To the editors of Pan African Medical Journal
Oxidative stress is the result of an imbalance in the body between the oxidizing system,
consisting mainly of free radicals, reactive oxygen species (ROS) and reactive nitrogen
species (RNS) [1], and antioxidant systems that neutralize these free radicals capable
of multiple deleterious effects. This oxidative stress is involved in aging [2] and
is found in certain chronic pathologies such as diabetes mellitus, cancers, hypertension,
coronary heart disease, etc. [3] and certain infections, particularly by the RNA viruses
[4], a family to which belong corona viruses [5]. The objective of this work is to
explain the role of oxidative stress in RNA virus infections and probably also in
Covid 19 infection, in order to propose measures for prevention and treatment of this
deadly infection which has already caused more than 118000 deaths worldwide [6]. This
is an analysis of literature about oxidative stress, ways to counteract it, known
links with certain RNA viruses and possible links with the new Corona virus.
Oxidative stress and reactive oxygen and nitrogen species (RONS): reactive Oxygen
and Nitrogen Species (RONS) are molecules characterized by the presence of unpaired
valence electrons, which cause them to react with various biological molecules [7,8].
Main ROS are hydroxyl radical (OHº), superoxide anion (O2º-), singlet oxygen (¹O2),
oxygen peroxide (H2O2) and ozone (O3), a powerful oxidant formed by endothermic reaction
from O2 [8]. For RNS it is nitric oxide (NO) peroxynitrite (ONOO-), the nitrosyl cation
(NO+), the nitrosyl anion (NO-), nitrous acid (NH2O2) .... [1,8] These free radicals
are natural byproducts of various cellular processes and the functioning of structures
such as mitochondria and the endoplasmic reticulum [4]. Under physiological conditions
these reactive species play an important role in cell signalling, regulation of cytokines,
growth factors, as immunomodulators, etc [1] and are involved in the natural aging
of the human organism [2]. But when the balance is broken between oxidizing agents
and antioxidant systems, which characterizes oxidative stress, these free radicals
will have deleterious effects on all biomolecules [7,8]. The most reactive, hydroxyl
radical can oxidize various molecules in its proximity, including DNA, phospholipids,
and proteins. The superoxide can generate other free radicals and come into contact
with nitric oxide (NO) to give the peroxynitrite radical (ONOO-), a powerful oxidant
with NO depletion. Hydrogen peroxide is converted to hydroxyl and can cross cell membranes.
Ozone is a powerful oxidant of lipid chains, it can generate other free radicals,
and interact with a large number of organic and inorganic compounds [8]. Damage caused
by these free radicals will affect cell membranes through the phenomenon of lipid
peroxidation, oxidation and denaturation of proteins, DNA damage which can induce
inflammatory immune responses, mutations and tumorigenesis risk, apoptosis [4]. So
oxidative stress is involved in the occurrence of certain pathologies such as cancers,
autoimmune diseases, cataract, Alzheimer’s and neurodegenerative diseases, diabetes
mellitus, cardiovascular diseases, chronic kidney disease etc [2,3,8].
What are the situations promoting oxidative stress? about our subject, it is known
that oxidative stress is triggered by a wide variety of viral infections [4,7] including
HIV 1, viral hepatitis B,C,D viruses, herpes viruses, respiratory viruses, most of
the RNA viruses [7] probably also corona viruses belonging to this family. Let us
remind that corona viruses are encapsulated RNA viruses with different types: the
classic coronaviruses, responsible for moderate respiratory infections in general,
the SARS-CoV and MERS-CoV involved in epidemics of more severe respiratory infections
[5] and the new coronavirus (SARS-CoV2) discovered in January 2020 responsible for
infectious disease called COVID-19 which is currently experiencing a worldwide outbreak
[6]. Generally, viral infections lead to an increase in production of free radicals
and a depletion of antioxidants [1]. The mode of action varies according to the viruses
as demonstrated by the analysis of the oxidative stress induced by different viruses
of the flaviviridae family [4] but we find these two phenomena increasing the oxidative
stress in these RNA viruses infections and for Ivanov [7] one of the sources of production
of these ROS could be the mitochondrial dysfunction caused by the penetration of the
virus into the cell. A “cytokine storm” with release of Il-2, Il-6, Il-7, TNF α etc.
as been described in COVID-19 [9]. These authors described a cytokine shock with hyperinflammation
accompanied by cytopenia, hyperferritinemia, [1,8] which is known to generate by the
Fenton reaction (Fe²+ + H2O2→ Fe³+ + HO‾ + HO‾) the production of ROS [7,8]. In addition,
cytokines and endotoxins will stimulate one of the isoforms of nitric oxide synthetase
(NOs), the inducible isoform iNOs, which will stimulate the production of nitric oxide
NO which will react with the superoxide ion to give the powerful oxidizing peroxynitrite
radical (ONOO‾) [1,8]. Other factors can promote the endogenous production of free
radicals, such as intense physical activity, high blood pressure, tissue ischemia,
the action of certain metals (lead, arsenic, cesium, mercury) counteracting the co-factors
of antioxidant enzymes, notably superoxide dismutase, NADPH oxidase, myeloperoxidase
which will lead to the production of the superoxide radical. Physical agents (ionizing
radiation, UV), solvents, various pollutants, an anesthetic agent halotane and even
paracetamol have also been incriminated in this genesis of free radicals [8]. Several
techniques can be used to evaluate the state of oxidative stress such as electron
paramagnetic resonance, direct evaluation of oxidative stress markers such as oxidized
glutathione, malonyl aldehyde, quantification of total antioxidant status etc [7].
How are these free radicals neutralized? there are multiple mechanisms to neutralize
these free radicals: glutathione a natural antioxydant which has also an effect on
viral replication [10], certain vitamins such as vitamin E and C, carotenoids and
polyphenol with scavenging effect, [8] the glutathione peroxidase| glutathione reductase
system allowing reduced glutathione (GSH) to bind to free radicals giving oxidized
glutathione which will be regenerated into GSH through this system, super oxide dismutase
(SOD) neutralizing superoxide anion (O2o‾), catalase eliminating H2O2, the peroxyredoxin
system that neutralizes the peroxidation of lipids, protecting them from oxidative
damage. Some trace elements such as Zinc and Selenium have an anti-oxidant effect
as co-factors of anti-oxidant enzymes [1,7,8].
What about covid-19 and oxidative stress? SARS-CoV2, probably like other RNA viruses
[4] can trigger an oxidative stress. This hypothesis can easily be checked by the
dosage of oxidative stress markers [7] in the blood of sick people of COVID-19. A
cytokin storm with hyper inflammation had been found in these patients [9] but researchers
should also chek for a possible oxidative storm with all he deleterious effects of
RONS, notably lipid peroxydation and proteins oxidation of membranes which can contribute
to the transformation, hyalinization of pulmonary alveolar membranes [11] with letal
respiratory distress. As elders and people suffering of diabetes, hypertension and
cardiovascular diseases have already a state of oxidative stress [2,3], viral infection
will increasae this stress, giving us one possible explanation of the severity of
COVID-19 in these categories of patients [12].
Suggestions for prevention and treatment of covid-19 infection: in frail people, we
propose to reduce their level of oxidative stress by providing them with substances
that increase their antioxidant system [2] such as Glutathione, some trace elements
like Zinc and Selenium, vitamin E and C, carotenoids and polyphenols [1]. Glutathione
has analogues and precursors such as N acetyl cysteine. Indeed, cysteine is one of
the three constituent amino acids of the major natural antioxidant Glutathione which
also has an immunomodulating effect and destructive action on viruses such as herpes,
influenza etc. by blocking viral replication [10]. There are also many antioxidants
food, and even food additives such as butylated hydroxyanisole, quercetin and curcumin
[1] could also be tested. In sick people, in addition to the various used treatments,
we suggest to add antioxidants mentionned above and especially, injectable N acetyl
cysteine [10] which has shown its effectiveness in hemorrhagic dengue fever [13] another
RNA virus infection [4]. Various antioxidant which have been experimentally used successfully
as melatonin, minocycline [1], can also be tested.
Conclusion
In the fight against Covid-19 infection, all the possible treatments deserve to be
taken into account. Relying on the complex pathophysiology of this viral infection,
we suggest tu use also antioxydants agents in the treatment.
Competing interests
The authors declare no competing interests.