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Abstract

SARS-CoV-2 infection has led to COVID-19 outbreak worldwide. To date, a specific antiviral drug does not exist to treat the disease and control the virus. In this paper, we have explored the potential utility of alpha lipoic acid, an anti-inflammatory and antioxidant molecule, for treatment. Alpha lipoic acid exhibits strong antioxidant properties and modulates the immune system by regulating T cell activation making it a useful therapeutic candidate for cytokine storm triggering SARS-CoV-2 infection. In the present communication, we focused on the therapeutic potential of ALA with respect to its potential role on reducing the severity of symptoms and the adverse effects of other antiviral drugs used. We consider different mechanisms by which modulating ACE2 levels after virus replication and preventing cytokine storm and also focus on a new therapeutic venue that utilizes ALA.
Research Article
Current Topics in Nutraceutical Research 172 May 2021 | Volume 19 | Article 7
CURRENT TOPICS IN NUTRACEUTICAL RESEARCH Vol. 19, No. 2, pp. 172–175, 2021
doi: https://doi.org/10.37290/ctnr2641–452X.19:172–175
ISSN 1540-7535 print, ISSN 2641-452X online, Copyright © 2021 by New Century Health Publishers, LLC
www.newcenturyhealthpublishers.com
All rights of reproduction in any form reserved
Research Article
Alpha Lipoic Acid as a Potential Treatment for
COVID-19 – A Hypothesis
1,2Serkan Sayıner, 3Ahmet Özer S¸ ehirli and 4Nedime Serakıncı
1Department of Biochemistry, Faculty of Veterinary Medicine, Near East University, Nicosia, Cyprus; 2Diagnostic Laboratory, Animal Hospital, Faculty of Veterinary Medicine,
Near East University, Nicosia, Cyprus; 3Department of Pharmacology, Faculty of Dentistry, Near East University, Nicosia, Cyprus and
4Famagusta Medical Hospital, Famagusta, Cyprus
Received October 28, 2020; Accepted November 17, 2020
Communicated By: Prof. Chandan Prasad
SARS-CoV-2 infection has led to COVID-19 outbreak worldwide. To date, a specific antiviral drug does not exist to treat the
disease and control the virus. In this paper, we have explored the potential utility of alpha lipoic acid, an anti-inflammatory
and antioxidant molecule, for treatment. Alpha lipoic acid exhibits strong antioxidant properties and modulates the immune
system by regulating T cell activation making it a useful therapeutic candidate for cytokine storm triggering SARS-CoV-2
infection. In the present communication, we focused on the therapeutic potential of ALA with respect to its potential role on
reducing the severity of symptoms and the adverse effects of other antiviral drugs used. We consider different mechanisms
by which modulating ACE2 levels after virus replication and preventing cytokine storm and also focus on a new therapeutic
venue that utilizes ALA.
Keywords: ACE2, Alpha lipoic acid, COVID-19, Cytokines, SARS-CoV-2, T cell
Abbreviations Used: Angiotensin-converting enzyme 2, ACE2; Alpha lipoic acid, ALA; Alanine aminotransferase, ALT; Aspartate
aminotransferase, AST; Dihydriolipoic acid, DHLA; Interferon-gamma, IFN-γ; Interleukin-6, IL-6; Monocyte chemoattractant
protein-1, MCP-1; Nuclear factor kappa B, NF-κB; Severe acute respiratory syndrome coronavirus 2, SARS-CoV-2;
Tumor necrosis factor-α, TNF-α
Corresponding Author: Dr. Nedime Serakinci, Famagusta Medical Hospital, Post Code: 99450, Famagusta, Cyprus;
E-mail: nedimeserakinci@gmail.com
INTRODUCTION
COVID-19 is a disease that is caused by SARS-CoV-2, which
has rapidly spread and evolved into a worldwide outbreak since
December 2019 leading to unsurmountable diculties for
healthcare systems globally (Contini et al., 2020). To date, no active
therapeutic agent has been found to cure severe COVID-19 (Hassan
et al., 2020; Padron-Regalado, 2020; Singhal, 2020; Wang et al.,
2020). Besides, multiple studies on developing vaccines continue
widely for prophylactic eects. To date, two vaccine candidates have
successfully been established recently, thus promising prophylaxis
(Walsh et al., 2020).
CORONAVIRUS INDUCED CYTOKINE
STORM AND ALPHA LIPOIC ACID
CoVs have been reported to be nonsegmented RNA viruses that
cause zoonotic infections and show steady mortality rate in humans
(Lu et al., 2020).ese viruses consist of four structural proteins
which are E, M, N, and S proteins (Rota et al., 2003). e S protein
is the key constituent that is responsible for invasion of CoV. It
mediates cell membrane fusion (Hulswit et al., 2016). e host cell
receptor for SARS-CoV-2 is the ACE2 present in numerous tissues
including alveolar epithelial cells, endothelial cells of blood vessels,
and smooth muscle cells (Kai et al., 2020). e invasion of SARS-
CoV-2 in host cells occurs via interaction of the S protein and ACE2
(Mathewson et al., 2008). In studies, it was determined that the sit-
uation where ACE2 receptors mediate and cause virus replication
during SARS-CoV-2 invasion causes a decrease in ACE2 levels,
leading to an increase in ACE1-mediated angiotensin II level and
thus lung and heart damage (Guo et al., 2020; Huang et al., 2020).
Angiotensin II eects the formation of free oxygen radicals by inu-
encing the metabolism of smooth muscle cells and increasing the
activity of NADPH oxidase. Free oxygen radicals play an essential
role in virus invasion, organ damage, and systemic inammatory
response (Zhang et al., 2007, 2020a). erefore, increasing ACE2
levels aer viral replication will provide protection (Kai et al., 2020).
Rapidly emerging literature and reports indicate that SARS-
CoV-2 infection aects the CD4 and CD8 proteins on T cells, and
Current Topics in Nutraceutical Research 173 May 2021 | Volume 19 | Article 7
Serkan Sayıner et al. ALA Treatment for COVID-19
plays a role in inammation due to overexpression of cytokines such
as IFN-γ, IL-6, MCP-1, and TNF-α and transcription factor, NF-κB
(Zhai et al., 2016). us, suggesting that cytokine storm may play a
role in the progression of COVID-19 (Liu et al., 2020; Saghazadeh
et al., 2020). erefore, eective suppression of cytokine storm will
be an important way to save the lives and help patients to ght against
COVID-19 (Fu et al., 2020; Ye et al., 2020; Zhang et al., 2020b). de
Queiroz et al. (2015) have shown that ALA plays a role in decreas-
ing cytokine expression by aecting CD4 and CD8 proteins on T
cells which will play a preventative role in tissue damage by increas-
ing the ACE2 activity. Upon SARS-CoV-2 invasion in the cell, viral
replication occurs and cause decrease in the ACE2 activity. is
leads to increase in cytokine expression associated with cardiopul-
monary damage. erapeutic use of ALA decreases ACE2 levels
aer viral replication which will increase the angiotensin II level
that will reduce cardiopulmonary damage. is is accomplished
through angiotensin II reducing the formation of free oxygen radi-
cals by increasing the activity of NADPH oxidase (Fig. 1). Previous
studies have demonstrated that ALA and its metabolite, DHLA with
two thiol groups per molecule, are more potent reductants than
glutathione that inhibits reactive oxygen species such as
superoxide, hydroxyl, and hypochloric acid by suppressing the
FIGURE 1 | SARS-CoV-2 reduces ACE2 levels, increases ACE1 levels through T cell activation after replication, thereby causing cytokine expression. ALA administration after
SARS-CoV-2 replication will alter ACE1 increase and ACE2 decline to prevent cytokine expression and thus cardiopulmonary damage.
Serkan Sayıner et al. ALA Treatment for COVID-19
Current Topics in Nutraceutical Research 174 May 2021 | Volume 19 | Article 7
NADPH oxidase activity (Dulundu et al., 2007; Cakir et al., 2015;
Wang et al., 2016; Savtekin et al., 2018; Aksoy et al., 2019;
Sehirli et al., 2019). Free oxygen radicals trigger the binding of
cytokines such as IFN-γ, TNF-α, MCP1, and IL-6, and the tran-
scription factor NF-κB to membrane receptors by aecting the T
cells. In this case, free oxygen radicals act as a secondary messenger
within the cell (Agostinis et al., 2015; Fei et al., 2016; Aksoy
et al., 2019; Sehirli et al., 2019). Besides, ALA has enhancer eects
also on dierent antioxidants such as coenzyme Q10, vitamins C
and E, and increases intracellular levels of these antioxidants (Busse
et al., 1992; Bharat et al., 2002). In line with these studies, ALA may
decrease the ACE2 activity aer replication of the SARS-CoV-2,
and reduce the NADPH oxidase activity leading to suppression of
the increase in cytokine expression (Fig. 1).
ANTIVIRAL EFFECTS OF ALPHA LIPOIC ACID
Several dierent treatment options that have been suggested as
a COVID-19 specic treatment include antiviral treatments,
immune enhancers, even some nutritional interventions, and
few other compounds with potential therapeutic administration.
Nutritional interventions that could have a positive eect on the
host immune response against viral infections have been suggested
as supportive treatment in conjunction with antiviral treatments.
Administration of ALA aer SARS-CoV-2 replication may dimin-
ish ACE1 increase and ACE2 decrease, thereby contributing to the
prevention of cardiopulmonary damage by preventing cytokine
expression. Previously, it has been shown that inuenza virus
(IVFujian01) increases NF-κB and caspase activities in MDCK
cells. Cells with low NF-κB activity are resistant to inuenza virus
infection (Nimmerjahn et al., 2004). us, preventing NF-κB
activation plays a major role in the treatment of inuenza virus
infection. ALA has been shown to inhibit inuenza spread by
blocking NF-κB activation (Bai et al., 2012). Another study has
shown that ALA prevents TNF-α-mediated apoptosis caused by
inuenza A virus (Severa et al., 2007).
Additionally, ALA has been demonstrated to inhibit HIV repli-
cation by regulating the T cell activity such as CD4+ and CD8+ and
by suppressing NF-κB and other cytokines (Jariwalla et al., 2008).
Further, ALA has been found to have a protective eect on alveolar
cells against HCoV 229E infection in pulmonary cells which are
under high oxidative stress due to HCoV 229E infection, and by
reducing the NADPH oxidase activities and increasing GSH levels
(Wu et al., 2008). In line with the above-mentioned studies, use of
ALA prevents growth against the vaccinia virus by regulating the
NK-kB and IFN-γ activations (Spisakova et al., 2009). In addition
to human studies, ALA has also been determined to be a potent
supportive agent in bovine rhinotracheitis disease ın veterinary
medicine (Schmidt et al., 2006).
ALA, a natural substance found in some foods and also syn-
thesized in the body (Reed, 1951), has been shown to ameliorate
heart, so tissue, and bone damage caused by Coxsackievirus B3
(Kim et al., 2013). It has also been stated that it improves ALT and
AST levels against the hepatitis C virus and shows protective eect
by reducing oxidative damage and cytokine expressions (Melhem
et al., 2005). ALA is also shown to be supportive in the therapy
of postinfection olfactory dysfunction. ALA was further shown to
signicantly improve the smell sensitivity measured by “threshold,
discrimination, and identication; TDI” score and lowered the rate
of “parosmia”/“troposmia” (Hummel et al., 2002).
CONCLUSION
We suggest that ALA, used aer viral replication, may alleviate the
prognosis of the disease by regulating T cell activity and suppressing
NF-κB. Besides, ALA being also used as an immunomodulator
allows us to speculate its potential use and benets of use in combi-
nation with antiviral agents may prove to be a more eective treat-
ment of choice by reducing the side eect potential of those drugs.
is is principally because of the fact that ALA will reduce the
NADPH oxidase activity resulting in decreased cytokine expres-
sion, free oxygen radicals, and thus tissue damage. Inhibiting virus
replication as well as limiting excess inammation is very import-
ant to the treatment of COVID-19. For this purpose, the agents
regulating the immune system should be considered together with
antiviral treatments. ALA, having the potential of inhibiting cyto-
kine expression, allows us to speculate on its potential benet of use
in balancing cytokine storm.
CONFLICT OF INTEREST DECLARATION
e authors state that there are no conicts of interest to disclose.
AUTHOR CONTRIBUTIONS
SS, AÖ, and NS conceived the idea for the manuscript, performed
literature search, and data analysis. SS and AÖ draed the
manuscript and NS critically revised the manuscript.
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SARS-CoV-2 infects host cells mainly through the interaction between the virus's Spike protein and the viral receptors namely Angiotensin-Converting Enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2). Both are highly expressed in the gastrointestinal tract, in the nasal and bronchial epithelium, as well as in the type II alveolar epithelial cells. The aim of this review is to report the evidences from the scientific literature on the pathophysiology and the available treatments for olfactory-gustatory disorders in patients with COVID-19. The mechanisms involved in these disorders are still unclear and studies on specific therapies are scarce. However, it has been hypothesized that a decrease in the sensitivity of the sensory neurons as well as the co-expression of ACE2 and TMPRSS2 in the alveolar epithelial cells are the main causes of olfactory-gustatory disorders. The possible mechanisms described in the literature for changes in taste perception in patients with COVID-19 include olfactory disorders and a competitive activity of COVID-19 on ACE2 receptors in the taste buds. In addition, SARS-CoV-2 can bind to sialic acid receptors in the taste buds. In general, evidences show that there is no specific treatment for olfactory-taste disorders induced by SARS-CoV-2, even though some treatments have been used and have shown some promising results, such as olfactory training, intranasal application of sodium citrate and vitamin A, as well as systemic use of omega-3 and zinc. Corticosteroids have also been used as a pharmacological approach to treat patients with olfactory dysfunction with some contradictory results. The knowledge of the mechanisms by which SARS-CoV-2 influences the sensory systems and how effective therapies can treat the loss of smell and taste will have important implications on the understanding and clinical management of olfactory-taste disorders.
... The fact that ACE2 and TMPRSS, which play a crucial role in the invasion of SARS-CoV-2, are also localized in the mouth. Thus, the virus may also influence inflammation in the periodontal tissues and cytokine storm [9,10]. ...
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Introduction: At the end of 2019, Wuhan, a city in China with a population of about 11 million, witnessed the outbreak of unusual pneumonia. As of March 29, 2020, the disease has spread to more 199 countries and territories worldwide. The 2019 novel coronavirus, 2019-nCoV, is known as the probable causative agent of the illness. Areas covered: Here, the epidemiological dynamics of the disease that stand in close relation to distinct immunogenetic characters of the pathogen are discussed, to understand the ability and inability of the immune system in combatting the 2019-nCoV infection. Expert opinion: The elderly population is at increased risk of developing and dying from the 2019-nCoV infection. Comorbidity is present in more than 30% of cases infected with the 2019-nCoV. Except for less than 1% of the total, a chronic condition has been found in all cases that died from 2019-nCoV. Men are more than 1.5 times more likely to die from the 2019-nCoV disease. Evidence links aging to cytokine dysregulation and T-cell repertoire reduction, male population to relatively reduced anti-viral immunity, and 2019-nCoV-related comorbidities to hyper inflammation. The transmission of 2019-nCoV is influenced by the host-related factors that are known to be associated with immune dysregulation.
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We noted that the DCt values of severe cases were significantly lower than those of mild cases at the time of admission (appendix). Nasopharyngeal swabs from both the left and right nasal cavities of the same patient were kept in a sample collection tube containing 3 mL of standard viral transport medium. All samples were collected according to WHO guidelines.5 The mean viral load of severe cases was around 60 times higher than that of mild cases, suggesting that higher viral loads might be associated with severe clinical outcomes. We further stratified these data according to the day of disease onset at the time of sampling. The DCt values of severe cases remained significantly lower for the first 12 days after onset than those of corresponding mild cases (figure A). We also studied serial samples from 21 mild and ten severe cases (figure B). Mild cases were found to have an early viral clearance, with 90% of these patients repeatedly testing negative on RT-PCR by day 10 post-onset. By contrast, all severe cases still tested positive at or beyond day 10 post-onset. Overall, our data indicate that, similar to SARS in 2002–03,6 patients with severe COVID-19 tend to have a high viral load and a long virus-shedding period. This finding suggests that the viral load of SARS-CoV-2 might be a useful marker for assessing disease severity and prognosis.