Here, we investigate the effects of quercetin supplementation to aspirin as a new treatment regimen to alleviate symptoms and improve gestational outcomes of rats with pre-eclampsia-like symptoms. The potential adverse effects associated with aspirin, which prohibits the use of a high dose of aspirin in pregnant women, as well as recent reports of suboptimal efficacies of aspirin in treating pre-eclampsia prompted us to investigate if supplementation with another biocompatible drug while achieving similar or even higher therapeutic effects can improve therapeutic efficacies. During pre-eclampsia development, inflammation intensifies, along with elevated lipid peroxidation products, reactive oxygen species, and anti-angiogenic factors including sFlt-1 and vascular endothelial growth factor in placental tissue and maternal circulation [
24]. Quercetin as a lead flavonoid in clinical development has garnered significant attention predominantly owing to its safety profile and strong anti-inflammatory efficacies. Prior studies support that flavonoid supplementation to aspirin is efficacious in stimulating platelet aggregation [
25], rendering enhanced antithrombotic effects. It is also recently reported that a potential interaction between quercetin and aspirin exists, thereby exerting a synergic, rather than additive, effect [
25] that makes this treatment regimen attractive. In an L-NAME-induced pre-eclampsia rat model, we showed that quercetin supplementation to aspirin indeed achieved higher effects of lowering systolic blood pressure, proteinuria, as well as improving gestational outcomes [
22]. The combinatory treatment also achieved a stronger effect in suppressing lipid peroxidation products. Inflammatory responses, measured by the production of IL-6 and IL-10, were also suppressed [
22]. Our data further confirmed the utility of such combinatory treatment in the LPS-induced PE rat model, which tested the efficacy of this combinatory approach in another animal model of pre-eclampsia, serving as important evidence that supports further development of such combinatory treatment as a clinical tool in managing pre-eclampsia.
One shining point of our study is that we also focused on investigating how the NLRP3 inflammasome was affected by quercetin/aspirin combinatory treatment, which has been rarely explored previously. NLRP3 is one of the most well-studied inflammasomes that in response to diverse stimuli binds to the inactive pro-caspase-1 enzyme and apoptosis-associated speck-like protein containing a caspase recruitment domain, forming an inflammasome complex that further promotes pro-inflammatory cytokine production [
23]. Yet there is scant information on the role NLRP3 inflammasome plays in pre-eclampsia, and the interaction between quercetin and NLRP3 has been demonstrated in studying neurotoxicity [
26]. It was recently demonstrated that expression of the NLRP3 inflammasome is pronouncedly higher in women with pre-eclampsia compared with normotensive pregnant women. The fact that quercetin/aspirin treatment greatly downregulates the expression of the NLRP3 inflammasome is consistent with attenuated cytokine production in pre-eclampsia rats. Our study also corroborated that quercetin may also serve as a new potent inhibitor of the NLRP3 inflammasome.
Despite demonstrating the remarkable efficacy of the quercetin/aspirin treatment in rat models, further studies that gauge the efficacy in human patients are extremely important. As both quercetin and aspirin have been used in humans, we foresee a shorter clinical path. Further, our study did not evaluate the effects of dose and treatment schedule on gestational outcomes, which needs to be addressed to facilitate translation.