title: Protocatechualdehyde synergizes with aspirin at the platelet cyclooxygenase-1 level.
abstract: Polyphenol-aspirin interactions were recently identified; however, the interaction mode and underlying mechanisms remained elusive. Here, we quantitatively assessed the potential interactions among two important polyphenolic compounds, caffeic acid (CA) and protocatechualdehyde (Pro), and aspirin in the AA-induced platelet aggregation model by applying the isobologram and universal response surface approach (URSA) methods. A molecular docking approach and an originally developed platelet-associated aspirin clearance approach (PAACA) were then applied to explore the potential interaction mechanisms. Although Pro and CA themselves exhibited weak inhibitory effect on arachidonic acid (AA)-induced platelet aggregation and the production of thromboxane B₂ (TXB₂), both Pro and CA potentiated aspirin action in a synergistic manner. The most prominent synergism was found between Pro and aspirin. Pro formed a stable complex into the cyclooxygenase-1 (COX-1) channel by in silico docking and significantly promoted the platelet-associated aspirin clearance, suggesting that the Pro interaction with COX-1 was favorable to the binding of aspirin with COX-1. Taken together, our findings suggest that the capacity of Pro and potentially other structurally similar polyphenolic compounds on promoting the binding of aspirin on platelet COX-1 might be the main mechanism of their synergism with aspirin.
authors: Key Lab of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
authors: Shiqing
authors: S
authors: Sun
authors: Haiping
authors: H
authors: Hao
authors: Ping
authors: P
authors: Gong
authors: Zhiyuan
authors: Z
authors: Tang
authors: Feiyan
authors: F
authors: Li
authors: Xiaohu
authors: X
authors: Chen
authors: Haibo
authors: H
authors: Shi
authors: Guangji
authors: G
authors: Wang
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000494:pharmacology; D001241:Aspirin / Q000378:metabolism* / Q000494:pharmacology; D001547:Benzaldehydes / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects; D002109:Caffeic Acids / Q000494:pharmacology*; D002396:Catechols / Q000494:pharmacology*; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D004357:Drug Synergism; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D011817:Rabbits
chemical_list: D000925:Anticoagulants; D000975:Antioxidants; D001547:Benzaldehydes; D002109:Caffeic Acids; D002396:Catechols; D010975:Platelet Aggregation Inhibitors; D016718:Arachidonic Acid; C005581:protocatechualdehyde; D051545:Cyclooxygenase 1; D001241:Aspirin; C040048:caffeic acid