A novel fused 1,2,4-triazine aryl derivative as antioxidant and nonselective antagonist of adenosine A2A receptors in ethanol-activated liver stellate cells

It has been detected that hepatic adenosine A2A receptors play an active role in the pathogenesis of hepatic fibrosis and suggest a novel therapeutic target in the treatment and prevention of hepatic cirrhosis. In this paper we examined if our new triazine derivative (IMT) can inhibit ethanol-induced activation of HSCs measured as increased α-SMA, collagen synthesis and enhanced oxidative stress in rat liver stellate cells. We also investigated its influence on cytokines (TGF-β, TNF-α) synthesis, MMP-2 and TIMP-1 production and ethanol-induced intracellular signal transduction. Moreover, with using of known adenosine A2A receptor agonist (CGS 21680), and antagonist (SCH 58261) we examined if this triazine derivative acts on adenosine receptors.We detected a strong antagonistic action of new triazine derivative (IMT) on ethanol-induced rat liver stellate cells activation, observed as a significant decrease in α-SMA, collagen synthesis, reactive oxygen species production, TGF-β, TNF-α, MMP-2 and TIMP-1 production as well as JNK, p38MAPK, NFκB, IκB, Smad3 phosphorylation. Moreover, IMT strongly inhibited activation of stellate cells by known selective agonist of adenosine A2A receptor (CGS 21680). When known A2A receptor antagonist (SCH 58261) was used together with IMT this effect was not spectacular. Additionally, only slight enhancement of inhibition was observed when cells were pretreated both IMT with SCH 58261, hence we suppose that IMT acts as nonselective antagonist of A2A receptors, and, besides its antioxidant activity, also by this way inhibited ethanol-induced stellate cell activation.

► Ethanol activates liver stellate cells. ► Chronic activation of stellate cells leads to liver fibrosis. ► New triazine derivative inhibit ethanol-induced activation of stellate cells. ► New triazine derivative acts as nonselective antagonist of A2A receptors.