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Glutathione and Covid-19 Infection

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Given that a vaccine for COVID-19 is quite possibly a long way off, it is more important than ever to explore other avenues of protecting your health. Even if a successful vaccine becomes available, it will be many years before entire populations can be immunized. Strong scientific evidence is now implicating oxidative stress in individual’s susceptibility to detrimental health outcomes with COVID-19 [1, 2].

Some recent studies have shown that profoundly serious infections with COVID-19, and its associated high risk of death, are due to glutathione deficiency [3]. Additionally, a preliminary pilot trial with two COVID-19 patients found some improvement in respiratory symptoms after dosing with glutathione [4]. This has led to several researches advocating the use of either glutathione itself [3, 5] or N-acetylcysteine [6] as a treatment for COVID-19 patients. Although the intention to increase cellular glutathione is likely to be of benefit for the reasons outlined below. The newly available precursor to glutathione called gamma-glutamylcysteine is more likely to be a more effective and rapid way of increasing cellular glutathione [7].

COVID-19, like the common influenza virus, belong to the family of RNA viruses. Much evidence has accumulated over the past decade suggesting that patients infected with such RNA viruses are under chronic oxidative stress [8] associated with glutathione depletion because oxidative stress, and the associated overproduction of reactive oxygen species, is a hallmark of RNA viruses. More importantly, an oxidative state promotes protein glutathionylation (S-S disulphide binding of glutathione to a cysteine residue). This provides a mechanism for RNA viruses to regulate and sequentially control the activity of the enzymes responsible for their replication cycle [3, 9]. This is particularly concerning if you already have low glutathione. An infection with COVID-19 could lower your glutathione below a critical point where oxidative stress progressively leads to tissue damage and organ failure.

Glutathione is the most important antioxidant defense in the lungs [10] and there is diverse scientific and medical literature that points to glutathione as a key player in not only preventing oxidative stress but also strengthening your immune system [11]. The elderly, and those affected by chronic disease, especially the respiratory and immuno- compromised, seem to be most vulnerable to COVID-19 infection and its complications [2]. This section of the population is well known to have lower than normal glutathione levels and often suffer extensively from oxidative stress [12-16].

There is also evidence to support that increasing your glutathione may also act as a prophylactic to viral infection. A study published in 2003 [17] demonstrated that glutathione has anti-influenza properties. COVID-19, just like influenza, affects the oral, nasal, and upper airway and therefore oxidative stress, or other conditions that deplete glutathione, make you more vulnerable to such RNA virus infections.

Until recently, it has not been possible to increase patient’s glutathione rapidly when needed. This is due to the many obstacles of glutathione supplementation. The most obvious solution, oral or intravenous glutathione, does not work effectively and neither does N-acetylcysteine. The latter has shown some improvement in influenza type symptoms, however they did not seem to significantly affect the rate of infection [18]. This is hardly surprising, since N-acetylcysteine is not an effective way of increasing cellular glutathione unless acutely depleted [19, 20]. Therefore it has been almost impossible to determine if increasing a patient’s glutathione is effective in antiviral therapy, and studies to that effect have consequently only been of limited success [18, 21-24]

There is some recent evidence coming out of China that supplementation with vitamin C is helpful in COVID-19 infection [25]. It is interesting to note that glutathione is responsible for recycling cellular vitamin C and, in turn, vitamin C helps to lessen glutathione depletion [26]. The recent availability of gamma-glutamylcysteine promises to be a game changer in the field of glutathione supplementation. It has been proven to be not only an effective way of supplementing glutathione, but also does so rapidly [7]. It is hypothesized that increasing glutathione by administration of gamma-glutamylcysteine will not only prevent but also treat the debilitating effects of oxidative stress on patient’s health. It will also potentially disrupt the COVID-19 virus replication cycle halting the progress of the disease.

Update

An Italian group have recently published further evidence on the role of glutathione in protecting against the severe inflammatory response triggered by COVID-19 [27].   There are also several clinical trials underway using N-acetylcysteine (NAC) to increase glutathione levels in COVID-19 patients [28]. However, the success of these trials is likely to be low due to the reasons given in the section NAC cannot increase cellular glutathione levels.

References

  1. Cecchini, R. and A.L. Cecchini, SARS-CoV-2 infection pathogenesis is related to oxidative stress as a response to aggression. Medical Hypotheses, 2020. 143: p. 110102-110102.
  2. Delgado-Roche, L. and F. Mesta, Oxidative Stress as Key Player in Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) Infection. Archives of medical research, 2020. 51(5): p. 384-387.
  3. Polonikov, A., Endogenous Deficiency of Glutathione as the Most Likely Cause of Serious Manifestations and Death in COVID-19 Patients. ACS infectious diseases, 2020. 6(7): p. 1558-1562.
  4. Horowitz, R.I., P.R. Freeman, and J. Bruzzese, Efficacy of glutathione therapy in relieving dyspnea associated with COVID-19 pneumonia: A report of 2 cases. Respiratory medicine case reports, 2020. 30: p. 101063-101063.
  5. Horowitz, R.I. and P.R. Freeman, Three novel prevention, diagnostic, and treatment options for COVID-19 urgently necessitating controlled randomized trials. Medical Hypotheses, 2020. 143: p. 109851.
  6. Poe, F.L. and J. Corn, N-Acetylcysteine: A potential therapeutic agent for SARS-CoV-2. Medical Hypotheses, 2020. 143: p. 109862.
  7. Zarka, M.H. and W.J. Bridge, Oral administration of γ-glutamylcysteine increases intracellular glutathione levels above homeostasis in a randomised human trial pilot study. Redox Biology, 2017. 11: p. 631-636.
  8. Reshi, M.L., Y.C. Su, and J.R. Hong, RNA Viruses: ROS-Mediated Cell Death. Int J Cell Biol, 2014. 2014: p. 467452.
  9. Checconi, P., et al., Role of Glutathionylation in Infection and Inflammation. Nutrients, 2019. 11(8): p. 1952.
  10. Cantin, A., et al., Normal alveolar epithelial lining fluid contains high levels of glutathione. Journal of applied physiology, 1987. 63(1): p. 152-157.
  11. Ghezzi, P., Role of glutathione in immunity and inflammation in the lung. International Journal of General Medicine, 2011. 4: p. 105-113.
  12. Teskey, G., et al., Glutathione as a Marker for Human Disease. Adv Clin Chem, 2018. 87: p. 141-159.
  13. Franco, R., et al., The central role of glutathione in the pathophysiology of human diseases. Archives Of Physiology And Biochemistry, 2007. 113(4-5): p. 234-258.
  14. Townsend, D.M., K.D. Tew, and H. Tapiero, The importance of glutathione in human disease. Biomedicine & Pharmacotherapy, 2003. 57(3-4): p. 145-55.
  15. Ballatori, N., et al., Glutathione dysregulation and the etiology and progression of human diseases. Biological Chemistry, 2009. 390(3): p. 191-214.
  16. Pérez, L.M., et al., Glutathione Serum Levels and Rate of Multimorbidity Development in Older Adults. The Journals of Gerontology: Series A, 2019.
  17. Cai, J., et al., Inhibition of influenza infection by glutathione. Free Radical Biology & Medicine, 2003. 34(7): p. 928-936.
  18. De Flora, S., C. Grassi, and L. Carati, Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment. Eur Respir J, 1997. 10(7): p. 1535-41.
  19. Rushworth, G.F. and I.L. Megson, Existing and potential therapeutic uses for N-acetylcysteine: The need for conversion to intracellular glutathione for antioxidant benefits. Pharmacology & Therapeutics, 2014. 141(2): p. 150-159.
  20. Aitio, M.-L., N-acetylcysteine – passe-partout or much ado about nothing? British Journal of Clinical Pharmacology, 2006. 61(1): p. 5-15.
  21. Sgarbanti, R., et al., Redox regulation of the influenza hemagglutinin maturation process: a new cell-mediated strategy for anti-influenza therapy. Antioxid Redox Signal, 2011. 15(3): p. 593-606.
  22. Fraternale, A., et al., Antiviral and immunomodulatory properties of new pro-glutathione (GSH) molecules. Curr Med Chem, 2006. 13(15): p. 1749-55.
  23. Fraternale, A., et al., GSH and analogs in antiviral therapy. Mol Aspects Med, 2009. 30(1-2): p. 99-110.
  24. Uchide, N. and H. Toyoda, Antioxidant therapy as a potential approach to severe influenza-associated complications. Molecules, 2011. 16(3): p. 2032-52.
  25. Liu, F., et al., Intravenous high-dose vitamin C for the treatment of severe COVID-19: study protocol for a multicentre randomised controlled trial. BMJ open, 2020. 10(7): p. e039519-e039519.
  26. Martensson, J. and A. Meister, Glutathione deficiency decreases tissue ascorbate levels in newborn rats: ascorbate spares glutathione and protects. Proc Natl Acad Sci U S A, 1991. 88(11): p. 4656-60
  27. Silvagno, F., A. Vernone, and G.P. Pescarmona, The Role of Glutathione in Protecting against the Severe Inflammatory Response Triggered by COVID-19. Antioxidants (Basel, Switzerland), 2020. 9(7): p. 624.
  28. Poe, F.L. and J. Corn, N-Acetylcysteine: A potential therapeutic agent for SARS-CoV-2. Medical Hypotheses, 2020. 143: p. 109862.

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