Ferulic Acid (FA) is an important polyphenol found in many traditional Chinese medicines (e.g., Ligusticum chuanxiong and Radix Angelicae Sinensis) and belongs to the cinnamic acid derivatives of phenolic acids, whose pharmacophore (catechol) possesses antioxidant, anti-inflammatory, and antimicrobial activities. In addition, this compound accelerates blood circulation, removes blood stasis and has a role in regulating coagulation. Studies have shown that ferulic acid exerts antithrombotic effects by inhibiting platelet aggregation and protecting endothelial cells. At the same time, ferulic acid promotes the formation and differentiation of haematopoietic progenitor cells, protects intestinal cells from damage, and has fewer side effects on platelets, leukocytes, and the gastrointestinal tract, making it a potential protectant against thrombotic diseases, such as cardiovascular dysfunction, pulmonary thromboembolism, and deep vein thrombosis.

Inhibitory effect of ferulic acid on platelet aggregation

Platelet aggregation can lead to thrombotic diseases such as pulmonary embolism and atherosclerosis. Therefore, inhibiting platelet aggregation is a key factor in the prevention and treatment of thrombotic diseases. At present, aspirin is the first choice for the prevention and treatment of thrombotic diseases. Ferulic acid, like aspirin, can significantly reduce the mortality of pulmonary thrombosis in mice. At the same time, FA can also prolong the bleeding and coagulation time of the tail of mice. FA also slightly changed the activated partial thromboplastin time, prothrombin time and thrombin time of rats. These coagulation parameters and platelets are the two most important factors in intravascular coagulation. The changes in coagulation parameters indicate that the antithrombotic activity of FA may be regulated by inhibiting platelet aggregation rather than inhibiting the release of thromboplastin or the formation of thrombin. Its mechanism of action may be to inhibit platelet aggregation through intracellular cyclic nucleotide signaling.

Protective effect of ferulic acid on vascular endothelial cells

Vascular endothelial cells play a vital role in thrombosis. Damaged vascular endothelial cells express excessive adhesion factors that promote leukocyte adhesion to endothelial cells and platelets. Leukocytes and endothelial cell/platelet complexes regulate platelet activation and coagulation cascades. Therefore, the overactivation of leukocytes during stress response and the adhesion of activated leukocytes to endothelial cells/platelets play an important role in the activation of the coagulation cascade. These two processes may affect blood flow and thrombus formation and induce a systemic procoagulant state. Studies have shown that ferulic acid attenuates the expression of intercellular cell adhesion molecule 1, vascular cell adhesion molecule 1, and vWF through the JNK signaling pathway. In addition, FA inhibits the adhesion of radiation-induced lymphoma to endothelial cells. Adhesion factors and collagen fibers are two key factors in the formation of vascular endothelial cell thrombosis. After more severe damage to vascular endothelial cells, collagen fibers are exposed. Platelets adhered to phosphatidylserine are expressed by exposed collagen fibers. In the process of close contact with collagen fibers, activated platelets proliferate layer by layer and are recruited and activated by secretory products, including TXA2, TXB2, and ADP19. Studies have shown that FA dose-dependently reduces the production of TXB2 activated by collagen or ADP4. Therefore, endothelial cell protection is another important evidence of FA's antithrombotic activity.

Side effects of ferulic acid

Thrombocytopenia, leukopenia, bleeding and gastrointestinal reactions are the main side effects of antithrombotic drugs currently used in clinical practice, and ferulic acid has a bidirectional regulatory effect on platelets and leukocytes. Studies have found that ferulic acid can significantly improve the recovery of platelets and leukocytes because it can increase the formation of hematopoietic progenitor cell clones, which can differentiate into platelets and leukocytes under the induction of corresponding cytokines. In addition, within the concentration range of 0-500 nM, FA has no cytotoxic effect on IEC-6, but shows a protective effect on intestinal epithelial barrier dysfunction caused by heat stress. Therefore, ferulic acid is expected to become an antithrombotic drug with fewer side effects.

References:

[1] SHUAI S, YUE G, BEIJING, et al. Ferulic Acid, A Potential Antithrombotic Drug[C]. 2018: 0. DOI:10.29245/2689-999x/2017/2.1127.