Synergistic interaction between choline and aspirin against acute inflammation induced by carrageenan and lipopolysaccharide

Abstract

The simultaneous use of drugs with different mechanisms of anti-inflammatory action is a strategy for achieving effective control of inflammation while minimizing dose-related side effects. Choline was described to potentiate the antinociceptive action of aspirin at small doses in several inflammatory pain models. However, these findings are only limited to alleviating pain, more associated data are required to confirm the effectiveness of the combined choline and aspirin therapy against inflammatory disorders. Moreover, no report is available regarding the mechanism responsible for their synergism. Here, we first investigated the anti-inflammatory activity and pharmacological mechanisms of co-administration of choline and aspirin in 2 commonly studied inflammation models, carrageenan-induced paw edema and lipopolysaccharide (LPS)-induced sepsis in mice. Isobolographic analysis revealed that combined choline and aspirin administration exhibited a strong synergistic interaction in reducing carrageenan-mediated edema, and the estimated combination index values at 50%, 75%, and 90% effective dose (ED50, ED75, and ED90) were 0.25, 0.32, and 0.44. Drug co-administration also afforded synergistic protection against LPS-induced sepsis and mortality, since aspirin or choline alone was inadequate to improve survival. The effects of choline-aspirin co-administration were blocked by methyllycaconitine, suggesting that activation of alpha 7 nicotinic acetylcholine receptor participates in the interaction between choline and aspirin. Furthermore, co-administration of choline and aspirin was more likely to inhibit the production of pro-inflammatory mediators induced by LPS. Our results indicated that combined choline and aspirin therapy represented a significant synergistic interaction in attenuating acute inflammatory response. This preclinical relevant evidence provides a promising approach to treat inflammation-based diseases such as arthritis and sepsis.