The Involvement of PPARγ In Anti-Inflammatory Activity of N-Stearoylethanolamide

Abstract

N-stearoylethanolamide (NSE)– a cannabinoid-like compound with wide range of biological activity. Anti-inflammatory properties of NSE have been indicated on different animal models of pathological conditions. However, the molecular mechanisms of anti-inflammatory action of NSE remain unclear. In the current study, the involvement of PPARγ in the NF-kB -dependent anti-inflammatory action of NSE was evaluated using different methodological approach. First method - molecular modeling, evaluated the possibility of NSE to bind with PPAR. Then, in ex vivo experiment, using selective synthetic agonist of PPARα/γ LY-171883 and selective antagonist of PPARγ - GW9662, the role of PPARα /PPARγ in the NSE’s effect on nuclear NF-kB translocation was examined in LPS-activated rat peritoneal macrophages. Finally, the NSE action on the mRNA level of several PPARγ- dependent genes was studied in liver of insulin-resistant rats. The molecular docking results showed that NSE could bind to PPARγ and compete for the binding with antagonist GW9662 and agonist LY171883 in the active site of PPARγ. It also has been found that NSE prevented the LPS-induced NF-kB translocation into the nuclei of rat peritoneal macrophages during pre-treatment with NSE before LPS application. When NSE was added before GW9662 and LPS treatment, the level of NF-kB translocation and IL-1β content reduced to control cells’ levels. These data confirmed a competitive binding of NSE with GW9662 for the ligand-binding domen of PPARγ. In addition, NSE administration to insulin resistant rats changed the mRNA expression of several PPARγ target gens, including FATP1 and IL1-ra.