Melatonin is a highly conserved molecule. Its presence can be traced back to ancient photosynthetic prokaryotes. A primitive and primary function of melatonin is that it acts as a receptor-independent free radical scavenger and a broad-spectrum antioxidant. The receptor-dependent functions of melatonin were subsequently acquired during evolution. In the current review, we focus on melatonin metabolism which includes the synthetic rate-limiting enzymes, synthetic sites, potential regulatory mechanisms, bioavailability in humans, mechanisms of breakdown and functions of its metabolites. Recent evidence indicates that the original melatonin metabolite may be N 1 -acetyl-N 2 -formyl-5-methoxykynuramine (AFMK) rather than its commonly measured urinary excretory product 6-hydroxymelatonin sulfate. Numerous pathways for AFMK formation have been identified both in vitro and in vivo. These include enzymatic and pseudo-enzymatic pathways, interactions with reactive oxygen species (ROS)/reactive nitrogen species (RNS) and with ultraviolet irradiation. AFMK is present in mammals including humans, and is the only detectable melatonin metabolite in unicellular organisms and metazoans. 6-Hydroxymelatonin sulfate has not been observed in these low evolutionary-ranked organisms. This implies that AFMK evolved earlier in evolution than 6-hydroxymelatonin sulfate as a melatonin metabolite. Via the AFMK pathway, a single melatonin molecule is reported to scavenge up to 10 ROS/RNS. That the free radical scavenging capacity of melatonin extends to its secondary, tertiary and quaternary metabolites is now documented. It appears that melatonin's interaction with ROS/RNS is a prolonged process that involves many of its derivatives. The process by which melatonin and its metabolites successively scavenge ROS/RNS is referred as the free radical scavenging cascade. This cascade reaction is a novel property of melatonin and explains how it differs from other conventional antioxidants. This cascade reaction makes melatonin highly effective, even at low concentrations, in protecting organisms from oxidative stress. In accordance with its protective function, substantial amounts of melatonin are found in tissues and organs which are frequently exposed to the hostile environmental insults such as the gut and skin or organs which have high oxygen consumption such as the brain. In addition, melatonin production may be upregulated by low intensity stressors such as dietary restriction in rats and exercise in humans. Intensive oxidative stress results in a rapid drop of circulating melatonin levels. This melatonin decline is not related to its reduced synthesis but to its rapid consumption, i.e. circulating melatonin is rapidly metabolized by interaction with ROS/RNS induced by stress. Rapid melatonin consumption during elevated stress may serve as a protective mechanism of organisms in which melatonin is used as a first-line defensive molecule against oxidative damage. The oxidative status of organisms modifies melatonin metabolism. It has been reported that the higher the oxidative state, the more AFMK is produced. The ratio of AFMK and another melatonin metabolite, cyclic 3-hydroxymelatonin, may serve as an indicator of the level of oxidative stress in organisms.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-079X.2006.00407.x

One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?

The paper briefly reviews the data which shows that the circadian production and secretion of melatonin by the pineal gland can impart both daily, i.e., clock, and seasonal, i.e., calendar, information to the organism. The paper summarizes the 3 patterns of nocturnal melatonin production that have been described. Clearly, regardless of the pattern of nocturnal melatonin production a particular species normally displays, the duration of nightime elevated melatonin is proportional to the duration of the night length. Since daylength under natural conditions changes daily the melatonin rhythm, which adjusts to the photoperiod sends time of year information to the organism. The melatonin receptors which subserve the clock message sent by the pineal gland in the form of a melatonin cycle may reside in the biological clock itself, namely, the suprachiasmatic nuclei (SCN). The melatonin receptors that mediate seasonal changes in reproductive physiology are presumably those that are located on the pars tuberalis cells of the anterior pituitary gland. Besides these receptors which likely mediate clock and calendar information, melatonin receptors have been described in other organs. Interestingly, the distribution of melatonin receptors is highly species-specific. Whereas the clock and calendar information that the melatonin cycle imparts to the organism relies on cell membrane receptors, a fact that is of some interest considering the high lipophilicity of melatonin, recent studies indicate that other functions of melatonin may require no receptor whatsoever.

The melatonin rhythm: both a clock and a calendar.

The discovery of melatonin and its derivatives as antioxidants has stimulated a very large number of studies which have, virtually uniformly, documented the ability of these molecules to detoxify harmful reactants and reduce molecular damage. These observations have clear clinical implications given that numerous age-related diseases in humans have an important free radical component. Moreover, a major theory to explain the processes of aging invokes radicals and their derivatives as causative agents. These conditions, coupled with the loss of melatonin as organisms age, suggest that some diseases and some aspects of aging may be aggravated by the diminished melatonin levels in advanced age. Another corollary of this is that the administration of melatonin, which has an uncommonly low toxicity profile, could theoretically defer the progression of some diseases and possibly forestall signs of aging. Certainly, research in the next decade will help to define the role of melatonin in age-related diseases and in determining successful aging. While increasing life span will not necessarily be a goal of these investigative efforts, improving health and the quality of life in the aged should be an aim of this research.

Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin.

Melatonin is a tryptophan-derived molecule with pleiotropic activities. It is present in almost all or all organisms. Its synthetic pathway depends on the species in which it is measured. For example, the tryptophan to melatonin pathway differs in plants and animals. It is speculated that the melatonin synthetic machinery in eukaryotes was inherited from bacteria as a result of endosymbiosis. However, melatonin's synthetic mechanisms in microorganisms are currently unknown. Melatonin metabolism is highly complex with these enzymatic processes having evolved from cytochrome C. In addition to its enzymatic degradation, melatonin is metabolized via pseudoenzymatic and free radical interactive processes. The metabolic products of these processes overlap and it is often difficult to determine which process is dominant. However, under oxidative stress, the free radical interactive pathway may be featured over the others. Because of the complexity of the melatonin degradative processes, it is expected that additional novel melatonin metabolites will be identified in future investigations. The original and primary function of melatonin in early life forms such as in unicellular organisms was as a free radical scavenger and antioxidant. During evolution, melatonin was selected as a signaling molecule to transduce the environmental photoperiodic information into an endocrine message in multicellular organisms and for other purposes as well. As an antioxidant, melatonin exhibits several unique features which differ from the classic antioxidants. These include its cascade reaction with free radicals and its capacity to be induced under moderate oxidative stress. These features make melatonin a potent endogenously-occurring antioxidant that protects organisms from catastrophic oxidative stress.

https://www.mdpi.com/1420-3049/20/10/18886/pdf

Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism.

A review of the literature on the relationship of exercise to mental health strongly suggests that the two are closely linked. Thus, physical activity has been reported to reduce depression symptoms and anxiety, and to improve coping with stress. Logically, many investigators have then tried to determine the physiological mechanisms that are responsible for this mood-elevating effect of exercise. Among the current hypotheses, those regarding the endorphin and the monoamine systems have received a great deal of attention. On that basis, the respective effects of physical exercise on brain dopamine, noradrenaline and serotonin transmission are reviewed herein. In addition, suggestions are advanced for future research in this field.

Physical exercise and brain monoamines: a review

Since the pineal gland is an end organ of the sympathetic nervous system, stress might increase the synthesis of its hormone, melatonin The stress of a 10 min swim, which elicits a marked rise in circulating catecholamines, causes a dramatic depression of high pineal melatonin levels at night within 15 min after swimming onset N-acetyltransferase (NAT) activity is unaffected by the treatment at 15 or 30 min after swimming onset Within 90 min after initiation of a 15 min swim, high nighttime pineal melatonin levels are restored while NAT values remain elevated The swimming-induced reduction in high pineal melatonin levels is not influenced by either hypophysectomy, superior cervical ganglionectomy, prazosin (α1-adrenergic receptor blocker) pretreatment, yohimbine (α2-adrenergic receptor blocker) pretreatment, or reserpine (amine depletor) pretreatment These results indicate that neither hormones secreted from the pituitary gland nor catecholamines secreted from the sympathetic nerves are involved in eliciting the dramatic reduction in elevated pineal melatonin levels in the rat

Neither the pituitary gland nor the sympathetic nervous system is responsible for eliciting the large drop in elevated rat pineal melatonin levels due to swimming.

The activity of N-acetyltransferase (NAT) and the content of melatonin (MEL) in the rat pineal have been shown to be sensitive to several types of stressors This study was designed to assess the role of the adrenals in mediating the effect of one such stressor, insulin-induced hypoglycemia, on pineal synthetic activity Intact and bilaterally adrenalectomized (ADX) adult male rats were kept under light:dark cycles of 14:10 (lights on 0600 h) and injected intraperitoneally with 10 IU insulin at 1300 h, and groups (n = 8) were killed 2, 3, or 4 h postinjection Plasma catecholamines were assayed by means of high performance liquid chromatography and radioimmunoassay was used to assess pineal NAT activity and MEL content All injected groups were rendered hypoglycemic by insulin administration Compared to uninjected controls, plasma epinephrine in hypoglycemic intact rats rose after 2 h, whereas epinephrine did not change in hypoglycemic ADX animals The increase in epinephrine in intact animals was correlated with a rise in NAT activity at 2 h Moreover, pineal MEL content at 2, 3, and 4 h was significantly greater than control values In contrast, no changes in pineal biosynthetic function were found in ADX rats This differential response by intact and ADX rats suggests that an adrenal product (possibly epinephrine) is responsible for mediating the stimulatory effects of acute insulin-induced hypoglycemic stress on the rat pineal

Adrenalectomy prevents changes in rat pineal melatonin content and N-acetyltransferase activity induced by acute insulin stress.

Female Syrian hamsters were kept in a light (14:10 h light:dark cycle, lights on 0600 h)- and temperature (22 or 30 degrees C)-controlled room; some groups were treated with an afternoon s.c. injection of melatonin (6.25, 12.5, or 25 micrograms/day) for 11 or 14 weeks. The melatonin-induced suppression of the reproductive system in hamsters maintained at 22 degrees C (as measured by vaginal cycles, uterine weights, ovarian histology, and plasma and pituitary prolactin levels) was delayed if hamsters were kept at 30 degrees C. The dose-related depression of thyroxine (T4) after melatonin injections for 14 weeks in 22 degrees C was not seen at 30 degrees C. Rather, the depression of plasma T4 and triiodothyronine (T3) seen at the end of 11 or 14 weeks of exposure to 30 degrees C without melatonin injections (vs. control levels at 22 degrees C) was offset by melatonin injections, raising T4 and T3 particularly at the lower doses. In contrast, there was no consistent effect of higher temperature alone on reproductive variables. The interactive effects of temperature and melatonin on the reproductive and thyroidal systems in female hamsters are apparently complex and probably provide a fine-tuning mechanism for the environmental control of endocrine physiology.

Elevated environmental temperature alters the responses of the reproductive and thyroid axes of female Syrian hamsters to afternoon melatonin injections.

Michael G. Tannenbaum

Papers

Neither the pituitary gland nor the sympathetic nervous system is responsible for eliciting the large drop in elevated rat pineal melatonin levels due to swimming.

Adrenalectomy prevents changes in rat pineal melatonin content and N-acetyltransferase activity induced by acute insulin stress.

Elevated environmental temperature alters the responses of the reproductive and thyroid axes of female Syrian hamsters to afternoon melatonin injections.