Modafinil exerts anti-inflammatory and anti-fibrotic effects by upregulating adenosine A2A and A2B receptors

Henderson NC, Rieder F, Wynn TA (2020) Fibrosis: from mechanisms to medicines. Nature 587(7835):555–566. https://doi.org/10.1038/s41586-020-2938-9

Article  CAS  PubMed  PubMed Central  Google Scholar 

Murtha LA, Schuliga MJ, Mabotuwana NS, Hardy SA, Waters DW, Burgess JK, Knight DA, Boyle A (2017) The processes and mechanisms of Cardiac and Pulmonary Fibrosis. Front Physiol 8:777. https://doi.org/10.3389/fphys.2017.00777

Article  PubMed  PubMed Central  Google Scholar 

Hecker L, Logsdon NJ, Kurundkar D, Kurundkar A, Bernard K, Hock T, Meldrum E, Sanders YY, Thannickal VJ (2014) Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Transl Med 6(231):231ra47. https://doi.org/10.1126/scitranslmed.3008182

Article  CAS  PubMed  PubMed Central  Google Scholar 

Duffield JS, Lupher M, Thannickal VJ, Wynn TA (2013) Host responses in tissue repair and fibrosis. Annu Rev Pathol 8:241–276. https://doi.org/10.1146/annurev-pathol-020712-163930

Article  CAS  PubMed  Google Scholar 

Mei Q, Liu Z, Zuo H, Yang Z, Qu J (2021) Idiopathic Pulmonary Fibrosis: an update on Pathogenesis. Front Pharmacol 12:797292. https://doi.org/10.3389/fphar.2021.797292

Article  CAS  PubMed  Google Scholar 

Maher TM, Bendstrup E, Dron L, Langley J, Smith G, Khalid JM, Patel H, Kreuter M (2021) Global incidence and prevalence of Idiopathic Pulmonary Fibrosis. Respir Res 22(1):197. https://doi.org/10.1186/s12931-021-01791-z

Article  PubMed  PubMed Central  Google Scholar 

Cholankeril G, Perumpail RB, Pham EA, Ahmed A, Harrison SA (2016) Nonalcoholic fatty Liver Disease: Epidemiology, Natural History, and Diagnostic challenges. Hepatology 64(3):954. https://doi.org/10.1002/hep.28719

Article  PubMed  Google Scholar 

Raker VK, Becker C, Steinbrink K (2016) The cAMP pathway as therapeutic target in Autoimmune and Inflammatory Diseases. Front Immunol 7:123. https://doi.org/10.3389/fimmu.2016.00123

Article  CAS  PubMed  PubMed Central  Google Scholar 

Insel PA, Murray F, Yokoyama U, Romano S, Yun H, Brown L, Snead A, Lu D, Aroonsakool N (2021) cAMP and Epac in the regulation of tissue fibrosis. Br J Pharmacol 166(2):447–456. https://doi.org/10.1111/j.1476-5381.2012.01847.x

Article  CAS  Google Scholar 

Campo GM, Avenoso A, D’Ascola A, Prestipino V, Scuruchi M, Nastasi G, Calatroni A, Campo S (2012) Protein kinase a mediated anti-inflammatory effects exerted by adenosine treatment in mouse chondrocytes stimulated with IL-1beta. BioFactors 38(6):429–439. https://doi.org/10.1002/biof.1040

Article  CAS  PubMed  Google Scholar 

Hewer RC, Sala-Neby GB, Wu YJ, Newby AC, Bond M (2011) PKA and Epac synergistically inhibit smooth muscle cell proliferation. J Mol Cell Cardiol 50(1):87–98. https://doi.org/10.1016/j.yjmcc.2010.10.010

Article  CAS  PubMed  PubMed Central  Google Scholar 

Choi S, Kim JA, Li H, Jo SE, Lee H, Kim TH, Kim M, Kim SJ, Suh SH (2021) Anti-inflammatory and anti-fibrotic effects of modafinil in nonalcoholic Liver Disease. Biomed Pharmacother 144:112372. https://doi.org/10.1016/j.biopha.2021.112372

Article  CAS  PubMed  Google Scholar 

Roach KM, Bradding P (2020) Ca(2+) signalling in fibroblasts and the therapeutic potential of K(ca)3.1 channel blockers in fibrotic Diseases. Br J Pharmacol 177(5):1003–1024. https://doi.org/10.1111/bph.14939

Article  CAS  PubMed  PubMed Central  Google Scholar 

Choi S, Kim MY, Joo KY, Park S, Kim JA, Jung JC, Oh S, Suh SH (2012) Modafinil inhibits K(ca)3.1 currents and muscle contraction via a cAMP-dependent mechanism. Pharmacol Res 66(1):51–59. https://doi.org/10.1016/j.phrs.2012.02.009

Article  CAS  PubMed  Google Scholar 

Brandao WN, Andersen ML, Palermo-Neto J, Peron JP, Zager A (2019) Therapeutic treatment with Modafinil decreases the severity of experimental autoimmune encephalomyelitis in mice. Int Immunopharmacol 75:105809. https://doi.org/10.1016/j.intimp.2019.105809

Article  CAS  PubMed  Google Scholar 

Pal China S, Pal S, Chattopadhyay S, Porwal K, Mittal M, Sanyal S, Chattopadhyay N (2018) The wakefulness promoting drug Modafinil causes adenosine receptor-mediated upregulation of receptor activator of nuclear factor kappaB ligand in osteoblasts: negative impact of the drug on peak bone accrual in rats. Toxicol Appl Pharmacol 348:22–31. https://doi.org/10.1016/j.taap.2018.04.006

Article  CAS  PubMed  Google Scholar 

Effendi WI, Nagano T, Kobayashi K, Nishimura Y (2020) Focusing on Adenosine Receptors as a potential targeted therapy in Human Diseases. Cells 9(3):785. https://doi.org/10.3390/cells9030785

Article  CAS  PubMed  PubMed Central  Google Scholar 

Scheibner KA, Boodoo S, Collins S, Black KE, Chan-Li Y, Zarek P, Powell JD, Horton MR (2009) The adenosine a2a receptor inhibits matrix-induced inflammation in a novel fashion. Am J Respir Cell Mol Biol 40(3):251–259. https://doi.org/10.1165/rcmb.2008-0168OC

Article  CAS  PubMed  Google Scholar 

Antonioli L, Csoka B, Fornai M, Colucci R, Kokai E, Blandizzi C, Blandizzi C, Hasko G (2014) Adenosine and inflammation: what’s new on the horizon? Drug Discov Today 19(8):1051–1068. https://doi.org/10.1016/j.drudis.2014.02.010

Article  CAS  PubMed  Google Scholar 

Linden J (2006) New insights into the regulation of inflammation by adenosine. J Clin Invest 116(7):1835–1837. https://doi.org/10.1172/JCI29125

Article  CAS  PubMed  PubMed Central  Google Scholar 

Vecchio EA, White PJ, May LT (2017) Targeting Adenosine receptors for the treatment of Cardiac Fibrosis. Front Pharmacol 8:243. https://doi.org/10.3389/fphar.2017.00243

Article  CAS  PubMed  PubMed Central  Google Scholar 

Prisinzano T, Podobinski J, Tidgewell K, Luo M, Swenson D (2004) Synthesis and determination of the absolute configuration of the enantiomers of modafinil. Tetrahedron-Asymmetry 15(6):1053–1058. https://doi.org/10.1016/j.tetasy.2004.01.039

Article  CAS  Google Scholar 

Matsumoto M, Hada N, Sakamaki Y, Uno A, Shiga T, Tanaka C, Ito T, Katsume A, Sudoh M (2013) An improved mouse model that rapidly develops fibrosis in non-alcoholic steatohepatitis. Int J Exp Pathol 94(2):93–103. https://doi.org/10.1111/iep.12008

Article  CAS  PubMed  PubMed Central  Google Scholar 

Salinthone S, Yadav V, Schillace RV, Bourdette DN, Carr DW (2010) Lipoic acid attenuates inflammation via cAMP and protein kinase A signaling. PLoS ONE 5(9):e13058. https://doi.org/10.1371/journal.pone.0013058

Article  CAS  PubMed  PubMed Central  Google Scholar 

Choi S, Kim JA, Li HY, Lee SJ, Seok YS, Kim TH, Han KH, Park MH, Cho GJ, Suh SH (2019) Altered Redox State modulates endothelial K(ca)2.3 and K(ca)3.1 levels in normal pregnancy and Preeclampsia. Antioxid Redox Signal 30(4):505–519. https://doi.org/10.1089/ars.2017.7038

Article  CAS  PubMed  Google Scholar 

Organ L, Bacci B, Koumoundouros E, Kimpton WG, Samuel CS, Nowell CJ, Bradding P, Roach KM, Westall G, Jaffar J, Snibson KJ (2017) Inhibition of the K(ca)3.1 Channel alleviates established pulmonary fibrosis in a large animal model. Am J Respir Cell Mol Biol 56(4):539–550. https://doi.org/10.1165/rcmb.2016-0092OC

Article  CAS  PubMed  Google Scholar 

Lee WR, Kim kh, An HJ, Kim JY, Lee SJ, Han SM, Pak KK (2014) Apamin inhibits hepatic fibrosis through suppression of transforming growth factor beta1-induced hepatocyte epithelial-mesenchymal transition. Biochem Biophys Res Commun 450(1):195–201. https://doi.org/10.1016/j.bbrc.2014.05.089

Article  CAS  PubMed  Google Scholar 

Zhou Y, Murthy JN, Zeng D, Belardinelli L, Blackburn MR (2010) Alterations in adenosine metabolism and signaling in patients with Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis. PLoS ONE 5(2):e9224. https://doi.org/10.1371/journal.pone.0009224

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hasko G, Csoka B, Nemeth AH, Vizi ES, Pacher P (2009) A(2B) adenosine receptors in immunity and inflammation. Trends Immunol 30(6):263–270. https://doi.org/10.1016/j.it.2009.04.001

Article  CAS  PubMed  PubMed Central  Google Scholar 

Frick JS, MacManus CF, Scully M, Glover LF, Eltzsching HK, Clogan SP (2009) Contribution of adenosine A2B receptors to inflammatory parameters of experimental Colitis. J Immunol 182(8):4957–4964. https://doi.org/10.4049/jimmunol.0801324

Article  CAS  PubMed  Google Scholar 

Hasko G, Linden J, Cronstein B, Pacher P (2008) Adenosine receptors: therapeutic aspects for inflammatory and immune Diseases. Nat Rev Drug Discov 7(9):759–770. https://doi.org/10.1038/nrd2638

Article  CAS  PubMed  PubMed Central 

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