Aspirin: The Mechanism of Action Revisited in the Context of Pregnancy Complications

Abstract

Aspirin is one of the most frequently used and cheapest drugs in medicine. It belongs to the non-steroidal anti-inflammatory drugs with a wide range of pharmacological activities, including analgesic, antipyretic, and antiplatelet properties. Currently, it is accepted to prescribe a low dose of aspirin to pregnant women who are at high risk of preeclampsia (PE) because it reduces the onset of this complication. Another pregnancy alteration in which a low dose of aspirin is recommended is the obstetric antiphospholipid syndrome (APS). The most recognized mechanism of action of aspirin is to inhibit the synthesis of prostaglandins but this by itself does not explain the repertoire of anti-inflammatory effects of aspirin. Later, another mechanism was described: the induction of the production of aspirin-triggered lipoxins (ATLs) from arachidonic acid by acetylation of the enzyme cyclooxygenase-2. The availability of a stable analog of ATL has stimulated investigations on the use of this analog and it has been found that, similar to endogenously produced lipoxins, ATL resolves inflammation and acts as antioxidant and immunomodulator. If we consider that in PE and in the obstetric APS, there is an underlying inflammatory process, aspirin might be used based on the induction of ATL. The objective of this review is to revisit the old and new mechanisms of action of aspirin. In particular, it intends to show other potential uses of this drug to prevent certain pregnancy complications in the light of its ability to induce anti-inflammatory and pro-resolving lipid-derived mediators.

Keywords: anti-inflammatory; aspirin-triggered lipoxins; obstetric antiphospholipid syndrome; preeclampsia; pregnancy complications; pro-resolving lipid-derived mediators.

Figure 1

Pharmacological and biological actions of aspirin by its salicylate and reactive acetyl group.

Figure 2

Synthesis of pro-inflammatory and pro-resolving lipid mediators from arachidonic acid (AA). By the action of cyclooxygenases-1 and -2, the prostanoids prostacyclins, prostaglandins and thromboxanes, are produced. These enzymes are inhibited by non-steroidal anti-inflammatory drugs, including aspirin. If AA interacts with 5-lypoxigenase (5-LO), leukotrienes, also important mediators of inflammation, are produced. In the control of inflammatory response, the metabolite 15(S)-hydroxy-eicosatetraenoic acid (15S-HETE) is produced from LO from different cellular sources. This metabolite, through interaction with 5-LO in leukocytes by transcellular biosynthesis, produces some lipid mediators so-called lipoxins. Additionally, as an exclusive property of aspirin, by its reactive acetate group, aspirin can acetylate the active site of cyclooxygenase (COX)-2. This interaction inhibits its catalytic activity as a COX but redirects it, leading to the production of 15R-HETE from AA. 15R-HETE is then also converted through transcellular biosynthesis, by white-cell 5-LO, into aspirin-triggered lipoxins.