Abstract
This study aimed to estimate the protective effect of a combination of S-Adenosyl-L-methionine (SAM) as a precursor of glutathione and oseltamivir as a specific inhibitor of virus replication on oxidative damages caused by influenza infection in the liver of infected mice. Albino mice were inoculated with 10×LD50 of influenza virus A/Aichi/2/68(H3N2). Oseltamivir was applied for five days after infection, twice per day, in a dose of 2.5 mg/kg. SAM was applied for ten days in a 100 mg/kg dose, starting five days before inoculation. Markers of oxidative stress, mortality rate, mean survival time, index, and protection coefficient were followed. Influenza infection causes severe oxidative damage to the liver. All combinations of SAM and oseltamivir restored the levels of the biochemical markers to those in healthy animals and improved the virological parameters. A combination of SAM 100 mg/kg and oseltamivir 2.5 mg/kg, which is 1/4 of the optimal therapeutic mice dose, exhibits protection index and affects most effectively all the tested parameters. This study provides an easy-to-apply approach with a good therapeutic potential for co-medicating influenza infection with a specific antiviral agent and an antioxidant precursor.
References
Zhao L, Yan Y, Dai Q, et al. Development of Novel Anti-influenza Thiazolides with Relatively Broad-spectrum Antiviral Potentials. Antimicrob Agents Chemother 2020; 64(7): e00222-20. https://doi.org/10.1128/AAC.00222-20
Arbeitskreis Blut U, Bewertung BK. Influenza Virus. Transfus Med Hemother 2009; 36(1): 32-39. https://doi.org/10.1159/000197314
WHO. Influenza and COVID-19 - similarities and differences. World Health Organization 2020. https://bit.ly/3iRt6i1.
Han SN, Meydani SN. Antioxidants, Cytokines, and Influenza Infection in Aged Mice and Elderly Humans. J Infect Dis 2000; 182(Supplement_1): S74-S80. https://doi.org/10.1086/315915
Mileva M, Dimitrova A, Krastev D, et al. Oseltamivir and S-Adenosyl-L-Methionine Combination as Effective Therapeutic Strategy for Suppression of Oxidative Damage in Lung Caused by Influenza Virus Infection in Mice. Drug Res (Stuttg) 2020; 70(6): 273-279. https://doi.org/10.1055/a-1147-8824
Liu M, Chen F, Liu T, Chen F, Liu S, Yang J. The role of oxidative stress in influenza virus infection. Microbes Infect 2017; 19(12): 580-586. https://doi.org/10.1016/j.micinf.2017.08.008
Papic N, Pangercic A, Vargovic M, Barsic B, Vince A, Kuzman I. Liver involvement during influenza infection: perspective on the 2009 influenza pandemic. Influenza Other Respi Viruses 2012; 6(3): e2-e5. https://doi.org/10.1111/j.1750-2659.2011.00287.x
Ortega-Alonso A, García-Cortés M, Fernández-Castañer A, Ruiz J, González-Amores Y, Andrade RJ. Acute hepatitis in a woman with influenza A virus: Cause or coincidence? Gastroenteroly Hepatol (English Ed 2016; 39(1): 20-21. https://doi.org/10.1016/j.gastre.2015.12.007
Pielak RM, Schnell JR, Chou JJ. Mechanism of drug inhibition and drug resistance of influenza A M2 channel. Proc Natl Acad Sci U S A 2009; 106(18): 7379-7384. https://doi.org/10.1073/pnas.0902548106
Davies BE. Pharmacokinetics of Oseltamivir: an oral antiviral for the treatment and prophylaxis of influenza in diverse populations. J Antimicrob Chemother 2010; 65(suppl_2): ii5-ii10. https://doi.org/10.1093/jac/dkq015
Shie J-J, Fang J-M. Development of effective anti-influenza drugs: congeners and conjugates – a review. J Biomed Sci 2019; 26(1): 84. https://doi.org/10.1186/s12929-019-0567-0
Moseley CE, Webster RG, Aldridge JR. Peroxisome proliferator-activated receptor and AMP-activated protein kinase agonists protect against lethal influenza virus challenge in mice. Influenza Other Respi Viruses 2010; 4(5): 307-311. https://doi.org/10.1111/j.1750-2659.2010.00155.x
Lieber CS. S-adenosyl-L-methionine: Its role in the treatment of liver disorders. Am J Clin Nutr 2002; 76(5): 1183S-1187S. https://doi.org/10.1093/ajcn/76.5.1183S
Mato JM, Lu SC. Role of S-adenosyl-L-methionine in liver health and injury. Hepatology 2007; 45(5): 1306-1312. https://doi.org/10.1002/hep.21650
Wu JH, Batist G. Glutathione and glutathione analogues; Therapeutic potentials. Biochim Biophys Acta - Gen Subj 2013; 1830(5): 3350-3353. https://doi.org/10.1016/j.bbagen.2012.11.016
Mileva M, Tancheva L, Bakalova R, Galabov A, Savov V, Ribarov S. Effect of vitamin E on lipid peroxidation and liver monooxigenase activity in experimental influenza virus infection. Toxicol Lett 2000; 114(1-3): 39-45. https://doi.org/10.1016/S0378-4274(99)00265-9
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193(1): 265-275. https://doi.org/10.1016/S0021-9258(19)52451-6
Tietze T. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: Applications to mammalian blood and other tissues. Anal Biochem 1969; 27(3): 502-522. https://doi.org/10.1016/0003-2697(69)90064-5
Beauchamp C, Fridovich I. Superoxide dismutase: Improved assays and an assay applicable to acrylamide gels. Anal Biochem 1971; 44(1): 276-287. https://doi.org/10.1016/0003-2697(71)90370-8
Gunzler WA, Vergin H, Muller I, Flohe L. [Glutathione peroxidase VI: the reaction of glutahione peroxidase with various hydroperoxides]. Hoppe Seylers Z Physiol Chem 1972; 353(6): 1001-1004.
Pinto RE, Bartley W. The effect of age and sex on glutathione reductase and glutathione peroxidase activities and on aerobic glutathione oxidation in rat liver homogenates. Biochem J 1969; 112(1): 109-115. https://doi.org/10.1042/bj1120109
Aebi H. Catalase in vitro. Methods Enzymol 1984; 105: 121-126. https://doi.org/10.1016/S0076-6879(84)05016-3
Grunert RR, McGahen JW, Davies WL. The in vivo antiviral activity of 1-adamantanamine (amantadine). I. Prophylactic and therapeutic activity against influenza viruses. Virology 1965; 26: 262-269. https://doi.org/10.1016/0042-6822(65)90273-4
Galabov AS, Simeonova L, Gegova G. Rimantadine and Oseltamivir demonstrate synergistic combination effect in an experimental infection with type A (H3N2) influenza virus in mice. Antivir Chem Chemother 2006; 17(5): 251-258. https://doi.org/10.1177/095632020601700502
Frankova V, Rychterova V. Inhalatory infection of mice with influenza A0/PR8 virus. II. Detection of the virus in the blood and extrapulmonary organs. Acta Virol 1975; 19(1): 35-40.
Whitworth JR, Mack CL, O’Connor JA, Narkewicz MR, Mengshol S, Sokol RJ. Acute Hepatitis and Liver Failure Associated With Influenza A Infection in Children. J Pediatr Gastroenterol Nutr 2006; 43(4): 536-8. https://doi.org/10.1097/01.mpg.0000232332.00677.3d
Arnheiter H, Haller O, Lindenmann J. Pathology of Influenza Hepatitis in Susceptible and Genetically Resistant Mice. Pathobiology 1976; 44(2): 95-107. https://doi.org/10.1159/000163103
Fislova T, Gocnik M, Sladkova T, et al. Multiorgan distribution of human influenza A virus strains observed in a mouse model. Arch Virol 2009; 154(3): 409-419. https://doi.org/10.1007/s00705-009-0318-8
Tiegs G. Cellular and cytokine-mediated mechanisms of inflammation and its modulation in immune-mediated liver injury. Z Gastroenterol 2007; 45(1): 63-70. https://doi.org/10.1055/s-2006-927397
Mileva M, Hadjimitova V, Tantcheva L, et al. Antioxidant properties of rimantadine in influenza virus infected mice and in some model systems. Zeitschrift fur Naturforsch - Sect C J Biosci 2000; 55(9-10): 824-829. https://doi.org/10.1515/znc-2000-9-1025
Hennet T, Peterhans E, Stocker R. Alterations in antioxidant defences in lung and liver of mice infected with influenza A virus. J Gen Virol 1992; 73(1): 39-46. https://doi.org/10.1099/0022-1317-73-1-39
Ghezzi P. Role of glutathione in immunity and inflammation in the lung. Int J Gen Med 2011; 4: 105-113. https://doi.org/10.2147/IJGM.S15618
Scott CL, Guilliams M. The role of Kupffer cells in hepatic iron and lipid metabolism. J Hepatol 2018; 69(5): 1197-1199. https://doi.org/10.1016/j.jhep.2018.02.013
Bonnardel J, T’Jonck W, Gaublomme D, et al. Stellate Cells, Hepatocytes, and Endothelial Cells Imprint the Kupffer Cell Identity on Monocytes Colonizing the Liver Macrophage Niche. Immunity 2019; 51(4): 638-654.e9. https://doi.org/10.1016/j.immuni.2019.08.017
Barrera C, Valenzuela R, Rincón MÁ, et al. Molecular mechanisms related to the hepatoprotective effects of antioxidant-rich extra virgin olive oil supplementation in rats subjected to short-term iron administration. Free Radic Biol Med 2018; 126: 313-321. https://doi.org/10.1016/j.freeradbiomed.2018.08.030
Thong-Ngam D, Samuhasaneeto S, Kulaputana O, Klaikeaw N. N-acetylcysteine attenuates oxidative stress and liver pathology in rats with non-alcoholic steatohepatitis. World J Gastroenterol 2007; 13(38): 5127-5132. https://doi.org/10.3748/wjg.v13.i38.5127
de Andrade KQ, Moura FA, dos Santos JM, de Araújo ORP, de Farias Santos JC, Goulart MOF. Oxidative Stress and Inflammation in Hepatic Diseases: Therapeutic Possibilities of N-Acetylcysteine. Int J Mol Sci 2015; 16(12): 30269-30308. https://doi.org/10.3390/ijms161226225
Guzmán DC, García EH, Brizuela NO, et al. Effect of Oseltamivir on catecholamines and select oxidative stress markers in the presence of oligoelements in the rat brain. Arch Pharm Res 2010; 33(10): 1671-1677. https://doi.org/10.1007/s12272-010-1017-4
Guzmán DC, Herrera MO, Brizuela NO, et al. Oseltamivir and indomethacin reduce the oxidative stress in brain and stomach of infected rats. APMIS 2018; 126(2): 128-134. https://doi.org/10.1111/apm.12794
Pavlova EL, Simeonova LS, Gegova GA. Combined efficacy of Oseltamivir, isoprinosine and ellagic acid in influenza A(H3N2)-infected mice. Biomed & Pharmacother = Biomed & Pharmacother 2018; 98: 29-35. https://doi.org/10.1016/j.biopha.2017.12.014
Lozano-Sepulveda SA, Bautista-Osorio E, Merino-Mascorro JA, et al. S-adenosyl-L-methionine modifies antioxidant-enzymes, glutathione-biosynthesis and methionine adenosyltransferases-1/2 in hepatitis C virus-expressing cells. World J Gastroenterol 2016; 22(14): 3746-3757. https://doi.org/10.3748/wjg.v22.i14.3746
Mato JM, Corrales FJ, Lu SC, Avila MA. S-Adenosylmethionine: a control switch that regulates liver function. FASEB J OffPubl Fed Am Soc Exp Biol 2002; 16(1): 15-26. https://doi.org/10.1096/fj.01-0401rev
Nieto N, Cederbaum AI. S-adenosyl-L-methionine blocks collagen I production by preventing transforming growth factor-beta induction of the COL1A2 promoter. J Biol Chem 2005; 280(35): 30963-30974. https://doi.org/10.1074/jbc.M503569200
Caro AA, Cederbaum AI. Antioxidant properties of S-adenosyl-L-methionine in Fe(2+)-initiated oxidations. Free Radic Biol Med 2004; 36(10): 1303-1316. https://doi.org/10.1016/j.freeradbiomed.2004.02.015
Cichoż-Lach H, Michalak A. Oxidative stress as a crucial factor in liver diseases. World J Gastroenterol 2014; 20(25): 8082-8091. https://doi.org/10.3748/wjg.v20.i25.8082
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
Copyright (c) 2022 Milka Mileva, Adriana Dimitrova-Koleva, Elina Tsvetanova, Dimo Krastev, Almira Georgieva, Albena Alexandrova, Angel Galabov