Antiplatelet effect of phloroglucinol is related to inhibition of cyclooxygenase, reactive oxygen species, ERK/p38 signaling and thromboxane A2 production

• Published in: Toxicology and applied pharmacology Vol. 263; no. 3; pp. 287 - 295
• Main Authors: Chang, Mei-Chi, Chang, Hsiao-Hua, Chan, Chiu-Po, Chou, Han-Yi, Chang, Bei-En, Yeung, Sin-Yuet, Wang, Tong-Mei, Jeng, Jiiang-Huei
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Inc 15.09.2012; Elsevier
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology; Animals; Anti-inflammatory; Antiplatelet; Arachidonic Acid - pharmacology; Biological and medical sciences; Blood Platelets - drug effects; Blood Platelets - metabolism; Cyclooxygenase; Cyclooxygenase 1 - drug effects; Cyclooxygenase 1 - metabolism; Cyclooxygenase 2 - drug effects; Cyclooxygenase 2 - metabolism; Dose-Response Relationship, Drug; Humans; Inhibitory Concentration 50; Interleukin-1beta - administration & dosage; Male; Medical sciences; Mice; Mice, Inbred ICR; p38 Mitogen-Activated Protein Kinases - metabolism; Phloroglucinol; Phloroglucinol - administration & dosage; Phloroglucinol - pharmacology; Phosphorylation - drug effects; Platelet aggregation; Platelet Aggregation - drug effects; Platelet Aggregation Inhibitors - administration & dosage; Platelet Aggregation Inhibitors - pharmacology; Rabbits; Reactive oxygen species; Reactive Oxygen Species - metabolism; Signal Transduction - drug effects; Thromboxane A2 - biosynthesis; Toxicology; AA; Reactive oxygen species; PMA; Phloroglucinol; Platelet aggregation; COX; PRP; DCFH-DA; LDH; PPP; Antiplatelet; Cyclooxygenase; TXB2; LOX; ROS; HBSS; Anti-inflammatory; ERK; Prostaglandin-endoperoxide synthase; Oxidative stress; Extracellular signal-regulated protein kinase; Biosynthesis; Aggregation; Signal transduction; Hemostasis; Eicosanoid; Inhibition; Enzyme; Arachidonic acid derivatives; Transferases; Thromboxane A2; Antiinflammatory agent; Mitogen-activated protein kinase; Antitussive agent; Antiplatelet agent; Platelet; Platelet function; Oxidoreductases
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2012.06.021

Platelet dysfunction is a major risk factor of cardiovascular diseases such as atherosclerosis, stroke and myocardial infarction. Many antiplatelet agents are used for prevention and treatment of these diseases. In this study, phloroglucinol (2.5–25μM) suppressed AA-induced platelet aggregation and thromboxane B2 (TXB2) production, but not U46619-induced platelet aggregation. Phloroglucinol (100–250μM) showed little cytotoxicity to platelets. Phloroglucinol inhibited the COX-1 and COX-2 activities by 45–74% and 49–72% respectively at concentrations of 10–50μM. At concentrations of 1 and 5μM, phloroglucinol attenuated the AA-induced ROS production in platelets by 30% and 53%, with an IC50 of 13.8μM. Phloroglucinol also inhibited the PMA-stimulated ROS production in PMN. Preincubation of platelets by phloroglucinol (10–25μM) markedly attenuated the AA-induced ERK and p38 phosphorylation. Intravenous administration of phloroglucinol (2.5 and 5μmol/mouse) suppressed the ex vivo AA-induced platelet aggregation by 57–71%. Phloroglucinol administration also elevated the mice tail bleeding time. Moreover, phloroglucinol inhibited the IL-1β-induced PGE2 production in pulp fibroblasts. These results indicate that antiplatelet and anti-inflammatory effects of phloroglucinol are related to inhibition of COX, ROS and TXA2 production as well as ERK/p38 phosphorylation in platelets. Phloroglucinol further suppress PMA-induced ROS production in PMN. The antiplatelet effect of phloroglucinol was confirmed by ex vivo study. Clinically, the consumption of phloroglucinol-containing food/natural products as nutritional supplement may be helpful to cardiovascular health. Phloroglucinol has potential pharmacological use. ► Phloroglucinol suppressed AA-induced platelet aggregation and thromboxane production. ► Phloroglucinol inhibited COX activity and IL-1b-induced PGE2 production in fibroblast. ► Phloroglucinol declined platelet and PMN ROS production and ERK/p38 phosphorylation. ► Phloroglucinol suppressed ex vivo AA-induced platelet aggregation. ► Phloroglucinol may prevent and for treatment of atherosclerosis/ vascular diseases.