The discovery of melatonin and its derivatives as antioxidants has stimulated a very large number of studies which have, virtually uniformly, documented the ability of these molecules to detoxify harmful reactants and reduce molecular damage. These observations have clear clinical implications given that numerous age-related diseases in humans have an important free radical component. Moreover, a major theory to explain the processes of aging invokes radicals and their derivatives as causative agents. These conditions, coupled with the loss of melatonin as organisms age, suggest that some diseases and some aspects of aging may be aggravated by the diminished melatonin levels in advanced age. Another corollary of this is that the administration of melatonin, which has an uncommonly low toxicity profile, could theoretically defer the progression of some diseases and possibly forestall signs of aging. Certainly, research in the next decade will help to define the role of melatonin in age-related diseases and in determining successful aging. While increasing life span will not necessarily be a goal of these investigative efforts, improving health and the quality of life in the aged should be an aim of this research.

Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin.

Mitochondria and chloroplasts are major sources of free radical generation in living organisms. Because of this, these organelles require strong protection from free radicals and associated oxidative stress. Melatonin is a potent free radical scavenger and antioxidant. It meets the criteria as a mitochondrial and chloroplast antioxidant. Evidence has emerged to show that both mitochondria and chloroplasts may have the capacity to synthesize and metabolize melatonin. The activity of arylalkylamine N-acetyltransferase (AANAT), the reported rate-limiting enzyme in melatonin synthesis, has been identified in mitochondria, and high levels of melatonin have also been found in this organelle. From an evolutionary point of view, the precursor of mitochondria probably is the purple nonsulfur bacterium, particularly, Rhodospirillum rubrum, and chloroplasts are probably the descendents of cyanobacteria. These bacterial species were endosymbionts of host proto-eukaryotes and gradually transformed into cellular organelles, that is, mitochondria and chloroplasts, respectively, thereby giving rise to eukaryotic cells. Of special importance, both purple nonsulfur bacteria (R. rubrum) and cyanobacteria synthesize melatonin. The enzyme activities required for melatonin synthesis have also been detected in these primitive species. It is our hypothesis that mitochondria and chloroplasts are the original sites of melatonin synthesis in the early stage of endosymbiotic organisms; this synthetic capacity was carried into host eukaryotes by the above-mentioned bacteria. Moreover, their melatonin biosynthetic capacities have been preserved during evolution. In most, if not in all cells, mitochondria and chloroplasts may continue to be the primary sites of melatonin generation. Melatonin production in other cellular compartments may have derived from mitochondria and chloroplasts. On the basis of this hypothesis, it is also possible to explain why plants typically have higher melatonin levels than do animals. In plants, both chloroplasts and mitochondria likely synthesize melatonin, while animal cells contain only mitochondria. The high levels of melatonin produced by mitochondria and chloroplasts are used to protect these important cellular organelles against oxidative stress and preserve their physiological functions. The superior beneficial effects of melatonin in both mitochondria and chloroplasts have been frequently reported.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/jpi.12026

Mitochondria and chloroplasts as the original sites of melatonin synthesis: a hypothesis related to melatonin's primary function and evolution in eukaryotes

Melatonin is a tryptophan-derived molecule with pleiotropic activities. It is present in almost all or all organisms. Its synthetic pathway depends on the species in which it is measured. For example, the tryptophan to melatonin pathway differs in plants and animals. It is speculated that the melatonin synthetic machinery in eukaryotes was inherited from bacteria as a result of endosymbiosis. However, melatonin's synthetic mechanisms in microorganisms are currently unknown. Melatonin metabolism is highly complex with these enzymatic processes having evolved from cytochrome C. In addition to its enzymatic degradation, melatonin is metabolized via pseudoenzymatic and free radical interactive processes. The metabolic products of these processes overlap and it is often difficult to determine which process is dominant. However, under oxidative stress, the free radical interactive pathway may be featured over the others. Because of the complexity of the melatonin degradative processes, it is expected that additional novel melatonin metabolites will be identified in future investigations. The original and primary function of melatonin in early life forms such as in unicellular organisms was as a free radical scavenger and antioxidant. During evolution, melatonin was selected as a signaling molecule to transduce the environmental photoperiodic information into an endocrine message in multicellular organisms and for other purposes as well. As an antioxidant, melatonin exhibits several unique features which differ from the classic antioxidants. These include its cascade reaction with free radicals and its capacity to be induced under moderate oxidative stress. These features make melatonin a potent endogenously-occurring antioxidant that protects organisms from catastrophic oxidative stress.

https://www.mdpi.com/1420-3049/20/10/18886/pdf

Melatonin as a Potent and Inducible Endogenous Antioxidant: Synthesis and Metabolism.

Exposure to a variety of toxins and/or infectious agents leads to disease, degeneration and death, often characterised by circumstances in which cells or tissues do not merely die and cease to function but may be more or less entirely obliterated. It is then legitimate to ask the question as to whether, despite the many kinds of agent involved, there may be at least some unifying mechanisms of such cell death and destruction. I summarise the evidence that in a great many cases, one underlying mechanism, providing major stresses of this type, entails continuing and autocatalytic production (based on positive feedback mechanisms) of hydroxyl radicals via Fenton chemistry involving poorly liganded iron, leading to cell death via apoptosis (probably including via pathways induced by changes in the NF-κB system). While every pathway is in some sense connected to every other one, I highlight the literature evidence suggesting that the degenerative effects of many diseases and toxicological insults converge on iron dysregulation. This highlights specifically the role of iron metabolism, and the detailed speciation of iron, in chemical and other toxicology, and has significant implications for the use of iron chelating substances (probably in partnership with appropriate anti-oxidants) as nutritional or therapeutic agents in inhibiting both the progression of these mainly degenerative diseases and the sequelae of both chronic and acute toxin exposure. The complexity of biochemical networks, especially those involving autocatalytic behaviour and positive feedbacks, means that multiple interventions (e.g. of iron chelators plus antioxidants) are likely to prove most effective. A variety of systems biology approaches, that I summarise, can predict both the mechanisms involved in these cell death pathways and the optimal sites of action for nutritional or pharmacological interventions.

/pdf/towards-a-unifying-systems-biology-understanding-of-large-29x7kqlt9i.pdf

Towards a unifying, systems biology understanding of large-scale cellular death and destruction caused by poorly liganded iron: Parkinson’s, Huntington’s, Alzheimer’s, prions, bactericides, chemical toxicology and others as examples

Melatonin receptors are seven transmembrane-spanning proteins belonging to the G protein-coupled receptor super-family. In mammals, two melatonin receptor subtypes exit MT1 and MT2 encoded by the MTNR1A and MTNR1B genes, respectively. The current review provides an update on melatonin receptors by the corresponding sub-committee of the International Union of Basic and Clinical Pharmacology. We will highlight recent developments of melatonin receptor ligands, including radioligands and give an update on the latest phenotyping results of melatonin receptor knockout mice. The current status and perspectives of the structure of melatonin receptor structures will be summarized. The physiological importance of melatonin receptor dimers and biologically important and type 2 diabetes-associated genetic variants of melatonin receptors will be discussed. The role of melatonin receptors in physiology and disease will be further exemplified by its functions in the immune system and the central nervous system. Finally, antioxidant and free radical scavenger properties of melatonin and its relation to melatonin receptors will be critically addressed.

https://www.hal.inserm.fr/inserm-01335656/document

Update on melatonin receptors: IUPHAR Review 20.

Purpose: The radioprotective ability of melatonin was investigated in the Indian tropical rodent, Funambulus pennanti during its reproductively inactive phase (RIP) when peripheral melatonin is high and the animal is under the influence of environmental stresses. Materials and methods: Fifty male squirrels were divided into two sets of 25 each; with set 1 receiving 0.9% saline and set 2 receiving 25 mg melatonin/100 g body weight/day for four weeks during evening hours. Five saline-treated and five-melatonin treated squirrels were sacrificed at times of 4, 24, 48 and 72 hours following 2.06 Gy X-ray radiation. Remaining squirrels that were not exposed to X-ray were used as control and melatonin treated, respectively. Total leukocyte count (TLC) and lymphocyte count (LC) in peripheral blood and lipid peroxidation (LPO) status, superoxide dismutase (SOD) activity, total antioxidant status (TAS), apoptotic percentage on the basis of morphological changes and DNA fragmentation and caspase3 activity were measured in the spleens of squirrels. Results: Peripheral blood and spleens with higher intrinsic levels of environmental and X-radiation induced free radical generation had inhibited TLC, LC, SOD activity and TAS and increased LPO and apoptosis. Melatonin pre-treatment significantly reduced and altered the changes brought on by X-radiation. Conclusion: Exogenous melatonin with its anti-apoptotic and antioxidant properties additively increased the immunity of the squirrels, by protecting their hematopoietic system and lymphoid organs against X-ray radiation induced cellular toxicity.

/pdf/effect-of-exogenous-melatonin-on-x-ray-induced-cellular-22sj7hynfd.pdf

Effect of exogenous melatonin on X-ray induced cellular toxicity in lymphatic tissue of Indian tropical male squirrel, Funambulus pennanti.

Purpose: Biological effects of X-ray irradiation and protection by melatonin on the immune status of a tropical rodent, Funambulus pennanti, was examined by estimating oxidative damage of peripheral blood and spleen and protection by melatonin treatment.Material and methods: Seventy squirrels were divided into 4 sets of 25, 25, 10 and 10 having subdivisions into a total of eight groups. Squirrels of set 1 (groups A and B) received only normal saline, set 2 (groups C and D) received 25 μg/100 g body weight (bwt) melatonin and set 3 (groups E and F) received 25 μg/100 g bwt vitamin E for four weeks. Groups G and H of set 4 received high doses of melatonin (0.5 mg/100 g bwt) 30 min prior to and 30 min after X-ray irradiation, respectively, and were sacrificed 1 h after irradiation. Groups B and D were sacrificed after 4 h, 24 h, 48 h and 72 h of irradiation for total leukocyte count (TLC) in peripheral blood, percent apoptotic cells and lipid peroxidation (LPO) in spleen while group F was sacrificed after 4 ...

/pdf/melatonin-prevents-x-ray-irradiation-induced-oxidative-4y8cgnwotm.pdf

Melatonin prevents X-ray irradiation induced oxidative damagein peripheral blood and spleen of the seasonally breeding rodent, Funambulus pennanti during reproductively active phase

Phenylhydrazine (PHZ) oxidation resulting in free iron release followed by free radical generation has increased frequency of cancer. This study aims towards the dose-dependent response of PHZ and the role of melatonin in comparison with vitamin E following PHZ-induced toxicity within the lymphoid tissue (spleen) of Indian tropical seasonal breeder, Funambulus pennanti, during reproductively active phase. An increase in the damages in terms of lipid peroxidation (LPO), apoptosis percentage, and splenomegaly was observed following different doses of PHZ treatment, i.e., 0.025, 0.5, and 1 mg/100 g body weight (b.wt.), where dose of 1 mg/100 g b.wt. showed more significant damages. Both melatonin (0.5 mg/100 g b.wt.) and vitamin E (1 mg/100 g b.wt.) administration ameliorated oxidative damages of 1 mg/100 g b.wt. PHZ-treated group. Melatonin altered PHZ-induced responses significantly to a greater degree than vitamin E as evidenced by LPO status, SOD activity, and ABTS radical cation scavenging activity of antioxidants. Thus, melatonin might be able to restrict carcinogenic property of PHZ-induced oxidative stress by protecting macromolecules of the cell from harmful effects of PHZ and instead preserving cell viability.

http://srbce.org/forum/PHZ%20Environ%20Toxic%20Sharma%20Haldar.pdf

Comparative effect of melatonin and vitamin E on phenylhydrazine-induced toxicity in the spleen of Funambulus pennanti.

Data suggests that UV radiation causes oxidative damage of the cells due to the release of inflammatory cytokines which in turn generates reactive oxygen species (ROS) that damages lipids, proteins and DNA. On the other hand, melatonin a potent antioxidant from the pineal gland under most of the conditions acts as a free radical scavenger. Our data suggests that melatonin pre-treatment (s.c. injections) significantly protected the diurnal squirrels from oxidative damages caused by UVC irradiation of 1528 mJ cm(-2) that induced suppression of delayed type hypersensitivity (DTH) responses. It also protected the rodents from UVC radiation induced increase in thiobarbituric acid reactive substances (TBARS) levels in spleen accompanied with a significant decrease in Superoxide Dismutase (SOD) activity indicating the occurrence of superoxide anion mediated damages following UVC exposure. Melatonin administration reduced the radiation induced oxidative stress in the spleen tissue as analyzed by reduced lipid damages and higher SOD activity. Under in vivo (100 μg/100g body wt.) and in vitro (250 pg/10(6) cells) conditions, melatonin pre-treatment prevented spleen tissues and splenocytes from radiation induced cell death. In conclusion we may suggest that melatonin could be one of the potent antioxidant and radio protector that may reduce UV radiation induced toxicity to the cells and hence may be clinically important.

Shweta Sharma

Papers

Effect of exogenous melatonin on X-ray induced cellular toxicity in lymphatic tissue of Indian tropical male squirrel, Funambulus pennanti.

Melatonin prevents X-ray irradiation induced oxidative damagein peripheral blood and spleen of the seasonally breeding rodent, Funambulus pennanti during reproductively active phase

Comparative effect of melatonin and vitamin E on phenylhydrazine-induced toxicity in the spleen of Funambulus pennanti.

The oxidative damages caused by ultraviolet radiation type C (UVC) to a tropical rodent Funambulus pennanti: role of melatonin.

Antifilarial efficacy of green silver nanoparticles synthesized using Andrographis paniculata