**2. Morphofunctional, molecular, genetic and biochemical basis of circadian rhythm regulation**

## **2.1. Morphofunctional features of suprachiasmatic nuclei and their connections with epiphysis**

**Circadian rhythms (CR)** are physiological and behavioral cycles, which are provided by the internal oscillator and remain in the absence of an external "regulator". The ability to maintain a 24-hour rhythm is a fundamental characteristic of a circadian system that allows the body to adapt to environmental conditions [1].

*Circadian system operates due to four key components*:

internal and external synergism, indicates a health status [1]. In the case of discrepancy of the CR, there is desynchronosis – a form of circadian pathology, a nonspecific manifestation of pathological conditions characterized by changes in the structure of the rhythm: an increase (decrease) in amplitude; inversion of acrophases; change the duration of the period [2]. The manifestation of many diseases, such as myocardial infarction, stroke, sudden death, etc., is closely associated with certain periods of the day [3–5]. The diurnal rhythms of biochemical processes and physiological functions are synchronized in time, or synchronous. Thus, the number of heart rate (HR) and respiration rate are correlated as 4:1 (72:18, 80:20), that ensures optimal oxygen supply to tissues and is consistent with the rhythms of metabolism. There are several theories about the nature of endogenous factors. In 1976, the chronohypothesis was developed. According to it there is a site in the DNA structure – "chronon," controlling biorhythms. According to the multi-oscillator model of biorhythms, there are many drivers of

External factors of general synchronization include geophysical factors: photoperiods (daynight), fluctuations in the geomagnetic field of the Earth, changes in the temperature of the environment, etc. For a modern person, the change in the phylogenetically formed stereotype

In the process of evolution, complex mechanisms of nervous and humoral regulation of biorhythms, their optimal synchronization were developed. The launching of circadian oscillations and their interconnection is carried out by the activity of the central nervous mechanism performing the pacemaker function, which is realized through the humoral regulating link [2]. Light is the main factor that determines the activity of suprachiasmatic nuclei (SCN) as a biological clock. The information on the light mode is fed into the SCN from the retina of the eye. They also receive signals from other parts of the brain (afferent inputs) and send impulses

Through the efferent pathways, the SCN are involved in the regulation of the rhythmic activity of the endocrine system, blood circulation, eating behavior and other functions. Another structure important for the rhythmic organization of functions is the epiphysis – neuroendocrine transducer, an organ that transmits information about the illumination of the environment from the nervous system to the endocrine. Biologically active substance-melatonin is

There are different methods for detecting biorhythmological personality: measuring body temperature, blood pressure, heart rate, breathing, sleep-wake cycle, metabolic rate during the day, determining the level of melatonin in the blood or its metabolites in saliva or urine [10]. The prevalence of sleep and wakefulness disturbances in patients with cardiovascular diseases (CVD) is very high. After a stroke, patients often experience sleep disorders such as insomnia, daytime sleepiness, fatigue, behavioral disturbances in the sleep phase with rapid eye movements and the restless legs syndrome, obstructive sleep

To detect sleep disorders, semi-quantitative scales and questionnaires, polysomnography are used [10]. Examination of Daily blood pressure and Holter monitoring of ECG allow to establish violations of daily dynamics of blood pressure and heart rate. Holter monitoring of ECG

rhythm-pacemakers in the body [6].

80 Circadian Rhythm - Cellular and Molecular Mechanisms

under the influence of social factors is very important [7].

to various brain structures (efferent inputs) [8].

synthesized in epiphysis cells [9].

apnea syndrome [11–16].


The central circadian oscillator is the suprachiasmatic nuclei of the hypothalamus (SCN), which are heterogeneous in structure and neurochemical organization and are subdivided into the rostral and caudal divisions [8, 9].

The SCN almost entirely determines dependence of brain activity on the state of external illumination. During the day, light entering the retina activates its photosensitive ganglion cells, the information from which is transmitted through the retinohypothalamic tract and further into the SCN. Signals from the SCN are transmitted to the paraventricular nucleus of the hypothalamus, and further, trough the intermediolateral column of the spinal cord, reach the upper cervical ganglion. Sympathetic postganglionic noradrenergic fibers innervate melatonin-secreting cells in the epiphysis. Norepinephrine acts on postsynaptic beta-1 and alpha-1-adrenergic receptors in the cells of the epiphysis, which trigger the synthesis of **melatonin**. There is a clear daily periodicity: the production of melatonin begins with the onset of darkness, reaches a maximum at midnight and stops in the light. In the light phase of the day,

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There are reciprocal relationships between the SCN and the epiphysis, and melatonin is able to make certain corrections to circadian dysrhythmia, including inhibiting the discharges of SCN neurons. Under the influence of melatonin, the CR phase shift is also described in humans, which allowed recommending it for the correction of latitudinal desynchronosis [29, 41].

By obeying the signals of the SCN, the epiphysis through melatonin can directly interfere with the functional activity of the limbic structures of the brain. Hyperactivity of the latter causes the development of dysrhythmia, accompanied by an increased level of anxiety. With steady stressing, the anxiety transforms into a depressive state. The SCN due to its direct efferent projections into the subcortical limbic nuclei, and indirectly (via melatonin) limits hippocampal excitability. Probably, this is one of the ways to realize anti-anxiety properties of the epiphyseal hormone. Thus, the disturbance of the interaction of SCN with the epiphysis

In addition to managing the CR of the psychoemotional state, along with other circadian fluctuations, the SCN provide regulation of the basal cycle of calm-activity. It is known, the patients with depression are characterized by night sleep disturbance and phase structure of sleep disorder. One of the probable causes is legitimately sought in violation of the normal activity of the central pacemaker. It has been established that the SCN lesion in animals along with other CR disturbance significantly disturbs the sleep [42, 43]. Insomnia in humans is often combined with neurodegenerative pathology (Alzheimer's disease (AD), etc.), which is usually accompanied by the SCN lesion. On the other hand, a rhythmic change in the states of sleep and wakefulness is quite an autonomous process and persists in people deprived of external time sensors, which

emphasizes the dependence of sleep on the activity of the leading pacemaker [44–48].

is often the changes in the circadian oscillations of the clock genes [49, 50].

According to modern concepts, the periodic nature of the sleep-wake cycle is determined by the co-operation of the brainstem formations in the ascending awakening system of the brain and the hypnogenic pathways, the impulse from which, following to the forebrain, along with other structures, involves ventrolateral preoptic nuclei. The latter provide alternating excitation of activating and inactivating (hypnogenic) mechanisms with rhythmic change of sleep and wakefulness states during 24 hours, demonstrating a switching function. The weakness of the rhythm-organizing properties of the SCN can be determined by the pathological reorganization of intranuclear processes at the molecular level. An important reason for this

this process is replaced by an increased synthesis of **serotonin** [7, 8, 41].

is one of the pathogenetic factors of anxiety and depression [42, 43].

Most of the SCN neurons are GABA and secrete different peptide neurotransmitters. GABA provides a link between the neuronal populations of the ventral and dorsal sections of the SCN. It participates in stabilizing the activity of the SCN and maintaining high-frequency oscillations of neurons in the CR. Many of the individual SCN neurons exhibit electrical and molecular rhythms in isolation, but the rhythms are weaker and less stable [8–10].

It is found, that light stimuli trigger the intra- and intercellular cascade of gene expression first in the center of the SCN, whence elements of peripheral parts are involved in the process through the GABA-ergic signaling pathways. Specific neuropeptides, gap junctions, astrocytes and GABA-ergic signaling realize interrelation between the SCN neurons. Vasoactive intestinal peptide (VIP) and arginine-vasopressin (AV), involved in the regulation of rhythms, are most studied. Studies show that VIP maintains and synchronizes rhythms of the SCN, while AV participates in maintaining high amplitude of the output signal from the SCN and in re-input pulse modulation [8–10].

Rhythmicity and synchronism of the nuclei operation in the diurnal regime is maintained in this way. The physiological role of the SCN, which reduces to the generation of circadian signals and the subordination of the activity of neighboring brain structures and peripheral organs, is entirely determined by the nature of their afferent and efferent connections [8].

Among the afferent projections of the SCN, the retinohypothalamic tract, which provides the nucleus with information about the state of photoperiodic processes, is of particular importance. It transmits to the SCN the main stream of optical impulses and is represented by collaterals of retinal ganglion cells. Its damage affects the dynamics of the CR in the form of a phase shift [8].

Another significant afferent input for SCN is the ascending axons of the neurons of the seam nuclei projecting here. The existence of direct raphohypothalamic tracts explains the high content of serotonin in the SCN. The electrical stimulation of the seam nuclei clearly inhibits the rhythmic of the hypothalamic neurons. In experiments on isolated SCN neurons, agonists and antagonists of serotonin receptors when applied locally, simulating the effect of light, were shown to be able to shift the phase of CR cells [8, 9].

The SCN forms neural connections with the nuclei of the stem, responsible for the regulation of sleep and wakefulness processes [10]. The SCN have direct connections with supraventricular and preoptic regions, dorsomedial divisions of the hypothalamus, arcuate and paraventricular nuclei. The direct and inverse relations of the SCN with the various elements of the limbic system and the motor centers have great functional significance. In particular, some nuclei of the amygdala and septa are projected onto the SCN [40].

A special place in the temporal organization of adequate adaptive behavior and the genesis of affective disorders is attributed to the interaction of the SCN with the **epiphysis and emotiogenic limbic structures.** Epiphysis is an important relay station and the leading link in the realization of circadian signals in relation to different functional indicators [8, 9].

The SCN almost entirely determines dependence of brain activity on the state of external illumination. During the day, light entering the retina activates its photosensitive ganglion cells, the information from which is transmitted through the retinohypothalamic tract and further into the SCN. Signals from the SCN are transmitted to the paraventricular nucleus of the hypothalamus, and further, trough the intermediolateral column of the spinal cord, reach the upper cervical ganglion. Sympathetic postganglionic noradrenergic fibers innervate melatonin-secreting cells in the epiphysis. Norepinephrine acts on postsynaptic beta-1 and alpha-1-adrenergic receptors in the cells of the epiphysis, which trigger the synthesis of **melatonin**. There is a clear daily periodicity: the production of melatonin begins with the onset of darkness, reaches a maximum at midnight and stops in the light. In the light phase of the day, this process is replaced by an increased synthesis of **serotonin** [7, 8, 41].

The central circadian oscillator is the suprachiasmatic nuclei of the hypothalamus (SCN), which are heterogeneous in structure and neurochemical organization and are subdivided

Most of the SCN neurons are GABA and secrete different peptide neurotransmitters. GABA provides a link between the neuronal populations of the ventral and dorsal sections of the SCN. It participates in stabilizing the activity of the SCN and maintaining high-frequency oscillations of neurons in the CR. Many of the individual SCN neurons exhibit electrical and

It is found, that light stimuli trigger the intra- and intercellular cascade of gene expression first in the center of the SCN, whence elements of peripheral parts are involved in the process through the GABA-ergic signaling pathways. Specific neuropeptides, gap junctions, astrocytes and GABA-ergic signaling realize interrelation between the SCN neurons. Vasoactive intestinal peptide (VIP) and arginine-vasopressin (AV), involved in the regulation of rhythms, are most studied. Studies show that VIP maintains and synchronizes rhythms of the SCN, while AV participates in maintaining high amplitude of the output signal from the SCN and

Rhythmicity and synchronism of the nuclei operation in the diurnal regime is maintained in this way. The physiological role of the SCN, which reduces to the generation of circadian signals and the subordination of the activity of neighboring brain structures and peripheral organs, is entirely determined by the nature of their afferent and efferent connections [8].

Among the afferent projections of the SCN, the retinohypothalamic tract, which provides the nucleus with information about the state of photoperiodic processes, is of particular importance. It transmits to the SCN the main stream of optical impulses and is represented by collaterals of retinal ganglion cells. Its damage affects the dynamics of the CR in the form of a

Another significant afferent input for SCN is the ascending axons of the neurons of the seam nuclei projecting here. The existence of direct raphohypothalamic tracts explains the high content of serotonin in the SCN. The electrical stimulation of the seam nuclei clearly inhibits the rhythmic of the hypothalamic neurons. In experiments on isolated SCN neurons, agonists and antagonists of serotonin receptors when applied locally, simulating the effect of light,

The SCN forms neural connections with the nuclei of the stem, responsible for the regulation of sleep and wakefulness processes [10]. The SCN have direct connections with supraventricular and preoptic regions, dorsomedial divisions of the hypothalamus, arcuate and paraventricular nuclei. The direct and inverse relations of the SCN with the various elements of the limbic system and the motor centers have great functional significance. In particular, some

A special place in the temporal organization of adequate adaptive behavior and the genesis of affective disorders is attributed to the interaction of the SCN with the **epiphysis and emotiogenic limbic structures.** Epiphysis is an important relay station and the leading link in the

realization of circadian signals in relation to different functional indicators [8, 9].

molecular rhythms in isolation, but the rhythms are weaker and less stable [8–10].

into the rostral and caudal divisions [8, 9].

82 Circadian Rhythm - Cellular and Molecular Mechanisms

in re-input pulse modulation [8–10].

were shown to be able to shift the phase of CR cells [8, 9].

nuclei of the amygdala and septa are projected onto the SCN [40].

phase shift [8].

There are reciprocal relationships between the SCN and the epiphysis, and melatonin is able to make certain corrections to circadian dysrhythmia, including inhibiting the discharges of SCN neurons. Under the influence of melatonin, the CR phase shift is also described in humans, which allowed recommending it for the correction of latitudinal desynchronosis [29, 41].

By obeying the signals of the SCN, the epiphysis through melatonin can directly interfere with the functional activity of the limbic structures of the brain. Hyperactivity of the latter causes the development of dysrhythmia, accompanied by an increased level of anxiety. With steady stressing, the anxiety transforms into a depressive state. The SCN due to its direct efferent projections into the subcortical limbic nuclei, and indirectly (via melatonin) limits hippocampal excitability. Probably, this is one of the ways to realize anti-anxiety properties of the epiphyseal hormone. Thus, the disturbance of the interaction of SCN with the epiphysis is one of the pathogenetic factors of anxiety and depression [42, 43].

In addition to managing the CR of the psychoemotional state, along with other circadian fluctuations, the SCN provide regulation of the basal cycle of calm-activity. It is known, the patients with depression are characterized by night sleep disturbance and phase structure of sleep disorder. One of the probable causes is legitimately sought in violation of the normal activity of the central pacemaker. It has been established that the SCN lesion in animals along with other CR disturbance significantly disturbs the sleep [42, 43]. Insomnia in humans is often combined with neurodegenerative pathology (Alzheimer's disease (AD), etc.), which is usually accompanied by the SCN lesion. On the other hand, a rhythmic change in the states of sleep and wakefulness is quite an autonomous process and persists in people deprived of external time sensors, which emphasizes the dependence of sleep on the activity of the leading pacemaker [44–48].

According to modern concepts, the periodic nature of the sleep-wake cycle is determined by the co-operation of the brainstem formations in the ascending awakening system of the brain and the hypnogenic pathways, the impulse from which, following to the forebrain, along with other structures, involves ventrolateral preoptic nuclei. The latter provide alternating excitation of activating and inactivating (hypnogenic) mechanisms with rhythmic change of sleep and wakefulness states during 24 hours, demonstrating a switching function. The weakness of the rhythm-organizing properties of the SCN can be determined by the pathological reorganization of intranuclear processes at the molecular level. An important reason for this is often the changes in the circadian oscillations of the clock genes [49, 50].

#### **2.2. Molecular mechanisms of circadian oscillations**

The molecular basis for the CR regulation is provided by the hour genes, whose work is carried out on the principle of loops of positive and negative feedback. The BMAL1 and CLOCK proteins accumulated during the day form the BMAL1/CLOCK complex. The BMAL1/CLOCK dimer activates the transcription of the PER genes (PER1, PER2, PER3) and CRY (CRY1, CRY2). Synthesized PER and CRY proteins also form a PER/CRY dimer acting on the principle of negative feedback. PER/CRY moves to the cell nucleus and inhibits the activity of the BMAL1/ CLOCK complex, which leads to a decrease in the expression of PER and CRY proteins. During the night, the PER/CRY complex is destroyed, and the 24-hour cycle begins anew [49, 50].

synthesis of this hormone has been found in many neuroendocrine cells of the airways, lungs, in the cortical layer of the kidneys and along the boundary between the cortical and medullary layer of the adrenal glands, under the hepatic capsule, in the paraganglia, ovaries, endometrium, prostate gland, placenta, gallbladder and inner ear. In recent year's studies, melatonin synthesis is found: in blood cells – mast cells, lymphocytes – natural killers, thrombocytes, eosinophilic leukocytes, in the thymus, pancreas, cerebellum, retina. Functionally, many melatonin-producing cells belong to the so-called diffuse neuroendocrine system – a universal system for adapting and maintaining the body's homeostasis. Thus, two links of melatonin-producing cells are distinguished: central (includes the pineal gland and cells of the visual system), in which the rhythm of melatonin secretion coincides with the rhythm of light-darkness, and peripheral – all other cells where the secretion of the hormone does not depend on illumination [1, 2, 29].

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Melatonin is transported by serum albumin, after liberation from albumin it binds to specific receptors on the membrane of target cells, penetrates into the nucleus and performs its action there. The biological half-life of melatonin is 45 minutes. This makes it difficult to collect material for research purposes. Melatonin is rapidly hydrolyzed in the liver and excreted in the urine (80–90%), the main metabolites are 6-hydroxymelatonin-sulfate (6-SOMT) and 6-hydroxyglycuronide. The concentration of melatonin metabolites in saliva and/or urine correlates well

which are expressed mainly on the cells of the anterior lobe of the pituitary gland, the hypo-

in some parts of the brain, in the retina and in the lungs. The nuclear receptors of melatonin of the subfamily RZR/ROR of retinoid receptors have recently been discovered. Many immuno-

During the first years of life, peak concentrations of melatonin increase and reach a maximum by 2–4 years, after which they begin to decrease and reach the plateau by the time of puberty. The secretion of melatonin continues to decrease yearly after the end of puberty [10]. Both basal and peak concentrations of melatonin decrease with age, the daily curve of melatonin

The daily fluctuations in the melatonin level in the blood (melatonin curve) looks like the following. Its concentration is minimal by day (1–3 pg./ml), it starts to increase 2 h before the usual time for going to sleep (if there is no bright light). After turning the light off in the bedroom, the concentration of melatonin increases rapidly (up to 100–300 pg./ml). In the prehour hours, a recession usually begins, which ends after awakening. For each person, the melatonin curve is stable from night to night, while in different people of the same gender and

In a number of experiments on animals, the *antioxidant properties* of melatonin have been demonstrated. The mechanism of antioxidant action is manifested in the fact that melatonin has a pronounced ability to bind free radicals, including those formed during peroxidation of hydroxyl radical lipids, and exogenous carcinogens, and it also activates glutathione peroxidase, a factor protecting the body from free radical damage. The main functions of the melatonin antioxidant action are aimed at protecting DNA [10, 29, 52, 55]. To a lesser extent on the protection of

) receptors,

) receptors, expressed

with the total level of melatonin in the blood during the sampling period [1, 10, 30]. It has been found that the effect of melatonin is realized through MTNR1A (MT<sup>1</sup>

stimulatory and antitumor effects of melatonin are mediated through them [52].

secretion is smoothed and the peak of night secretion decreases [10, 52–54].

age the curves differ significantly, so one can speak of an individual curve [10, 52].

thalamus SCN and in many peripheral organs; as well as MTNR1B (MT2

Another clock gene involved in the regulation of this cycle is REV-ERB-alpha. The BMAL1/ CLOCK complex activates the transcription of the gene, which leads to the accumulation in the cell of the protein REVERB-alpha. The REVERB-alpha protein in turn inhibits the transcription of the BMAL1 gene and presumably the CLOCK and CRY1 genes [51].

#### **2.3. Melatonin involvement in the circadian rhythms regulation**

The leading regulator of biological rhythms is the epiphyseal hormone melatonin (N-acetyl-5-methoxytryptamine) acting on circadian systems via MT1- and MT2-melatonin receptors in the hypothalamus SCN [1, 28, 29].

The melatonin donor is the amino acid tryptophan, which participates in the synthesis of the neurotransmitter serotonin, which under the influence of the enzyme N-acetyltransferase turns into melatonin (**Figure 1**) [29].

Melatonin is an indole derivative of serotonin and is produced at night with the participation of N-acetyltransferase and hydroxyindole-O-methyltransferase enzymes [29].

Extrapineal sources of melatonin synthesis are enterochromaffin cells of the gastrointestinal tract (EC-cells), the main depot cells of serotonin (contain up to 95% of all endogenous serotonin). The

**Figure 1.** Мelatonin synthesis scheme.

synthesis of this hormone has been found in many neuroendocrine cells of the airways, lungs, in the cortical layer of the kidneys and along the boundary between the cortical and medullary layer of the adrenal glands, under the hepatic capsule, in the paraganglia, ovaries, endometrium, prostate gland, placenta, gallbladder and inner ear. In recent year's studies, melatonin synthesis is found: in blood cells – mast cells, lymphocytes – natural killers, thrombocytes, eosinophilic leukocytes, in the thymus, pancreas, cerebellum, retina. Functionally, many melatonin-producing cells belong to the so-called diffuse neuroendocrine system – a universal system for adapting and maintaining the body's homeostasis. Thus, two links of melatonin-producing cells are distinguished: central (includes the pineal gland and cells of the visual system), in which the rhythm of melatonin secretion coincides with the rhythm of light-darkness, and peripheral – all other cells where the secretion of the hormone does not depend on illumination [1, 2, 29].

Melatonin is transported by serum albumin, after liberation from albumin it binds to specific receptors on the membrane of target cells, penetrates into the nucleus and performs its action there. The biological half-life of melatonin is 45 minutes. This makes it difficult to collect material for research purposes. Melatonin is rapidly hydrolyzed in the liver and excreted in the urine (80–90%), the main metabolites are 6-hydroxymelatonin-sulfate (6-SOMT) and 6-hydroxyglycuronide. The concentration of melatonin metabolites in saliva and/or urine correlates well with the total level of melatonin in the blood during the sampling period [1, 10, 30].

It has been found that the effect of melatonin is realized through MTNR1A (MT<sup>1</sup> ) receptors, which are expressed mainly on the cells of the anterior lobe of the pituitary gland, the hypothalamus SCN and in many peripheral organs; as well as MTNR1B (MT2 ) receptors, expressed in some parts of the brain, in the retina and in the lungs. The nuclear receptors of melatonin of the subfamily RZR/ROR of retinoid receptors have recently been discovered. Many immunostimulatory and antitumor effects of melatonin are mediated through them [52].

During the first years of life, peak concentrations of melatonin increase and reach a maximum by 2–4 years, after which they begin to decrease and reach the plateau by the time of puberty. The secretion of melatonin continues to decrease yearly after the end of puberty [10]. Both basal and peak concentrations of melatonin decrease with age, the daily curve of melatonin secretion is smoothed and the peak of night secretion decreases [10, 52–54].

The daily fluctuations in the melatonin level in the blood (melatonin curve) looks like the following. Its concentration is minimal by day (1–3 pg./ml), it starts to increase 2 h before the usual time for going to sleep (if there is no bright light). After turning the light off in the bedroom, the concentration of melatonin increases rapidly (up to 100–300 pg./ml). In the prehour hours, a recession usually begins, which ends after awakening. For each person, the melatonin curve is stable from night to night, while in different people of the same gender and age the curves differ significantly, so one can speak of an individual curve [10, 52].

In a number of experiments on animals, the *antioxidant properties* of melatonin have been demonstrated. The mechanism of antioxidant action is manifested in the fact that melatonin has a pronounced ability to bind free radicals, including those formed during peroxidation of hydroxyl radical lipids, and exogenous carcinogens, and it also activates glutathione peroxidase, a factor protecting the body from free radical damage. The main functions of the melatonin antioxidant action are aimed at protecting DNA [10, 29, 52, 55]. To a lesser extent on the protection of

**Figure 1.** Мelatonin synthesis scheme.

the hypothalamus SCN [1, 28, 29].

turns into melatonin (**Figure 1**) [29].

**2.2. Molecular mechanisms of circadian oscillations**

84 Circadian Rhythm - Cellular and Molecular Mechanisms

The molecular basis for the CR regulation is provided by the hour genes, whose work is carried out on the principle of loops of positive and negative feedback. The BMAL1 and CLOCK proteins accumulated during the day form the BMAL1/CLOCK complex. The BMAL1/CLOCK dimer activates the transcription of the PER genes (PER1, PER2, PER3) and CRY (CRY1, CRY2). Synthesized PER and CRY proteins also form a PER/CRY dimer acting on the principle of negative feedback. PER/CRY moves to the cell nucleus and inhibits the activity of the BMAL1/ CLOCK complex, which leads to a decrease in the expression of PER and CRY proteins. During the night, the PER/CRY complex is destroyed, and the 24-hour cycle begins anew [49, 50].

Another clock gene involved in the regulation of this cycle is REV-ERB-alpha. The BMAL1/ CLOCK complex activates the transcription of the gene, which leads to the accumulation in the cell of the protein REVERB-alpha. The REVERB-alpha protein in turn inhibits the tran-

The leading regulator of biological rhythms is the epiphyseal hormone melatonin (N-acetyl-5-methoxytryptamine) acting on circadian systems via MT1- and MT2-melatonin receptors in

The melatonin donor is the amino acid tryptophan, which participates in the synthesis of the neurotransmitter serotonin, which under the influence of the enzyme N-acetyltransferase

Melatonin is an indole derivative of serotonin and is produced at night with the participation

Extrapineal sources of melatonin synthesis are enterochromaffin cells of the gastrointestinal tract (EC-cells), the main depot cells of serotonin (contain up to 95% of all endogenous serotonin). The

scription of the BMAL1 gene and presumably the CLOCK and CRY1 genes [51].

of N-acetyltransferase and hydroxyindole-O-methyltransferase enzymes [29].

**2.3. Melatonin involvement in the circadian rhythms regulation**

proteins and lipids. Its addition to the ration of rats resulted in an increase in life expectancy and testosterone levels in males [52, 56]. In the study of V.A. Lesnikov and W. Pierpaoli transplantation of the pineal gland from young to older individuals increased their lifespan by 42% and, conversely, transplantation of the epiphysis of older individuals reduced it by 29% [57]. Against the background of the use of melatonin in aging mice, not only the duration of life but also the volume of thymus, adrenals and testes increased, which was accompanied by an increase in the level of testosterone and thyroid hormones in the blood. Thus, a decrease in melatonin synthesis probably plays an important role in aging processes [53].

In a comparative analysis of autonomic control of the rhythms of the cardiovascular system (CVS) in young and elderly healthy people in Ukraine, it was shown that circadian regulation

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There are reports that chronobiological disorders are detected in patients with arterial hypertension [70–72], diabetes mellitus [73–75], cardiac ischemia [11, 12, 14, 61, 66], dementia [67–70], etc. Nowadays there is a lot of data on the existence of chronobiological patterns in the devel-

It is known that Ischemic stroke (IS) develops more often in the early morning hours [10]. This may be due to an increase in the activity of the coagulating system of blood at this time [71], as well as with a violation of the daily regulation of blood pressure and heart rhythm in these patients [72, 73]. In epidemiological studies, increased frequency of sudden cardiac death, MI and transient myocardial ischemia, pulmonary embolism and critical ischemia of the lower

The second small peak of incidence is noted in the early evening [74]. European researchers

In the epidemiological study conducted in Hawaii, it was found that the MI in local population of the Caucasoid race occurs most often between 04:00 and 12:00, and in Japanese visitors – from 12:00 to 16:00, which corresponds to the morning hours in Japan [76]. Similar daily dynamics of MI and stroke development early in the morning and between 12:00 and 18:00 was noted in a prospective study conducted in India involving 158 elderly patients [77]. Such a pattern of development of MI and stroke in the morning can be associated with an increase in platelet aggregation capacity in the morning hours with a peak at 09:00 [71–73]. Also in the early morning, endothelial cells reduce the synthesis of tissue activator plasminogen, nitric oxide and prostacyclin, the tone of the myocytes of the vascular wall is reduced, which pro-

In addition, there is a seasonal and cyclical decompensation of the CNS. As a rule, exacerbations occur in the spring and autumn. There is evidence that hemorrhagic stroke (HS) often manifests in winter and spring, and IS in summer and autumn [78]. Daylight saving time transgresses the CR and shifts the picture of the diurnal variation at the beginning of the

Effects of 2004–2013 daylight saving time (DST) transitions on IS hospitalizations and in-hospital mortality were studied nationwide in Finland. Hospitalizations during the week following DST transition (study group, n = 3033) were compared to expected hospitalizations (control group, n = 11,801), calculated as the mean occurrence during 2 weeks prior to and 2 weeks after the index week. DST transitions appear to be associated with an increase in IS hospitalizations during the first 2 days after transitions. Susceptibility to effects of DST transitions on occurrence of ischemic stroke may be modulated by gender, age and malignant

Disorders of CR are associated with an increased risk of IS. A monitoring of blood pressure for 5 days after a previous IS or HS, conducted in 50 patients (India), indicates a decrease in natural circadian fluctuations with an increase in blood pressure during the night [77].

of blood pressure and heart rate is impaired in elderly people. [25].

opment of stroke and myocardial infarction (MI) [11, 12, 14].

extremities, as well as rupture of the aortic aneurysm at dawn.

point to an increased incidence of stroke and MI in winter [75].

stroke, but the effect on the IS frequency is unknown.

motes thrombosis [71].

comorbidities [79].

Reducing melatonin concentrations in the elderly is probably one of the main factors in the development of age-related neurodegenerative diseases. A retrospective analysis of 6-year-old data in patients with depression revealed a disruption in the regulation of the synthesis and metabolism of catecholamines, neurotransmitters, melatonin and immunological proteins [42]. It has also been shown that melatonin supports the optimal mitochondrial membrane potential and preserves mitochondrial functions. In addition, mitochondrial biogenesis and its dynamics are also regulated by melatonin. Mitochondrial dynamics demonstrates an oscillatory pattern that corresponds to the CR of the secretion of melatonin in the pinealocytes and, possibly, in other cells [28, 52, 55]. A number of recent scientific studies have identified the neuroprotective effect of melatonin, which is manifested by affecting the proliferation and differentiation of neural stem cells, increasing the content of myelin and oligodendrocytes [58, 59].

In other studies, melatonin demonstrated a *neuroprotective effect* in neurodegenerative diseases. Melatonin reduces the toxicity of beta-amyloid and prevents the death of cells in experimental AD models, and also reduces oxidative stress in PD models [44–46, 48].

In addition, the experiment demonstrated the effect of melatonin *on the proliferation and differentiation of stem nerve cells.* Depending on the dose of melatonin introduced into the mice cortex, the proliferation rate of oligodendrocytes, the percentage of the main myelin protein, as compared with the control group, increased. Thus, melatonin may have a potential therapeutic effect for some neurological diseases associated with oligodendrocyte pathology and myelinopathy [59].

In recently published papers it is reported that melatonin synchronizes not only central but also peripheral biorhythms, which allows to synchronize biological functions by means of CR with respect to periodic changes in the environment and, therefore, facilitates adaptation of the individual to the external environment [28, 52].

The large number and diversity of the main effects of melatonin opens up important prospects for measuring the level of melatonin as a biomarker for the purpose of clinical, preventive and therapeutic use [10, 32].
