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
ISSN 1540-7535 print, ISSN 2641-452X online, Copyright © 2021 by New Century Health Publishers, LLC
All rights of reproduction in any form reserved
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;
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 diculties 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 eects. 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 eects the formation of free oxygen radicals by inu-
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 inammatory
response (Zhang et al., 2007, 2020a). erefore, increasing ACE2
levels aer viral replication will provide protection (Kai et al., 2020).
Rapidly emerging literature and reports indicate that SARS-
CoV-2 infection aects 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 inammation 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, eective 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 aecting 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
aer 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 aecting 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 eects
also on dierent 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 aer 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 dierent treatment options that have been suggested as
a COVID-19 specic 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 eect on the
host immune response against viral infections have been suggested
as supportive treatment in conjunction with antiviral treatments.
Administration of ALA aer 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 inuenza virus
(IVFujian01) increases NF-κB and caspase activities in MDCK
cells. Cells with low NF-κB activity are resistant to inuenza virus
infection (Nimmerjahn et al., 2004). us, preventing NF-κB
activation plays a major role in the treatment of inuenza virus
infection. ALA has been shown to inhibit inuenza spread by
blocking NF-κB activation (Bai et al., 2012). Another study has
shown that ALA prevents TNF-α-mediated apoptosis caused by
inuenza 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 eect 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 eect
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
signicantly improve the smell sensitivity measured by “threshold,
discrimination, and identication; TDI” score and lowered the rate
of “parosmia”/“troposmia” (Hummel et al., 2002).
We suggest that ALA, used aer 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 benets of use in combi-
nation with antiviral agents may prove to be a more eective treat-
ment of choice by reducing the side eect 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 inammation 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 benet of use
in balancing cytokine storm.
CONFLICT OF INTEREST DECLARATION
e authors state that there are no conicts of interest to disclose.
SS, AÖ, and NS conceived the idea for the manuscript, performed
literature search, and data analysis. SS and AÖ draed the
manuscript and NS critically revised the manuscript.
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