ACTA BIOMEDICA SCIENTIFICA, 2020, Volume 5, No.

DOI: 10.29413 / ABS.2020-5.1.4

Free radical oxidation in sleep disorders

in andro- and menopause (literature review)

Semenova N.V., Madayeva I.M., Kolesnikova L.I.

FSBIU “Scientific Center for Family Health and Human Reproduction” (664003, Irkutsk, 16 Timiryazev St., Russia)

Corresponding author: Semenova Natalya Viktorovna, e-mail: natkor_84@mail.ru

Summary
This review presents data on changes in the physiology of sleep during reproductive aging. It was noted that the main sleep disorders are
insomnia and obstructive sleep apnea syndrome (OSAS). The results of foreign and domestic studies in the field of free radical oxidation
during sleep deprivation in animal models are presented, indicating the dependence of the processes on the duration of sleep
deprivation. The largest number of studies of free radical processes in a person with somnological pathology was carried out in the study
of OSAS. Blood, urine, saliva, condensate of exhaled air can be a biomaterial for determining the parameters of free radical oxidation. It
was shown that the intensity of oxidative stress depends on the severity of OSAS, as evidenced by positive correlations of the level of
active products of thiobarbituric acid, the products of oxidation of proteins and carbonyl groups with the apnea / hypopnea index,
determining the development of not only oxidative, but also carbonyl stress in patients with severe OSA. Biomarkers such as thioredoxin,
malondialdehyde, superoxide dismutase, and reduced iron have shown a more stable relationship between increased oxidative stress
and OSA. Despite the results obtained, the question of the association of oxidative stress and hypoxia in OSA remains debatable, which
is associated with the opposite results of some studies. Insomnia, found mainly in females, it is accompanied by a high content of the
level of end products of lipid peroxidation with a decrease in the activity of antioxidants such as paraoxonase, the enzymatic link of the
glutathione system. Along with this, menopausal women have a low level of uric acid, which correlates with high scores of the Pittsburgh
sleep quality index questionnaire. Recent studies have identified an association between the activity of the lipid peroxidation –
antioxidants system and the 3111T / C polymorphism of the Clock gene in menopausal women of the Caucasian race, indicating the
protective role of the minor allele.

Keywords: oxidative stress, carbonyl stress, sleep disturbances, andropause, menopause

For citation: Semenova N.V., Madayeva I.M., Kolesnikova L.I. Free radical oxidation in sleep disorders in andro- and menopause (literature review). Acta biomedica
scientifica. 2020; 5 (1): 31-41. doi: 10.29413 / ABS.2020-5.1.4

Free Radical Oxidation and Sleep Disorders in Andro- and Menopause

(Literature Review)

Semenova NV, Madaeva IM, Kolesnikova LI

Scientific Center for Family Health and Human Reproduction Problems (Timiryazeva str. 16, Irkutsk 664003, Russian Federation)

Corresponding author: Natalya V. Semenova, e-mail: natkor_84@mail.ru

Abstract
This review presents data on changes in the physiology of sleep during reproductive aging. It is noted that insomnia and obstructive sleep apnea
syndrome (OSAS) are the main sleep disorders. The results of foreign and domestic studies in the field of free radical oxidation during sleep
deprivation in animal models are presented, indicating the dependence of processes on the duration of sleep deprivation. The largest number of
studies of free radical processes in a person with somnological pathology was carried out in the study of OSAS. Blood, urine, saliva, condensate of
exhaled air can be biomaterial for determining the parameters of free radical oxidation. It was shown that the intensity of oxidative stress depends
on the severity of OSAS, as evidenced by the positive correlation of the level of active products of thio-barbituric acid, the products of oxidation of
proteins and carbonyl groups with the apnea / hypopnea index, determining the development of not only oxidative, but also carbonyl stress in
patients with a severe degree OSAS. Biomarkers such as thioredoxin, malondialdehyde, superoxide dismutase, and reduced iron have shown a
more stable relationship between increased oxidative stress and OSA. Despite the results obtained, the question of the association of oxidative
stress and hypoxia in OSA remains debatable, which is associated with the opposite results of some studies. Insomnia, which occurs mainly in
females, is accompanied by a high level of end products of lipid peroxidation with a decrease in the activity of antioxidants such as paraoxonase,
an enzymatic component of the glutathione system. Along with this, menopausal women present low levels of uric acid, which correlates with high
scores of the Pittsburgh sleep quality index questionnaire. Recent studies have identified an association between the activity of the
"lipoperoxidation - antioxidants" system and the Clock 3111T / C gene polymorphism in menopausal Caucasian women, indicating the protective
role of the minor allele.

Key words: oxidative stress, carbonyl stress, sleep disorders, andropause, menopause

For citation: Semenova NV, Madaeva IM, Kolesnikova LI Free Radical Oxidation and Sleep Disorders in Andro- and Menopause (Literature Review). Acta biomedica
scientifica. 2020; 5 (1): 31-41. doi: 10.29413 / ABS.2020-5.1.4

Internal illnesses 31
ACTA BIOMEDICA SCIENTIFICA, 2020, Vol. 5, N 1
DREAM AND ITS DISORDERS IN ANDRO AND MENOPAUSE
Sleep is a vital physiological state with a periodic change in
wakefulness and is characterized in humans by a lack of conscious
mental activity, as well as a significant decrease in reactions to external
stimuli. Every day, a person goes through a series of functional states
having various psycho-vegetative, motor-physiological, and behavioral
characteristics. These conditions include intense wakefulness, slumber,
a shallow slow sleep, deep slow sleep, and fast sleep. The fullness of
sleep, in which a person spends about a third of his life, determines the
overall level of health and quality of life, measured in terms of social,
mental, emotional and physical well-being [1].
It is known that the course of the "sleep - wake" continuum, followed by dysregulation of
the integrative mechanisms of sleep, changes with the onset of age-related androgen and
estrogen deficiency with a change in the direction and severity of most physiological and
biochemical processes directly or indirectly associated with these states. Thus, inhibitory
mediators, neurochemical sleep factors, hormones, peptides, as well as a large group of
neurotransmitters present in the extracellular space, cerebrospinal fluid, and blood are involved
in the regulation of sleep processes. Sleep in people with the onset of sex steroid deficiency
undergoes changes, represented by fragmentation of sleep, an increase in the latent period, an
increase in the number of spontaneous awakenings, which leads to an increase in the time of
wakefulness during the night and in bed after morning awakening. The percentage of surface
stages of sleep and the reduction of the deep stages of slow-wave sleep increase to 5–10% of
the total duration of sleep. At the same time, the representation of stage I of the phase of slow
sleep shifts, and there is also a slight tendency to increase the phase of REM sleep by the
second half of the night [2]. It should be noted the influence of gender on the structure of sleep
with age. So, in women, in comparison with men, sleep is more fragmented, sleep efficiency is
worse, segmental organization of sleep is more disturbed, as evidenced by the long duration of
the first stage of the slow sleep phase and the lower representation of the fast sleep phase and
deep stages of slow-wave sleep [3]. The reason for such features may be changes in the
secretion of hormones such as estrogens, progesterone, cortisol in women with the onset of
menopause. Studies with hormone replacement therapy have shown that estrogens affect the
duration of the REM phase, increasing it, latency to sleep with its decrease, the number of
spontaneous awakenings per night, which significantly increases the total duration of sleep [4].
An age-related decrease in progesterone can also contribute to an increase in the duration of
falling asleep. This is explained by its direct sedative effect through stimulation of
benzodiazepine receptors, which leads to the production of the most important inhibitory
mediator of the brain - gamma-aminobutyric acid [5]. Cortisol, the level of which increases with a
deficiency of sex steroids, contributes to low sleep efficiency with a reduction in the duration of
stages II, III and IV of sleep [6]. that estrogens affect the duration of the REM phase, increasing
it, latency to sleep with its decrease, the number of spontaneous awakenings per night, which
significantly increases the total duration of sleep [4]. An age-related decrease in progesterone
can also contribute to an increase in the duration of falling asleep. This is explained by its direct
sedative effect through stimulation of benzodiazepine receptors, which leads to the production of
the most important inhibitory mediator of the brain - gamma-aminobutyric acid [5]. Cortisol, the
level of which increases with a deficiency of sex steroids, contributes to low sleep efficiency with
a reduction in the duration of stages II, III and IV of sleep [6]. that estrogens affect the duration
of the REM phase, increasing it, latency to sleep with its decrease, the number of spontaneous
awakenings per night, which significantly increases the total duration of sleep [4]. An age-related
decrease in progesterone can also contribute to an increase in the duration of falling asleep.
This is explained by its direct sedative effect through stimulation of benzodiazepine receptors,
which leads to the production of the most important inhibitory mediator of the brain -
gamma-aminobutyric acid [5]. Cortisol, the level of which increases with a deficiency of sex
steroids, contributes to low sleep efficiency with a reduction in the duration of stages II, III and IV
of sleep [6]. An age-related decrease in progesterone can also contribute to an increase in the
duration of falling asleep. This is explained by its direct sedative effect through stimulation of
benzodiazepine receptors, which leads to the production of the most important inhibitory
mediator of the brain - gamma-aminobutyric acid [5]. Cortisol, the level of which increases with a
deficiency of sex steroids, contributes to low sleep efficiency with a reduction in the duration of stages II, III and IV of sleep [6]. An age-related decrease in progesterone can also contribute to an increase in the duration of fallin
32
Currently, there is a significant increase in violations of the "sleep -
wake" cycle, which, in turn, is the cause of cognitive disorders in the
form of distracted attention, decreased ability to remember, irritability
and impaired social interactions. Patients with moderate cognitive
impairment most often complain of increased daytime drowsiness,
circadian rhythm disturbance “sleep - wakefulness”, insomnia,
respiratory failure in sleep, parasomnia [7]. Somnological pathology is
widespread among the population with reproductive aging, reaching
more than 60% in this age period. The most common sleep disorders
with sex steroid deficiency are insomnia and OSAS [8].
Insomnia, a clinical syndrome with the presence of repeated
disturbances in the initiation, duration, consolidation, or quality of sleep,
occurring despite the presence of a sufficient amount of time and
conditions for sleep, and manifested by violations of daytime activity of
various kinds [1], is more often detected in women, and gender
differences in the prevalence of this somnological pathology becomes
more significant with age [9]. The results of the studies carried out to
date have not shown the unambiguity of the main symptoms of insomnia
in menopausal women. Thus, the results of some studies have shown
difficulty falling asleep as the main symptom of insomnia in
postmenopausal women [10]. According to other scientific papers that
studied complaints of sleep disturbances depending on the phase of the
menopause, a greater number of nocturnal awakenings in
postmenopausal women were shown without differences in the difficulty
of falling asleep, morning and afternoon fatigue between peri- and
postmenopausal women [11]. Moreover, when evaluating insomnia
complaints depending on ethnicity, a greater frequency of difficulty
falling asleep and difficulties of morning awakenings in perimenopause,
as well as a greater number of frequent night awakenings in
postmenopausal women of the Caucasian race, were found, while
representatives of the Mongoloid race did not find any or any differences
in the structure of insomic disorders between the phases of menopause
[12]. An important role in the pathogenesis of insomnia in menopausal
women is given to vasomotor symptoms, the presence of which 1.85
times increases the risk of nocturnal awakenings [13]. With pronounced
vasomotor reactions, polysomnographic monitoring data indicate a
decrease in sleep efficiency, a change in its “architecture” and a longer
wakefulness during the night [14]. Depression, in the pathogenesis of
which the key role belongs to the disruption of the serotonergic brain
systems, is another factor that plays a significant role in the
development of insomnia in menopausal women [15].
This is due to the fact that female sex hormones have a
neuroprotective role, affect the synthesis and metabolism of
monoamines, including serotonin, and are involved in the maturation of
many brain functions [16]. A study of the association of depressive
disorders and insomnia in postmenopausal women revealed a
relationship not only with difficulties
Internal diseases

falling asleep and early morning awakenings [13], but also night
awakenings [17].
OSAS is a condition in which recurring episodes of complete or partial obstruction of the
upper respiratory tract during sleep are recorded, with complete or partial cessation of the
oronasal respiratory flow lasting at least 10 seconds [1]. The incidence of OSA in women is 2–8
times lower than among men, however, with the onset of reproductive aging, gender differences
in the occurrence of this pathology are “erased” [18]. The reason for this, firstly, is a decrease in
progesterone in menopausal women, which is a respiratory analeptic [19], and secondly, obesity
developing under conditions of estrogen deficiency, which is one of the important factors in the
development of OSAS, with accumulation of subcutaneous fat in the chest and neck, increasing
the risk of upper respiratory tract collapse [20]. Thirdly, Recent studies have shown that
vasomotor symptoms may be another risk factor for developing OSAS in women with steroid
deficiency [21]. In addition, both men and women increase with age the amount of
near-pharyngeal adipose tissue, as well as the resistance of muscles and ligaments, a decrease
in pharyngeal diameter with a decrease in pharyngeal reflex [22]. Thus, age-related changes in
the structure and functional state of the upper respiratory tract are factors contributing to the
development of OSAS, increasing the prevalence of this somnological pathology in individuals
with androgen and estrogen deficiency. in women, the amount of near-pharyngeal adipose
tissue, as well as the resistance of muscles and ligaments, increase with age, there is a
decrease in the diameter of the pharynx with a decrease in the pharyngeal reflex [22]. Thus,
age-related changes in the structure and functional state of the upper respiratory tract are
factors contributing to the development of OSAS, increasing the prevalence of this somnological
pathology in individuals with androgen and estrogen deficiency. in women, the amount of
near-pharyngeal adipose tissue, as well as the resistance of muscles and ligaments, increase
with age, there is a decrease in pharyngeal diameter with a decrease in pharyngeal reflex [22].
Thus, age-related changes in the structure and functional state of the upper respiratory tract are
factors contributing to the development of OSAS, increasing the prevalence of this somnological
pathology in individuals with androgen and estrogen deficiency.
Sleep disorders with a deficiency of sex steroids are often
associated with musculoskeletal pain syndrome, which is chronic and
characterized by local soreness and stiffness of the muscles of the
whole body. This syndrome is called fibromyalgia and is more common
among the female population. With fibromyalgia, increased muscle
fatigue is observed, aggravated by various physical exercises,
depressive symptoms, anxiety, and cognitive impairment are noted. A
patient suffering from this syndrome has problems falling asleep and
frequent night awakenings. In the pathogenesis of fibromyalgia, an
important role belongs to substance P, which is the central nociceptive
neuropeptide in the brain. An increase in its level entails a decrease in
the content of serotonin and dopamine in the central nervous system,
which, in turn, leads to chronic pain, as well as the appearance of
depressive symptoms. The structure of sleep in patients with
fibromyalgia is impaired, as evidenced by a decrease in the duration of
the deep stages of sleep and the presence of an alpha rhythm on the
electroencephalogram during slow-wave sleep [1].
The heterogeneity of age-related changes in the sleep-wake cycle
and the multifactorial nature of their regulation is one of the reasons for
conflicting data and mutually exclusive hypotheses about the
neurochemical profiles of age-related modulation of neurobiological
markers of sleep disorders, which requires the search for new
endogenous factors included in the cellular and molecular mechanisms
of regulation of sleep and their relationship with the integrative activity of
somnogenic brain structures.
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ACTA BIOMEDICA SCIENTIFICA, 2020, Volume 5, No. 1
DEPRIVATION OF SLEEP AND FREE RADICAL
OXIDATION ON ANIMAL MODELS
To date, a sufficient amount of data has been accumulated
confirming the free radical theory of aging, according to which changes
in the metabolism of proteins, fats, carbohydrates, nucleic acids, and
water-electrolyte metabolism occur due to the development of oxidative
stress. The age-dependent development of an imbalance between
prooxidants and antioxidants can contribute to damage to tissues of the
whole body, including brain cells, which can lead to disruption of
neurotransmitters, in particular, melatonin and a change in the
integrative activity of brain structures [23]. In this regard, both in Russia
and abroad, for more than 20 years, scientific studies have been
conducted that evaluate the relationship between oxidative stress and
sleep deprivation, not only in experiment, but also with the participation
of people.
The first suggestion about the possible accumulation of free
radicals and toxic products of lipid peroxidation processes in the body
during wakefulness and their inactivation during deep sleep was made
in 1994. According to the researcher, in a dream the rate of their
formation decreases while increasing the efficiency of the antioxidant
defense system (AOD) [24]. To confirm this hypothesis, a series of
experimental studies were carried out with determination of the
parameters of lipid peroxidation processes and the AOD system in the
tissues of organs such as the brain, skeletal muscles, and liver. The
high content of polyunsaturated fatty acids in the membranes of brain
cells determines its high sensitivity to the development of oxidative
stress, which develops with sleep deficiency [25]. An analysis of the
published experimental data indicates that the parameters of the “lipid
peroxidation - antioxidant defense” system depend on the duration of
sleep deprivation. So, with sleep deprivation for 6 hours in the cerebral
cortex, brain stem, and basal forebrain, an increase in the level of the
restored form of glutathione is noted with a simultaneous increase in the
activity of glutathione peroxidase in the cerebellum and hippocampus
[26]. Sleep deprivation for 48 and 72 hours entails an increase in the
level of malondialdehyde compared with 24 and 96 hours of deprivation
[27]. With a 5–10-day absence of sleep, a decrease in the activity of Cu
/ Zn superoxide dismutase is noted in the hippocampus and brain stem
[28]. With sleep deprivation at 1–2 weeks in the brain, liver and skeletal
muscles, no changes in the activity of Mn- and Cu / Zn-superoxide
dismutase were detected,
Free radical oxidation in animal models is also actively being
studied with OSAS. Thus, by creating 12-second respiratory arrests in
rats every minute for 1 hour in rats, the researchers did not reveal a
change in the levels of malondialdehyde in both male and female
individuals, however, there was an increase in the products of protein
oxidation and end glycosylation products in both gender groups.
indicating the development of not only oxidative, but also carbonyl
stress [30]. Along with this, experiment
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ACTA BIOMEDICA SCIENTIFICA, 2020, Vol. 5, N 1
It has been shown by mental studies that reactive oxygen species
formed in large quantities during hypoxia, as well as during aging, can
lead to a decrease in the expression and / or structural modification of
metallopeptidases, such as neprilysin, neprilysin 2, endothelin
converting enzymes 1 and
2, which regulate some neuropeptides and are the main enzymes that
destroy β-amyloid [31]. It was demonstrated that neprilysin mRNA
expression after hypoxia in the neurons of the hippocampus and the
cerebral cortex of mice decreases. In addition, after hypoxia, an
increase in the demethylation of histone H3 of lysine 9 and a decrease
in acetylation of histones H3 in the region of the promoter of the
neprilysin gene were detected. Moreover, hypoxia causes increased
regulation of histone methyl transferase G9a and histone deacetylases
HDAC-1 [32]. Thus, hypoxia promotes the accumulation of β-amyloid in
brain cells with the formation of amyloid plaques. At the same time, the
experimental results showed a decrease in amyloid plaques with an
increase in the duration of slow-wave sleep [33], which confirms the
drainage function of the deep stages of sleep. In 2012 As a result of
studies in mice, the glyphatic system was discovered, which is an
anatomical cerebrospinal fluid pathway for excreting the waste products
of brain cells [34]. Recent studies have shown the greatest activity of the
glyphatic system during the deep stages of sleep, which is caused by
increased synaptic plasticity during slow-wave sleep [35]. At the same
time, the full mechanism of the glyphatic system is still not clear.
FREE RADICAL OXIDATION
AT SOAS
The largest number of studies of free radical processes in a person
with a somnological pathology was carried out in the study of obstructive
sleep apnea syndrome. This is due to the fact that this pathological
condition is accompanied by hypoxia, which is a stressor that changes
free radical homeostasis. It is known that reactive oxygen species and
oxidative stress are involved in the initiation and spread of inflammatory
reactions, which is mediated by leukocyte activation and altered
adaptive and immune / inflammatory signaling pathways. A large
number of transcription factors and signaling pathways are modulated
using reactive oxygen species. Thus, hypoxia in OSAS induces factor-1
alpha (HIF-1a), nuclear factor “kappa-bi” (NF-kB), protein activator-1
(AP-1), factor-2, associated with erythroid nuclear factor ( Nrf2).
Plasma and biomaterial for studying the parameters of free radical
oxidation processes in OSAS in a wide variety of studies, indicating the
intensification of lipid peroxidation, were
34
blood leukocytes, urine, exhaled breath condensate, saliva [37–41]. It
was shown that the result of a change in free radical homeostasis during
OSAS may be oxidation of DNA, as evidenced by an increase in the
level of 8-hydroxy-2 ›-deoxyguanosine. An increase in the level of this
biomarker directly reflects the dependence of oxidized guanine bases,
which are most vulnerable to the action of free radicals. Being the final
form, this compound does not undergo further disposal. When
comparing patients with severe OSAS (mean age -
48.8 ± 11.0 years) in relation to the group with a mild degree of OSA
comparable in age, a higher level of this indicator in urine was revealed,
which positively correlated with apnea / hypopnea and oxygen
desaturation indices. Moreover, the desaturation index in this study is
considered as the best predictor of an increase in the level of
8-hydroxy-2'-deoxyguanosine, since it reflects the frequency of episodes
of hypoxemia followed by reoxygenation, during which reactive oxygen
species are intensively produced [42]. As a result of DNA oxidation,
dysregulation of genes involved in the modulation of reactive oxygen
species, as well as enzymatic antioxidants, is possible, which may
cause a decrease in the overall activity of the antioxidant defense
system during OSAS [40]. In the study,
- the only scientific institution in Russia where for more than 10 years
they have been studying free radical homeostasis in patients with
somnological pathology, a correlation between the severity of OSAS
and the intensity of oxidative stress has been shown. The study involved
males from 14 to 55 years of age, with different OSAS durations. As a
result of the study, it was shown that the preclinical manifestations of
respiratory disorders during sleep do not cause an imbalance in the
system of “lipid peroxidation - antioxidants”. However, with the
aggravation of the pathological condition and the duration of clinical
manifestations, a gradual change in free radical homeostasis occurs,
and in severe hypoxia with an OSA duration of about 10 years (men in
andropause), the adaptive-compensatory mechanisms of the
lipoperoxidation – antioxidants system are depleted, which is manifested
by inhibition of both the prooxidant and antioxidant units of the system
[37]. The results of this study are also confirmed in the works of foreign
scientists. So, when comparing groups of patients with moderate to
severe OSAS (average age
45.3 ± 14.4 and 52.8 ± 14.2 years, respectively), including both men
and women, an increase in serum levels of active products of
thiobarbituric acid and carbonyl groups of proteins was shown with a
severe degree of OSA [43]. The use of CPAP therapy for 1 month has
been shown to reduce the level of highly toxic lipid peroxidation
products in the blood of patients [44]. Along with this, positive
correlations of the level of active products of thiobarbituric acid with the
apnea / hypopnea index and desaturation index and a negative
correlation with the oxygen content in the blood were revealed [45]. The
level of oxidation products of proteins and carbonyl groups
Internal diseases

also correlates with the apnea / hypopnea index [44, 46, 47],
determining the development of carbonyl stress in patients with severe
OSAS with the accumulation in the blood of the final glycosylation
products, carbonyl groups of proteins, fructosamine [44]. A recent study
to determine the parameters of free radical oxidation in saliva in patients
older than 50 years with an apnea / hypopnea index> 30 before bedtime
and immediately after waking up showed a higher content of active
thiobarbituric acid products, protein oxidation products and final
glycosylation products in the morning portion of biological material
collected on the first diagnostic night. The use of CPAP therapy on the
second diagnostic night significantly improved these parameters [41].
>  30 [48] and decreases after treatment with CPAP therapy [49].
In a review by AB Lira et al. (2016), whose goal was to search for
the most significant markers of oxidative stress in patients with OSA, it
is shown that these are thioredoxin, malondialdehyde, superoxide
dismutase, and reduced iron. It was these biomarkers that showed a
more stable relationship between increased oxidative stress and OSA.
Moreover, interesting results in the form of a decrease in oxidative
stress were obtained with respect to vitamin C and N-acetylcysteine,
which can be considered as antioxidant therapy in patients with this
somnological pathology [50]. A recent study in which patients with
moderate severity of OSA (mean age 52.6 ± 13.3 years) participated,
showed
The study of oxidative stress in case of somnological pathology is
also of interest from the standpoint of its pathogenetic role in the
formation of amyloid plaques in the brain. Recent studies have shown
that in men with androgen deficiency with a severe degree of OSA,
serum β-amyloid-42 level is lower than in the control, which is probably
due to the inability to cleanse the brain of this protein due to disruption
of the enzymes that destroy it . Another reason may be the insufficient
functioning of the glyphatic system, which is most active during the deep
stages of sleep, the lack of which is observed in patients with OSAS
[52].
Currently, the question of the association of oxidative stress and
hypoxia in OSAS remains a controversial one. This is due to the
opposite results of some studies [53, 54]. Moreover, it has been
suggested that factors such as smoking and obesity have a greater
influence on the development of oxidative stress, and hypoxia in OSAS,
in turn, enhances the already existing oxidative stress [55].
FREE RADICAL OXIDATION
AT INSOMNIA
Studies of free radical processes in insomnia are currently scarce.
Not-
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ACTA BIOMEDICA SCIENTIFICA, 2020, Volume 5, No. 1
long-term studies have shown the dependence of lipid concentration on
the circadian system [56] and suggested a possible regulatory role of
sleep in lipid homeostasis [57], which in conditions of sleep deficiency
explains the accumulation of substrate support of lipid peroxidation
processes. In some studies, the main groups are not divided by gender,
although the influence of sex on lipid peroxidation processes and the
activity of the antioxidant defense system is shown [58]. In this regard,
the demonstrated decrease in the overall antioxidant status and
increase in the oxidative link with the assumption of an important role in
this reduction of paraoxonase activity is doubtful [59]. Studies on women
with insomnia present data indicating a decrease in the activity of the
enzymatic link of the glutathione system with a constant activity of
myeloperoxidase and superoxide dismutase with an increase in the level
of glutathione and end products of lipid peroxidation [60]. In
postmenopausal women with insomnia, an increase in the level of active
products of thiobarbituric acid was observed in the absence of changes
in the activity of the enzymatic link of the antioxidant defense system —
catalase and superoxide dismutase [61]. Determining the level of
another important antioxidant - uric acid - in patients with insomnia
showed a low level in blood serum, which, according to the results of
logistic regression, correlated with high scores of the Pittsburgh sleep
quality index questionnaire. When comparing the level of this antioxidant
in patients with insomnia, depending on gender, it was found to be lower
in women. Along with this, no differences were found in the level of uric
acid depending on the use of sleeping pills, no correlations were found
between the antioxidant content and age, as well as the duration of
insomnia [62].
The results of the study of the Federal State Budget Scientific
Institution Scientific Center for Crisis in Women with the participation of
menopausal women showed that the development of oxidative stress
depends not only on the menopause phase, but also on the ethnicity of
the patient. So, in the perimenopausal period, the accumulation of
intermediate products occurs, and in the postmenopausal period there is
an accumulation of the final products of lipid peroxidation. Common to
both ethnic groups is a decrease in the overall antioxidant status with
comorbidity of insomnia with OSA in postmenopausal women. Ethnic
differences are in the nature of changes in the activity of the antioxidant
defense system. So, representatives of the Buryat ethnic group showed
a decrease in the activity of superoxide dismutase in perimenopause
and an increase in the level of the restored form of glutathione in
postmenopause [63, 64]. 3111T / With gene Clock in women of the
Caucasian race. Thus, patients with insomnia - carriers of the TT
genotype had a significantly higher level of active products of
thiobarbituric acid and glutathione peroxidase activity compared with
patients - carriers of minor 3111C- allele. A comparative analysis of the
parameters in women of the main and control groups showed higher
levels of primary and final lipoperoxidation products and lower levels
35
ACTA BIOMEDICA SCIENTIFICA, 2020, Vol. 5, N 1
retinol, glutathione, glutathione reductase activity in women with
insomnia - carriers of the TT genotype. Carriers of a minor allele with
insomnia have higher levels of primary lipid peroxidation products and
lower glutathione peroxidase activity compared to control [65]. One of
the reasons for the change in free radical homeostasis depending on
this polymorphism may be a shift in the peak of melatonin secretion in
the early morning hours in women with insomnia - carriers TT polymorphism
genotype
3111T / C gene Clock [ 66]. If we compare the antioxidant properties of
melatonin with glutathione and tocopherol, they are more pronounced in
the hormone and are realized not only through direct action on free
radicals, but also through the activation of the enzymatic link of the
antioxidant defense system, involving enzymes such as catalase,
superoxide dismutase, glutathione reductase, glutathioneper
glucose-6-phosphate dehydrogenase [67].
In addition, this study demonstrated a content below the threshold
glutathione in women with insomnia - carriers TT polymorphism
genotype 3111T / C gene Clock which is probably the result of a violation
of the activity of glutathione reductase, which restores the disulfide bond
of oxidized glutathione to its sulfhydryl form. Considering the antioxidant
effect of glutathione, realized through participation in the work of
antioxidant enzymes, as well as through direct interaction with free
radicals of organic compounds formed by the action of reactive oxygen
species, a decrease in cellular glutathione below the threshold level is
considered as an apoptotic signal that initiates the activation of the
death receptor or mitochondrial apoptotic signaling [23]. Taking into
account the function of melatonin as an activator of glutathione
reductase, a change in its chronobiological rhythms in women with
insomnia
- carriers of TT genotype polymorphism 3111T / C gene
Clock may be the cause of the revealed decrease in the level of reduced
glutathione [65].
Considering the antioxidant properties of melatonin and the
hypothesis of elimination of toxic products of free radical oxidation
during slow-wave sleep, changes in hormone secretion can lead to a
shift in the time of inactivation of free radicals, thereby contributing to
the development of oxidative stress. Along with this, as a result of
oxidative stress, epigenetic changes are possible, including chromatin
remodeling by modification of histones, which leads to metabolic
disturbances and neurodegeneration. One of the genes associated with
circadian rhythms is Sirtuin1, defects of which lead to disruption of the
suprachiasmatic nuclei of the hypothalamus with the subsequent
development of desynchronosis and changes in the production of
melatonin [68].
Taking into account the results of these studies, we can assume
that 3111C- polymorphism allele 3111T / C gene Clock performs a
protective function from the development of oxidative stress in women of
the Caucasian race with a deficiency of sex steroids and suffering from
insomnia. The protective role of the minor polymorphism allele 3111T / C gene
Clock in the development of pathological conditions has also been
demonstrated in
36
some studies concerning the metabolic syndrome, in the pathogenesis
of which oxidative stress plays an important role [69]. The results
indicate the need for a personalized approach for the prevention and
correction of oxidative stress in women with age-related sleep disorders.
FREE RADICAL OXIDATION
AT FIBROMIALGIA
Fibromyalgia is another sleep disorder, in the pathogenesis of
which an important role is given to the development of oxidative stress.
Studies in this area indicate a decrease in the overall antioxidant status,
as well as the level of coenzyme Q10 with an increase in the production
of reactive oxygen species in patients with fibromyalgia, which are
indicators of their mitochondrial dysfunction [70].
When studying the state of thiol-disulfide homeostasis in women
with fibromyalgia, lower levels of thiols with an increase in the content of
disulfide groups in pathology were shown, indicating a change in the
functioning of the antioxidant defense system. Moreover, the
researchers found correlations between the scores of the questionnaire
evaluating the functional state of fibromyalgia (FIQ) and the level of
thiols (negative correlation) and disulfides (positive correlation) in
patients [71].
The results of a study of the activity of the enzymatic link of the
antioxidant defense system showed a higher superoxide dismutase
activity at control values ​of glutathione peroxidase activity in patients
with fibromyalgia, which is probably associated with an intensification of
lipid peroxidation processes. Given that polymorphism Ala9val gene MnSOD2
causes changes in the signal sequence of the mitochondrial enzyme
Mn-SOD and affects its transport to the mitochondria, leading to
changes in the functioning and localization of the enzyme, the
researchers first attempted to search for significant differences between
the frequencies of genotypes and alleles of this polymorphism in
patients with fibromyalgia. Along with this, the prevalence of another
polymorphism was analyzed - Pro198Leu gene GPX1, which, by
replacing proline with leucine, which affects the binding of selenium,
which is necessary for the functioning of glutathione peroxidase,
contributes to a decrease in enzymatic activity. However, significant
differences in the frequency of genotypes and alleles of these
polymorphisms in patients with fibromyalgia were not found [72].
The results of a recent study involving patients older than 45 years
(2/3 were women) demonstrated not only the relationship of fibromyalgia
with OSA, but also a higher level of malondialdehyde with a decrease in
catalase, superoxide dismutase, glutathione peroxidase with comorbidity
of two somnological pathologies in compared not only with the control
group, but also with patients suffering only OSAS [73].
CONCLUSION
A review of the literature indicates an imbalance between
prooxidants and antioxidants in sleep disorders accompanied by
Internal diseases

hypoxia, changes in chronobiological rhythms, fibromyalgia, as
evidenced by both experimental studies and studies involving patients.
One of the factors influencing the ambiguity of the results of numerous
studies obtained so far is: the small number of samples on which
studies are conducted; inclusion in the main groups of patients without
dividing them by gender; conclusions about the development of
oxidative stress in one or two markers, including the level of active
products of thiobarbituric acid, which can interact not only with
malondialdehyde formed during lipid peroxidation, but also with other
compounds. All this indicates the need for a more complete study of free
radical oxidation, taking into account the study of protein oxidation
processes, 
Given the important role of oxidative stress in the pathogenesis of
various diseases, including somnological pathology, as well as those
identified as a result of numerous studies of the relationship of sleep
disorders with depression [74], obesity [75], and cardiovascular
diseases [76, 77 ], diabetes mellitus [78], oncology [79], Alzheimer's
disease [80], etc., the risk of developing which increases with the onset
of age-related deficiency of sex steroids, resulting in comorbidity and, as
a consequence, aggravation of physical health disorders, antioxidant
therapy can not only be included in the complex of therapeutic
interventions to improve the health of people suffering from sleep
disorders during reproductive aging, but its application should be subject
to a personalized approach.
Financing
The study was carried out with the financial support of the Russian Federal
Property Fund and the Government of the Irkutsk Region as part of the scientific project
No. 20-415-380001.
Conflict of interests
No conflict of interest information.
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Information about authors

Semenova Natalya Viktorovna - Doctor of Biological Sciences, Leading Researcher at the Laboratory of Pathophysiology, Federal State Budgetary Institution Scientific Center for Family Health and Human Reproduction,
e-mail: natkor_84@mail.ru , https://orcid.org/0000-0002-6512-1335

Madaeva Irina Mikhailovna - Doctor of Medical Sciences, Leading Researcher at the Laboratory of Pathophysiology, Head of the Somnology Center, Federal State Budgetary Institution Scientific Center for Family Health
and Human Reproduction, e-mail: nightchild@mail.ru , https://orcid.org/0000-0003-3423 -7260

Kolesnikova Lyubov Ilinichna - Academician of the Russian Academy of Sciences, Doctor of Medical Sciences, Professor, Scientific Director of the Scientific Center for Family Health and Human Reproduction, e-mail:
iphr@sbamsr.irk.ru , https://orcid.org/0000-0003-3354- 2992

Information about the authors

Natalya V. Semenova - Dr. Sc. (Biol.), Leading Research Officer at the Laboratory of Pathophysiology, Scientific Center of the Family Health and Human Reproduction Problems, e-mail: natkor_84@mail.ru ,
https://orcid.org/0000-0002-6512-1335

Irina M. Madaeva - Dr. Sc. (Med.), Leading Research Officer at the Laboratory of Pathophysiology, Director of Somnological Center, Scientific Center of the Family Health and Human Reproduction Problems, e-mail:
nightchild@mail.ru , https://orcid.org/0000- 0003-3423-7260

Lyubov I. Kolesnikova - Academician of RAS, Dr. Sc. (Med.), Professor, Scientific Director of the Scientific Center of the Family Health and Human Reproduction Problems, e-mail: iphr @ sbamsr.irk.ru,
https://orcid.org/0000-0003-3354-2992

Received: 01.20.2020. Article accepted: 02/07/2020. Article published: 02.26.2020.

Received: 01/20/2020. Accepted: 02/07/2020. Published: 02.26.2020.

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