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

Abstract

Small- and intermediate-conductance Ca2+-activated K+ channels, KCa2.3 and KCa3.1, are involved in cellular signaling processes associated with inflammation and fibrosis. KCa2.3 and KCa3.1 are upregulated by proinflammatory cytokines and profibrotic growth factors. Cyclic AMP, which downregulates KCa2.3 and KCa3.1, is elevated by modafinil in cells; accordingly, we investigated whether modafinil exerts anti-inflammatory and anti-fibrotic responses via KCa2.3- and KCa3.1-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. KCa2.3 and KCa3.1 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 KCa2.3, KCa3.1, collagen, and α-smooth muscle actin and downregulation of catalase were reversed by modafinil, polyethylene glycol catalase, N-acetylcysteine, siRNA against KCa2.3 or KCa3.1, and Epac inhibitors. Our investigation revealed that modafinil attenuated inflammatory and fibrotic progression via KCa2.3- and KCa3.1-mediated pathways in nonalcoholic hepatitis, suggesting that inhibiting KCa2.3- and KCa3.1-mediated signaling may serve as a novel therapeutic approach for inflammatory and fibrotic liver diseases.

• Authors: Shinkyu Choi, Ji Aee Kim, Haiyan Li, Seong-Eun Jo, Huisu Lee, Tae Hun Kim, Minje Kim, Seong-Jin Kim, Suk Hyo Suh
• Journal: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie (Biomed Pharmacother) Vol. 144 Pg. 112372 (Dec 2021) ISSN: 1950-6007 [Electronic] France
• PMID: 34794237 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier Masson SAS.

Chemical References

• Actins
• Anti-Inflammatory Agents, Non-Steroidal
• Intermediate-Conductance Calcium-Activated Potassium Channels
• Kcnn3 protein, mouse
• Kcnn4 protein, mouse
• Small-Conductance Calcium-Activated Potassium Channels
• Thioacetamide
• Collagen
• Modafinil

Topics

• Actins (biosynthesis)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology, therapeutic use)
• Cell Line
• Collagen (metabolism)
• Diet, High-Fat
• Fatty Liver (drug therapy)
• Hepatic Stellate Cells
• Humans
• Intermediate-Conductance Calcium-Activated Potassium Channels (drug effects)
• Liver Cirrhosis (drug therapy)
• Male
• Mice
• Mice, Inbred C57BL
• Modafinil (therapeutic use)
• Non-alcoholic Fatty Liver Disease (drug therapy)
• Small-Conductance Calcium-Activated Potassium Channels (drug effects)
• Stereoisomerism
• Thioacetamide (toxicity)