General features of melatonin
Melatonin is a hormone, which is thought to play an important role in daily processes of humans’ lives, being secreted by the pineal gland, which is an endocrine gland, located in the middle of the brain. After its discovery the first function (which later gave the name to this hormone) was the ability of this hormone to lighten one’s skin color. This experiment was conducted on frogs, however even nowadays everybody knows that our sunbathing results in suntan due to activity of melatonin. This is a so-called skin-darkening effect of melatonin.
First discoveries of this hormone were done in 1917, during which its function, described above, was found out by two different scholars, namely Carey Pratt McCord and Floyd P. Allen. However, it obtained its name as well as scientific recognition in 1958 after professor Aaron B. Lerner from Yale University managed to isolate the hormone itself from pineal gland extracts in order to prove that this hormone can be used in the field of treating dermatological diseases [Lerner, Case, Takahashi, 1992].
Other discoveries, particularly those relating to its role as an antioxidant, were made during 90-s, when the first patent which was granted to Richard Wurtman for his drugs for treating sleep disorders in 1995.
Melatonin is produced in all the mammals, in particular, in humans as well as three other groups of animals also have the same hormone produced, namely birds, amphibians and reptiles. In those mentioned animals melatonin plays important role in other processes, besides sleep cycle periods, including those relating to the issue of the seasonal biology, such as reproductive function of these groups, namely it together with other hormones, stimulates the animals to search for a partner during reproductive cycle; behavioral function consisting in taking part in formation of certain actions of the animals and so on.
The level of melatonin secretion, production in animals often depends on a seasonal clock, meaning that it could change. It is affected by different duration of night during, for instance, summer and winter. Such change is thought to be a biological singal for adoption of certain organizational seasonal functions of the animals [Arendt, Skene, 2005], including mentioned above reproduction, behavior and camouflage coloring in seasonal animals.
In women melatonin affects the reproductive function as well, determining the frequency and length of the menstrual cycles, thus if we have too much melatonin it can lead to changes in menstrual cycles and even to certain disorders.
Moreover, melatonin plays a role of antioxidant, being, as the researches have proven, “twice as effective as vitamin E, and believed to be the most effective lipophilic antioxidant” [Pieri, Marra, Moroni, Recchioni, Marcheselli, 1994], affecting the other antioxidants in order to increase their effectiveness, being able to cross cell membranes.
It displays high lipid and water solubility, which allows it to diffuse easily through most cell membranes, including the blood-brain barrier. Its half-life is about 30 minutes, and it is cleared mostly through the liver and subsequently excreted in the urine as urinary 6-sulfatoxymelatonin [Khullar, 2012]
Also, melatonin is thought to be engaged in immune system processes, particularly being called “pineal-immune system sensory organ, having pineal sensitivity to substances of immunologic origin such as cytokines or thymic hormones suggest the existence of a bidirectional flow of information between the pineal gland and the immune system”[Maestroni, 1993].
It is controlled, as we have mentioned above, by the pineal gland, located in the brain. But what, in fact, stimulates it and what are the causes for its secretion? It is stated that melatonin is controlled by a so-called circadian clock, which has been called, if talk about the one, located in the brain, the suprachiasmatic nuclei which has specific link, connection with pineal gland through nervous system. Secretion itself is regulated by norepinephrine. What makes them work? The answer is light, which resets a specific area of the brain regulating the temporal period of the melatonin production. Melatonin receptors are located in the hypothalamus of the brain (in the mentioned nuclei), blood vessels and in ovaries.
Most of its effects resulting from its functions come through two main receptors, which are called MT1 and MT2, which are mostly located in the already mentioned suprachiasmatic nuclei in hypothalamus, being, though spread in other organs [Khullar, 2012]
Notwithstanding, melatonin is claimed to have its main functions in the sphere of regulation of day-night cycles, particularly because of regulating of circadian rhythm. By the way, this function starts being regular and affecting our cycles just after three months after our birth and gradually it decreases. The highest level of its activity was measured approximately at 8:00 A.M [Ardura, Gutirerez, Andres & Agapito, 2003].
Other researchers have shown that it starts secretion between 3 and 4 A.M., mentioning that the time before its secretion is the least likely for a person to fall asleep. If we compare what level of melatonin can be found in teenager and in a child the results will be totally different, thus in this paper we will analyze what key functions melatonin plays as well as how will it affect representatives of different age groups.
The circadian rhythm cycle function consists in mediating dark signals with simultaneous providing of the information at night, that is why this hormone is sometimes called “a hormone of darkness” along with the term “sleep hormone”. The latest researches have shown that “the most consistent effect found in those studies was that sleep latency was shorter after melatonin, even at rather low doses; on the other hand, sleep consolidation or sleep efficiency was not affected by night-time melatonin administration whereas, during daytime, an improvement in sleep efficiency could be found” (Cajochen, Krauchi and Wirz-Justice, 2003]. About certain role in such processes of melatonin we will talk further.
In addition, we need to concentrate on the importance of the melatonin from the point of view of the disorders it can be used to treat. Mostly, melatonin is used in case of sleep disorders and can be given to everybody, except for those having diabetes and certain other illnesses. The question is whether melatonin can “facilitate phase-shifting in night-shift workers”. Recent laboratory researches have shown different results depending on the amount of melatonin given to a participant: during one of the researches the portion was 5 mg, while during the other one it was approximately 4 mg. portion.
. The aim of the experiment consisted in measuring the circadian rhythms before and after a large shift in the sleep/wake schedule. “During the first experiment melatonin in the amount of 5 mg was given to a participant during the phase-advance portion of the PRC that succeeded in producing larger circadian phase shifts than placebo, which also was given to the other participant.
The other study changed the quantity of melatonin, given to a participant and it was approximately 4 mg of melatonin (or placebo) per subject of experiment before and during their daytime sleep. Under such circumstances, melatonin did not produce a larger phase delay than placebo. During night -shift field study, the result was such that only seven among 24 of the participants were found to produce larger circadian phase than placebo” [Cajochen, Krauchi and Wirz-Justice, 2003]. These researches have not given certain and detailed results, since not all the participants could be controlled as well as their sleep cycle was hard to estimate.
Melatonin and Circadian Rhythm
It is unbelievable how many physical and mental processes of paramount importance would become impossible or would last in a wrong or harmful way without direct or indirect impact of melatonin. Despite the fact that this hormone is irreplaceable for several processes, I am going to pay the crucial attention to its significant role in circadian sleep rhythm.
In order to understand such complicated interrelation comprehensively, it is necessary to define clearly what circadian rhythms are, their distinctive features and necessity. To begin with, the scientific exploration of this very issue has not begun from human examples. In fact, first signs of circadian rhythms were noticed in plants, namely constant slow and subtle movements of Mimosa’s leaves were logically combined with the changes of day and night. Consequently, the scientific conclusion of interdependence between biological rhythms and change of darkness and light were approved by examination of life circles of other plants, behavior of different animals and eventually – human’s behavior.
The daily sleep cycle is affected by two main components, particularly circadation and sleep, while melatonin affects both processes greatly, having two main effects on them. Firstly, “it entrains and shifts the circadian rhythm (process C) in a “chronobiotic” function. Second, it promotes sleep onset and continuity in a “hypnotic” function by increasing the homeostatic drive to sleep (process S) [Khullar, 2012]
Obviously, there are different kinds of aforementioned rhythms, but melatonin is a crucial substance for very special kind of them – circadian sleep rhythms. It is commonly known that humans do not have established sleep rhythm from the very moment they have born. However, this rhythm is important for normal work of our bodies, so such patterns are slowly, but surely established in children’s habits with every single day. Usually the consolidation of sleep during the night, and in contrary – wakefulness during the day emerges at the age of 16 weeks (Reite, Weissberg, Ruddy, 2009). It is like a natural way to accommodate for 24-hour day, common for human activity and time for full recharging of batteries.
As in the example of Mimosa, which reacts on the light, it is the most important activator for human circadian rhythms too. It is widely known that bright light may irritate our eyes and complicate out ability to fall asleep. Simultaneously, semi-dark or dark space works like a favorable and cozy environment to fall into sleepy dreams.
However, light is a most common and understandable reason, triggering factor of circadian rhythms, but not the only one. In order for circadian rhythm to be identified, scientific community proposes the classic phase markers for measuring the timing of a mammal's circadian rhythm, which are the following: melatonin secretion by the pineal gland, core body temperature minimum and plasma level of cortisol (Benloucif, Guico, Reid, 2005).
Melatonin serves as window to view the functioning of the “internal clock”, the circadian time keeping system of the body, it even deserves a name of “chronobiotic” and “internal Zeitgeber” (Cardinali, Pandi-Perumal, 2010). Such importance and priceless role of melatonin is explained by special character of circadian sleep rhythm (in comparison with other rhythms) and its ability to influence the sleep-awake processes.
The aforementioned peculiarity of circadian sleep rhythms is in the existence of free running period with duration up to 24 hours, which is possible to be entrained only by time cue, but if they are absent, cycle rhythms are easily to become irregular at all. Hence, exclusively melatonin can alter the timing of mammalian circadian rhythms and can reset disturbed ones to their correct phase position (Cardinali, Pandi-Perumal, 2010).
All these explanations lead us to obvious conclusions on the importance of melatonin in medicine as valuable measure of natural cure. Many researches and experiments have been concluded with the same positive result of applying melatonin for the treatment of people, who suffer from serious sleep disorders – from general problems, connected with unreasonable anxiety and disturbed sleep to such serious disorders as insomnia, diabetes, liver diseases etc .
Fortunately, exogenous melatonin can fulfill role of chronobiotic – drug that shifts circadian sleep rhythms in the desired direction and acts as a zeitgeber to maintain this stable phase (Watson 2011). In other words, melatonin is a natural regulator of biological processes of crucial importance. Its miracle is embodied in both its natural producing by pineal gland and also by the possibility to apply it artificially as treatment for restoring of disturbed circadian circles and general refreshing.
Scientists also have come to the conclusion that the role of melatonin in the sphere of treating sleep disorders is overestimated, since these processes are regulated by circadian pacemaker that drives the rhythms of melatonin synthesis, thermoregulation, sleep consolidation and EEG activation during wakefulness[Cajochen, Krauchi and Wirz-Justice, 2003], mentioning that there are also people, not secreting melatonin at all, who sleep normally.
How melatonin can help those having problem with circadian rhythm, namely having sleep disorders? According to latest researches, in cases of primary insomnia among middle-aged category of people, who daily used 2 mg. of melatonin, there was clear and positive improvement, which was indicated by quantitive analysis of the data, obtained during the experiment [Leger, Laudon and Zisapel, 2004]
Other large study, conducted by the American scientists, have resulted in positive results as well. However, in this case positive consequences of using of melatonin occurred with elder patients, who are aged more than 55 [Wade, Crawford, Ford, 2011].
Additionally, melatonin is thought to be effective, if it is applied to treat psychiatric disorders, particularly those relating to sleep disturbance and depressions between which, according to different researches there is correltion. Particularly, A number of studies suggest that sleep problems lead to the development or relapse of mood disorders, while I=indirect data point toward sleep disturbance as an important etiological factor in the development of depressive disorders [Lusterg, Reynolds, 2000]
Taking into account such disorder as seasonal affective one or bipolar scetrum illness[Srinivasan, Smits and Spence, 2006], we can conclude that they are most determined by the lack of sleep which is under direct causation of production of melatonin. In case the level of secretion of melatonin decreases a person can feel uncomfortable, his biorhythm changes, it leads to mood disorders, lack of time to deal with one’s own problems, which later cause depressions. Those patients having mood disorders have to analyze on the matter of changes of melatonin secretion under the conditions of response to light. And the results proved previoiusly made assumptions.
Summarizing the above-mentioned statements, we can also refer to the list of functions of melatonin, defined by professor Maestroni. Among them are: enhanced antibody response, enhanced AMLR, enhanced mitogenic response, restoration of depressed mitogenic response, anti-stress and anti-corticosteroid effect, enhanced cancer immunotherapy and the others[Maestroni, 1993]
All the previously made observations make us claim that melatonin plays an important role in daily cycles, organizing one of the key biological process, namely our sleep, due to its impact on chyrcian rhythm. Melatonin can be used in medical treatments aims, as we have previously stated, to treat different disorders, including psychiatric ones as well.
It is thought that melatonin is more effective than other pharmaceuticals, used in the same sphere. Especially, previously made experiments prove that middle-aged people as well as elder ones should use melatonin in order to harmonize their nervous system and to prevent mood disorders as well as insomnia. Of course, usage of melatonin needs to be supervised by the professionals, though its safety and tolerability have been proven.
Hence, the main conclusion we have come to is that melatonin affects sleep-wake cycle, particularly two main processes of it: cirdacian process as well as sleep itself. It is due to its lipid and water solubility allowing to diffuse easily through most cell membranes, including the blood-brain barrier, being regulted by suprachiasmatic nuclei.
The main function that melatonin performs, as we have already mentioned, is mediation of the dark signals and provide night information, being called a “hormone of darkness” or a “hormone of sleep”.
Also melatonin and that was the central issue if this paper, “stabilizes and reinforces various circadian rhythms in the body”[Saper, Chou, Gooley, 2005] These functions are performed due to two main receptor of melatonin – MT1 and MT2, when first one deals with the sleep processes and second one is to regulate circadian rhythms.
All the features of melatonin makes it an important hormone in aspect of providing homestasis of the body that is why it has become popular in pharmaceutical industry, being nowadays used to treat different disorders and having less adverse effects than other similar drugs do.
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