Melatonin is uncommonly effective in reducing oxidative stress under a remarkably large number of circumstances. It achieves this action via a variety of means: direct detoxification of reactive oxygen and reactive nitrogen species and indirectly by stimulating antioxidant enzymes while suppressing the activity of pro-oxidant enzymes. In addition to these well-described actions, melatonin also reportedly chelates transition metals, which are involved in the Fenton/Haber-Weiss reactions; in doing so, melatonin reduces the formation of the devastatingly toxic hydroxyl radical resulting in the reduction of oxidative stress. Melatonin's ubiquitous but unequal intracellular distribution, including its high concentrations in mitochondria, likely aid in its capacity to resist oxidative stress and cellular apoptosis. There is credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant. Melatonin's capacity to prevent oxidative damage and the associated physiological debilitation is well documented in numerous experimental ischemia/reperfusion (hypoxia/reoxygenation) studies especially in the brain (stroke) and in the heart (heart attack). Melatonin, via its antiradical mechanisms, also reduces the toxicity of noxious prescription drugs and of methamphetamine, a drug of abuse. Experimental findings also indicate that melatonin renders treatment-resistant cancers sensitive to various therapeutic agents and may be useful, due to its multiple antioxidant actions, in especially delaying and perhaps treating a variety of age-related diseases and dehumanizing conditions. Melatonin has been effectively used to combat oxidative stress, inflammation and cellular apoptosis and to restore tissue function in a number of human trials; its efficacy supports its more extensive use in a wider variety of human studies. The uncommonly high-safety profile of melatonin also bolsters this conclusion. It is the current feeling of the authors that, in view of the widely diverse beneficial functions that have been reported for melatonin, these may be merely epiphenomena of the more fundamental, yet-to-be identified basic action(s) of this ancient molecule.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jpi.12360

Melatonin as an antioxidant: under promises but over delivers.

Successful implantation is the result of reciprocal interactions between the implantation-competent blastocyst and receptive uterus. Although various cellular aspects and molecular pathways of this dialogue have been identified, a comprehensive understanding of the implantation process is still missing. The receptive state of the uterus, which lasts for a limited period, is defined as the time when the uterine environment is conducive to blastocyst acceptance and implantation. A better understanding of the molecular signals that regulate uterine receptivity and implantation competency of the blastocyst is of clinical relevance because unraveling the nature of these signals may lead to strategies to correct implantation failure and improve pregnancy rates. Gene expression studies and genetically engineered mouse models have provided valuable clues to the implantation process with respect to specific growth factors, cytokines, lipid mediators, adhesion molecules, and transcription factors. However, a staggering amount of information from microarray experiments is also being generated at a rapid pace. If properly annotated and explored, this information will expand our knowledge regarding yet-to-be-identified unique, complementary, and/or redundant molecular pathways in implantation. It is hoped that the forthcoming information will generate new ideas and concepts for a process that is essential for maintaining procreation and solving major reproductive health issues in women.

Molecular cues to implantation

In this article, Axelrod applied signal transduction theory to his research on the metabolic function of serotonin, even describing
 the pineal gland as a "neurochemical transducer."

https://science.sciencemag.org/content/sci/184/4144/1341.full.pdf

The pineal gland: a neurochemical transducer.

Melatonin is a ubiquitous molecule and widely distributed in nature, with functional activity occurring in unicellular organisms, plants, fungi and animals. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light/dark cycle via the suprachiasmatic nucleus. Pinealocytes function as 'neuroendocrine transducers' to secrete melatonin during the dark phase of the light/dark cycle and, consequently, melatonin is often called the 'hormone of darkness'. Melatonin is principally secreted at night and is centrally involved in sleep regulation, as well as in a number of other cyclical bodily activities. Melatonin is exclusively involved in signaling the 'time of day' and 'time of year' (hence considered to help both clock and calendar functions) to all tissues and is thus considered to be the body's chronological pacemaker or 'Zeitgeber'. Synthesis of melatonin also occurs in other areas of the body, including the retina, the gastrointestinal tract, skin, bone marrow and in lymphocytes, from which it may influence other physiological functions through paracrine signaling. Melatonin has also been extracted from the seeds and leaves of a number of plants and its concentration in some of this material is several orders of magnitude higher than its night-time plasma value in humans. Melatonin participates in diverse physiological functions. In addition to its timekeeping functions, melatonin is an effective antioxidant which scavenges free radicals and up-regulates several antioxidant enzymes. It also has a strong antiapoptotic signaling function, an effect which it exerts even during ischemia. Melatonin's cytoprotective properties have practical implications in the treatment of neurodegenerative diseases. Melatonin also has immune-enhancing and oncostatic properties. Its 'chronobiotic' properties have been shown to have value in treating various circadian rhythm sleep disorders, such as jet lag or shift-work sleep disorder. Melatonin acting as an 'internal sleep facilitator' promotes sleep, and melatonin's sleep-facilitating properties have been found to be useful for treating insomnia symptoms in elderly and depressive patients. A recently introduced melatonin analog, agomelatine, is also efficient for the treatment of major depressive disorder and bipolar affective disorder. Melatonin's role as a 'photoperiodic molecule' in seasonal reproduction has been established in photoperiodic species, although its regulatory influence in humans remains under investigation. Taken together, this evidence implicates melatonin in a broad range of effects with a significant regulatory influence over many of the body's physiological functions.

Melatonin: Nature's most versatile biological signal?

Endogenous melatonin is synthesized from tryptophan via 5-hydroxytryptamine. It is considered an indoleamine from a biochemical point of view because the melatonin molecule contains a substituted indolic ring with an amino group. The circadian production of melatonin by the pineal gland explains its chronobiotic influence on organismal activity, including the endocrine and non-endocrine rhythms. Other functions of melatonin, including its antioxidant and anti-inflammatory properties, its genomic effects, and its capacity to modulate mitochondrial homeostasis, are linked to the redox status of cells and tissues. With the aid of specific melatonin antibodies, the presence of melatonin has been detected in multiple extrapineal tissues including the brain, retina, lens, cochlea, Harderian gland, airway epithelium, skin, gastrointestinal tract, liver, kidney, thyroid, pancreas, thymus, spleen, immune system cells, carotid body, reproductive tract, and endothelial cells. In most of these tissues, the melatonin-synthesizing enzymes have been identified. Melatonin is present in essentially all biological fluids including cerebrospinal fluid, saliva, bile, synovial fluid, amniotic fluid, and breast milk. In several of these fluids, melatonin concentrations exceed those in the blood. The importance of the continual availability of melatonin at the cellular level is important for its physiological regulation of cell homeostasis, and may be relevant to its therapeutic applications. Because of this, it is essential to compile information related to its peripheral production and regulation of this ubiquitously acting indoleamine. Thus, this review emphasizes the presence of melatonin in extrapineal organs, tissues, and fluids of mammals including humans.

Extrapineal melatonin: sources, regulation, and potential functions.

Retinal Localization of the Hydroxyindole-O-methyl Transferase (HIOMT) in the Rat

IN MAMMALS, hydroxyindole 0-methyl transferase (HIOMT; S-adenosylmethionine: N-acetylserotonin 0-methyl transferase; EC2.1.1.4), the enzyme responsible for the biosynthesis of melatonin and other endocrinologically active 5-methoxyindoles, has been reported to occur exclusively in the pineal gland (AXELROD and WEISSBACH, 1961). We have recently observed HIOMT activity in the retina of the rat (unpublished results). Because of the similarities in embryological origins of the retina and pineal gland (WURTMAN, AXELROD and KELLY, 1968), we carried out the experiments reported here to examine the characteristics of the metabolism of serotonin by the rat retina. Retinae of adult male Wistar rats were used. Pooled retinae from five animals were incubated in vitro with 2 pCi of serotonin [2-\"T]binoxalate (New England Nuclear Co., Boston, Mass; specific radioactivity, 15.3 mCi/rnmol) in 0.5 ml of 0.1 M-phosphate buffer (pH 7.9) containing: 125 mglucose; 30 mM-nicotinamide; 10 mwcysteine hydrochloride; 4 mM-MgC1, and 1 mM-EDTA. The incubations were carried out in a Dubnoff metabolic shaker for 4 h a t 37°C with air as the gas phase. A blank, containing no tissue, was included in each series of incubations. Portions of 20 pl of the incubation media plus 20 pl of a mixture (4 pg each) of authentic serotonin, 5-methoxyserotonin, 5-hydroxyindoleacetic acid, 5-methoxyindoleacetic acid, 5-hydroxytryptophol, 5-methoxytryptopho1, N-acetylserotonin and melatonin (K and K Laboratories, Plainview, N.Y.), were chromatographed in a bidimensional TLC system, as described by KLEIN and NOTIDES (1969). Precoated 10 x 20 cm plates (Silica Gel FZs4, E. Merck, A. G. Darmstadt, Germany) were activated at 110°C for 1 h and sprayed with 0.5 % (w/v) ascorbic acid in methanol before use. The plates were developed twice with chloroform-methanol-glacial acetic acid (93 :7: 1, by vol.), rotated through 90°, and developed

Metabolism of serotonin by the rat retina in vitro

Preincubation of synaptosome-rich homogenates of rat hypothalamus with melatonin resulted in significant decreases of norepinephrine, serotonin, dopamine and glutamate uptake. Melatonin inhibition was noncompetitive; apparent Km's of initial uptake processes were: (2.5 +/- 0.3) x 10(-7) M for norepinephrine, (2.6 +/- 0.3) x 10(-7) M for serotonin, (2.4 +/- 0.4) x 10(-7) M for dopamine and (1.0 +/- 0.3) x 10(-7) M for glutamate. Apparent Ki's for melatonin inhibition of transmitter uptake were: 0.64 +/- 0.14 mM (norepinephrine), 0.23 +/- mM (serotonin), 0.51 +/- 0.08 mM (dopamine) and 1.21 +/- 0.10 mM (glutamate). Transmitter release evoked by increasing [K+] in medium to 30 mM was augmented by melatonin in a dose-dependent manner. Maximal effects were observed on serotonin release. Accumulation of 3H-melatonin within synaptosome-rich homogenates did not exhibit differences between 0 and 37 degrees C, indicating that the uptake of the hormone was not an active process. These results suggest that exogenously-administered melatonin may affect neurotransmitter accumulation and release in the hypothalamus by modification of the transmitter uptake mechanism rather than by competition with the transmitter for its uptake pump.

Effects of melatonin on neurotransmitter uptake and release by synaptosome-rich homogenates of the rat hypothalamus

Control of estrogen and androgen receptors in the rat pineal gland by catecholamine transmitter.

The effects of estradiol on pineal function haveinsofar been studied by administering supramaximal, non-physiological doses of the hormone. The present experiments were undertaken to assess estradiol-

Jorge M. Rosner

Papers

Retinal Localization of the Hydroxyindole-O-methyl Transferase (HIOMT) in the Rat

Metabolism of serotonin by the rat retina in vitro

Effects of melatonin on neurotransmitter uptake and release by synaptosome-rich homogenates of the rat hypothalamus

Control of estrogen and androgen receptors in the rat pineal gland by catecholamine transmitter.

Effects of Estradiol on Melatonin and Protein Synthesis in the Rat Pineal Organ