Elsevier

Biochemical Pharmacology

Volume 56, Issue 10, 15 November 1998, Pages 1265-1272
Biochemical Pharmacology

Commentaries
Antioxidant properties of melatonin—an emerging mystery

https://doi.org/10.1016/S0006-2952(98)00180-4Get rights and content

Abstract

Over three centuries ago, the French philosopher René Descartes described the pineal gland as “the seat of the soul.” However, it was not until the late 1950s that the chemical identity and biosynthesis of melatonin, the principal hormone secreted by the pineal body, were revealed. Melatonin, named from the Greek melanos, meaning black, and tonos, meaning color, is a biogenic amine with structural similarities to serotonin. The mechanisms mediating the synthesis of melatonin are transcriptionally regulated by the photoperiodic environment. Once synthesized, the neurohormone is a biologic modulator of mood, sleep, sexual behavior, reproductive alterations, immunologic function, and circadian rhythms. Moreover, melatonin exerts its regulatory roles through high-affinity, pertussis toxin-sensitive, G-protein (or guanine nucleotide binding protein) coupled receptors that reside primarily in the eye, kidney, gastrointestinal tract, blood vessels, and brain. Additional evidence also indicates a role for melatonin in aging and age-related diseases, probably related to its efficient free radical scavenger (or antioxidant) activity. The potential clinical benefit of melatonin as an antioxidant is remarkable, suggesting that it may be of use in the treatment of many pathophysiological disease states including various cancers, hypertension, pulmonary diseases, and a variety of neurodegenerative diseases such as Alzheimer’s disease. This review summarizes the biosynthesis of melatonin and its many endocrine and physiological functions, including its therapeutic potential in human disease states. Emphasis is placed on the recent speculations indicating that this pineal hormone serves as an endogenous antioxidant agent with proficient free radical scavenging activity.

Section snippets

Physiology, synthesis, and metabolism of melatonin

The pineal gland secretes an indoleamide called melatonin, so named because it has the ability in certain fish, reptiles, and amphibians to temporarily turn the skin a dark color (produced by the chemical pigment melanin) [8]. In the human brain, the pineal gland is located on the dorsal surface of the hypothalamus, occupying a central position between the two cerebral hemispheres [1]. The highly vascularized tissue of the pineal gland consists of two types of cells: pinealocytes and neuroglia.

Melatonin receptors and mechanisms of action

Two pharmacologically distinct families of membrane-bound melatonin receptors known as ML1 and ML2 have been identified. Using the potent melatonin agonist 2-[125I]iodomelatonin, the ML1 receptors have been shown to be high-affinity receptors with a Kd of ∼75 pM in chick and rabbit retina [14]. In contrast, the ML2 receptors have a lower affinity for the same melatonin receptor agonist (Kd > 2 nM in hamster brain; > 1 nM in human brain) [14]. The genes encoding the human melatonin receptors,

Clinical applications of melatonin

It is quite apparent that the hormonal role for melatonin is functionally related to neuroendocrine physiology, with a strong association also existing between its secretion and the normal occurrence of sleep and (other) circadian rhythms. The onset of normal sleep is characterized by a rapid increase in melatonin concentrations, and it is believed that the overall quality of sleep is contingent upon the natural oscillating pattern of melatonin secretion [13]. In this regard, it is interesting

Melatonin as an antioxidant

Oxygen comprises 21% of the earth’s atmosphere [39] and is essential for the life of aerobic organisms. However, a major paradox is that oxygen, in certain states, can be lethal to the body tissue of organisms that depend on it for life. The majority of oxygen inspired is used to generate energy in the form of ATP 39, 40. However, a relatively large amount—approximately 5%—of inspired oxygen is converted to free radicals, many of which are extremely toxic [7]. A certain cause of age-related

Conclusion

The biosynthesis of melatonin is largely regulated by the photoperiodic environment. Although the circadian and endocrine effects of melatonin are moderately well understood, the potential role that melatonin plays as a free radical scavenger is only beginning to surface. As our geriatric population continues to grow, so does the incidence of neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease, the primary dementia in modern society. Furthermore, as people age, they

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