Journal of Endocrinology and Reproduction

Ruediger Hardeland ¹

Affiliations
1 Johann Friedrich Blumenbach Institute of Zoology and Anthropology, University of Goettingen, Berliner Str. 28, D-37073 Goettingen, DE

Abstract

Melatonergic treatment can be successful under conditions of (i) decreased melatonin levels caused by aging and various diseases, (ii) circadian perturbations or dysfunction, including mood disorders with an etiology of circadian malfunction, (iii) sleep difficulties, and (iv) some metabolic disorders concerning energy metabolism and insulin resistance. In addition to melatonin, which is available as immediate- and prolonged-release formulations, several synthetic melatonergic drugs have been developed. Properties of melatonin are compared with those of β-methyl-6-chloromelatonin (TIK-301), piromelatine, agomelatine, ramelteon, GR 196429 and tasimelteon. The article emphasizes the necessity of distinguishing between promising approaches based on short but repeated actions and others aiming at a substitution therapy, which is not easily achieved. Short actions on sleep initiation and circadian phase shifting are already successful with low doses of melatonin. Such a chronobiotic approach may be also possible in bipolar and seasonal affective disorders. Longer actions are required for promoting sleep maintenance. Prolonged-release melatonin and agonists having a longer half-life in the circulation can be used, however, with a moderate outcome. Direct antidepressant actions are observed with compounds combining properties of melatonergic agonists and 5-HT2C serotonergic antagonists. Moreover, agonists that may be suitable for improving metabolic disorders including insulin resistance are discussed.

Keywords

Aging, Agomelatine, Circadian Dysfunction, Melatonin, Piromelatine, Ramelteon, Sleep, Tasimelteon, TIK-301.

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Ruediger Hardeland ¹, Beata K. Zsizsik ¹, Isaac Antolin ², Susanne Burkhardt ¹, Ana Coto-Montes ², Burkhard Poeggeler ¹

Affiliations
1 Institute of Zoology, Anthropology and Developmental Biology, University of Goettingen, Berliner Str. 28, D-37073 Goettingen, DE
2 Department of Morphology and Cell Biology, University of Oviedo, Julian Claveria, s/n, E-33006 Oviedo, ES

Abstract

In the bioluminescent, marine dinoflagellate Lingulodinium polyedrum [syn. Gonyaulax polyedra], light emission Is sensitive to oxidative stress in a dual way: (a) The nocturnal glow maximum, which depends on the melatonin metabolite 5-methoxytryptamine (5-MT), is decreased by 5-MT depletion following oxidation of its precursor melatonin, which easily undergoes radical reactions; attenuations of the glow maximum are typical for sublethal oxidative stress, (b) Since luciferin availability is triggered by proton translocation to the scintillons (bioluminescent microsources which form cytoplasmic intrusions into acidic vacuoles), lethal oxidative stress causes strong rises in bioluminescence ("dying peaks") as a consequence of cytoplasmic acidification, which results from impaired proton pumping into vacuoles under ATP deficiency and/or proton leakage through damaged membranes. Sublethal concentrations of paraquat or buthionine sulfoximine decrease the circadian glow peak, in a dose-dependent fashion. These effects can be reverted by exogenous melatonin, although this indoleamine itself does not stimulate but rather slightly diminishes light emission. After a lethal dose of hydrogen peroxide, a dying peak appears, which can be rapidly terminated by adding catalase to the medium. Sublethal and lethal effects of the endogenous oxidotoxin 3-hydroxykynurenine can be distinguished on the basis of the differently timed glow and dying peaks.

Keywords

Bioluminescence, Buthionine Sulfoximine, 3-Hydroxykynurenine, Lingulodinium, Melatonin, Oxidative Stress, Paraquat.

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