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ejpmr, 2019,6(3), 66-78 SJIF Impact Factor 4.897 EUROPEAN JOURNAL OF PHARMACEUTICAL Review Article Tulina et al. AND MEDICAL E uropeanRESEARCH Journal of Pharmaceutical and Medical ReISSNsearch 2394 -3211

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MELATONIN, PINEAL GLAND AND DISORDERS: FROM THEORY TO PRACTICE

Dina Tulina*, Patricia Pan and Dmitry Klokol

European Wellness International Group (EU, APAC), Stellar Biomolecular Research (Germany).

*Corresponding Author: Dina Tulina

European Wellness International Group (EU, APAC), Stellar Biomolecular Research (Germany).

Article Received on 31/12/2018 Article Revised on 20/01/2019 Article Accepted on 11/02/2019

ABSTRACT The article discusses the of sleep and mechanisms of sleep disorders. Possible therapeutic solutions to treat sleep disorders can be provided through functional and holistic biological , which employs a number of device-based treatments, stem cells and therapy with pineal gland cell extracts.

KEYWORDS: Pineal gland, sleep, sleep disorders, , stem cells.

The conundrum of sleep has always drawn special suffer from some form of .[1-3] In some not only as a biological process but also due to severe cases, which are relatively uncommon, substantial its psychological and even mystical peculiarities. Albeit leads to severe mental disorders, the complete biological purpose of sleep is yet to be intolerable torture incompatible with life that as an uncovered, to this date, we managed to understand some extreme manifestation can be well illustrated by central of its mechanisms and observe the effects of sleep hypoventilation syndrome a.k.a. Ondine‘s curse. disturbances on health and quality of life. Similar to many other biological processes sleep has a cyclic Driven by both homeostatic and circadian mechanisms nature. This phenomenon has a name of sleep consists of five stages – four stages of a slow wave and it applies in particular to the change of sleep, a.k.a. Non-REM sleep (non-rapid eye movement), and sleep, which under normal conditions is and fast wave sleep – REM sleep (rapid eye movement). characterized by relative stereotyping, but may be If the onset of slow wave sleep is associated with disrupted, for instance, in long-distance flights with time neuropeptides and increased ―sleep drive‖, then a fast zone changes or in connection with work associated with sleep is associated with the frontal cortex inhibition and periodic night duty, as well as by chronic stress, diseases disinhibition of the . Sleep is associated and the intake of various medications. with effects of various , which may stimulate the onset of sleep via GABA and receptors or Sleep is a functional state characterised by changes of the act as modulators of wakefulness and REM sleep via state of and bodily movements that at any choline, epinephrine, dopamine, histamine, and stage can be interrupted by physical stimuli. A regular systems.[1-5] person spends about a third of his life sleeping. Sleep arises from the influence of somnogenic mechanisms, PHYSIOLOGY AND NEUROENDOCRINE tonic systems of the , subcortical MECHANISMS OF SLEEP REGULATION formations and reticular substance. Therefore sleep Physiological duration of sleep in healthy individuals disturbances can arise due to pathological disturbances at varies according to their age. The need for a longer sleep any level.[1,2] is greater in children and subsequently decreases towards old age. Normally human adult‘s need for sleep varies Changes in the level of wakefulness (i.e. anxiety, from 5 to 10 hours a day, averaging at 6-8 hours. The lethargy, asthenia, etc.), as well as sleep disorders (from quality of sleep and its duration largely depend on the insomnia to and the whole range of other person's well-being and the general state of health, , intermediate and relevant disarrays), can have a very physical and mental activities. significant effect on the person's activity, ability to work, general health and mental state. Albeit having a great Normally, when falling asleep, slow wave sleep starts significance in maintaining a good quality of life sleep first, during which a subsequent change of its stages disorder rarely reaches the level when it becomes a (from I to IV) takes place followed by a fast wave sleep. dangerous condition. However, a rough estimate is that The duration of each of these cycles (6-8 per night) nearly half of the global population does nevertheless during the night sleep can fluctuate. The duration of slow

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wave sleep in an adult is normally 75-80% of the entire Melatonin (N-acetyl-5-hydroxytryptamine) is an indolic period of night sleep. During the slow wave sleep, such derivative of serotonin, which synthesis is catalysed by vital signs as blood pressure, heart and respiratory rates enzymes N-acetyltransferase and hydroxyindole-O- and body temperature tend to decrease. During the slow methyltransferase. Structurally melatonin is close to wave sleep muscle tone is preserved, the sleeping person serotonin, N, N-dimethyltryptamine, 5-methoxy-N, N- tends to change the pose, and fast eye movements are dimethyltryptamine, and other similar chemical absent.[1,7] compounds widely present in animal and plant kingdoms.[29] Human adults produce about 30 μg of REM-sleep, a.k.a. paradoxical phase of sleep is melatonin per day and its concentration in serum at night characterised by rapid eye movements and loss of muscle is 30 times greater than during the day. Melatonin is tone (except the outer eye muscles and some transported bound to serum albumin. After melatonin is nasopharyngeal muscles). When suddenly awakened released from albumin, it binds to specific receptors on during a fast wave sleep most people remember bright, the membrane of target cells, penetrates the nucleus often emotionally charged .[1,7,8] where it performs its action. Melatonin is rapidly hydrolysed in the liver and excreted in the urine. The The phase of fast sleep changes slowly 90-100 minutes main melatonin‘s metabolite is 6-hydroxymelatonin after the onset of sleep, and in an adult, it makes 20-25% sulfate, the content of which allows you to judge the of the total duration of sleep. During a fast sleep production of melatonin by the pineal gland indirectly. thermoregulatory mechanisms are inhibited, and although respiratory centre reacts to the concentration of CO2 in the blood, respiration sometimes becomes irregular. Irregularity and fluctuations are observed in blood pressure and pulse rate as well.[1,7,8]

The slow/fast sleep ratio changes with age. In newborns, fast sleep takes approximately half of the time. Later the duration of fast sleep gradually decreases. The transition between wakefulness and sleep, as well as the change in phases of sleep, depending on the activity.[9]

Sleep is governed by the parasympathetic , so erections occurring during sleep are used for differentiation between psychological (functional) and organic impotence, since in case of organic impotence there is no erection occurring even in sleep.

There is a growth secretion (STH) increase during the first two hours of sleep. Peak levels of STH are observed in the III and IV stages of slow wave sleep (during the delta sleep period). At the same time, the Graph 1: Biosynthesis of melatonin. production of decreases while secretion increases. The release of ACTH and cortisol increases Melatonin secretion is subject to the diurnal rhythm, [6,10] which, in turn, determines the rhythm of gonadotropic towards the end of sleep, closer to awakening. [6,10] effects and sexual function. The synthesis and Shortly before awakening, precursors of the end of sleep secretion of melatonin depend on the illumination - an gradually appear: the sleeping person changes position excess of light reduces its formation, and a decrease in more often, body temperature increases to the baseline illumination increases the synthesis and secretion of the value, and the concentration of corticosteroids decreases. hormone. A person with a regular daily routine and sleeping at night has about 70% of the 24-hours Epiphysis or pineal gland - the endocrine gland of a melatonin production occurring during the night. It was neurogenic group, is a size of a pea organ located in the established in a clinical setting that sleep deprivation region of the quadrangular medulla. The pineal gland is leads to disruption of the 24-hours melatonin production the main source of melatonin – a biochemical regulator - the production at night decreases and approaches the of the circadian rhythm. In humans, up to 80% of day-time level of production. melatonin is produced in the pineal gland. Retinal exposure to light inhibits melatonin synthesis, while The effect of light on the pineal gland is carried out darkness triggers melatonin production.[11] through the nerve pathways that make up the photoneuroendocrine system. The main light signal goes through the retinohypothalamic pathway that starts from the retinal photosensitive cells and reaches the

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of the . Other neuromodulator in many animals and an ―ancestral pathways i.e. geniculohypothalamic and neuromodulator‖, according to Andrew R. Gallimore, tracts indirectly modulate the activity of the PhD) and sleep, we would abstain from touching this suprachiasmatic pacemakers. Signals from the topic in this paper until more data is available.[29] suprachiasmatic nuclei, which vary by the circadian rhythm, are transmitted to the paraventricular nucleus of Dreams manifest mainly during the fast phase of sleep, the hypothalamus, and from there as part of the which completes each of its cycles and during the night it intermediolateral column of the spinal cord reach the is usually repeated several times. Upon awakening from upper cervical ganglion. Sympathetic postganglionic the slow phase of sleep, as a rule, traces of the are noradrenergic fibres innervate melatonin-secreting cells not stored in memory, but it is recognized that in the pineal gland. Noradrenaline‘s action on memorable can be associated with the slow postsynaptic β1 and α1-adrenergic receptors of pineal phase of sleep; in such cases the awakening is sometimes gland trigger melatonin synthesis. The excitation of the accompanied by a state of temporary disorientation or suprachiasmatic nucleus causes inhibition of even fear.[25,26,28] release in upper cervical node neurons that respectively reduces melatonin secretion.[12-17] BIOLOGICAL EFFECTS OF MELATONIN Melatonin neutralizes the damaging effects of oxidative The activity of pineal gland and amount of melatonin it stress. Its antioxidant potential is manifested through the makes gradually reduces with age. The reduction of ability to bind to free radicals including hydroxyl melatonin production contributes to the development of radicals formed during lipid peroxidation and exogenous insomnia. Melatonin supplementation may help to carcinogens. It also activates glutathione peroxidase - a ameliorate insomnia. Disturbances in the circadian factor protecting the body from free radical damage. Said rhythm such as jet lag, night shifts, etc. are associated make melatonin the most powerful endogenous with decreased melatonin production.[24] scavenger of free radicals. In recent years, there has been evidence that melatonin can be located not only in The sleeping state is characterised by periodic dreams - plasma but also in cell nuclei and protect the illusory phenomena that arise during sleep, which can be macromolecules of the nucleus from oxidative damage in of varying degrees of brightness and complexity. Indeed, all subcellular compartments.[18,19] the content of dreams is influenced by the current, usually inadequately evaluated information, entering the In the early stages of embryonic development biogenic from extero- and interoceptors exposed to amines including melatonin play the role of specialised influences during sleep. However, the nature of dreams cellular signalling molecules that regulate cell renewal is somewhat predisposed by previous events and thought processes. It has been established that melatonin can processes. According to Hobson‘s activation-synthesis suppress cell proliferation with the strength of its effect model, dreams are produced by chaotic bottom-up being not inferior to colchicine - a powerful cytotoxic activation of sensorial cortex in the during agent. In a number of studies on laboratory animals and REM sleep, activation of the , and in tumour tissue cultures it was found that melatonin has secondary interpretation and synthesizing by mnemonic an oncostatic effect. The mechanisms of action of and higher-order frontal areas.[17,23] melatonin on tumour growth are diverse: it affects the synthesis and secretion of pituitary and sex hormones, In addition, the sleeping person does not only see dreams modulates the immune response in the presence of but also emotionally reacts to their content, which is tumour cells and has a direct cytotoxic effect. There are sometimes manifested by motor reactions and effects on suggestions that melatonin may enhance the expression the emotional state of a person upon awakening. of adhesion molecules and thus inhibit tumour growth since it is known that in most malignant tumours there At this point, we should mention neurohormone are abnormalities in cell adhesion and defects in oxytocin, which is known to be responsible for emotional intercellular connections.[20-22] bonding, social interactions, and empathy and so on. Apart from that, there is strong evidence that oxytocin The melatonin can attenuate the proliferating cell nuclear influences sleep. Levels of oxytocin peak during REM antigen (PCNA) - a reliable marker of proliferative sleep. Oxytocin levels are also correlated with slow wave activity of tumour cells. Under the influence of sleep. Dreams from the 2nd stage of slow wave sleep and melatonin, in some forms of cancer (breast, ovary, further through REM sleep are filled with social prostate, etc.), a decrease in the proliferative capacity of communications. Oxytocinergic activity is regulated by cells was observed, and the number of cancer cells the paraventricular nucleus in the hypothalamus, which entering the apoptosis is increased (oncostatic effect).[21- is in close proximity to centres that regulate and 23] sleep-wake states.[27] As for the possible (and totally plausible as a matter of fact) link between endogenous In vitro, melatonin suppressed the growth of melanoma N,N-dimethyltryptamine (which is found in abundance in cells. Although the effect of the hormone depended on plant kingdom, an extremely widely spread the intensity of tumour proliferation, the tumour growth

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was inhibited in lesions with moderate but not with high of late falling asleep is characterised by a late onset of proliferative cell activity. The effects of melatonin are sleep and late awakening, but the absence of sleep dose-dependent, and the exact mechanism of oncostatic disorders. There is a violation of the regime in which the action remains not completely clear. Epidemiological actual onset of sleep comes about 3 hours after the data show that women working on night shifts, aviation individual would attempt to fall asleep. With the employees (flight attendants, dispatchers), radio and syndrome of early sleep, which is usually observed in the telegraph operators, have an increased risk of developing elderly, patients describe excessive drowsiness, which breast cancer, while women who are primarily blind (i.e., usually starts in the evening hours and early awakening deprived of light) have this risk two times less.[21-23,51] that starts from 3 to 5 am.[1,2]

Experimental data, as well as clinical observations, give As criteria of normal sleep, the following should be a notion that pineal gland and melatonin that it produces applied: are involved in the body's defence systems against non-  Rapid immersion in a dream (for 10-15 minutes). specific stressors. In case of prolonged stressful stimuli,  Continuity of sleep, without prolonged awakenings: a two-phase reaction is observed: the initial decline in normally there are small awakenings to roll over, to epiphyseal activity during the resistant phase of stress change the pose from leaking muscles. Normally, with its further sharp rise. In experiments on rats, it was these awakenings are short-lived, and the person shown that melatonin is capable of changing the negative does not remember them. emotional state and reducing anxiety. According to  Healthy sleep is characterised by a sufficient numerous observations, the hormone stabilises the duration and ensuring the quality of life: feelings of activity of various endocrine systems disorganised by vivacity, restoration of strength and energy. stress, including eliminating excessive stress-related adrenal hypercorticism. However, it is necessary to The International Association of Sleep Research Centers mention that oversupply of melatonin may cause has developed a classification of sleep and wakefulness [23] symptoms of depression. disorders, based on the characteristics of their clinical manifestations. An important consequence of prolonged stress is immunodeficiency. Melatonin contributes to the It is based on four groups of syndromes: normalisation of immunological parameters. 1) disorders of sleep and sleep duration ( or insomnia); Melatonin and other epiphyseal hormones can be 2) excessive duration of sleep (hypersomnia); classified as geroprotective. The relationship between the 3) disorders of the sleep-wake cycle; degree of age-related involution of the pineal gland and 4) various disorders associated with sleep or awakening. the decrepitude of tissues was established. It is known that during the degree of immunological Later A.M. Wayne and K. Hecht published their own protection decreases, and melatonin, as it has been more detailed clinical classification based on this repeatedly stated, has immunomodulating activity. document. Melatonin participates in the regulation of the thymic function that results in increased T-cells‘ and I. Insomnia [30] phagocytes‘ activity. 1) psychophysiological: a. temporary, situationally conditioned, Various experimental data shows that lack of melatonin b. constant, situationally conditioned; contributes to faster ageing, earlier onset of menopause, 2) with neuroses; obesity, development of cancer and insulin resistance, 3) with endogenous mental illness; and accumulated free radical cell damage. 4) abuse of psychotropic drugs and alcohol; 5) under the influence of other toxic factors; SLEEP DISORDERS 6) with endocrine-metabolic diseases; In some patients with insomnia or hypersomnia, 7) with organic brain diseases; disturbances in the distribution of sleep time during the 8) with diseases of internal organs; day are more pronounced than those of sleep itself. Such 9) due to syndromes that occur during sleep: disorders can be endogenous and have an organic nature a. (respiratory arrest), due to the internal defect of the driver of the circadian b. motor disorders in sleep (nocturnal , rhythm (suprachiasmatic nucleus of the hypothalamus) restless legs syndrome, etc.); or exogenous (associated with the environment) due to 10) caused by a change in the usual sleep-wake cycle; the disintegration of incoming stimuli. With such 11) constitutionally conditioned shortening of the disorders, it may be necessary to examine patients under duration of sleep. the conditions of the "day-night" cycle. Transient sleep disorders that can occur in many patients include the II. Hypersomnia long awakening syndrome (60 million people/year) and 1) paroxysmal: sleep disorders associated with shift work. The syndrome a) ,

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b) Pickwick syndrome, and post- (early awakening followed by c) Klein-Levine's syndrome, inability to continue to sleep, usually accompanied by a d) hypersomnia in the picture of paroxysmal conditions feeling of discomfort, weakness, fatigue, etc). In associated with other diseases, addition, transient insomnia may last for several days e) periodic hibernation syndrome; (due to the move or extreme situations), short-term 2) permanent: insomnia lasting from several days to 3 weeks (due to a) syndrome, illness, situational neurotic reaction), and chronic b) psychophysiological hypersomnia: insomnia often associated with chronic physical illness i. a temporary, situationally conditioned, or with a primary sleep disorder. Intrinsically sleep ii. a constant, disorders can be caused by dysfunction of the limbic- c) with neuroses, reticular system.[34] d) when taking psychotropic drugs and other toxic effects, In a practically healthy person (from the point of view of e) with endocrine-metabolic diseases, a neuropathologist and a psychiatrist) the temporary f) for organic diseases; sleep disorders (violation of the duration of sleep, sleep 3) due to syndromes that occur during sleep: and wakefulness formulas) may be caused by unmet a) sleep apnea, needs (thirst, hunger, etc.), disparity of quality and b) motor disorders in sleep (nocturnal myoclonus, quantity of food and/or medications. Transitory changes restless leg syndrome, etc.), in the quality of sleep or shortening of its duration can be 4) caused by a change in the habitual rhythm of sleep- associated with uncontrolled pain, pruritus, nocturia and wakefulness; emotional distress.[31] 5) constitutionally conditioned lengthened night's sleep. Sleep disorders can be triggered by a violation of sleep and wakefulness (night time shifts, frequent long- III. distance flights with the intersection of time zones, etc.). 1) motor: A disorganised, constantly changing the schedule of a. somnambulism, sleep-wakefulness is often associated with irritability, b. speaking in a dream, affective disorders, and at times even with sociopathic c. bruxism, behaviour. d. changing the position of the head in a dream, e. myoclonus of legs, Frequently the origins of circadian rhythm‘s disturbances f. nocturnal "paralysis"; root in the emotional sphere, the state of distress, and 2) mental: situational neurosis. At the same time disturbance of the a) nightmares, sleep-wakefulness regulation affects the characteristics b) awesome dreams, of the person's emotional status, can lead to the c) the phenomenon of "intoxication" from sleep; development of negative , contribute to the 3) vegetative: advance of neurotic reactions, and hinder optimal a) , professional activity. Patients suffering from insomnia b) respiratory (apnea, asthma, sudden death syndrome), often worry or even fear that they are not able to fall c) cardiovascular (cardiac arrhythmias), asleep and that sequentially leads to a sleep disorder. d) headaches, Thus, a particularly vicious circle is created: neurotic e) gastroenterological (gastroesophageal reflex); reactions provoke insomnia; insomnia leads to expansion 4) associated with a change in humoral regulation: of the neurotic disorders, the growth of their severity and a) paroxysmal hemoglobinuria, the development of even more pronounced sleep b) familial hypokalemic periodic paralysis; disorders.[33] 5) epileptic seizures associated with sleep. Patients with functional insomnia often resort to the use INSOMNIA of sleeping pills, alcohol and other substances, which Insomnia (dyssomnia) - in practice it is rather correct to often results in adverse outcomes. Insomnia associated treat insomnia as dissatisfaction with sleep. According to with alcohol and drug intake (in particular ICD-10, the main diagnostic criteria of insomnia are: 1) antidepressants, psychostimulants, diuretics, antiepileptic poor quality of sleep; 2) frequency of sleep disorders at drugs, beta-blockers, xanthine derivatives, nicotine, least 3 times a week for at least 1 month; 3) concern caffeine) and insomnia arising in connection with the about insomnia and its consequences, both at night and cessation of drug intake (primarily sedatives and during the day; 4) pronounced distress or an obstacle to hypnotics) are called exogenous. social and professional functioning due to unsatisfactory duration and/or quality of sleep. There is a rare form of primary idiopathic insomnia that may have a familial trait. This form of insomnia starts to Insomnia can be presumed (in the form of disturbed manifest itself in childhood or youth and persists sleep), intermittent or transitory (frequent awakenings) throughout life. It is characterised by a relatively short,

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fragmented sleep, increased fatigue during the day and hypersomnia is combined with mental disorders, in often irritability and depression. particular with depression. Sometimes patients themselves establish a connection between falling asleep HYPERSOMNIA at the wrong time and unpleasant experiences or anxiety. Hypersomnia (somnolence) is described as pathological Unlike narcolepsy with functional hypersomnia, attacks drowsiness, excessive yawning, and overwhelming of daytime sleep are not combined with paroxysms of desire to sleep occurring during the day time. A person motor disorders like ; there are neither can fall asleep while working, eating or driving a car. manifestations of "sleep paralysis" nor hypnagogic The total sleep time per day is usually significantly hallucinations.[37] higher than normal. It is important, from a practitioner‘s point of view, to distinguish hypersomnia from Staying in a state resembling a normal dream during the pronounced asthenia or depression. day is called lethargy. The syndrome of lethargic sleep (periodic hibernation syndrome) is a consequence of the Temporary hypersomnia can be the result of prolonged disturbance of the awakening mechanisms of the sleep deprivation or intake of medications (tranquillizers, reticular formation in the mesencephalic-diencephalic neuroleptics, antihistamines, hypotensive drugs, etc.). area of the brain. It is manifested by periodic attacks of The cause of persistent hypersomnia may be associated insuperable sleep lasting from several hours to 2-4 with somatic diseases like hypothyroidism, chronic liver weeks. Sleep is accompanied by muscle hypotension, or kidney failure. tendon hyporeflexia or areflexia, arterial hypotension, and lack of control over the pelvic organs‘ function.[38-42] Another distinct form of hypersomnia is narcolepsy. Narcolepsy is characterised by occasional short-term The Pickwick syndrome is primarily manifested by attacks of insurmountable sleep, provoked by either pronounced sleepiness in the daytime, obesity, as well as inactivity or stereotyped activity (driving, working on hypoventilation, cardiopulmonary syndrome, machinery, etc.). Narcolepsy manifests itself more often polycythemia and fascicular twitching. The syndrome at the age of 15-25 years, but its debut may happen in a was described by A. Auchingross and colleagues in much wider age range - from 5 to 60 years. Attacks of 1955, and in 1956 M. Burwell proposed to call it narcolepsy last about 15 minutes and individuals usually "Pickwick" after the character from the novel by Charles wake up during a phase of rapid (paradoxical) sleep. Dickens "Posthumous notes of the Pickwick Club" During the narcolepsy attacks the hypnagogic whose description being "red-faced, obese, drowsy" hallucinations decreased muscle tone or repetitive corresponded to the description of this syndrome. stereotyped movements without reacting to external stimuli may occur. Upon waking up individuals feel Persistent episodic hypersomnia with cognitive and refreshed, reinvigorated and the effect lasts for about 2 mood changes comprise Klein-Levin syndrome. hours. Later between attacks patients become sluggish Emerging bouts of sleep last from several days to several and lose their attention. Their night sleep is usually weeks. Upon awakening patients usually experience disturbed by frequent awakenings and accompanied by unusual hunger (bulimia), unstable mood (dysphoria), .[32] motor anxiety, increased sexual activity, decreased muscle tone, hallucinations, disorientation, memory loss. Cataplexy is the phenomenon of falling asleep and It occurs more often in adolescents or young males. The awakening during which patients with preserved origin of the Klein-Levine syndrome is unknown. orientation are not able to speak or move. In 80% of Sometimes it occurs after the encephalitis or cases, narcolepsy is combined with attacks of cataplexy. craniocerebral trauma. It is assumed that the emergence This combination confirms the conditionality of of Klein-Levine syndrome is due to the impaired hypersomnia attacks with narcolepsy and allows not functions of the hypothalamic and limbic structures[43-46]. resorting to additional examinations of patients.[52] The syndrome was described by the German neuropathologist W. Kleine and the English physician M. Essential narcolepsy frequently combines with cataplexy Levin. (Lowenfeld-Henneberg syndrome), which manifests as a short-term (not more than 1-2 min) immobility due to a PARASOMNIA sudden loss of muscle tone. Individuals with Lowenfeld- Parasomnias include abnormal episodic conditions that Henneberg syndrome manifest jaw drop, head falling on occur during sleep: , sleepwalking, night the chest, weakness in legs, etc. However, the onset of terrors, nightmarish dreams, nighttime cardiac rhythm cataplexy is often limited only to the sagging of the disorders, hypnotic myoclonic twitching, congenital lower jaw and head, loss of speech, weakness in central hypoventilation syndrome, teeth grinding limbs.[32,35] (bruxism), etc. Their origin is mainly psychogenic.[36]

Hypersomnia can be related to neurosis. In such cases, it The most striking manifestation of parasomnia is is associated with drowsiness and sleep attacks during somnambulism - sleepwalking (from Latin somnus - the day in the absence of sleep disorder at night. Often sleep + ambulare - to walk). It is more common in

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children and young individuals. Usually, it is combined with night fears, concoction. It occurs during the first third of the night sleep under the influence of external stimuli (moonlight, table lamp, etc.). However it can occur spontaneously. While sleepwalking patients perform automated complex actions: get out of bed, say something, try to go somewhere, at times even commit health or life-threatening actions, while retaining the functions of sensory systems and movement coordination that allows them to overcome dangerous situations. It requires considerable effort to wake up such person. Somnambulistic episodes develop during a period of slow sleep and usually last up to 15 minutes, and it takes a considerable effort to wake a sleepwalker up. Somnambulism is often observed in emotional and hypersensitive individuals. It is considered to be a Graph 2. During the sleep, VLPO inhibits the manifestation of neurosis and even psychopathy.[47,48,62] wakefulness centres. Legend: LTD / PPT - pathways of the laterodorsal tegmentum / MORPHOLOGICAL BACKGROUND FOR SLEEP pedunculopontine nucleus; BF - cholinergic DISORDERS projections of the basal part of the forebrain; LC / PB Serotonergic neurons of the raphe nuclei are playing an / PC / DR - and important role in the process of falling asleep. If this projections of the blue spot / parabrachial core / sub- system is damaged or the pharmacological blockade of spot / suture nuclei; vPAG / TMN - glutamatergic and serotonin occurs, complete or partial insomnia may near-conductor gray matter / tubero- occur.[60,61] mammillary nucleus; VLPO / MnPO - GABAergic ventrolateral preoptic region / median preoptic GABA-ergic system of ventrolateral preoptic nucleus nucleus. (Source: Saper et al., Neuron., 2011). (VLPO) is the main brain‘s inhibitory system that keeps the wake centres off. Electrical stimulation of this area Diagnostic Tools For Sleep Disorders by the current of any frequency invariably causes [57] The most common method of studying sleep disorders is sleep. . This examination is conducted in a special laboratory where individual should spend the The ascending reticular activating system (ARAS), also night. During sleep, many sensors simultaneously record known as the extrathalamic control modulatory system or the bioelectric activity of the brain (EEG), cardiac the reticular activating system (RAS) described by Italian activity (ECG), respiratory movements of the chest and neurophysiologist Giuseppe Moruzzi in 1961. It is a anterior abdominal wall, inhaled and exhaled airflow, network of nuclei located in the brainstem, pons Varolii, blood oxygen saturation, etc. Such survey enables medulla, and hypothalamus. studying of the brain activity and functioning of the main body systems during each of the five stages of sleep that, Nonspecific thalamic nuclei is an "open the gate" for the in its turn, helps to identify abnormalities and to find out flow of sensory information to the cortex during the cause of sleep disturbance. wakefulness and "close" them down during sleep. The irritation of these nuclei by the low-frequency current Another method of diagnosing sleep disorders is to synchronises the potentials of the brain stimulating its investigate the average latency (SOL). It is descent into sleep. Sleep that occurs as a result of used to identify the cause of drowsiness and plays an irritation of these nuclei is indistinguishable from normal important role in the diagnosis of narcolepsy. The study physiological sleep.[2,4] consists of five attempts to fall asleep, which are carried out during waking hours. Each attempt lasts 20 minutes with the interval between attempts being 2 hours. The SOL more than 10 minutes is considered to be the norm, from 10 to 5 minutes - borderline, less than 5 minutes - pathological sleepiness.

TREATMENT STRATEGIES FOR SLEEP DISORDERS Treatment of sleep disorders depends on the etiological factors causing it. In the case of somatic pathology, treatment should target underlying disease. It is also necessary to avoid the factors triggering sleep disorder.[49,50,53-56] For that purpose some simple rules

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should be observed: 1) try to adhere to the sleep- carried out in concurrence with an, at wakefulness regime with a sufficient amount of sleep, times, medicinal treatment. which varies largely individually and normally changes with age; 2) maintain the quiet environment in a Activation of alpha brain rhythms (in the range of 8-12 darkened, well-ventilated bedroom; bed should be Hz) leads to a state of relaxation, which reduces stress, comfortable, but not too soft; 3) avoid abundant food, normalises the mood, and regulates the perception of coffee, alcohol, smoking, emotional stress at least 3 various types of pain. hours before sleep; 4) instead recommend some calming activity before going to bed (i.e. reading, knitting, etc.), a Microcurrents of complex sequence activate specific short-term walk, warm bath, etc. groups of neurons that are located in the brain stem. These groups of nerve cells produce serotonin and In case if sleep disorders are caused by somatic diseases , which affect the chemical activity. By (i.e. lung, heart or gastrointestinal pathology, i.e. changing the electrical and chemical activity of certain bronchial asthma, angina, thyrotoxicosis, peptic ulcer, neurons in the brain stem, this procedure regulates the etc.).[58,59] activity of neurochemical brain systems. As a result, the brain produces electrical activity of a certain type, known Traditionally public‘s approach to management of as the alpha state, which can be measured by recording insomnia would be an administration (often self- the EEG (frequency 8-13 Hz). Alpha rhythms are administration) of hypnotic drugs although their side accompanied by a sense of calm, relaxation and stimulate effects can be quite significant (dizziness, memory loss, mindfulness. confusion, etc.). It has been recognised that sleeping pills affect not only the state of sleep but also disturbs Transcranial micropolarization of the brain allows you to cognitive function, tends to accumulate in the blood, activate parts of the brain without external intervention. affect the level of wakefulness during the day, reduce This technique provides an opportunity to investigate the attention and level of mental alertness. All this implicates excitability of neurons in the cerebral cortex and the the need to resort to the use of hypnotic pharmacological consistency of the functions of its individual parts. drugs only when its necessity is absolutely justified.[63-69] Among the other additional effects of transcranial Prolonged intake of tranquillizers and sleeping pills, in electrostimulation are: addition to its direct effect, causes depletion of the  The decrease in the severity of neurotic symptoms, brain‘s reserves of serotonin and norepinephrine that the removal of tension, feelings of anxiety, various carries detrimental effects on cognitive function and fears. psycho-emotional status. VLPO is activated by  The emotional background acquires a positive substances that cause sleep (serotonin, and colour. GABA) but is inhibited by mediators that support  During the session, the patient experiences a state of wakefulness (norepinephrine and acetylcholine). rest, muscle relaxation (muscle clips are removed).  Due to the regulation of the processes of excitation Transcranial electrostimulation and inhibition, the affective tension is removed, on Transcranial electrostimulation - the effect on brain stem the one hand, and the inhibition (depressive state), structures with small amplitude pulses (up to 3mA) with on the other. a rectangular bipolar asymmetric pulse shape.  Unlocking the mechanisms of psychological Transcranial electrostimulation is a method of defence. neurotherapy that is used for treatment and prevention of  The effect of analgesia, which allows relieving pain depression, neuroses, insomnia, addictions, for pain symptoms with concomitant somatic diseases control purposes. (myalgia, cardialgia, neuralgia, headaches of various origin). The principle of therapeutic effect of transcranial stimulation is based on activation of brain alpha-rhythms Electrobiosleep and modulation of brain electrical activity pertinent to Rectangular pulsed currents of low frequency and low physiological sleep, increase of the concentration of power have proved themselves in the treatment of serotonin, acetylcholine, met-enkephalin and beta- patients with some diseases in the pathogenesis of which endorphins. There is an effect on the subcortical functional disorders of the nervous system predominate. structures of the brain by microcurrents through special The treatment is carried out from the Biosleep at a pulse electrodes. frequency of 10 Hz; the current strength is from 2 to 2.5 mA, the duration of the procedure is 30 minutes, every Transcranial electrostimulation is an effective alternative other day, for 10-15 procedures. to medications, especially in conditions requiring long sessions of psychotherapy. During the session, there is a After the procedure is over and the device is turned off pleasant feeling of relaxation, lightness in the body, patients continue to sleep for another 30 minutes - 1 clarity of thoughts. Transcranial stimulation is usually hour. A deep refreshing sleep, similar to physiologic

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sleep, promotes a good state of health. The electrical  peripheral - all other cells, where the secretion of the resistance contributes to the restoration of the impaired hormone does not depend on light. function of the central nervous system and higher vegetative-endocrine centres. It also has a mild The amount of hormone that is produced in the pineal hypotensive effect and normalises cardiac rhythm. gland is not enough to ensure the numerous biological effects of melatonin. Studies have shown that after Phototherapy removal of the pineal gland in experimental animals If the circadian rhythm is disturbed, phototherapy is a significant amounts of melatonin are detected in the good effect, since stimulation of hypothalamic nuclei blood. At present, it has been firmly established that the responsible for the synthesis of melatonin occurs through pineal gland is not the monopoly organ of melatonin the optical receptors. Phototherapy should be performed production. in a hospital environment since the essence of treatment is that a person is exposed to either sunlight or bright As the pineal gland is not the monopoly organ of white light from artificial sources with certain melatonin production the stem cell therapy of chronic wavelengths. As a source of illumination the light- sleep disorder target most important organs and enfolds emitting diodes, lasers, fluorescent lamps, dichroic lamps as many of them as possible depending on exact case to or very bright light having a full spectrum of daylight stimulate the own melatonin production. The cells of the can be used. The optimal time of phototherapy is pineal gland produce peptides to correct and enhance the determined individually depending on the features of the gland function. sleep disorder of the individual patient. As a part of a treatment paradigm for hypersomnia stem The effect of phototherapy is aimed at the cell therapy primarily targets systemic disorders resynchronisation of biological clocks and the long-term triggered by dysfunction of the liver, kidneys, adrenal adjustment of the required time for falling asleep and cortex (in case of hypocorticoidism), pancreas, awakening. In order to achieve the effect, the session hypothalamus, thyroid (hypothyroidism), thymus (acute should be conducted as early as possible after a and chronic infections) and many others. spontaneous (late) or early (forced) awakening of a person. Besides, phototherapy is effective in a number of Stem cells maximally naturally affect the pineal gland by skin diseases, arterial hypertension, migraine, pain restoring the production of their own melatonin in the syndrome, mental disorders and seasonal depression. body in the quantity and frequency that is genetically programmed - no other drug is capable of that! This Darsonvalization ensures a high efficiency of Stem cells, the complete Darsonvalization is a therapeutic method in which pulsed absence of side effects and the ability to combine it with high-frequency currents of low strength are used, safe for any therapy. humans. Under the influence of these currents, the following processes occur in the tissues: It was demonstrated by multiple studies and observations  acceleration; that even though immediate period after stem cell  vasodilation; implantation may be associated with either excessive  improves blood and lymph circulation; sleepiness or, on the contrary, hyperactivity, difficulty  promotes faster dissolve of hematomas; falling asleep and a certain level of non-restorative sleep,  anti-inflammatory effect. within 2 weeks post-implantation most of the patients experience reinstatement of normal sleep pattern. Darsonval consists of a generator of high-frequency impulse currents and glass electrodes through which Let us further analyse the possible mechanisms of these currents are conducted to the body. Local transitory sleep disorders occurring during initial stages darsonvalization is usually conducted using two post implantation and contemplate on mechanisms of methods: contact and non-contact. Darsonvalization of beneficial therapeutic effect of stem cells on the sleep. the head is used for metabolic disorders, insomnia, hypertension, hair loss, neurosis, migraine. Needless to say, that stem cell treatment, as any medical procedure, inevitably is a stressful experience, especially CELL THERAPY IN MANAGEMENT OF SLEEP for patients with underlying psychological distress, DISORDERS including both depression and anxiety. It is well known Functionally, many cells producing melatonin belong to that depression and anxiety are associated with disrupted the so-called diffuse neuroendocrine system - the sleep; hence the transitory sleep disorders post stem cell universal system of and maintenance of implantation is entirely justified. It is also accepted as the of the body. Within this system, two links of fact that the extent of baseline psychological distress, melatonin-producing cells are distinguished: including symptoms of anxiety and depression, is  central (includes the pineal gland and cells of the directly linked to the level of sleep disorders. visual system), in which the melatonin secretion rhythm coincides with the light-dark rhythm;

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Another reason for transitory sleep disorders may be a The positive effect of exogenous administration of pineal short-term inflammatory reaction few days after stem gland peptides/cell extracts was demonstrated in multiple cell implantation mediated by cytokines and interleukins. clinical studies over the decades. It has been established However, shortly after the initial period of pro- that exogenous pineal cell extracts act as a potent anti- inflammatory reaction the actual anti-inflammatory inflammatory and anti-oxidative stress agents, moderate effect of stem cells, modulated via secretion of anti- endogenous production of pineal hormones and inflammatory factors, is triggered that greatly contributes neuromodulators that ultimately results in a massive anti- to restoration of good quality sleep. ageing effect, contribute to the normalization of endocrine function, and stabilise sleep pattern in a very Stem cells play a pivotal role in the development of a rapid manner.[30] protective and reparative homeostatic response in obstructive sleep apnea, particularly concerning its It was demonstrated in an experimental model that cardiovascular consequences. The potential interactions pineal-gland peptides have immunomodulatory, between the obstructive sleep apnea co-morbidities that anxiolytic, antioxidant properties and their high are associated with cardiovascular risk (i.e. obesity, bioavailability can be achieved even with intranasal metabolic syndrome, hypertension, diabetes) and their administration.[71] It was also noticed that pineal-gland effects on the protective and reparative mechanisms of peptides have a positive effect on reproductive cycles of stem cells should also be considered as a powerful the observed animals.[70] The prospective mechanisms of therapeutic tool. action can be attributed to modulation of electrical activity of cells of the pineal gland and to the ability of PEPTIDES AND CELL EXTRACTS IN pineal-gland cell extracts to stimulate syntheses of other MANAGEMENT OF SLEEP DISORDERS hormones and , like oxytocin and many Peptides are tiny informational molecules made up by others.[70-72] amino acids that directly impact the genes function. Different tissues produce peptides involving into The pineal gland is producing a number of monoamine metabolism. Their principal task is to initiate DNA neurotransmitters - indolamines. A tryptophan scanning and as a consequence they activate the nonapeptide delta-sleep-inducing peptide, which is production of protein by appropriate cells and monitor produced in the pineal gland, is influencing the secretion their further correct work. It was discovered that the of indolamines. A delta-sleep-inducing peptide of the shortage of peptides would provoke disturbance on cells pineal gland is stimulating melatonin, 5- operation, rapid ageing of tissues, appearance and methoxytryptophol and serotonin synthesis and release. aggravation of pathological processes. These effects do not occur through the noradrenergic or opioidergic systems and do not appear to activate one of Both experimental research data and clinical the adenylate-cyclase-linked receptors, and its exact observations demonstrated the beneficial effect of mechanism of action is remaining unclear.[73] naturally occurring peptides extracted from stem cells‘ culture on maintenance of biological homeostasis in Another interesting fact worth giving attention is that ageing individuals who are otherwise considered healthy Alzheimer‘s disease patients show impaired melatonin as well as in individuals with chronic systemic and acute production and altered expression of the 2 G protein- conditions. It was indicated that peptides contribute to coupled melatonin receptors MT1 and MT2. The role of the management of cell function, embedded in the amyloid β peptides in dysfunction of the melatonergic process of metabolism and even restore the cell system has been established. Hence, restoring the pineal functions. gland functional activity and rescuing receptors function may be of therapeutic value in the management of The pineal gland contains a wide range of factors and patients with Alzheimer‘s disease.[72] peptides, which in turn produce peptides that are responsible for the normal function of pineal gland cells. Pineal gland cell extracts are available in two forms: as The protein molecules of pineal gland tissue consist of nanomized peptides and as ―Mito Organelles‖ cell many organic compounds that are essential constituents extracts (SBI, Germany). The former one, known as of living cells. Nano Organo Peptides (NOP), is suitable for parenteral administration and for sublingual. Due to its small The major role of pineal gland peptides is to trigger the molecular linear size and a molecular weight less than 10 transcription of information from the DNA code in the kDa, it has the capacity to be easily absorbed in the oral cells of the pineal gland. Peptides modulate the normal mucosa. Such way of administration allows active function of the pineal gland to operate as required by ingredients to escape the first pass metabolism and is nature in youthful cells. The abnormal work of pineal non-invasive in the same time. The recommended dose gland peptides will resume to different disturbances of and frequency of administration of NOP is one vial every the endocrine system. Consequently, sufficient presence alternate day. of pineal gland peptides is the absolute need for normal endocrine function.

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As for ―Mito Organelles‖ pineal extracts, its molecular 13. Halle M, Berg A, Garwers U, Grathwohl D, Knisel weight is somewhat higher than in NOP, ranging W, Keul J (1999): Concurrent reductions of serum between 45 to 65 kDa. It makes the route of leptin and lipids during weight loss on obese men administration either subcutaneous or intramuscular. with type II diabetes. Amer J Physiol, 277: E277– However, the higher concentration allows reducing the E282. frequency of administration to 2 times per week. Both 14. Horvath TL, Diano S, van den Pol A (1999a): types of pineal cell extracts have supreme bioavailability Synaptic interaction between hypocretin (orexin) and outstanding efficacy. In most of the cases of chronic and neuropeptide Y cells in the rodent and primate insomnia, it is possible to see positive dynamics in hypothalamus: A novel circuit implicated in quality of sleep two weeks after the beginning of metabolic and endocrine regulations. J Neurosci, 19: therapy. 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