Anti-inflammatory and anti-fibrotic effects of modafinil in nonalcoholic liver disease.

Small- and intermediate-conductance Ca-activated K channels, K2.3 and K3.1, are involved in cellular signaling processes associated with inflammation and fibrosis. K2.3 and K3.1 are upregulated by proinflammatory cytokines and profibrotic growth factors. Cyclic AMP, which downregulates K2.3 and K3.1, is elevated by modafinil in cells; accordingly, we investigated whether modafinil exerts anti-inflammatory and anti-fibrotic responses via K2.3- and K3.1-mediated pathways in high-fat diet (HFD)- or thioacetamide-induced liver disease models in mice. Modafinil was administered orally in the form of a racemate, (R)-isomer, or (S)-isomer. We also determined whether the treatment targeted the profibrotic activity of hepatic stellate cells using immortalized human hepatic stellate cells (LX-2 cells). Modafinil improved HFD- or thioacetamide-induced changes compared to the control, leading to a reduced inflammatory response, collagen deposition, and α-smooth muscle actin expression both in vivo and in vitro. However, modafinil did not relieve HFD-induced steatosis. There were no significant differences in the effects of the (R)- and (S)-isomers of modafinil. K2.3 and K3.1 were upregulated and catalase was downregulated in liver tissues from thioacetamide- or HFD-induced liver disease models or in TGF-β-treated LX-2 cells. TGF-β-induced upregulation of K2.3, K3.1, collagen, and α-smooth muscle actin and downregulation of catalase were reversed by modafinil, polyethylene glycol catalase, N-acetylcysteine, siRNA against K2.3 or K3.1, and Epac inhibitors. Our investigation revealed that modafinil attenuated inflammatory and fibrotic progression via K2.3- and K3.1-mediated pathways in nonalcoholic hepatitis, suggesting that inhibiting K2.3- and K3.1-mediated signaling may serve as a novel therapeutic approach for inflammatory and fibrotic liver diseases.