I Introduction UNTIL 35 yr ago, most scientists did not take research on the pineal gland seriously The decade beginning in 1956, however, provided several discoveries that laid the foundation for what has become a very active area of investigation These important early observations included the findings that, 1), the physiological activity of the pineal is influenced by the photoperiodic environment (1–5); 2), the gland contains a substance, N-acetyl-5-methoxytryptamine or melatonin, which has obvious endocrine capabilities (6, 7); 3), the function of the reproductive system in photoperiodically dependent rodents is inextricably linked to the physiology of the pineal gland (5, 8, 9); 4), the sympathetic innervation to the pineal is required for the gland to maintain its biosynthetic and endocrine activities (10, 11); and 5), the pineal gland can be rapidly removed from rodents with minimal damage to adjacent neural structures using a specially designed trephine (12) Since the mid 1960s, research on t

Pineal Melatonin: Cell Biology of Its Synthesis and of Its Physiological Interactions*

Bright artificial light suppressed nocturnal secretion of melatonin in six normal human subjects. Room light of less intensity, which is sufficient to suppress melatonin secretion in other mammals, failed to do so in humans. In contrast to the results of previous experiments in which ordinary room light was used, these findings establish that the human response to light is qualitatively similar to that of other mammals.

https://science.sciencemag.org/content/sci/210/4475/1267.full.pdf

Light Suppresses Melatonin Secretion in Humans

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?

Three centuries ago, the French philosopher Rene Descartes described the pineal gland as “the seat of the soul,” but it was not until the late 1950s that melatonin, the principal substance secreted by the pineal gland, was identified.1 There is now evidence that melatonin may have a role in the biologic regulation of circadian rhythms, sleep, mood, and perhaps reproduction, tumor growth, and aging (Table 1). However, uncertainties and doubts still surround the role of melatonin in human physiology and pathophysiology. This review summarizes current knowledge about melatonin in humans and its clinical implications. Physiology and Pharmacology In humans, the . . .

Melatonin in humans.

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.

Isolation of melatonin, the pineal gland factor that lightens melanocytes1

Structure of melatonin1

Isolation of melatonin and 5-methoxyindole-3-acetic acid from bovine pineal glands.

Part III: General Considerations of Skin Pigmentation: Pigment Cell Regulatory Factors1

MELATONIN is a hormone, isolated from beef pineal glands, that lightens the colour of frog melanocytes either after injection into the frog or after in vitro incubation with pieces of frog skin1. In addition, this hormone can block and reverse the darkening actions of the melanocyte-stimulating hormones and also of adrenocorticotrophic hormone. Melatonin is a 5-hydroxyindole derivative in which the hydroxy group is blocked2. Its melanocyte-lightening properties are more than ten thousand times greater than those of noradrenaline, which previously was considered to be the most potent lightening agent known3. In our early experiments melatonin could be detected only in extracts from pineal glands and not from other tissues. With improvement in extraction techniques we have been able to identify the presence of a lightening agent that is most likely melatonin in peripheral nerves of man, monkey and cow. A detailed mapping of the location of melatonin in the nervous system has not been completed.

James D. Case

Papers

Isolation of melatonin, the pineal gland factor that lightens melanocytes1

Structure of melatonin1

Isolation of melatonin and 5-methoxyindole-3-acetic acid from bovine pineal glands.

Part III: General Considerations of Skin Pigmentation: Pigment Cell Regulatory Factors1

Melatonin in Peripheral Nerve