The role of Epithalon in restoring the proper circadian rhythm and improving sleep quality

Action restoring the balance of the circadian rhythm and improving the quality and duration of sleep. Peptide therapy against insomnia and disturbances in melatonin production.

Abstract: Epithalon is a synthetic peptide created based on a natural peptide present in the pineal gland; it is a peptide used as a sleep regulator improving its quality. Additionally, peptide therapy using Epithalon allows for the elimination of insomnia problems and disturbances in melatonin production.

Keywords: epithalon; circadian rhythm; sleep; sleep quality; melatonin; balance; insomnia; sleep phases; metabolism; synthesis; release; sleep disorders; melatonin receptors; telomere shortening; stimulation List of abbreviations: SCN- SPZ- NREM; ALA; ASP; GLU  

Introduction

In the latest studies, it has been noted that NL Epithalon stimulates the pineal gland to produce melatonin – sleep hormone. These observations are supported by experiments involving both animals and humans, where in both cases the effect on nighttime melatonin production was positive. This mechanism also contributes to the regulation of the circadian rhythm and rejuvenating effects, because with advancing age the ability to produce melatonin deteriorates and sleep quality weakens, and consequently, other aspects of health may also decline.

WHAT IS SLEEP 

Sleep occurs as a functional state central nervous system, cyclically appearing and passing in circadian rhythm, during which there is a suspension of consciousness and immobility. Physiological sleep is characterized by full reversibility under the influence of external factors   

SLEEP PHASES

MELATONIN

Considering the chemical nature of melatonin, it is a small molecule compound that dissolves well in water and fats. Melatonin, as a hormone produced by the pineal gland in the brain, is regulated in a daily cycle and even in specific seasons of the year, and it participates in regulating many behavioral behaviors and physiological processes. Melatonin levels vary and fluctuate during different phases of the cycle. The substance itself is not stored in the body, and the rate of its synthesis is proportional to the rate of its release into the bloodstream.   

MELATONIN SYNTHESIS

In the body, melatonin synthesis occurs thanks to the action of its precursor, which is tryptophan taken from the blood. The main enzyme involved in melatonin synthesis is N-acetyltransferase. The site of synthesis is the aforementioned pineal gland; small amounts of melatonin are produced by the retina and lens of the eye, the epithelium of the digestive tract, and blood cells. Information about environmental lighting conditions reaches the pineal gland via a complex neuronal pathway starting in the retina of the eye: retina → retinohypothalamic tract → SCN → paraventricular nucleus → medial forebrain bundle → midbrain tectum → intermediolateral nucleus of the spinal cord → superior cervical ganglion → postganglionic sympathetic fibers → pinealocytes of the pineal gland   

MELATONIN METABOLISM

Circulating melatonin in the blood undergoes rapid metabolic transformations in the liver, primarily hydroxylation at position 6, followed by conjugation of 6-hydroxymelatonin with sulfuric or glucuronic acid. The resulting inactive hormone metabolites are excreted from the body with urine. The biological half-life of exogenous melatonin in humans is short, ranging from 10 to 60 minutes.   

MELATONIN RELEASE

Postsynaptic receptors located in the innervating pituitary, superior cervical ganglion regulate melatonin release. The suprachiasmatic nuclei of the hypothalamus receive stimuli from the retina, giving them the character of an anatomical biological clock related to the light cycle. At night, stimuli are sent from the suprachiasmatic nuclei reaching the receptors of the superior cervical ganglion and the pineal gland, leading to the secretion of the hormone melatonin. Melatonin synthesized in the pineal gland is rapidly and pulsatilely released into the bloodstream and cerebrospinal fluid, from where it is distributed to organs and tissues throughout the body.   

MELATONIN RECEPTORS

Activation of melatonin receptors determines the subsequent biological effects. The main melatonin receptors are the membrane receptors MT1 and MT2, which are coupled with regulatory proteins that bind guanylate nucleotides, i.e., G proteins. The second group of melatonin receptors, called nuclear receptors, belongs to the family of receptors from the ROR or RZR group. Melatonin interaction through membrane receptors with G proteins leads to a decrease in intracellular cAMP with a simultaneous increase in calcium ion concentration and activation of phospholipase C. Membrane receptors also participate in regulating the activity of calcium and ion channels and cell detoxification. ROR/RZR receptors, on the other hand, are involved in regulating immune processes, differentiation of the central nervous system, and maturation of T lymphocytes.  

MELATONIN SECRETION DEPENDING ON AGE 

The onset of melatonin secretion in humans during the circadian rhythm begins after the sixth week of life. A significant increase in nighttime hormone secretion is observed with age. During puberty, melatonin secretion levels decrease, which slowly decline further with age. After reaching 65/70 years of age, the circadian rhythm of melatonin secretion almost completely disappears.   

MELATONIN IN SLEEP DISORDERS

Melatonin as a hormone regulating the day-night circadian rhythm and seasonal biorhythm also participates in the process of mood, sleep, and its quality. It has been found that administering an analogue of this hormone in tablets leads to the expected sleepiness or desire to sleep and improves its quality for faster and more effective regeneration and rest. Observations conducted so far in humans have shown that daily and seasonal changes in melatonin levels lead to disturbances in the sleep process, insomnia, and affective disorders described as depressive states, most often occurring in winter. In humans, melatonin accelerates falling asleep, reduces the number of nighttime awakenings, prolongs the total duration of sleep, and improves its quality.   

SLEEP REGULATION PROCESSES

Two processes participate in sleep regulation: homeostatic and circadian. The first mentioned process depends on the duration of sleep, while the second, circadian, regulates the transition into sleep and wakefulness. All stages of NREM sleep, constituting over 80% of total sleep, are controlled by the homeostatic process. The suprachiasmatic nucleus interacts with regulatory mechanisms and is most likely responsible for disturbances in the main circadian clock function, playing a significant role in sleep-wake disorders. Neurons located in the ventral subparaventricular zone of the hypothalamus, which send projections to the dorsomedial hypothalamus, are also essential for the circadian sleep-wake cycle. Thus, the sleep-wake rhythm is controlled by a circuit with two relays – the first part runs from the suprachiasmatic nucleus to the ventral subparaventricular zone of the hypothalamus (SPZ), and the second connects it with the dorsomedial hypothalamus.   

CIRCADIAN RHYTHM

The circadian rhythm is a fundamental mechanism affecting the length, quality, and timing of sleep. Technological progress, widespread exposure to artificial lighting in the evening and nighttime hours with low exposure to sunlight during the day, lack of physical activity, prolonged mental activity during the day and often also in the period immediately preceding going to sleep, irregular meal times, shift work and/or irregular work rhythms cause circadian rhythm sleep-wake disorders manifested, among other things, by poor sleep quality and decreased psychophysical performance during the day, to be common health problems in developed countries. It should be remembered that the circadian rhythm determines the proper functioning of the body. Unfortunately, it is often disrupted with age. It is clearly visible that this is accompanied by a decrease in melatonin production and deterioration in sleep quality.  

NL EPITHALON

NL Epithalon is a synthetic tetrapeptide with a specific amino acid sequence Ala-Glu-Asp-Gly, molecular formula C14H22N4O9, and molecular weight of 390.35 g/mol. NL Epithalon originates from epithalamin, a naturally occurring polypeptide in the body produced in the pineal gland. The main property of NL Epithalon is its ability to increase telomerase activity in somatic cells. This helps cells regenerate telomeres, which are essential protective parts of our DNA, resulting, among other things, in regulatory abilities of the circadian rhythm and sleep disorders by normalizing melatonin levels, promoting deeper sleep, and strong antioxidant properties.   

SLEEP EFFECT OF NL EPITHALON 

The results gathered so far indicate the beneficial effects of NL Epithalon as a therapy for sleep disorder problems, causing, among others, faster onset of evening fatigue and drowsiness, shortening sleep latency, accelerating the time of falling asleep and waking up, speeding up the resynchronization of biological rhythms to a new time zone, and reducing sleep disturbances.   

TELOMERE SHORTENING

The telomere is an important region of repeating nucleotide sequences at each end of a chromosome, which protects the chromosome end from destruction or fusion with neighboring chromosomes. As a result of each cell division, the ends of telomeres shorten; during chromosome replication, DNA-replicating enzymes cannot continue replication to the very end of the chromosome, so with each replication the chromosome end is shortened (this is because the synthesis of fragments requires the attachment of RNA primers to the lagging strand). This means that with each cell division (each time the cell undergoes mitosis), the telomeres at the ends of each chromosome shorten again. After many divisions, telomeres reach a critical length, causing the cell to ultimately lose the ability to further divide to replace worn-out, damaged, or diseased cells. Further cell division becomes impossible, and the cell ages. At this point, the cell has reached the so-called Hayflick limit.  

EXPERIENCE REGARDING TELOMERE SHORTENING 

Mothers who slept less than 7 hours per day had significantly shorter telomeres in their white blood cells. Telomeres are small DNA fragments located at the ends of each chromosome. They act like protective caps, shielding the chromosome from damage during copying. Shortened telomeres have long been associated with a higher risk of cancer, cardiovascular disease, and others, as well as premature death.  

NL EPITHALON PROMOTING BETTER SLEEP QUALITY BY PREVENTING TELOMERE SHORTENING 

NL Epithalon is used to increase the natural production of telomerase, a natural enzyme that helps cells regenerate telomeres, which are protective parts of our DNA. This ultimately leads to slowing down the aging of the cell population. Thanks to these processes, NL Epithalon can be used to restore and normalize melatonin levels or to protect cells from oxidative stress. It has also been shown that NL Epithalon helps restore and normalize melatonin production by the pineal gland, as well as restore the normal daily rhythm of cortisol production, which ensures better sleep at night.  

MELATONIN STIMULATION BY NL EPITHALON 

With aging, a reduced nocturnal daily level of melatonin in blood plasma and a reduced amplitude of the daily hormonal rhythm are observed, indicating disturbances in the pineal gland's melatonin release function. The peptide preparation NL Epithalon restores nocturnal secretion of endogenous melatonin and leads to normalization of the hormonal daily rhythm in blood plasma. In elderly individuals, NL Epithalon modulates the functional state of the pineal gland: functional insufficiency of the pineal gland is countered by an increase in melatonin levels at night. Additionally, NL Epithalon effectively increases melatonin concentration and does not cause side effects.   

EXPERIENCE REGARDING MELATONIN STIMULATION BY NL EPITHALON 

NL Epithalon tetrapeptide (Ala-Glu-Asp-Gly) was synthesized based on the amino acid composition of Epithalamin. The effect of NL Epithalon on melatonin and cortisol secretion was examined in individuals of different ages.  

EXPERIMENT RESULTS: 

The experiment clearly shows that NL Epithalon increased melatonin concentration in the evening hours. The melatonin content of individuals treated with NL Epithalon was more than 3 times higher than in the control group. NL Epithalon not only stimulated melatonin synthesis but also normalized the circadian rhythms of cortisol concentration in peripheral blood.  

RESTORATION OF NORMAL CIRCADIAN RHYTHM THROUGH NL EPITHALON

The study of the effect of NL Epithalon on circadian rhythms disturbed by the neurotoxic compound DMH showed a return to the daily dynamics of NE in the MPA. This peptide prevents xenobiotic-induced disturbances of the circadian rhythm of DA, maintaining the level of this metabolite low at 5 AM (CT) and its increase at 11 AM (CT). The obtained data suggest that the pineal gland is important for normalizing the circadian signal needed for gonadoliberin release. 

EXPERIENCE REGARDING THE RESTORATION OF NORMAL CIRCADIAN RHYTHM BY NL EPITHALON

A small study involving 14 people of various ages showed that NL Epithalon improved melatonin production in all study participants.

BIBLIOGRAPHY

1.C.Boureima, R.Rozencwaig, F. Polyak, C.Gamberi, Cyst Reduction by Melatonin in a Novel Drosophila Model of Polycystic Kidney Disease. 2020, 23: 16-67

2.M.Kvietkauskas, V.Zitkute, B.Leber, K.Strupas, P.Stiegler, P.Schemmer, The role of melatonin in colorectal cancer treatment: a comprehensive review. 2020, 17: 1-90

3.V.Khavinson, F.Diomede, E.Mironova, N.Linkova, S.Trofimova, O.Trubiani, S. Caputi, B.Sinjari, AEDG Peptide (Epitalon) Stimulates Gene Expression and Protein Synthesis during Neurogenesis: Possible Epigenetic Mechanism. 2020, 30:26-46