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.

Ependym und Circumventriculäre Organe

Exposure of female Holtzman rats to constant light (24 hr/day) immediately after birth significantly increased 9,10-dimethyl-1,2-benzanthracene-induced mammary cancer. Such “functionally pinealectomized” animals also revealed significant increase in the circulating level of prolactin and exaggerated development and proliferative activity of mammary epithelium, as measured by quantitation of terminal end buds and alveolar buds from the whole mounts and by DNA synthesis, respectively. Administration of melatonin (500 µg/day/rat i.p. given from 52 to 145 days of age) completely abolished the effect of functional pinealectomy by sharply reducing 9,10-dimethyl-1,2-benzanthracene-induced cancer incidence from 95% to 25% during the post-9,10-dimethyl-1,2-benzanthracene observation period which lasted up to 180 days. On the other hand, administration of melatonin to surgically pinealectomized animals exposed to constant light reversed the effect only partially by reducing the cancer incidence from 83% to 53%. Further, melatonin treatment in intact and surgically pinealectomized animals exposed to a short photoperiod revealed qualitatively similar differences in suppression of the cancer incidence. From these results, it is concluded that, to have an impressive antitumor effect, presence of the pineal gland is essential, and the probable site of melatonin action appears to be at both the pineal gland and the hypothalamus.

https://cancerres.aacrjournals.org/content/canres/44/8/3403.full.pdf

Effect of Melatonin on Mammary Carcinogenesis in Intact and Pinealectomized Rats in Varying Photoperiods

Melatonin induced marked testicular regression in hamsters maintained on photostimulatory long days (light-dark 14 : 10). In animals maintained on nonstimulatory short days (light-dark 6 : 18), small amounts of melatonin (50 micrograms per day; 100 millimeters capsule length) prevented testicular regression; but testicular atrophy occurred in hamsters that received larger amounts of melatonin (75 to 100 micrograms per day; 150 to 200 millimeters capsule length) and in control hamsters that received none. The results demonstrate that melatonin can exert either pro- or antigonadal effects and emphasize that the effects of melatonin on the testis cannot be properly assessed unless account is taken of the dosage and mode of melatonin administration and the photoperiod on which experimental animals are maintained.

http://science.sciencemag.org/content/sci/190/4211/280.full.pdf

Melatonin: Antigonadal and progonadal effects in male golden hamsters

Exposure of male hamsters to short daily photoperiods (1 hour of light and 23 hours of darkness daily for 9 weeks led to total involution of the testes and accessory sex organs (seminal vesicles and coagulating glands). Pituitary levels of immunoreactive prolaction also decreased by about 60 percent after dark exposure. The inhibitory effects of darkness on the reproductive organs were prevented either by pinealectomy or by the subcutaneous implantation of a melatonin-beeswax pellet into the animals each week. Both pinealectomy and melatonin treatment also returned pituitary levels of prolactin toward normal. The results suggest that melatonin is not the pineal antigonadotrophic factor in the male golden hamster.

M.J. Matthews

Papers

Localization of a sheep pineal antigonadotropin