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Recebido para publicação 18/11/14 Aprovado em 02/10/15
DOI: 10.5433/1679-0359.2016v37n3p1431
Oxidative stress in dogs
Estresse oxidativo em cães
Claudia Russo1*; Ana Paula Frederico Rodrigues Loureiro Bracarense2
Abstract
Reactive oxygen species (ROS), also known as free radicals, are generated during cellular respiration.
its antioxidant defenses. In the case of an imbalance between oxidants and antioxidants, free radical
production exceeds the capacity of organic combustion, resulting in oxidative stress. Of all the cellular
and permeability. With lipid peroxidation of the cell membrane, some by-products can be detected
stress is commonly used to quantify lipid peroxidation of the cell membrane in humans, a species in
which ROS can be considered as a cause or consequence of oxidative stress-related diseases. In dogs,
knowledge relating to oxidative stress diseases and their detection in dogs.
Key words: Oxidative stress. Lipid peroxidation. Free radicals. Dogs.
Resumo
Nos processos decorrentes da respiração celular, são gerados produtos denominados espécimes reativos
de oxigênio (EROS), conhecidos também como radicais livres. Em condições normais, o organismo
possui capacidade de neutralizar os efeitos dos radicais livres utilizando suas defesas antioxidantes. Em
situações de desequilíbrio entre agentes oxidantes e antioxidantes, a produção de radicais livres excede
a capacidade orgânica de neutralização, resultando na condição conhecida como estresse oxidativo.
Dentre todos os componentes celulares atingidos pelos efeitos nocivos dos EROS, as membranas
celulares são as estruturas mais severamente acometidas, devido à peroxidação lipídica, que leva,
invariavelmente, a alterações estruturais e também na sua permeabilidade. Na peroxidação lipídica da
membrana celular, alguns subprodutos podem ser detectados e mensurados nos tecidos, sangue e outros
consideradas como causa ou consequência de doenças relacionadas ao estresse oxidativo. Nos cães,
alguns poucos estudos demonstram essa correlação. A presente revisão tem como principal objetivo
às doenças em cães bem como as possíveis formas de detecção de biomarcadores na espécie canina.
Palavras-chave: Estresse oxidativo. Lipoperoxidação. Radicais livres. Cães.
1
Brasil. E-mail: russo.claudia@hotmail.com
2 Profª Drª Associada, Departamento de Medicina Veterinária Preventiva, UEL, Londrina, PR. E-mail: anapaula@uel.br
* Autor para correspondência
REVISÕES/REVIEWS
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Russo, C. ; Bracarense, A. P. F. R. L.
Introduction
on tissues and cells have been a leading topic in a
over 40 years (SALVADOR; HENRIQUES, 2004).
More recently, this subject has been gaining ground
for conducting research on the correlation of
oxidative stress to diseases. Free radical production
body (ARAUJO et al., 2010), the use of antioxidants,
of this review is to provide the veterinarian with an
overview of the topic, addressing dogs in particular.
Development
During cellular respiration, oxygen, the key
element required to produce energy for the cellular
metabolism and oxidation of organic compounds,
is consumed and reduced, generating a series
of highly reactive chemical substances called
reactive oxygen species (ROS), also known as
free radicals (DALLAQUA; DAMASCENO,
a highly reactive molecule or atom, having one or
more unpaired electron in the last electron layer.
At high concentrations, ROS can interact with
the biomolecules that are present in tissues, cell
membranes, and organelles, causing cell injury
(VALKO et al., 2007). Under normal conditions,
the free radicals by using its antioxidant defenses.
However, in situations of imbalance between
oxidant and antioxidant agents, the production of
free radicals exceeds the neutralizing capacity of
organic compounds, resulting in oxidative stress
Of all the cellular components compromised by
which invariably leads to alterations in the
membrane structure and permeability (FERREIRA;
generated during oxidative stress is questionable
owing to their very low concentrations and the high
speed at which they react with other biomolecules.
ROS; that is, in the measurement of its by-products
During lipid peroxidation of cell membranes,
certain by-products can be detected and measured
Determination of malondialdehyde (MDA) in
the serum is commonly used to quantify the lipid
peroxidation of cell membranes in living organisms,
where the ROS are seen as a cause or consequence
of diseases related to oxidative stress (FERREIRA;
Human medical research has been studying
on the living organism for many years. Studies in
Initially, emphasis was given to understanding the
that the energy released by this type of radiation
leads to changes in the orbits of electrons, making
the atoms, especially oxygen, highly reactive,
leading to the formation of molecules such as
molecular oxygen and hydrogen peroxide (H2O2),
which are considered free radicals (SALVADOR;
HENRIQUES, 2004). Currently, the association
between oxidative stress and diseases such
as cancer,
autoimmune disorders, in addition to aging-related
processes, is well established (HALLIWELL;
animals of interest to veterinary medicine, studies
on these associations are recent and still scarce
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Oxidative stress in dogs
Reactive oxygen species
It can be said that ROS are present in all
biological systems. During aerobic cellular
metabolism under physiological conditions, oxygen
undergoes tetravalent reduction by accepting four
electrons, which results in the formation of water
(H2O) and other reactive intermediate compounds,
such as the radicals superoxide (O2
-), hydroxyl
(•OH), and H2O2 2
- occurs in
almost all aerobic cells and is produced during the
activation of neutrophils, monocytes, eosinophils,
and macrophages. Although it is considered to be
only mildly reactive, some secondary biological
lesions have been observed in systems that generate
O2
-
2
-,
since it demonstrates the ability to easily induce
damage in biological membranes (HALLIWELL;
considered to be the most reactive of all ROS
in biological systems. It can rapidly combine
with other radicals or metals at the site where it
was produced, leading to DNA deactivation or
mutations, inactivation of proteins, and oxidation
of fatty acids in cell membranes (HALLIWELL;
2O2 is not
considered a free radical per se, it is very harmful
because it does not have an unpaired electron.
production of •OH, which is highly toxic to the
cell. In addition to having a long half-life, H2O2
is capable of crossing lipid layers and binding to
proteins bound to iron, as occurs in erythrocytes,
and therefore its toxicity increases in the presence
Elements such as metals (particularly iron,
which exists in abundance in the body) have been
use of iron chelating agents has been indicated for
certain diseases, such as head trauma in humans
nitrogen (reactive nitrogen species (RNS)), sulfur,
copper, and manganese may also be considered
free radicals in biological systems and can be
associated with cell damage through oxidative
stress (VASCONCELOS et al., 2007).
Biomarkers of oxidative stress
biomolecules is the formation of substances that can
be used as markers of oxidative damage. Currently,
numerous studies are being conducted to validate
uncertainty over which of the available biomarker
detection methods is the most accurate, or the more
humans, genetic, nutritional, environmental, and
even cultural factors may change the redox balance
(balance between oxidizing reactive species and the
antioxidant system) of a population (KADIISKA et
Despite this fact, some biomarkers are
can be detected directly through electron
paramagnetic resonance, but the cost and technical
requirements hamper its routine use (FERREIRA;
used nowadays detect the action of ROS indirectly,
either by measuring the products generated from
its action on biomolecules or by measuring the
quality and quantity of antioxidants, thereby
commonly used are the spectrophotometric and
chromatographic methods that measure the activity
of antioxidant enzymes, such as superoxide
peroxidase. SOD catalyzes the dismutation of
O2
- to H2O2 2O2 to
H2O and O2; and glutathione peroxidase acts on
components of the enzymatic antioxidant system.
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Russo, C. ; Bracarense, A. P. F. R. L.
A series of non-enzymatic substances are also
part of the antioxidant system. In the extracellular
medium (serum and plasma), several non-enzymatic
antioxidant agents (e.g., vitamin C, vitamin E, and
idea of measuring antioxidant substances as a way
to assess the presence of oxidative damage, using
considers the cumulative action of all antioxidants
present. Other authors suggest that this method
necessarily desirable, as the antioxidant enzymes
are not always decreased in disease conditions
of the presence of oxidative stress can be performed
through measurement of biomarkers for the damage
caused by ROS, RNS, and other radicals, such
as MDA, isoprostanes, lipoperoxides, and other
derivatives of lipid peroxidation of cell membranes.
MDA is currently regarded as a general
biomarker
of oxidative damage in the plasma
biological systems is an important parameter for the
assessment of cellular oxidative stress (PILZ et al.,
cytotoxic and genotoxic, and should be considered
more than just a biomarker of oxidative damage,
owing to its interaction with DNA and other
proteins. High levels of MDA are routinely used as
a way to detect oxidative stress in several human
diseases, such as systemic lupus erythematosus,
diabetes, pulmonary diseases, Alzheimer’s disease,
and cancer, which allow us to have funding for the
measuring MDA is the thiobarbituric acid reactive
reactive to barbituric acid, among which MDA is
the main component. However, the technique has
Nowadays, other biomarkers of lipid
peroxidation, such as isoprostanes and acrolein,
are also considered as important for determining
oxidative damage in humans and, more recently, in
animals (LIMA; ABDALLA, 2001; MARQUIS et
Oxidative stress and related diseases
showing that many diseases are related to the
or RNA of the cell. When a break occurs in the
DNA strand, it can reconnect in another position,
of the processes causing mutation, which can be
related to oncogenesis. Likewise, changing the
sequence of the amino acids of a protein that act
as an enzyme can lead to a loss of or change in its
the active and passive transport systems and can
lead to rupture of the membrane and subsequent
cell death. When lipid peroxidation occurs
in the blood, it aggravates the vessel walls,
favoring the accumulation of lipids, which can
trigger atherosclerosis, stroke, infarction, or
of neoplasms in humans in search for information
on the behaviors of ROS and their relationship with
diseases. In a study comparing the intestinal mucosa
of healthy individuals with those of colorectal cancer
patients, the levels of oxidative damage to the DNA
with the neoplasm. Interestingly, the normal
tissue also had some level of oxidative damage,
demonstrating the importance of ROS in the initial
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Oxidative stress in dogs
aggression to the intestinal mucosa (RIBEIRO et
al., 2007). Another study demonstrated the presence
of oxidative stress in women with breast cancer
serum MDA levels were also higher than those of
the control group (SENER et al., 2007).
In veterinary oncology, oxidative stress in canine
lymphoma is also detected via MDA and isoprostane
the concentrations of antioxidants agents such as
with multicentric lymphoma (MACEDO, 2010). In
another study, dogs with multicentric lymphoma
presence of anemia and oxidative stress, detected
Recently, a study compared the levels of MDA
between a group of 101 healthy dogs and a group
suggesting that these animals were under oxidative
serum MDA concentration was determined by the
the serum of substances reactive to barbituric acid,
where the MDA is the main component. Several
studies have also indicated the relationship between
oxidative stress and the development of mammary
tumors in dogs, mainly by correlating serum and
well as the levels of antioxidants such as vitamin E and
vitamin C (SZCZUBIAL et al., 2004; FRANCISCO
of MDA and nitric oxide (NO) and decreased serum
concentrations of vitamin C (considered to be the
malignant breast neoplasms. According to this
author, in addition to the oxidative stress detected,
the decrease of antioxidant defenses such as vitamin
C could be related to carcinogenesis.
considered antioxidant and cytoprotective was
evaluated in cultured canine aortic endothelial
cells, submitted to the oxidative action of H2O2
(RIPOLL et al., 2012). In that study, the authors
and -carnitine, both antioxidant agents already
in use for the treatment of canine cardiopathies,
extract. Since the presence of oxidative stress in
canine cardiopathies has already been established
capacity like the ones studied above, so that they can
be included and prescribed as part of the treatment
of canine heart diseases. In veterinary medicine,
oxidative stress has also been linked with kidney
healthy dogs and dogs with prerenal azotemia was
compared, showing that the diseased dogs had a
lower antioxidant capacity. Moreover, in these
animals, there was an acceleration of neutrophil
other hand, oxidative metabolism should occur in
a physiological manner and is part of the immune
response against antigens. For example, after the
phagocytosis of microorganisms, it is expected
that normal neutrophils will lead the microbial
cells to death via the action of lysosomal enzymes
and oxidizing agents. An ex vivo study showed
that neutrophils from healthy dogs, exposed to the
metabolism, due to changes in O2
- production,
was similar to what occurs in humans with chronic
kidney failure, a situation in which the inhibition of
ROS production is harmful to the body (BARBOSA
et al., 2010).
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Russo, C. ; Bracarense, A. P. F. R. L.
ischemia-reperfusion injury has been extensively
of substances with antioxidant potential that can
be included in therapeutic procedures. Natural
substances containing phenolic derivatives, such
inhibiting the action of free radicals, preventing lipid
peroxidation, and therefore improving endothelial
and neuroprotective functions (MENDES, 2012).
It should also be mentioned here that a recent
study observed an increase in the concentrations
of isoprostanes and acrolein in the spinal cord of
the nerve degeneration was due to oxidative stress,
similar to what occurs in humans with recurrent
neurodegeneration of the spinal cord after injury
Other infections, including cutaneous conditions
such as demodicosis, can also be related to
oxidative stress (ROMANUCCI et al., 2011).
According to authors who observed decreased
levels of endogenous antioxidants (e.g., glutathione
localized and generalized demodicosis, the disease
is related to the occurrence of oxidative stress,
suggesting supplementation with antioxidants as
study, the presence of oxidative stress in the eyeball
was compared between a group with intraocular
lens implant and a group without lens implant. It
was found through quantitative determination of
proteins in the aqueous humor and evaluation of total
antioxidant activity (also in the aqueous humor) that
the presence of the implanted lens contributed to
the occurrence of oxidative stress in the intraocular
have sought to relate oxidative stress with fertility,
by identifying and quantifying the antioxidant
substances in the seminal plasma of fertile and
sub-fertile dogs, in addition to analyzing the
diet with antioxidants (ANDRADE et al., 2010;
LOPES et al., 2011). Another study, also in the
activity and serum concentrations of biomarkers
of oxidative damage in dogs subjected to an
even after several days post-operation, suggesting
that these dogs would be more susceptible to
diseases related to oxidative stress (SZCZUBIAL
Nonpathological conditions in which oxidative
stress can occur should also be considered. A
glutathione peroxidase enzyme was observed
in dogs submitted to intense exercise for a short
period of time (POLIZEL, 2011). In that study, the
increased levels of glutathione peroxidase were
related to an increased production of free radicals, a
by the body during physical exertion.
Conclusion
stress or even of antioxidant substances in the
studies that show the relationship between free
radicals and diseases, either as a cause, or as an
of the use of antioxidants as adjuvant treatment
that aims to minimize oxidative damage can also
be studied in canine medicine. Studies that seek to
of parameters that can be used as references in
to basic research and to therapeutic targeting in the
routine clinical setting.
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Oxidative stress in dogs
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