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Drug Res (Stuttg) 2020; 70(06): 273-279
DOI: 10.1055/a-1147-8824
Original Article

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

Milka Mileva
1   The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
,
Adriana Dimitrova
1   The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
,
Dimo Krastev
2   Medical University of Sofia, Medical College, Sofia, Bulgaria
,
Albena Alexandrova
3   Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
,
Elina Tsvetanova
3   Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
,
Almira Georgieva
3   Institute of Neurobiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
,
Angel Galabov
1   The Stephan Angeloff Institute of Microbiology, Bulgarian Academy of Sciences, Sofia, Bulgaria
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Abstract

Background and objectives The pathogenesis of influenza infection is associated with two general processes in the body: (a) lung damage based on virus replication; (b) overproduction of free radicals, antioxidant deficiency, and development of oxidative stress. To attack these aspects of flu pathogenesis, we explored the combined effect of the antiviral agent oseltamivir, and s-adenosyl-l-methionine (SAM) as a precursor of the endogenous antioxidant glutathione, in mice infected with influenza virus.

Methods After inoculation of albino mice with 10 MLD50 of influenza virus A/Aichi/2/68 (H3N2), oseltamivir was applied twice a day, for five days post-infection in doses of 1.25 and 2.5 mg/kg. SAM was administered once a day for 10 days, starting 5 days before infection in doses of 50, 100 and 150 mg/kg.

Results Monotherapy with SAM did not influence the markers of oxidative stress in the lung. Combination of SAM 50 mg/kg and oseltamivir 2.5 mg/kg affected best the virological parameters - viral titer, protection index, and mean survival time, as well as the biochemical markers of oxidative stress.

Interpretation and conclusions Combining of SAM and oseltamivir in a dose of 1/4 of optimal therapeutic could be considered as a perspective therapy of influenza viral infection.

Key words:

influenza infection - oxidative stress - antioxidant - glutathione


Publication History

Received: 12 February 2020

Accepted: 25 March 2020

Article published online:
21 April 2020

© Georg Thieme Verlag KG
Stuttgart · New York

 

  • References

  • 1 Han SN, Meydani SN. Antioxidants, cytokines, and influenza infection in aged mice and elderly humans. J Infect Dis 2002; 182: S74-S80 2002
    PubMedSearch in Google Scholar
  • 2 Taubenberger JK, Morens DM. The pathology of influenza virus infections. Annu Rev Pathol Mech Dis 2007; 071015171337001
    PubMed
  • 3 Kuiken T, Riteau B, Fouchier RAM. et al. Pathogenesis of influenza virus infections: The good, the bad and the ugly. Current Opinion in Virology. 2012
    PubMedSearch in Google Scholar
  • 4 Sood MM. et al. Acute kidney injury in critically ill patients infected with 2009 pandemic influenza A(H1N1): report from a Canadian Province. Am J Kidney Dis 2010; 55: 848-855
    CrossrefPubMedSearch in Google Scholar
  • 5 Peterhans E. Reactive oxygen species and nitric oxide in viral diseases. Biological Trace Element Research 1997; 107-116
    PubMedSearch in Google Scholar
  • 6 Anitha TA, Rajadurai M. Antioxidative potential of chrysin, a flavone in streptozotocin-nicotinamide-induced diabetic rats. Biomed Prev Nutr 2014; 4: 511-517
    CrossrefPubMedSearch in Google Scholar
  • 7 Mileva M. 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: 824-829
    PubMedSearch in Google Scholar
  • 8 Nencioni L. et al. Influenza A virus replication is dependent on an antioxidant pathway that involves GSH and Bcl-2. FASEB J 2003; 17: 758-760
    CrossrefPubMedSearch in Google Scholar
  • 9 Taylor EW. Selenium and viral diseases: Facts and hypotheses. J Orthomol Med 1997; 12: 227-239
    PubMedSearch in Google Scholar
  • 10 Mileva M, Tancheva L, Bakalova R. et al. Effect of vitamin E on lipid peroxidation and liver monooxigenase activity in experimental influenza virus infection. Toxicol Lett 2000; 114: 39-45
    CrossrefPubMedSearch in Google Scholar
  • 11 Galabov AS, Mileva M, Simeonova L. et al. Combination activity of neuraminidase inhibitor oseltamivir and alpha-tocopherol in influenza virus A (H3N2) infection in mice. Antivir Chem Chemother 2015; 24: 83-91
    CrossrefPubMedSearch in Google Scholar
  • 12 Mato JM, Lu SC. Role of S-adenosyl-L-methionine in liver health and injury. Hepatology 2007; 45: 1306-1312
    CrossrefPubMedSearch in Google Scholar
  • 13 Medici V. et al. S-adenosyl-L-methionine treatment for alcoholic liver disease: A double-blinded, randomized, placebo-controlled trial. Alcohol Clin Exp Res 2011; 35: 1960-1965
    CrossrefPubMedSearch in Google Scholar
  • 14 Sueblinvong V, Kerchberger VE, Saghafi R. et al. Chronic alcohol ingestion primes the lung for bleomycin-induced fibrosis in mice. Alcohol Clin Exp Res 2014; 38: 336-343
    CrossrefPubMedSearch in Google Scholar
  • 15 Yoon SY, Hong GH, Kwon HS. et al. S-adenosylmethionine reduces airway inflammation and fibrosis in a murine model of chronic severe asthma via suppression of oxidative stress. Exp Mol Med 2016; 48: e236
    CrossrefPubMedSearch in Google Scholar
  • 16 Reed LJ, Muench H. A simple method of estimating fifty per cent endpoints. Am J Epidemiol 1938; 27: 493-497
    CrossrefPubMedSearch in Google Scholar
  • 17 Lowry OH, Rosebrough NJ, Farr AL. et al. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265-275
    CrossrefPubMedSearch in Google Scholar
  • 18 Tietze F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: Applications to mammalian blood and other tissues. Anal Biochem 1969; 27: 502-522
    CrossrefPubMedSearch in Google Scholar
  • 19 Beauchamp C, Fridovich I. Superoxide dismutase: Improved assays and an assay applicable to acrylamide gels. Anal Biochem 1971; 44: 276-287
    CrossrefPubMedSearch in Google Scholar
  • 20 Cartier P, Leroux JP, Marchand JC. Methods of determination of tissue glycolytic enzymes. Ann Biol Clin (Paris) 1967; 25: 109-136
    PubMedSearch in Google Scholar
  • 21 Gunzler WA, Vergin H, Muller I. et al. Glutathione peroxidase VI: the reaction of glutahione peroxidase with various hydroperoxides. Hoppe Seylers Z Physiol Chem 1972; 353: 1001-1004
    CrossrefPubMedSearch in Google Scholar
  • 22 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: 109-115
    CrossrefPubMedSearch in Google Scholar
  • 23 Aebi H. Catalase in vitro. Methods Enzymol 1984; 105: 121-126
    PubMedSearch in Google Scholar
  • 24 Ghezzi P, Ungheri D. Synergistic combination of n-acetylcysteine and ribavirin to protect from lethal influenza viral infection in a mouse model. Int J Immunopathol Pharmacol 2004; 17: 99-102
    CrossrefPubMedSearch in Google Scholar
  • 25 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: 251-258
    CrossrefPubMedSearch in Google Scholar
  • 26 Kamps B, Hoffmann Ch., Preiser W. Influenza Report 2006. J of Geoph Res; 2006
    PubMedSearch in Google Scholar
  • 27 Cai J, Chen Y, Seth S. et al. Inhibition of influenza infection by glutathione. Free Radic Biol Med 2003; 34: 928-936
    CrossrefPubMedSearch in Google Scholar
  • 28 Garozzo A, Tempera G, Ungheri D. et al. N-acetylcysteine synergizes with oseltamivir in protecting mice from lethal influenza infection. Int J Immunopathol Pharmacol 2007; 20: 349-354
    CrossrefPubMedSearch in Google Scholar
  • 29 Kim BY. et al. Concurrent progress of reprogramming and gene correction to overcome therapeutic limitation of mutant ALK2-iPSC. Exp Mol Med 2016; 48: e237
    CrossrefPubMedSearch in Google Scholar
  • 30 Amatore D. et al. Influenza virus replication in lung epithelial cells depends on redox-sensitive pathways activated by NOX4-derived ROS. Cell Microbiol 2015; 17: 131-145
    CrossrefPubMedSearch in Google Scholar