M. Antiplatelet therapy: in search of the ”magic bullet”.  Nat Rev Drug Discov. 2003;  2 775-89
• 4 Yamamoto J, Yamada K, Naemura A, Yamashita T, Arai R. Testing various herbs for antithrombotic effect.  Nutrition. 2005;  21 580-7
• 5 Tognolini M, Barocelli E, Ballabeni V, Bruni R, Bianchi A, Chiavarini M. et al . Comparative screening of plant essential oils: phenylpropanoid moiety as basic core for antiplatelet activity.  Life Sci. 2006;  78 1419-32
• 6 Chan M M, Ho C T, Huang H I. Effects of three dietary phytochemicals from tea, rosemary and turmeric on inflammation-induced nitrite production.  Cancer Lett. 1995;  96 23-9
• 7 Sotelo-Felix J I, Martinez-Fong D, Muriel P, Santillan R L, Castillo D, Yahuaca P. Evaluation of the effectiveness of Rosmarinus officinalis (Lamiaceae) in the alleviation of carbon tetrachloride-induced acute hepatotoxicity in the rat.  J Ethnopharmacol. 2002;  81 145-54
• 8 Jin Y R, Cho M R, Lee K S, Lee J J, Lim Y, Han X H. et al . An antithrombotic agent, NQ301, inhibits thromboxane A receptor and synthase activity in rabbit platelets.  Basic Clin Pharmacol Toxicol. 2005;  97 162-7
• 9 Born G V, Cross M J. The aggregation of blood platelets.  J Physiol. 1963;  168 178-95
• 10 Jin Y R, Cho M R, Ryu C K, Chung J H, Yuk D Y, Hong J T. et al . Antiplatelet activity of J78 (2-chloro-3-[2′-bromo-4′-fluoro-phenyl]-amino-8-hydroxy-1,4-naphthoquinone), an antithrombotic agent, is mediated by thromboxane (TX) A₂ receptor blockade with TXA₂ synthase inhibition and suppression of cytosolic Ca²⁺ mobilization.  J Pharmacol Exp Ther. 2005;  312 214-9
• 11 Jin Y R, Ryu C K, Moon C K, Cho M R, Yun Y P. Inhibitory effects of J78, a newly synthesized 1,4-naphthoquinone derivative, on experimental thrombosis and platelet aggregation.  Pharmacology. 2004;  70 195-200
• 12 Holmsen H, Dangelmarier C A. Measurement of secretion of serotonin. Methods Enzymol 1989: 205-10
• 13 Needleman P, Turk J, Jakschik B A, Morrison A R, Lefkowith J B. Arachidonic acid metabolism.  Annu Rev Biochem. 1986;  55 69-102
• 14 Blockmans D, Deckmyn H, Vermylen J. Platelet activation.  Blood Rev. 1995;  9 143-56
• 15 McNicol A, Shibou T S. Translocation and phosphorylation of cytosolic phospholipase A₂ in activated platelets.  Thromb Res. 1998;  92 19-26