Melatonergic Treatment: Focus on Metabolism and Chronobiology

Abstract

Introduction: Melatonin is produced in various organs, but its preferentially nocturnal synthesis and release by the pineal gland is decisive for its chronobiological actions. The short half-life of circulating melatonin has been reason for developing synthetic melatonergic agonists. With regard to age-and disease-related dysfunction of the melatonergic system, treatment with melatonin or its synthetic analogs may be used for alleviating health problems with a respective etiology. This review addresses limitations arising from drug-specific metabolism and disregarded chronobiological rules. Metabolism: Differences are illustrated by comparing the metabolism of melatonin and two approved synthetic melatonergic agonists, ramelteon and agomelatine. Apart from hydroxylation and dealkylation reactions, melatonin can be converted to methoxylated kynuramines, a route absent in the two synthetic drugs. An unsual property is present in the ramelteon metabolite M-II, which still displays melatonergic activity, but attains 30 to 100 times higher levels than the parent compound. Two double-hydroxylated agomelatine metabolites may be involved in sometimes occurring hepatotoxicity. Chronobiology of Melatonergic Drugs: Sleep latency facilitation and readjustment of circadian rhythms require only short actions. Circadian entrainment must consider the phase response curve and requires repetitive well-timed administration. Findings in nocturnally active rodents cannot be generally translated to humans, especially not regarding sleep and, perhaps, not in insulin resistance. Conclusions: Melatonin and synthetic analogs can be suitable for treating sleep-onset difficulties, circadian rhythm sleep disorders and subtypes of depression with an etiology of circadian dysfunction. Applications in the field of metabolic syndrome and insulin resistance have to be seen with caution.

Melatonin and the pathologies of weakened or dysregulated circadian oscillators

“…This should be immediately obvious in the case of sleep, although some studies have, in fact, used melatonergic agonists in nocturnal rodents for investigating sleep effects. However, an observed sedation should only reflect central depression rather than sleep and a translation to humans would be highly questionable . Another field in which the nocturnality/diurnality might be of comparable importance may be that of the complex “metabolic syndrome, obesity, type 2 diabetes, insulin resistance.” However, the consideration of circadian aspects should not be restricted to the direct relationship between melatonin and activated nocturnal and inhibited diurnal functions.…”

“…The fundamental difference that does not allow a simple translation from the laboratory animals to the human is of chronobiological nature. 176,177 In the nocturnally active rats and mice, melatonin is associated with elevated physical and neuronal activity, food intake, and respective regulation mechanisms concerning metabolism of nutrients, energy sensing, and mitochondrial function. However, in a diurnally active species such as the human, the pineal hormone is associated with rest, sleep, and, usually, no eating, correlations that have to result in an opposite circadian phasing of metabolic control mechanisms.…”

“…In fact, they are not necessarily contradictory to the opposite effects observed in rodents. The fundamental difference that does not allow a simple translation from the laboratory animals to the human is of chronobiological nature . In the nocturnally active rats and mice, melatonin is associated with elevated physical and neuronal activity, food intake, and respective regulation mechanisms concerning metabolism of nutrients, energy sensing, and mitochondrial function.…”

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“…Therefore, it will be of utmost importance to study in detail and on a broader scale the changes that can be induced by melatonin in aging mammals, as far as possible, including the human. However, researchers have to be aware that findings obtained in nocturnally active rodents are not necessarily translatable to the diurnally active human [24, [112][113][114]. Moreover, it is important to strictly discriminate between effects obtained in nontumor and in tumor cells, in which completely opposite actions of melatonin have been observed, notably, concerning the aging suppressor and accessory oscillator component SIRT1 [11,24,52,114].…”