Open access peer-reviewed chapter

An Overview of Melatonin as an Antioxidant Molecule: A Biochemical Approach

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Aysun Hacışevki and Burcu Baba

Submitted: March 1st, 2018 Reviewed: June 11th, 2018 Published: November 5th, 2018

DOI: 10.5772/intechopen.79421

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Melatonin is an endogenous hormone derived from tryptophan that is mainly released from the pineal gland in the dark. Melatonin regulates many biological functions such as sleep, circadian rhythm, immunity, and reproduction. Melatonin has a free radical scavenger, anti-inflammatory, and antioxidant effects. It scavenges reactive oxygen and nitrogen species and increases antioxidant defenses, thus it prevents tissue damage and blocks transcriptional factors of pro-inflammatory cytokines. Due to its small size and amphiphilic nature, it increases the efficacy of mitochondrial electron transport chain and reduces electron leakage. Melatonin prevents degenerative changes in the central nervous system in models of Alzheimer’s and Parkinson’s disease and reduces free radical damage to DNA which may lead to cancer and many other situations. Consequently, melatonin has beneficial effects including stimulation of antioxidant enzymes, inhibition of lipid peroxidation, and so it contributes to protection from oxidative damages.


  • melatonin
  • antioxidant
  • free radical
  • oxidative stress
  • anti-inflammatory
  • neurohormone
  • tryptophan
  • disease

1. Introduction

Melatonin, N-acetyl-5-methoxytryptamine, which was first isolated from bovine pineal glands [1], is an endogenous neurohormone derived from tryptophan [2]. Melatonin controls various physiologic processes, including circadian rhythms, mood regulation, anxiety, sleep, appetite, immune responses, and cardiac functions [3]. The sleep–wake cycle is the most overt circadian rhythm [4]. More or less sleep shows negative effects on biological and physiological processes including alterations in metabolic, endocrine, and immune pathways that lead to health problems involving obesity, diabetes, hypertension, and respiratory diseases [4, 5, 6]. Timing of melatonin secretion is closely associated with the timing of sleep propensity, and it also coincides with decreases in core body temperature, alertness, and performance [7]. Melatonin regulates memory formation by directly affecting hippocampal neurons. There are antinociceptive, antidepressant, anxiolytic, antineophobic, and locomotor activity regulating effects of melatonin [3, 8]. Melatonin plays important roles in neurogenesis, neuroprotection, maintenance of oxidant/antioxidant balance, modulation of cardiovascular and/or immune system, and diabetes control. It exerts a direct antioxidant effect on tissues/organs and antiapoptotic effects on cells [9]. Other actions of melatonin include inhibition of dopamine release in the hypothalamus and retina, involvement in the aging process and pubertal development, blood pressure control, and free radical scavenging [7]. Melatonin dysfunction may contribute to many divergent diseases, such as neurodegenerative diseases, circadian and mood disorders, insomnia, type 2 diabetes, and pain [3]. Low levels of melatonin have been shown in Parkinson’s disease (PD), Alzheimer’s disease (AD), insomnia, epilepsy, ischemic injury, and neuropsychiatric disorders; in addition, roles for melatonin in the development of cataracts, aging, and retinitis have also been reported [10]. Melatonin has been utilized in several countries for circadian rhythm disorders, sleep disturbances, jet lag, and sleep–wake cycle disturbances in blind people and shift workers [7, 11, 12].

Melatonin is secreted primarily by the pineal gland in response to darkness [2, 13, 14]. It was later found to be also present or synthesized in extrapineal sites such as retina, Harderian gland, lymphocytes, gastrointestinal tract, bone marrow cells, platelets and skin [13, 15, 16, 17]. The neurohormone melatonin is not stored in the pineal gland but rather is released into the bloodstream and can penetrate all body tissues [18]. The synthesis of melatonin shows a clear circadian rhythm with low levels during the daytime and its secretory peak at night [19, 20]. The nocturnal synthesis and release of melatonin by the pineal gland are strictly controlled by the suprachiasmatic nucleus (SCN) clock and inhibited by lighting conditions [19, 21]. In humans and other mammals, detection of light drives activity in retinal ganglion cells that project to the SCN in the hypothalamus, causing the release of inhibitory γ-amino butyric acid that suppresses the circuit controlling melatonin synthesis and release [22]. Serum melatonin reaches a peak value (80–150 pg/mL) between midnight and 3 a.m., while its concentration during the day is low (10–20 pg/mL) [23]. Both normal melatonin patterns and the influence of light can vary considerably between individuals, either in terms of personal characteristics or as a consequence of aging or a chronic disease [24]. Serum concentrations of melatonin vary considerably with age, and infants secrete very low levels of melatonin before 3 months of age. Amplitude of the nocturnal peak in melatonin secretion reaches the highest levels between the 4th and 7th year of age [15, 19]. Other factors that alter melatonin levels are nightwork, impaired light–dark cycles, and obesity. Additionally, some nutritional factors could change melatonin production [13].

Melatonin, hormone of darkness, is synthesized from tryptophan, which is an essential amino acid by the pineal gland. The synthesis of melatonin is a multistep process. Firstly, tryptophan is hydroxylated by tryptophan-5-hydroxylase (TPH) to form 5-hydroxytryptophan, which is subsequently decarboxylated to 5-hydroxytryptamine (serotonin) by L-aromatic amino acid decarboxylase (AADC). Serotonin is N-acetylated by arylalkylamine N-acetyltransferase (AA-NAT, also called “Timezyme,” is the rate-limiting enzyme for melatonin synthesis), to form N-acetylserotonin, which is converted to N-acetyl-5-methoxytryptamine (melatonin) by N-acetylserotonin-O-methyltransferase (ASMT, also called hydroxyindole-O-methyltransferase or HIOMT). The last step is the rate-limiting step in the biosynthesis of melatonin (Figure 1) [18, 20, 25, 26, 27, 28].

Figure 1.

Biosynthesis of melatonin from tryptophan (TPH, tryptophan-5-hydroxylase; AADC, L-aromatic amino acid decarboxylase; AA-NAT, arylalkylamine N-acetyltransferase; HIOMT, hydroxyindole-O-methyltransferase).

Melatonin synthesis depends on intact beta-adrenergic receptor function. Norepinephrine activates the N-acetyltransferase, and beta-receptor blockers depress melatonin secretion [29]. Both AA-NAT and ASMT activities are controlled by noradrenergic and neuropeptidergic projections to the pineal gland. The pineal gland receives input from postganglionic fibers, leading to the release of norepinephrine. Norepinephrine induces its α1/β-adrenoceptors that activate adenylate cyclase-cAMP system. Thus, intracellular levels of the second messengers include cAMP, Ca2+, phosphatidylinositol, diacetylglycerol, and protein kinase C increase. These messengers induce the expression and activity of AA-NAT and HIOMT [7, 14, 15, 18, 30].

The pineal gland is located outside the blood brain barrier, and loses it connections with the central nervous system, having sympathetic innervation as its main source. This may explain for the pineal gland ability to have a large uptake of tryptophan leading to a high melatonin production and secretion in response to darkness [18]. Once synthesized, melatonin is quickly released into the systemic circulation to reach central and peripheral target tissues. The effects of melatonin depend on the localization and types of melatonin receptors [15]. Melatonin activates two high-affinity G-protein-coupled receptors, termed MT1 and MT2. The MT1 and MT2 lead to an inhibition of the adenylate cyclase in target cells and regulate a variety of cellular and physiological processes including neuronal firing, arterial vasoconstriction, cell proliferation, immune responses, and reproductive and metabolic functions [8, 16, 27, 31, 32, 33]. MT1 and MT2 receptors are 350 and 362 amino acids long, located on chromosome 4q35.1 and chromosome 11q21-q22, respectively. MT1 receptors are expressed in the brain, cardiovascular system, immune system, testes, ovary, skin, liver, kidney, adrenal cortex, placenta, breast, retina, pancreas, and spleen. MT2 has been found in the immune system, brain, retina, pituitary, blood vessels, testes, kidney, gastrointestinal tract, mammary glands, adipose tissue, and the skin [27, 31, 32]. The MT3 receptor has a low affinity, unlike MT1 and MT2; it is not coupled to G proteins; it has a nanomolar affinity for melatonin, and it is not sensitive to Na+2, Mg+2, and Ca+2. The MT3 is equivalent to enzyme quinone reductase II [27]. The relationship between multiple physiological function of melatonin and this enzyme is possibly involved in the regulation of cellular redox status, although the exact role of this relationship remains unclear [16, 34]. Melatonin appears to be a natural ligand for the retinoid-related orphan nuclear hormone receptor family (RZR/ROR). RZR/RORα is expressed in a variety of organs, whereas RZRβ is specific for the brain and retina [35]. In addition, melatonin interacts with intracellular proteins such as calmodulin, calreticulin, or tubulin and antagonizes the binding of Ca2+ to calmodulin [7]. ROR/RZR has been proposed to work in coordination with the plasma membrane receptors MT1/MT2 to regulate gene expression. The low-affinity interaction between melatonin and calmodulin may be involved in its antioxidant action as well as other signaling processes [15, 16]. The membrane receptors have been defined in the central nervous system and in peripheral organs, such as liver, gastrointestinal tract, skin, kidney, heart, and adipose and lymphoid tissues in many mammalians [33]. Melatonin also acts through nonreceptor-mediated mechanisms, for example, serving as a scavenger for reactive oxygen species (ROS) and reactive nitrogen species (RNS) [27]. Melatonin and its metabolites have potent antioxidative and radioprotective properties [36]. Melatonin has been proven to be an efficient oxidant scavenger of a variety of radical and nonradical reactants [37].

In the circulation, melatonin is partially bound to albumin and can also bind to hemoglobin [38]. Melatonin metabolism is a rapid process, and its half-life in humans varies between 10 and 60 min following exogenous administration. It is deactivated mostly by the liver and excreted in the urine [13, 26]. There are three major pathways of melatonin degradation: (1) the classical hepatic degradation pathway that generates 6-hydroxymelatonin, (2) the alternative indolic pathway that produces 5-methoxyindole acetic acid (5-MIAA) or 5-methoxytryptophol (5-MTOL), and (3) the kynurenic pathway that produces the main brain metabolites of melatonin, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK), and its deformylated product N1-acetyl-5-methoxykynuramine (AMK). These metabolites are highly remarkable and are generated enzymatically, pseudoenzymatically, by free radical, and via photochemical processes. Recently, it was reported that AFMK and AMK detoxify reactive species and preserve tissues from damage by reactive intermediates [39]. This chapter summarizes effects of melatonin and its metabolites as antioxidants and their clinical significance in several diseases.


2. Free radicals

Free radicals are atoms or molecules that containing one or more unpaired electrons in the external orbitals of the molecules, usually unstable and highly reactive. The free radical chemical reactivity is directly associated with the damage that they can inflict to biological molecules. In biology system, oxygen-derived radicals and nitrogen-derived radicals are two types of free radicals. Oxygen-derived radicals, such as superoxide (O2•−), hydroxyl radicals (OH), alkoxyl radicals (RO), as well as nonradicals such as hydrogen peroxide (H2O2), ozone and hypochlorous acid, are defined as reactive oxygen species (ROS). ROS are produced during the oxygen metabolism. Nitrogen-derived radicals and nonradicals, such as nitrogen dioxide (NO2), nitric oxide radicals (NO), and peroxynitrite (ONOO), are known as reactive nitrogen species (RNS) which are derived from nitric oxide and superoxide by inducible nitric oxide synthase (iNOS) and NADPH oxidase, respectively [16, 40, 41, 42, 43, 44]. Oxidants are produced as a result of normal intracellular metabolism in mitochondria and peroxisomes, as well as from diverse cytosolic enzyme systems such as lipoxygenases, NADPH oxidase, and cytochrome P450. Furthermore, various external agents including ionizing radiation, ultraviolet light, environmental toxins, inflammatory, and cytokines can trigger ROS production [16, 44]. Mitochondria are the major source of ROS and RNS production [45]. Generation of O2•− during oxidative phosphorylation takes place mainly in the mitochondria. O2•− is quickly converted to H2O2 enzymatically by superoxide dismutases (SODs). After that, H2O2 is converted into water or highly toxic hydroxyl radical [16]. Although hydroxyl radical formation can occur in several ways, by far the most important mechanism in vivo is likely to be the transition metal-catalyzed decomposition of superoxide anion and hydrogen peroxide [46]. Hydroxyl radicals are generated from hydrogen peroxide during cellular oxygen metabolism via the Fenton and Haber-Weiss reactions (Figure 2) [47], in the presence of free iron or copper ions [48]. The OH is formed during the Fenton reaction when H2O2 interacts with transition metals (Fe2+, Cu1+, etc.) [16, 40, 41]. It can also be produced by ultraviolet and ionizing radiations [41].

Figure 2.

Fenton and Haber-Weiss reactions.

Alkoxyl radicals that are formed from the reduction of peroxides, are less reactive than OH and significantly more reactive than ROO radicals, provided that R is the same in both species. Therefore, they are suggested to be ideal candidates to evaluate the efficiency of antioxidants and also the reactivity of any species reacting with ROS. As regards RNS, the chemical reactivity and direct toxicity of NO are quite low. However, it reacts with O2•− forming peroxynitrite, which is a powerful oxidant. NO2 is a mild oxidant, and its reactivity is between those of NO and ONOO [41, 42, 44].

In healthy organisms, there is a delicate balance between the production and the removal of free radicals, which guarantees that they remain in low/moderate concentrations. Under such conditions, free radicals have beneficial effects [41]. ROS and RNS play important roles in regulation of a wide variety of physiology functions like gene expression, cellular growth, differentiation, modulation of chemical reactions, and induction of transcription factors such as nuclear factor-kappa B (NF-кB) and activator protein-1 (AP-1) and activation of signal transduction pathways. They also participate in blood pressure control, are mediators in the biosynthesis of prostaglandins, function in embryonic development, and act as signaling molecules within the individual cell and among cells during their life span [44, 45, 46]. The harmful and useful effects of ROS/RNS are associated with their concentrations, the cell type and the subcellular compartments that are produced, and their timing of production [16]. An imbalance between excessive ROS and RNS generation and rate of their elimination by the antioxidant capacity leads to oxidative stress [49, 50]. It has been shown that oxidative stress is involved in over 100 diseases, as their cause or consequence [51]. Oxidative stress results in macromolecular damage and is implicated in various disease states such as atherosclerosis, diabetes, cancer, neurodegeneration, and aging [52]. The cellular dysfunctions caused by excessive ROS and/or RNS might produce loss of energy metabolism, altered cell signaling and cell cycle, gene mutations, and impaired cellular transport mechanisms. The oxidative stress promotes decreased biological activities, immune activation, and inflammation [50]. It seems that both high levels of ROS (oxidative stress) and excessively low levels of ROS (reductive stress) are deleterious and apparently play a causative role in the pathologies caused by malfunctioning processes related to the dramatic change of redox environment [53].


3. Antioxidants

Based on the oxidative stress related to free radical theory, the antioxidants are the first line of choice to take care of the stress [45]. Antioxidants act as free radical scavengers and can prevent oxidative reactions that lead to various diseases [54]. The antioxidant defense system includes endogenous (enzymatic and nonenzymatic) and exogenous (dietary) antioxidants that interact in establishing redox homeostasis in the body [49]. Endogenous antioxidants, which are products of the body’s metabolism, may be enzymatic or nonenzymatic compounds localized generally in the cytoplasm and diverse cell organelles [45, 49]. In eukaryotics, various antioxidant enzymes, for instance, SOD, catalase (CAT), and some peroxidases, transform ROS into more stable molecules (e.g., water and O2) via complex cascade of reactions [45]. One of the most effective intracellular enzymatic antioxidants is SOD. In humans, there are three forms of SOD: cytosolic CuZn-SOD, mitochondrial Mn-SOD, and extracellular SOD. SOD catalyzes the dismutation of O2•− to H2O2, decreasing the amount of O2•− and thereby lowering the formation of ONOO [44, 50]. Other important enzymatic antioxidants include CAT, glutathione peroxidase (GPx), glutathione reductase (GR), and peroxiredoxins (Prxs). These enzymes neutralize hydrogen peroxide, yielding water (CAT, GPx) and oxygen molecule (CAT) [45, 49]. CAT which is found in the peroxisomes and cytoplasm [55] presents a molecule of ferric ion at its active site and converts two molecules of H2O2 into one molecule each of water and diatomic oxygen [37]. Glutathione peroxidase can be found in many subcellular compartments including the mitochondria and nucleus depending on the family member [55]. Selenium, as a selenocysteine, is a component of the active site of GPx [37, 55, 56]. GPx uses reduced glutathione (GSH) as a substrate to transfer electrons to H2O2 (and other peroxides), thereby converting it into two molecules of water [37]. When hydrogen peroxide is metabolized by glutathione peroxidase, reduced glutathione is oxidized to glutathione disulfide (GSSG) which is converted back to GSH by the enzyme GR [57, 58, 59].

Small molecular nonenzymic antioxidants (e.g., GSH, NADPH, thioredoxin, vitamin E (α-tocopherol), vitamin C (ascorbic acid), and trace metals, such as selenium) also function as direct scavengers of ROS [45]. In particular, glutathione plays a central role in defense against oxidative stress [54]. The antioxidant properties of GSH which is a tripeptide, γ-l-glutamyl-l-cysteinyl-glycine, depend on the presence of a peptide bond between the amino group of cysteine and the alpha-carboxyl group, which provide an excellent protection against aminopeptidases, and the expression of the thiol group which derive from the cysteine residue. Complexation of metal ions, participation in the oxidation reactions, and formation of thiol radicals and disulfides are the most important functions of thiol groups in the biological systems [49]. Maintaining or reestablishment of redox homeostasis are ensured by endogenous and exogenous antioxidants that act synergistically [49, 60], such as during the regeneration of vitamin E by GSH or vitamin C to prevent lipid peroxidation, which can affect membrane fluidity and damage membrane proteins [60, 61]. Vitamin E and Vitamin C are the most frequently used antioxidant vitamins [62] that are thought to have a protective effect by either reducing or preventing oxidative damage [63]. Vitamin E belongs to the group of fat-soluble vitamins existing in eight different forms. The methylation pattern of the chroman ring determines the classification as α, β, γ, and δ tocopherols. These compounds have antioxidant properties. Vitamin E scavenges peroxyl radicals and hence acts to break the chain reaction of lipid peroxidation [64]. Besides its antioxidant role, vitamin E might also have a structural role in stabilizing membranes [46, 65, 66]. Vitamin C, which is readily water soluble, is an important antioxidant and thus works in aqueous environments of the body [46, 57, 67]. As an antioxidant, ascorbate is an efficient scavenger, or reducing antioxidant, capable of donating its electrons to ROS and eliminating them [44]. Loss of one electron generates the ascorbyl radical intermediate, and loss of two electrons generates dehydroascorbate (DHA, which can also be formed via dismutation of the ascorbyl radical) [61, 68]. It makes ascorbate a powerful important antioxidant [44]. Vitamin C serves as a co-antioxidant with vitamin E to regenerate α-tocopherol from α-tocopherol radicals in membranes and lipoproteins and protect protein thiol group against oxidation by increasing intracellular levels of GSH [46, 61, 69]. Vitamin C can also neutralize ROS (e.g., hydrogen peroxide) [46, 70]. Recently, toxicity of ascorbic acid has also been attributed to its autoxidation [45].

An efficient antioxidant should not only be ubiquitous but should also be present in adequate amounts in cells and easily reacts with a wide variety of free radicals which have short half-life due to high reactivity. A good antioxidant has the ability to cross physiologic barriers and to be quickly transported into the cells. Thus, it must be available to all cells. It is also important for an antioxidant to be available. Antioxidants should be available when needed. They should be easily acquired through the diet or produced in situ. Antioxidants should be suitable for regeneration. The reaction between an antioxidant and a free radical yields an oxidized form of the antioxidant which has less scavenging activity than the original compound. Therefore, many antioxidants have physiologically reducing mechanisms, or its oxidized forms can still efficiently react with new free radicals. An ideal antioxidant should be conserved by the kidneys. Otherwise, large urinary losses would occur and the half-life will be short. An important aspect to consider for evaluating the suitability of a compound as an antioxidant is its toxicity. It should be nontoxic prior to and after the free radical scavenging process takes place. In addition, it is also important to be aware of possible interactions with any drug that may be concurrently consumed [41, 71, 72].

Melatonin is a potent direct scavenger of free radicals. Unlike most of other radical scavengers, it is a multifunctional antioxidant. Melatonin can easily pass through cell membranes because of its high lipophilicity and hydrophilicity [73]. Melatonin is also widespread within cells. Its concentrations in human serum and cerebrospinal fluid vary widely. Melatonin is endogenously generated, and it is ingested in the food as it is widely available in fruits and vegetables. Hence, melatonin is produced internally and is also ingested in the diet. Only small amounts of melatonin are excreted into the urine in its unchanged form. It has minimal toxicity. Numerous in vivo studies on animals involving massive doses of melatonin have shown that acute and chronic toxicity of melatonin is extremely low [41, 74]. Unlike most small molecule biological antioxidants such as ascorbic acid, α-tocopherol, lipoic acid, etc., melatonin does not undergo redox cycling and, thus, does not promote oxidation. Melatonin can be considered a suicidal or terminal antioxidant. It undergoes molecular rearrangement, effectively removing the free electron from the system. Each of these products of rearrangement is also a potent antioxidant in its own right. Furthermore, most of these processes involve more than one ROS per step, so that one melatonin molecule has the capacity to scavenge up to 10 ROS versus the classic antioxidants that scavenge one or less ROS [17, 20, 70, 74]. It has been found that melatonin promotes the repair of oxidized DNA. This is probably due to the melatonin’s capability of transforming guanosine radical to guanosine by electron transfer [42]. It was shown that melatonin reduced the formation of 8-hydroxy-2′-deoxyguanosine (8-OH-dG), a damaged DNA product, 60–70 times more effective than some classic antioxidants (ascorbate and α-tocopherol) [75]. Additionally, the relative position of melatonin and its metabolites in the antioxidant “pecking order” (electrochemical potential) may contribute greatly to its utility in biological systems [76]. Melatonin protects lipids, proteins, and nuclear DNA from oxidative damage suggests that its intracellular distribution is wide [17]. Melatonin turned out to be considerably more efficient than the majority of its naturally occurring structural analogs, indicating that the substituents of the indole moiety strongly influenced reactivity and selectivity [77].


4. Melatonin and its metabolites as antioxidants

Melatonin is an indoleamine with two side chains, a 5-methoxy group and 3-amide group. Its molecular weight is 232.2 g/mol [42]. Melatonin has multifunctional activities in addition to its function as a synchronizer of the biological clock and seasonal reproduction [78, 79]. One such activity is its antioxidant capacity. Melatonin and its metabolites were found to have important antioxidant properties owing to their direct and indirect antioxidant actions. Melatonin can easily cross cell membranes [80] and the blood brain barrier [78] and protects various biomolecules against damage caused by free radicals by acting as a direct scavenger to detoxify reactive oxygen and nitrogen species. In addition, melatonin can indirectly reduce oxidative stress by increasing the activities of antioxidative defense systems; stimulating the expression and function of a number of antioxidant enzymes, as well as glutathione, another very important nonenzymatic, low molecular weight antioxidant; interacting synergistically with other antioxidants; and increasing the efficiency of the mitochondrial electron transport chain [40, 78, 79, 80, 81, 82]. Also, melatonin has a chelating property which may contribute in reducing metal-induced toxicity [83]. Melatonin was shown to be much more specific than its structural analogs in undergoing reactions, which lead to the termination of the radical reaction chain and in avoiding prooxidant, C- or O-centered intermediates [33, 38]. Moreover, it has been shown that it has an ability to scavenge free radicals, including hydroxyl radicals, hydrogen peroxide, peroxyl radicals, singlet oxygen, nitric oxide, and peroxynitrite. It was demonstrated that melatonin inhibits the activity of NO synthase, beside it’s NO and peroxynitrite scavenging activity [84].

Melatonin, an endogenously produced indoleamine, is a highly effective antioxidant and free radical scavenger [82]. Melatonin has been reported to neutralize the most toxic oxidizing agents, hydroxyl radical and the peroxynitrite anion, generated within the cells. Moreover, melatonin reportedly scavenges singlet oxygen (1O2), superoxide anion radical, hydrogen peroxide, nitric oxide, and hypochlorous acid (HClO) [17]. Due to the electron-deficient nature of halide ions, haloperoxyl radicals are significantly more reactive than the alkylperoxyl radical; accordingly, the trichloromethylperoxyl radical (CCl3OO) was found to be potently trapped by melatonin [85]. Not only melatonin but also several of its metabolites that are formed when it functions as a direct free radical scavenger, i.e., cyclic 3-hydroxymelatonin (c3OHM), AFMK, AMK, etc., are also radical scavengers [57, 86]. Melatonin and its metabolites work in a “task-division” way, with some of them acting mainly as free radical scavengers, while others act as metal chelating agents and inhibitors of the hydroxyl radical (OH) production [87]. The sequential scavenging of ROS by melatonin and its metabolites is known as melatonin’s antioxidant cascade [16]. The efficiency of AMK for scavenging ROS and preventing protein oxidation has been reported to be higher than that of AFMK. Therefore, it seems that at least in general, their protective activities against oxidative stress follow the order AMK > melatonin > AFMK [88] (Table 1).

ROS/RNS neutralized by melatonin and its metabolites Antioxidative enzymes that are stimulated by melatonin
Hydroxyl radical Superoxide dismutase
Hydrogen peroxide Glutathione peroxidase
Superoxide anion radical Catalase
Nitric oxide Glutathione reductase
Alkoxyl radical Glutamyl-cysteine ligase
Peroxynitrite Cyclooxygenase
Singlet oxygen Heme oxygenase
Hydrogen peroxide Nitric oxide synthase
Hypochlorous acid Paraoxonase
Others Myeloperoxidase

Table 1.

Antioxidant effects of melatonin and its metabolites [89].

4.1. Effects of melatonin and its metabolites on reactive oxygen species

Electron donation is the principal mechanism by which melatonin detoxifies the free radicals [17]. While melatonin has the capability of donating one or more electrons to free radicals resulting in their detoxification, the metabolites that are formed during this process, i.e., c3OHM, AFMK, and AMK, also have similar capabilities [90]. After donating an electron to OH, melatonin becomes a free radical itself, the indolyl radical cation. However, its reactivity is very low, and, therefore, it is not toxic to cells [41]. Oxidation of melatonin by hydroxyl radicals leads to several hydroxylated products which can be explained by interaction of melatonin with two hydroxyl radicals, one acting by hydrogen abstraction and the other by combining with the reaction partner especially, at the sides C2, C3, C6, and C7 [91].

6-Hydroxymelatonin (6OHM) is the major hepatic metabolite and photodegradation product of melatonin. It is an efficient metabolite for protecting against oxidative damage induced by UV irradiation. Due to its capability of scavenging 1O2 and O2•−, 6OHM can reduce neurotoxicity induced by quinolinic acid. It also lowers Fe(II)-induced neurotoxicity and iron-induced lipid peroxidation. It also inhibits the oxidative damage induced by this metal, UV radiation, thiobarbituric acid, and cyanide. It may be more efficient than melatonin in this capacity. Moreover, it inhibits oxidative stress induced by Cu+2-ascorbate mixtures and OH production by sequestering Cu+2 ions. 6OHM also protects DNA damage induced by Fenton reagents and UV radiation [84, 92].

It was showed that the main hydroxylated metabolite of melatonin interaction with hypochlorous acid is 2-hydroxymelatonin (2OHM). Subsequently, 2OHM and its keto tautomer, melatonin 2-indolinone, were the oxidative products of melatonin’s interaction with oxoferryl hemoglobin or OH [93]. 4-Hydroxymelatonin (4OHM) is an excellent peroxyl radical scavenger and also a preventing antioxidant by inhibiting Cu(II). This effect would reduce the Cu(I) availability, which is the redox state required for the OH to be formed, via Fenton-like reactions. 4OHM terminates the oxidant effects of copper-ascorbate mixtures. The key structural feature in the antioxidant activity of 4OHM is the presence of phenolic group, unlike 2OHM which has a relative low antioxidant protection [94]. 4OHM and 2OHM are generated during the UV-induced metabolism of melatonin. Further investigation needs to understand the antioxidant activity of these two compounds, as well as their potential role in protecting biomolecules against oxidative damage [87].

7-Hydroxymelatonin has been rarely considered, although the calculated activation energy for the respective reaction is as low as that for 6-hydroxylation. 3-Hydroxylation leads to an unusual compound cyclic 3-hydroxymelatonin (c3-OHM) [91]. c3-OHM is an intermediate metabolite of melatonin [16]. c3-OHM effectively scavenges OH, ABTS•+ (2,20-azino-bis(3-ethylbenzthiazoline-6-sulphonic acid)) [95], and peroxyl radicals [96] and can also chelate Cu(II), preventing its reduction and the consequent OH production via Fenton-like reactions [93, 97]. It is demonstrated that c3-OHM inhibits oxidative DNA damage and 8-OHdG lesions, induced by Fenton reagents, under in vitro conditions [98]. Indeed, c3-OHM is considered a footprint molecule, excreted in small amounts in the urine, and evidence of the in vivo scavenging activity of melatonin [41]. c3-OHM also undergoes oxidation resulting in the formation of AFMK [16, 77, 99].

AFMK is one of the metabolites of melatonin and can be formed by both enzymatic or pseudoenzymatic and nonenzymatic metabolic pathways [10, 88]. Pyrole ring cleavage of melatonin by varied enzymes including indoleamine 2,3-dioxygenase (IDO), myeloperoxidase (MPO), and hemoperoxidases, varied pseudoenzymatic catalysts such as oxoferryl hemoglobin and in varied reactions with ROS involving free radicals and singlet oxygen, generates AFMK [39, 88, 100]. Melatonin oxidation by MPO and IDO generally requires O2•− that produced in large amounts in inflammatory circumstances [100]. Besides, there are also multiple hydroxylations, which are formed in the peroxidase and peroxidase-like reactions and in the conversion of c3-OHM to AFMK [39]. Nonenzymatically, direct reaction of melatonin with highly reactive oxygen species (e.g., hydroxyl radical and singlet oxygen) formed AFMK [100]. The formation of AFMK by singlet oxygen deserves attention, as this reactive oxygen species is formed under the influence of UV light [101]. In light of these findings, it appears that AFMK is a product common to several interactions of melatonin with oxygen-based reactants [85]. The generation of AMK occurs via deformylation of AFMK [10, 16, 77]. These compounds are also major melatonin metabolites in detoxifying ROS and reducing oxidative stress [10, 16]. AFMK is obviously more stable than many other oxidative metabolites or its secondary product, AMK [39]. AFMK reduces lipid peroxidation and oxidative DNA damage induced by a variety of oxidative stressors under various conditions [16]. It protects neuronal cell from injuries caused by hydrogen peroxide and amyloid-β (Aβ) peptide [85, 88, 93]. It has been suggested that neuroprotection of AFMK against radiation-induced oxidative damage to the brain is due to its free radical scavenging function [88].

Lipid peroxidation is a natural metabolic process under normal aerobic conditions, and it is one of the most investigated consequences of ROS action on membrane structure and function [44]. Alterations in the fluidity of membranes result in negative effects on their functions such as signal transduction processes and implicate in aging as well as in diseases [102]. Melatonin is known to be a stabilizer or protector of cell and organelle membranes because of its inhibitory effects on lipid peroxidation. Melatonin and its metabolites scavenge free radicals and thus terminate the initiation and propagation of lipid peroxidation [103]. Although melatonin and its metabolites, AFMK and AMK, are peroxyl radical scavengers, it is indicated that melatonin’s ability to resist lipid peroxidation may also involve its metabolite, c3-OHM [104]. For the reaction with the peroxyl radical, c3-OHM was several orders of magnitude faster than melatonin, AFMK and AMK, and it was roughly 100-fold faster than water soluble vitamin E (Trolox) [96, 105]. Melatonin also directly scavenges the alkoxyl radical, a product resulting from the transition metal-catalyzed degradation of lipid peroxides. This is important for the control of lipid peroxidation since the alkoxyl radical can abstract a hydrogen atom from a polyunsaturated fatty acids; the resulting peroxyl radical can obviously continue the propagation of lipid degradation [104, 106].

4.2. Effects of melatonin and its metabolites on reactive nitrogen species

Reactive nitrogen species represent another category of potentially destructive substances, which react with melatonin [77]. ONOO itself is a very damaging species able to react with proteins, lipids, and DNA. Therefore, the reaction between two rather innocuous free radicals produces a much more reactive one [41]. Melatonin readily combines with a superoxide releasing NO, thus preventing the formation of peroxynitrite, a free radical even more harmful than NO. It has been described as a direct peroxynitrite scavenger [40].

Scavenging of nitric oxide by melatonin in a nitrosation reaction is well documented. Whether this can be regarded as a detoxification reaction keeping NO from forming, the more dangerous peroxynitrite is uncertain because nitrosomelatonin easily decomposes, thereby releasing NO. Melatonin also scavenges peroxynitrite, but it is difficult to discriminate direct reactions with peroxynitrite and with hydroxyl radicals generated by decomposition of peroxynitrous acid. The interaction with products from the peroxynitrite-CO2 adduct (ONOOCO2) which carbonate radicals (CO3•−) and NO2 seems to be more important than direct scavenging of peroxynitrite [33, 77]. There is evidence for the formation of cyclic 2-hydroxymelatonin, cyclic 3-hydroxymelatonin, and 6-hydroxymelatonin about the reaction of melatonin with ONOO. It was suggested that one electron is transferred from melatonin to ONOO in the melatonin +ONOO reaction and/or nitrated intermediates occur in the oxidation. In addition, the 6-hydroxymelatonin is not generated in the presence of CO2. Therefore, it was suggested that formation of 6-hydroxymelatonin required an activated peroxynitrite that can only exist in the absence of bicarbonate [41, 107, 108]. AFMK has the ability to interact with the ABTS cation radical as well as with ROS/RNS to form AMK. When AMK interacts with the ABTS cation radical or with ONOO, it forms products that may also be ROS and RNS scavengers [59]. AMK was described as better a NO scavenger than melatonin or AFMK [88]. AMK effectively inhibits neuronal nitric oxide synthase activity and reduces intracellular NO levels [93].

4.3. Effects of melatonin and its metabolites on antioxidant enzymes

Cells are protected against oxidative stress by an interacting network of antioxidant enzymes [70]. Antioxidative enzymes provide a major defense mechanism against free radical damage either by metabolizing them to less reactive species or to nontoxic by-products [85]. The activities of antioxidative enzymes depend on the duration and severity of oxidative stress. Under prolonged oxidative stress conditions, free radicals directly damage the antioxidant enzymes or reduce enzyme activities [90, 109]. Besides its ability to directly neutralize a number of free radicals and reactive oxygen and nitrogen species, melatonin stimulates several antioxidative enzymes which increase its efficiency as an antioxidant [58]. The major antioxidative enzymes such as intracellular superoxide dismutases (CuZn-SOD and Mn-SOD), the selenium-containing glutathione peroxidases and catalase, are stimulated by melatonin under basal conditions [43, 75, 110]. Melatonin plays a significant role in maintaining indirect protection versus free radical injury by stimulating gene expression of antioxidant enzymes including those for SOD and GSH-Px [43, 58, 62, 111]. Melatonin affects both antioxidant enzyme activity and cellular mRNA levels for these enzymes under physiological circumstances and during increased oxidative stress, presumably through epigenetic mechanisms. These properties in a single molecule are unique for an antioxidant, and both actions protect against pathologically generated free radicals [43, 62].

The concentration of the intracellular antioxidant, glutathione, is very high in many cells. During high oxidative stress conditions total glutathione levels can be reduced [90]. Melatonin maintains the activities of enzymes that enhance intracellular levels of reduced GSH. The recycling of GSH may well be a major effect of melatonin in reducing oxidative stress. GSH is oxidized to its disulfide, GSSG, which is then quickly reduced back to GSH by GR, an enzyme which has been demonstrated to be stimulated by melatonin. The ability of melatonin to regulate the GSH/GSSG balance by modulating enzyme activities seems to involve an action of melatonin at a nuclear binding site [85, 112]. The other GSH-metabolizing enzyme, i.e., CAT, also increases its activity in response to melatonin [85]. Furthermore, one of the melatonin actions is stimulation of gamma-glutamylcysteine synthetase that is the rate-limiting enzyme in glutathione production, thus glutathione levels do not drop significantly [36, 43, 58, 75, 77, 85, 86, 90, 110, 112, 113].

There are a number of prooxidative enzymes in multicellular organisms which generate free radicals [90]. Melatonin not only upregulates the expression of genes involved in detoxifying free radicals, but it also suppresses the activity or expression of genes involved in the generation of free radicals [16, 113]. Melatonin inhibits the prooxidative enzyme nitric oxide synthase which generates NO and lipoxygenase which result in the formation of the superoxide anion [90, 113, 114]. Although NO is not a strong free radical, when it couples with O2•−, it forms the peroxynitrite anion which is potently reactive and damaging [90]. Lipoxygenase reaction is another possible source of ROS and other radicals. It catalyzes the hydroperoxidation of polyunsaturated fatty acids [115]. The prooxidative enzymes inhibited by melatonin also include myeloperoxidase and eosinophil peroxidase [110]. As a result,free radical and/or toxic reactant generation is alleviated [90, 114]. In addition, AFMK and AMK also have the ability to downregulate prooxidative and pro-inflammatory enzymes including iNOS [102] and cyclooxygenase-2 (COX-2) and to carry out free radical avoidance functions [93].

4.4. Effects of melatonin and its metabolites on the mitochondria

Mitochondria are critical in the control of metabolism and responsible for orchestrating cellular energy production. Therefore, they are central to the maintenance of life and the gatekeepers of cell death [116]. The production of energy in the form of ATP is crucial to optimal cell function, including aiding in repairing any cellular damage that has occurred and in improving survivability of the cell, of the tissue, and of the organism [90]. Up to 95% of the ATP produced in aerobic cells is a result of mitochondrial oxidative phosphorylation [59]. The ETC which is coupled to oxidative phosphorylation [59] is a system of oxidoreductase protein complexes (complexes I, II, III, and IV) [85]. Deficiencies in the ETC can result in the leakage of electrons which thereafter generate free radicals and other toxic reactants which leads to molecular damage in mitochondria; this damage culminates in and promotes what are referred to as mitochondria-related diseases [85]. Mitochondria are the primary source of free radicals [44, 45]. Increased free radical generation, enhanced mitochondrial iNOS activity, enhanced NO production, decreased respiratory complex activity, impaired electron transport system, and opening of mitochondrial permeability transition pores have all been suggested as factors responsible for impaired mitochondrial function [117].

Melatonin has important actions at the level of mitochondria [85]. Melatonin exhibits remarkable functional versatility to protect the morphological and functional aspects of the cell membrane scavenging free radicals, enhancing the activity of the antioxidant enzymes, and optimizing the transfer of electrons through the ETC in the inner mitochondrial membrane [118]. Melatonin increases the efficiency of the ETC and thus reduces electron leakage and free radical generation [38, 75, 105] that is a consequence of the respiratory process by stimulating complex I and complex IV of the mitochondrial respiratory chain that are involved in oxidative phosphorylation [38, 58, 59, 118]. By directly detoxifying ROS/RNS, melatonin enhances ATP production via maintaining high levels of mitochondrial GSH, protects mitochondrial proteins and DNA from oxidative damage, and improves ETC activity [16, 90, 118]. Moreover, AMK, like its precursor melatonin, promotes mitochondrial complex I activity to elevate ATP production by lowering electron leakage and inhibiting the opening of the mitochondrial permeability transition pore [93].

4.5. Effects of melatonin and its metabolites on transition metals

Heavy metals are known to cause oxidative deterioration of biomolecules by initiating free radical-mediated chain reaction resulting in lipid peroxidation, protein oxidation, and oxidation of nucleic acid like DNA and RNA [119]. The ability of antioxidants to chelate and deactivate transition metals prevents such metals from participating in the initiation of lipid peroxidation and oxidative stress through metal-catalyzed reaction [120]. Chemical mean of inhibiting metal-induced oxidation is chelation. This particular process is directly involved in the OH-inactivating ligand (OIL) behavior of antioxidants. There are two different ways of action in the protection exerted by OIL species against OH-induced oxidative damage: (i) inhibiting the reduction of metal ions; thus, their reduced forms are not available for Fenton-like reactions or (ii) deactivating OH after being produced by Fenton-like reactions [87].

Melatonin is able to prevent the oxidative actions of metals by neutralizing the produced ROS and capturing such metals to form chelates [83]. It was demonstrated that the interplay of melatonin with metals such as aluminum, cadmium, copper, iron, lead, and zinc depended on concentration. Melatonin chelates both iron(III) and iron(II), which is the form that attends the Fenton reaction. If iron is bound to a protein (e.g., hemoglobin), melatonin restores the highly covalent iron such as oxyferryl (FeIV-O) hemoglobin back to iron(III), thereby reestablishing the biological activity of the protein [89]. It is suggested that, under physiological circumstances, direct chelation mechanism would be the major chelation route for Cu(II). It was demonstrated that melatonin and its metabolites, 3OHM, AFMK, and AMK, fully inhibited the oxidative stress induced by Cu(II)-ascorbate mixtures, via Cu(II) chelation [97]. Melatonin decreases the Cu(II)/H2O2-induced damage to proteins and protects against copper-mediated lipid peroxidation, which led to the suggestion that the antioxidant and neuroprotective effects of melatonin may involve removing toxic metals from the central nervous system [42].


5. Melatonin and its metabolites as anti-inflammatory agents

Inflammation is an essential response to tissue injuries induced by physical, chemical, or biological insults [17]. The production of inflammatory cytokines including TNF-α (tumor necrosis factor-α), IL-1β (interleukin-1β), or IL-6 attenuates by melatonin in numerous experimental models of inflammation [2]. Melatonin has several additional anti-inflammatory effects, which are probably related to a direct interaction with specific binding sites located in lymphocytes and macrophages [103]. Anti-inflammatory activity of melatonin includes inhibition of the activation of COX-2 and iNOS, as well as blocking of the transcriptional factors that triggers pro-inflammatory cytokine production. These include not only NF-кB but also HIF, Nrf2, cAMP, CREB, STAT, PPARs, and AP-1 [2, 43, 121]. Melatonin may be useful for the treatment of inflammatory disease, as it reduces inflammatory injury by blocking transcription factors and NF-κB, thereby decreasing further ROS formation within cells [43]. In peripheral monocytes, melatonin and, even more, AFMK suppressed TNF-α and IL-8 production and, in macrophages, COX-2 and iNOS expression. Moreover, melatonin was found to be efficiently oxidized to AFMK by macrophages [91]. AMK was reported to downregulate COX-2—but not COX-1—expression in macrophages, an effect shared by its precursors AFMK and melatonin [122].


6. The clinical significance of melatonin

Melatonin plays important roles in neurogenesis, neuroprotection, maintenance of oxidant/antioxidant balance, and modulation of cardiovascular and/or immune system. It also exerts a direct antioxidant effect on tissues/organs and antiapoptotic effects on cells [9]. Melatonin has been investigated in a wide range of diseases, such as neurodegenerative, cardiovascular, liver, and kidney diseases, cancer, and diabetes [43].

Melatonin is a ubiquitously acting direct free radical scavenger and also an indirect antioxidant. Melatonin and its metabolites are efficient in scavenging ROS and RNS. It plays an effective role in regulating mitochondrial homeostasis [33, 38]. Mitochondrial dysfunction, i.e., cell energy impairment, apoptosis, and overproduction of ROS, is a final common pathogenic mechanism in aging and in neurodegenerative disease [43, 123]. Melatonin may be possible to treat neurodegenerative disorders by inhibiting mitochondrial cell death pathways. It may easily protect brain mitochondrial membranes from free radical attack, stabilizing them. The ability of melatonin to prevent GSH loss probably reflects its effect on the activities of the GSH redox cycle enzymes [33, 38, 83, 103]. Moreover, several neurological diseases including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and Wilson’s disease (hepatolenticular degeneration) are characterized by an overload of copper and/or other metals. Melatonin and its metabolites, c3OHM, AFMK, and AMK, have the copper sequestering ability [89].

Excessive and/or sustained increase in ROS generation plays a pivotal role in the initiation, progression, and clinical consequences of cardiovascular diseases (CVDs) [64, 124]. Clinically, melatonin is being increasingly recognized in the pathophysiology of CVD. Low levels of serum melatonin as well as its urinary metabolite, 6-sulphatoxymelatonin, have been reported in various CVDs including coronary heart disease, angina, congestive heart failure, and myocardial infarcts [125]. Melatonin plays an important role in the regulation of several parameters of the cardiovascular system, including blood pressure, and is considered to be a putative antihypertensive agent [126]. It may have cardio-protective properties via its direct free radical scavenger activity and its indirect antioxidant activity together with its significant anti-inflammatory properties [127, 128]. Mitochondrial respiration, mainly at the level of complex I and complex III, is an important source of ROS generation and hence a potential contributor of cardiac reperfusion injury [129]. Most of the beneficial actions of melatonin at the heart level may depend on its effect on mitochondrial bioenergetics mediated through various mechanisms including general antioxidant actions at the level of ETC dysfunction, electron leakage, and mitochondrial oxidative damage and also through a direct action of melatonin on mitochondrial permeability transition pore opening [127]. It was reported that melatonin protects against mitochondrial dysfunction associated with cardiac ischemia reperfusion, by preventing alterations to several parameters involved in mitochondrial bioenergetics [17].

Melatonin may also exhibit anticancer and protective oncostatic activity through several mechanisms, including inhibition of cancer cell proliferation, decrease in oxidative stress, and increase in immune system activity [130, 131]. Oxidative stress has complex and different effects on each type of cancer development [132]. Oxidation of cellular lipids and proteins can adversely affect several steps of the carcinogenic process through changes in a variety of cell regulatory functions, including signal transduction and gene expression. ROS are postulated to be involved in carcinogenesis process, especially in the stages of initiation and promotion [133]. It appears that the DNA damage is predominantly linked with the initiation process [132]. Free radicals and ROS generated by environmental carcinogens, or by metabolic alterations, cause DNA damage and genetic instability [134]. Furthermore, DNA damage, apoptosis resistance, enhanced proliferation, mutation, COX-2 upregulation, oxidative stress, tumor vascularity, and metastatic potential may be caused by nitric oxide synthase overexpression and increased nitric oxide and other RNS productions [132]. A growing body of evidence implicates melatonin’s antioxidant/free radical scavenging actions in the inhibition of cancer development and growth [75]. Melatonin is a powerful scavenger of ROS, such as hydroxyl radical, peroxyl radical, singlet oxygen, and nitric oxide, as well as a stimulator of the antioxidant enzymes, SOD, GPx, and CAT, all leading to a decrease in DNA damage [135]. Additionally, this indole stimulates antioxidant enzymes that remove ROS before they can inflict damage and aids in the repair of damaged DNA [136]. Melatonin could be an excellent candidate for the prevention and treatment of several cancers, such as breast cancer, prostate cancer, gastric cancer, and colorectal cancer [137].

A variety of antioxidants protect the liver from free radical-mediated damage, one of the best of which is melatonin. Clinical studies have confirmed that melatonin protects the liver from nonalcoholic liver disease and also during the surgical procedure of partial liver resection [138]. Melatonin is a well-known natural antioxidant and has many bioactivities. Melatonin exerts antioxidant effects in hepatocytes and epithelium of the liver by reducing lipid peroxidation and increasing the level of reduced liver glutathione. Melatonin is a highly valuable OH and H2O2 scavenger, during its metabolism to AFMK. It also induces several antioxidative enzymes such as glutathione peroxidase, glutathione reductase, and SOD and increases the synthesis of GSH [2, 88]. Melatonin exhibits potent anti-inflammatory, antioxidant, and fibrosuppressive activities against thioacetamide-induced hepatic fibrogenesis via the suppression of oxidative stress, DNA damage, pro-inflammatory cytokines, and fibrogenic gene transcripts [139]. Melatonin protects against lipid-induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice [140].

Inflammation and increased oxidative stress are also common features in chronic kidney disease patients [130, 141]. Oxidative stress and inflammation promote renal injury via damage to molecular components of the kidney by different mechanisms of action. ROS lead to the loss of significant functional properties, lipid peroxidation of cell membrane, decrease membrane viability, and cleavage, and cross-linking of renal DNA occurs leading to harmful mutations by oxidizing amino acids in the nephron. Furthermore, other ROS interactions in the nephron increase secondary radical production [130, 142]. Diabetes-associated hyperglycemia leads to mitochondrial ETC dysfunction culminating in a rise in ROS production [143]. Experimental evidence suggests that the indoleamine hormone melatonin is capable of influencing in development of diabetic complications by neutralizing the unnecessary ROS generation and protection of beta cells, as they possess low antioxidant potential and normalize redox state in the cell [144]. Melatonin acts as a cell survival agent by modulating autophagy in various cell types and under different conditions through amelioration of oxidative stress, ER stress, and inflammation [143].


7. Conclusion

Melatonin is a circulating neurohormone secreted predominantly at night, thereby called as hormone of darkness. It can cross all physiological barriers to exert widespread regulatory effects on body tissues. Melatonin is a universal antioxidant with multifunctional activities such as anti-inflammatory, antiapoptotic, and antioxidant effects in addition to its function as a synchronizer of the biological clock and seasonal reproduction. Melatonin and its derivatives have been shown to be powerful direct free radical scavengers. Besides direct scavenging of ROS/RNS, melatonin also stimulates antioxidant enzymes; suppresses prooxidant enzymes; improves mitochondrial function, hence reducing radical formation; and reduces metal-induced toxicity. Results from previous studies support these effects on several diseases including cancer, diabetes, neurodegenerative, cardiovascular, liver; and kidney diseases.


Conflict of interest

The authors do not have any conflict of interest to declare.


  1. 1. Lerner AB, Case JD, Takahashi Y. Isolation of melatonin, a pineal factor that lightens melanocytes. Journal of the American Chemical Society. 1958;80:2587
  2. 2. Eghbal MA, Eftekhari A, Ahmadian E, Yadollah Azarmi Y, Parvizpur A. A review of biological and pharmacological actions of melatonin: Oxidant and prooxidant properties. Pharmaceutical Bioprocessing. 2016;4(4):069-081
  3. 3. Comai S, Gobbi G. Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: A novel target in psychopharmacology. Journal of Psychiatry & Neuroscience. 2014;39(1):6-21
  4. 4. Yin J, Jin X, Shan Z, Li S, Huang H, Li P, Peng X, Peng Z, Yu K, Bao W, Yang W, Chen X, Liu L. Relationship of sleep duration with all-cause mortality and cardiovascular events: A systematic review and dose-response meta-analysis of prospective cohort studies. Journal of the American Heart Association. 2017;6(9):1-15
  5. 5. Altman NG, Izci-Balserak B, Schopfer E, Jackson N, Rattanaumpawan P, Gehrman PR, Patel NP, Grandner MA. Sleep duration versus sleep insufficiency as predictors of cardiometabolic health outcomes. Sleep Medicine. 2012;13(10):1261-1270
  6. 6. Cappuccio FP, Cooper D, D'Elia L, Strazzullo P, Miller MA. Sleep duration predicts cardiovascular outcomes: A systematic review and meta-analysis of prospective studies. European Heart Journal. 2011;32(12):1484-1492
  7. 7. Pandi-Perumal SR, Trakht I, Srinivasan V, Spence DW, Maestroni GJ, Zisapel N, Cardinali DP. Physiological effects of melatonin: Role of melatonin receptors and signal transduction pathways. Progress in Neurobiology. 2008;85(3):335-353
  8. 8. Emet M, Ozcan H, Ozel L, Yayla M, Halici Z, Hacimuftuoglu A. A review of melatonin, its receptors and drugs. Eurasian Journal of Medicine. 2016;48:135-141
  9. 9. Onaolapo OJ, Onaolapo AY. Melatonin, adolescence, and the brain: An insight into the period-specific influences of a multifunctional signaling molecule. Birth Defects Research. 2017;109(20):1659-1671
  10. 10. Singh M, Jadhav HR. Melatonin: Functions and ligands. Drug Discovery Today. 2014;19(9):1410-1418
  11. 11. Kubatka P, Zubor P, Busselberg D, Kwon TK, Adamek M, Petrovic D, Opatrilova R, Gazdikova K, Caprnda M, Rodrigo L, Danko J, Kruzliak P. Melatonin and breast cancer: Evidences from preclinical and human studies. Critical Reviews in Oncology/Hematology. 2018;122:133-143
  12. 12. Rios ER, Venâncio ET, Rocha NF, Woods DJ, Vasconcelos S, Macedo D, Sousa FC, Fonteles MM. Melatonin: Pharmacological aspects and clinical trends. The International Journal of Neuroscience. 2010;120(9):583-590
  13. 13. Peuhkuri K, Sihvola N, Korpela R. Dietary factors and fluctuating levels of melatonin. Food & Nutrition Research. 2012;56:1-9
  14. 14. Konturek SJ1, Konturek PC, Brzozowska I, Pawlik M, Sliwowski Z, Cześnikiewicz-Guzik M, Kwiecień S, Brzozowski T, Bubenik GA, Pawlik WW. Localization and biological activities of melatonin in intact and diseased gastrointestinal tract (GIT). Journal of Physiology and Pharmacology. 2007;58(3):381-405
  15. 15. Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, Fougerou C. Melatonin: Pharmacology, functions and therapeutic benefits. Current Neuropharmacology. 2017;15(3):434-443
  16. 16. Zhang HM, Zhang Y. Melatonin: A well-documented antioxidant with conditional pro-oxidant actions. Journal of Pineal Research. 2014;57(2):131-146
  17. 17. Anwar MJ, Muhammad BY, Bader AA, Abdulghani M, Mahmood D, Haider M. An insight into the scientific background and future perspectives for the potential uses of melatonin. Egyptian Journal of Basic and Applied Sciences. 2015;2:139-152
  18. 18. Masters A, Pandi-Perumal SR, Seixas A, Girardin JL, McFarlane SI. Melatonin, the hormone of darkness: From sleep promotion to ebola treatment. Brain Disorders and Therapy. 2014;4(1):1-10
  19. 19. Karasek M, Winczyk K. Melatonin in humans. Journal of Physiology and Pharmacology. 2006;57(5):19-39
  20. 20. Tan DX, Manchester LC, Esteban-Zubero E, Zhou Z, Reiter RJ. Melatonin as a potent and inducible endogenous antioxidant: Synthesis and metabolism. Molecules. 2015;20(10):18886-18906
  21. 21. Pevet P, Challet E. Melatonin: Both master clock output and internal time-giver in the circadian clocks network. Journal of Physiology, Paris. 2011;105(4-6):170-182
  22. 22. Bedrosian TA, Herring KL, Walton JC, Fonken LK, Weil ZM, Nelson RJ. Evidence for feedback control of pineal melatonin secretion. Neuroscience Letters. 2013;542:123-125
  23. 23. Maitra S, Baidya DK, Khanna P. Melatonin in perioperative medicine: Current perspective. Saudi Journal of Anaesthesia. 2013;7(3):315-321
  24. 24. De Almeida EA, Di Mascio P, Harumi T, Spence DW, Moscovitch A, Hardeland R, Cardinali DP, Brown GM, Pandi-Perumal SR. Measurement of melatonin in body fluids: Standards, protocols and procedures. Child's Nervous System. 2011;27(6):879-891
  25. 25. Ren W, Liu G, Chen S, Yin J, Wang J, Tan B, Wu G, Bazer FW, Peng Y, Li T, Reiter RJ, Yin Y. Melatonin signaling in T cells: Functions and applications. Journal of Pineal Research. 2017;62(3):1-15
  26. 26. Zawilska JB, Skene DJ, Arendt J. Physiology and pharmacology of melatonin in relation to biological rhythms. Pharmacological Reports. 2009;61(3):383-410
  27. 27. Slominski RM, Reiter RJ, Schlabritz-Loutsevitch N, Ostrom RS, Slominski AT. Melatonin membrane receptors in peripheral tissues: Distribution and functions. Molecular and Cellular Endocrinology. 2012;351(2):152-166
  28. 28. Chattoraj A, Liu T, Zhang LS, Huang Z, Borjigin J. Melatonin formation in mammals: In vivo perspectives. Reviews in Endocrine & Metabolic Disorders. 2009;10(4):237-243
  29. 29. Malhotra S, Sawhney G, Pandhi P. The therapeutic potential of melatonin: A review of the science. Medscape General Medicine. 2004;6(2):1-45
  30. 30. Mahmood D, Muhammad BY, Alghani M, Anwar J, el-Lebban N, Haider M. Advancing role of melatonin in the treatment of neuropsychiatric disorders. Egyptian journal of basic and applied sciences. 2016;3:203-218
  31. 31. Liu J, Clough SJ, Hutchinson AJ, Adamah-Biassi EB, Popovska-Gorevski M, Dubocovich ML. MT1 and MT2 melatonin receptors: A therapeutic perspective. Annual Review of Pharmacology and Toxicology. 2016;56:361-383
  32. 32. Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, Cecon E, Zlotos DP. Update on melatonin receptors: IUPHAR review 20. British Journal of Pharmacology. 2016;173(18):2702-2725
  33. 33. Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR. Melatonin—A pleiotropic, orchestrating regulator molecule. Progress in Neurobiology. 2011;93(3):350-384
  34. 34. Mailliet F, Ferry G, Vella F, Berger S, Cogé F, Chomarat P, Mallet C, Guénin SP, Guillaumet G, Viaud-Massuard MC, Yous S, Delagrange P, Boutin JA. Characterization of the melatoninergic MT3 binding site on the NRH:Quinone oxidoreductase 2 enzyme. Biochemical Pharmacology. 2005;71(1-2):74-88
  35. 35. Ekmekcioglu C. Melatonin receptors in humans: Biological role and clinical relevance. Biomedicine & Pharmacotherapy. 2006;60:97-108
  36. 36. Najafi M, Shirazi A, Motevaseli E, Geraily G, Norouzi F, Heidari M, Rezapoor S. The melatonin immunomodulatory actions in radiotherapy. Biophysical Reviews. 2017;9(2):139-148
  37. 37. Rodriguez C, Mayo JC, Sainz RM, Antolín I, Herrera F, Martín V, Reiter RJ. Regulation of antioxidant enzymes: A significant role for melatonin. Journal of Pineal Research. 2004;36(1):1-9
  38. 38. Srinivasan V, Spence DW, Pandi-Perumal SR, Brown GM, Cardinali DP. Melatonin in mitochondrial dysfunction and related disorders. International Journal of Alzheimer's Disease. 2011;2011:326320
  39. 39. Hardeland R, Tan DX, Reiter RJ. Kynuramines, metabolites of melatonin and other indoles: The resurrection of an almost forgotten class of biogenic amines. Journal of Pineal Research. 2009;47(2):109-126
  40. 40. Loren P, Sánchez R, Arias ME, Felmer R, Risopatrón J, Cheuquemán C. Melatonin scavenger properties against oxidative and Nitrosative stress: Impact on gamete handling and in vitro embryo production in humans and other mammals. International Journal of Molecular Sciences. 2017;18(6):1-17
  41. 41. Galano A, Tan DX, Reiter RJ. Melatonin as a natural ally against oxidative stress: A physicochemical examination. Journal of Pineal Research. 2011;51:1-16
  42. 42. Galano A, Castañeda-Arriaga R, Pérez-González A, Tan DX, Reiter RJ. Phenolic melatonin-related compounds: Their role as chemical protectors against oxidative stress. Molecules. 2016;21(11):1-42
  43. 43. Bonnefont-Rousselot D, Collin F. Melatonin: Action as antioxidant and potential applications in human disease and aging. Toxicology. 2010;278(1):55-67
  44. 44. Kohen R, Nyska A. Oxidation of biological systems: Oxidative stress phenomena, antioxidants, redox reactions, and methods for their quantification. Toxicologic Pathology. 2002;30(6):620-650
  45. 45. Rahal A, Kumar A, Singh V, Yadav B, Tiwari R, Chakraborty S, Dhama K. Oxidative stress, prooxidants, and antioxidants: The interplay. BioMed Research International. 2014;2014:761264
  46. 46. Kurutas EB. The importance of antioxidants which play the role in cellular response against oxidative/nitrosative stress: Current state. Nutrition Journal. 2016;15(71):1-22
  47. 47. Patel M, Ramavataram DV. Non transferrin bound iron: Nature, manifestations and analytical approaches for estimation. Indian Journal of Clinical Biochemistry Indian. 2012;27(4):322-332
  48. 48. Łuczaj W, Gęgotek A1, Skrzydlewska E. Antioxidants and HNE in redox homeostasis. Free Radical Biology & Medicine. 2017;111:87-101
  49. 49. Mirończuk-Chodakowska I, Witkowska AM, Zujko ME. Endogenous non-enzymatic antioxidants in the human body. Advances in Medical Sciences. 2018;63(1):68-78
  50. 50. Peyrot F, Ducrocq C. Potential role of tryptophan derivatives in stress responses characterized by the generation of reactive oxygen and nitrogen species. Journal of Pineal Research. 2008;45(3):235-246
  51. 51. Poljsak B, Šuput D, Milisav I. Achieving the balance between ROS and antioxidants: When to use the synthetic antioxidants. Oxidative Medicine and Cellular Longevity. 2013;2013(956792):1-11
  52. 52. Ray PD, Huang BW, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cellular Signalling. 2012;24(5):981-990
  53. 53. Zorov DB, Juhaszova M, Sollott SJ. Mitochondrial reactive oxygen species (ROS) and ROS-induced ROS release. Physiological Reviews. 2014;94(3):909-950
  54. 54. Sarangarajan R, Meera S, Rukkumani R, Sankar P, Anuradha G. Antioxidants: Friend or foe? Asian Pacific Journal of Tropical Medicine. 2017;10(12):1111-1116
  55. 55. Weydert CJ, Cullen JJ. Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue. Nature Protocols. 2010;5(1):51-66
  56. 56. Wołonciej M, Milewska E, Roszkowska-Jakimiec W. Trace elements as an activator of antioxidant enzymes. Postȩpy Higieny i Medycyny Doświadczalnej. 2016;70:1483-1498
  57. 57. Reiter RJ, Tan DX, Gitto E, Sainz RM, Mayo JC, Leon J, Manchester LC, Vijayalaxmi KE, Kilic U. Pharmacological utility of melatonin in reducing oxidative cellular and molecular damage. Polish Journal of Pharmacology. 2004;56(2):159-170
  58. 58. Reiter RJ, Tan DX, Osuna C, Gitto E. Actions of melatonin in the reduction of oxidative stress. A review. Journal of Biomedical Science. 2000;7(6):444-458
  59. 59. Reiter RJ, Paredes SD, Korkmaz A, Jou MJ, Tan DX. Melatonin combats molecular terrorism at the mitochondrial level. Interdisciplinary Toxicology. 2008;1(2):137-149
  60. 60. Bouayed J, Bohn T. Exogenous antioxidants–Double-edged swords in cellular redox state: Health beneficial effects at physiologic doses versus deleterious effects at high doses. Oxidative Medicine and Cellular Longevity. 2010;3(4):228-237
  61. 61. Hacışevki A. An overview of ascorbic acid biochemistry. Journal of Faculty of Pharmacy of Ankara University. 2009;38(3):235-257
  62. 62. Korkmaz A, Reiter RJ, Topal T, Manchester LC, Oter S, Tan DX. Melatonin: An established antioxidant worthy of use in clinical trials. Molecular Medicine. 2009;15(1-2):43-50
  63. 63. Ryan MJ, Dudash HJ, Docherty M, Geronilla KB, Baker BA, Haff GG, Cutlip RG, Alway SE. Vitamin E and C supplementation reduces oxidative stress, improves antioxidant enzymes and positive muscle work in chronically loaded muscles of aged rats. Experimental Gerontology. 2010;45(11):882-895
  64. 64. Hacışevki A, Torun M, Çengel A. Effect of short-term α-tocopherol supplementation on biomarkers of oxidative stress and antioxidant defence in subject with angina pectoris. Oxidation Communications. 2012;35(1):128-137
  65. 65. Schmölz L, Birringer M, Lorkowski S, Wallert M. Complexity of vitamin E metabolism. World Journal of Biological Chemistry. 2016;7(1):14-43
  66. 66. Schubert M, Kluge S, Schmölz L, Wallert M, Galli F, Birringer M, Lorkowski S. Long-chain metabolites of vitamin E: Metabolic activation as a general concept for lipid-soluble vitamins? Antioxidants (Basel). 2018;7(1):1-54
  67. 67. Bozkır A, Şimşek B, Güngör A, Torun M. Ascorbic acid and uric acid levels in lung cancer patients. Journal of Clinical Pharmacy and Therapeutics. 1999;24:43-47
  68. 68. Pullar JM, Bayer S, Carr AC. Appropriate handling, processing and analysis of blood samples is essential to avoid oxidation of vitamin C to dehydroascorbic acid. Antioxidants (Basel). 2018;7(2):1-26
  69. 69. Rahman K. Studies on free radicals, antioxidants, and co-factors. Clinical Interventions in Aging. 2007;2(2):219-236
  70. 70. Lobo V, Patil A, Phatak A, Chandra N. Free radicals, antioxidants and functional foods: Impact on human health. Pharmacognosy Reviews. 2010;4(8):118-126
  71. 71. Galano A. Free radicals induced oxidative stress at a molecular level: The current status, challenges and perspectives of computational chemistry based protocols. Journal of the Mexican Chemical Society. 2015;59(4):231-262
  72. 72. Rose RC, Bode AM. Biology of free radical scavengers: An evaluation of ascorbate. The FASEB Journal 1993;7(12):1135-1142
  73. 73. Tamura H, Takasaki A, Taketani T, Tanabe M, Kizuka F, Lee L, Tamura I, Maekawa R, Aasada H, Yamagata Y, Sugino N. The role of melatonin as an antioxidant in the follicle. Journal of Ovarian Research. 2012;5:1-9
  74. 74. Tan DX, Manchester LC, Reiter RJ, Qi WB, Karbownik M, Calvo JR. Significance of melatonin in antioxidative defense system: Reactions and products. Biological Signals and Receptors. 2000;9(3-4):137-159
  75. 75. Anisimov VN, Popovich IG, Zabezhinski MA, Anisimov SV, Vesnushkin GM, Vinogradova IA. Melatonin as antioxidant, geroprotector and anticarcinogen. Biochimica et Biophysica Acta. 2006;1757(5-6):573-589
  76. 76. Johns JR, Platts JA. Theoretical insight into the antioxidant properties of melatonin and derivatives. Organic & Biomolecular Chemistry. 2014;12(39):7820-7827
  77. 77. Hardeland R, Pandi-Perumal SR. Melatonin, a potent agent in antioxidative defense: Actions as a natural food constituent, gastrointestinal factor, drug and prodrug. Nutrition & Metabolism (London). 2005;2(22):1-42
  78. 78. Swarnakar S, Paul S, Singh LP, Reiter RJ. Matrix metalloproteinases in health and disease: Regulation by melatonin. Journal of Pineal Research. 2011;50(1):8-20
  79. 79. Vázquez J, González B, Sempere V, Mas A, Torija MJ, Beltran G. Melatonin reduces oxidative stress damage induced by hydrogen peroxide in Saccharomyces cerevisiae. Frontiers in Microbiology. 2017;8:1066, 1-14
  80. 80. Kratz EM, Piwowar A. Melatonin, advanced oxidation protein products and total antioxidant capacity as seminal parameters of prooxidant-antioxidant balance and their connection with expression of metalloproteinases in context of male fertility. Journal of Physiology and Pharmacology. 2017;68(5):659-668
  81. 81. Bisquert R, Muñiz-Calvo S, Guillamón JM. Protective role of intracellular melatonin against oxidative stress and UV radiation in Saccharomyces cerevisiae. Frontiers in Microbiology. 2018;9(318):1-11
  82. 82. Gitto E, Aversa S, Reiter RJ, Barberi I, Pellegrino S. Update on the use of melatonin in pediatrics. Journal of Pineal Research. 2011;50:21-28
  83. 83. Romero A, Ramos E, de Los Ríos C, Egea J, Del Pino J, Reiter RJ. A review of metal-catalyzed molecular damage: Protection by melatonin. Journal of Pineal Research. 2014;56(4):343-370
  84. 84. Aydogan S, Yerer MB, Goktas A. Melatonin and nitric oxide. Journal of Endocrinological Investigation 2006;29(3):281-287
  85. 85. Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J, Czarnocki Z. Melatonin as an antioxidant: Biochemical mechanisms and pathophysiological implications in humans. Acta Biochimica Polonica. 2003;50(4):1129-1146
  86. 86. Reiter RJ, Tan DX, Korkmaz A, Rosales-Corral SA. Melatonin and stable circadian rhythms optimize maternal, placental and fetal physiology. Human Reproduction Update. 2014;20(2):293-307
  87. 87. Galano A, Tan DX, Reiter RJ. Melatonin: A versatile protector against oxidative DNA damage. Molecules. 2018;23(3):1-36
  88. 88. Galano A, Tan DX, Reiter RJ. On the free radical scavenging activities of melatonin's metabolites, AFMK and AMK. Journal of Pineal Research. 2013;54(3):245-257
  89. 89. Reiter RJ, Mayo JC, Tan DX, Sainz RM, Alatorre-Jimenez M, Qin L. Melatonin as an antioxidant: Under promises but over delivers. Journal of Pineal Research. 2016;61(3):253-278
  90. 90. Reiter RJ, Tan DX, Manchester LC, Pilar Terron M, Flores LJ, Koppisepi S. Medical implications of melatonin: Receptor-mediated and receptor-independent actions. Advances in Medical Sciences. 2007;52:11-28
  91. 91. Hardeland R. Melatonin metabolism in the central nervous system. Current Neuropharmacology. 2010;8(3):168-181
  92. 92. Álvarez-Diduk R, Galano A, Tan DX, Reiter RJ. N-acetylserotonin and 6-hydroxymelatonin against oxidative stress: Implications for the overall protection exerted by melatonin. The Journal of Physical Chemistry. 2015;119(27):8535-8543
  93. 93. Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ. One molecule, many derivatives: A never-ending interaction of melatonin with reactive oxygen and nitrogen species? Journal of Pineal Research. 2007;42(1):28-42
  94. 94. Pérez-González A, Galano A, Alvarez-Idaboy JR, Tan DX, Reiter RJ. Radical-trapping and preventive antioxidant effects of 2-hydroxymelatonin and 4-hydroxymelatonin: Contributions to the melatonin protection against oxidative stress. Biochimica et Biophysica Acta. 2017;1861(9):2206-2217
  95. 95. Tan DX, Hardeland R, Manchester LC, Poeggeler B, Lopez-Burillo S, Mayo JC, Sainz RM, Reiter RJ. Mechanistic and comparative studies of melatonin and classic antioxidants in terms of their interactions with the ABTS cation radical. Journal of Pineal Research. 2003;34(4):249-259
  96. 96. Galano A, Tan DX, Reiter RJ. Cyclic 3-hydroxymelatonin, a key metabolite enhancing the peroxyl radical scavenging activity of melatonin. RSC Advances. 2014;4:5220-5227
  97. 97. Galano A, Medina ME, Tan DX, Reiter RJ. Melatonin and its metabolites as copper chelating agents and their role in inhibiting oxidative stress: A physicochemical analysis. Journal of Pineal Research. 2015;58(1):107-116
  98. 98. López-Burillo S, Tan DX, Rodriguez-Gallego V, Manchester LC, Mayo JC, Sainz RM, Reiter RJ. Melatonin and its derivatives cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine and 6-methoxymelatonin reduce oxidative DNA damage induced by Fenton reagents. Journal of Pineal Research. 2003;34:178-184
  99. 99. Paredes Royano SD, Reiter RJ. Melatonin: Helping cells cope with oxidative disaster. Cell Membranes and Free Radical Research. 2010;2(3):99-111
  100. 100. Silva SO, Ximenes VF, Livramento JA, Catalani LH, Campa A. High concentrations of the melatonin metabolite, N1-acetyl-N2-formyl-5-methoxykynuramine, in cerebrospinal fluid of patients with meningitis: A possible immunomodulatory mechanism. Journal of Pineal Research. 2005;39(3):302-306
  101. 101. Hardeland R. Taxon- and site-specific melatonin catabolism. Molecules. 2017;22(11):1-23
  102. 102. Reiter RJ, Fuentes-Broto L, Paredes SD, Tan DX, Garcia JJ. Melatonin and the pathophysiology of cellular membranes. Marmara Pharmaceutical Journal. 2010;14:1-9
  103. 103. Esposito E, Cuzzocrea S. Antiinflammatory activity of melatonin in central nervous system. Current Neuropharmacology. 2010;8(3):228-242
  104. 104. Reiter RJ, Tan DX, Galano A. Melatonin reduces lipid peroxidation and membrane viscosity. Frontiers in Physiology. 2014;5(377):1-4
  105. 105. Manchester LC, Coto-Montes A, Boga JA, Andersen LP, Zhou Z, Galano A, Vriend J, Tan DX, Reiter RJ. Melatonin: An ancient molecule that makes oxygen metabolically tolerable. Journal of Pineal Research. 2015;59(4):403-419
  106. 106. Zavodnik IB, Domanski AV, Lapshina EA, Bryszewska M, Reiter RJ. Melatonin directly scavenges free radicals generated in red blood cells and a cell-free system: Chemiluminescence measurements and theoretical calculations. Life Sciences. 2006;79(4):391-400
  107. 107. Zhang H, Squadrito GL, Pryor WA. The reaction of melatonin with peroxynitrite: Formation of melatonin radical cation and absence of stable nitrated products. Biochemical and Biophysical Research Communications. 1998;251(1):83-87
  108. 108. Zhang H, Squadrito GL, Uppu R, Pryor WA. Reaction of peroxynitrite with melatonin: A mechanistic study. Chemical Research in Toxicology. 1999;12:526-534
  109. 109. Gönenç A, Hacışevki A, Tavil Y, Çengel A, Torun M. Oxidative stress in patients with essential hypertension: A comparison of dippers and non-dippers. European Journal of Internal Medicine. 2013;24:139-144
  110. 110. Reiter RJ, Tan DX, Galano A. Melatonin: Exceeding expectations. Physiology (Bethesda, Md.). 2014;29(5):325-333
  111. 111. Kotler M, Rodríguez C, Sáinz RM, Antolín I, Menéndez-Peláez A. Melatonin increases gene expression for antioxidant enzymes in rat brain cortex. Journal of Pineal Research. 1998;24(2):83-89
  112. 112. Bhatti GK, IPS S, Bhatti JS. Protective effect of melatonin against malathion induced alterations in antioxidant defense system and morphology of erythrocytes in Wistar rats. Journal of Basic & Applied Sciences. 2013;9:438-446
  113. 113. Hardeland R. Neuroprotection by radical avoidance: Search for suitable agents. Molecules. 2009;14(12):5054-5102
  114. 114. Reiter RJ, Acuña-Castroviejo D, Tan DX, Burkhardt S. Free radical-mediated molecular damage: Mechanisms for the protective actions of melatonin in the central nervous system. Annals of the New York Academy of Sciences. 2001;939:200-215
  115. 115. Blokhina O, Virolainen E, Fagerstedt KV. Antioxidants, oxidative damage and oxygen deprivation stress: A review. Annals of Botany. 2003;91:179-194
  116. 116. Osellame LD, Blacker TS, Duchen MR. Cellular and molecular mechanisms of mitochondrial function. Best Practice & Research. Clinical Endocrinology & Metabolism. 2012;26(6):711-723
  117. 117. Ganie SA, Dar TA, Bhat AH, Dar KB, Anees S, Zargar MA, Masood A. Melatonin: A potential anti-oxidant therapeutic agent for mitochondrial dysfunctions and related disorders. Rejuvenation Research. 2016;19(1):21-40
  118. 118. García JJ, López-Pingarrón L, Almeida-Souza P, Tres A, Escudero P, García-Gil FA, Tan DX, Reiter RJ, Ramírez JM, Bernal-Pérez M. Protective effects of melatonin in reducing oxidative stress and in preserving the fluidity of biological membranes: A review. Journal of Pineal Research. 2014;56(3):225-237
  119. 119. Flora SJ, Shrivastava R, Mittal M. Chemistry and pharmacological properties of some natural and synthetic antioxidants for heavy metal toxicity. Current Medicinal Chemistry. 2013;20(36):4540-4574
  120. 120. Adefegha SA, Oboh G. Water extractable phytochemicals from some Nigerian spices inhibit Fe2+-induced lipid peroxidation in Rat’s brain–in vitro. Journal of Food Processing and Technology. 2011;2(1):1-6
  121. 121. Cardinali DP, Vigo DE, Olivar N, Vidal MF, Brusco LI. Melatonin therapy in patients with Alzheimer's disease. Antioxidants (Basel). 2014;3(2):245-277
  122. 122. Hardeland R. Melatonin, hormone of darkness and more: Occurrence, control mechanisms, actions and bioactive metabolites. Cellular and Molecular Life Sciences. 2008;65(13):2001-2018
  123. 123. Gonenc A, Hacisevki A, Erdemoglu AK, Dagkiran ME, Torun M. Evaluation of oxidative stress markers and antioxidant status in Alzheimer disease, vascular dementia and the Parkinson disease. Oxidation Communications. 2013;36(1):235-245
  124. 124. Csányi G, Miller FJ Jr. Oxidative stress in cardiovascular disease. International Journal of Molecular Sciences. 2014;15:6002-6008
  125. 125. Baker J, Kimpinski K. Role of melatonin in blood pressure regulation: An adjunct anti-hypertensive agent. Clinical and Experimental Pharmacology & Physiology. 2018:1-12. DOI: 10.1111/1440-1681.12942. [Epub ahead of print]
  126. 126. Pechanova O, Paulis L, Simko F. Peripheral and central effects of melatonin on blood pressure regulation. International Journal of Molecular Sciences. 2014;15(10):17920-17937
  127. 127. Favero G, Franceschetti L, Buffoli B, Moghadasian MH, Reiter RJ, Rodella LF, Rezzani R. Melatonin: Protection against age-related cardiac pathology. Ageing Research Reviews. 2017;35:1-366
  128. 128. Dominguez-Rodriguez A, Abreu-Gonzalez P, Sanchez-Sanchez JJ, Kaski JC, Reiter RJ. Melatonin and circadian biology in human cardiovascular disease. Journal of Pineal Research. 2010;49(1):14-22
  129. 129. Petrosillo G, Di Venosa N, Pistolese M, Casanova G, Tiravanti E, Colantuono G, Federici A, Paradies G, Ruggiero FM. Protective effect of melatonin against mitochondrial dysfunction associated with cardiac ischemia- reperfusion: Role of cardiolipin. The FASEB Journal. 2006;20(2):269-276
  130. 130. Sánchez A, Calpena AC, Clares B. Evaluating the oxidative stress in inflammation: Role of melatonin. International Journal of Molecular Sciences. 2015;16(8):16981-17004
  131. 131. Bukowska A. Anticarcinogenic role of melatonin--potential mechanisms. Medycyna Pracy. 2011;62(4):425-434
  132. 132. Matés JM, Segura JA, Alonso FJ, Márquez J. Intracellular redox status and oxidative stress: Implications for cell proliferation, apoptosis, and carcinogenesis. Archives of Toxicology. 2008;82:273-299
  133. 133. Hacışevki A, Baba B, Gönenç A, Aslan S. Protein carbonyl content as the most general and well-used biomarker of severe oxidative stress, oxidation. Communication. 2012;35(2):413-422
  134. 134. Srinivasan V, Spence DW, Pandi-Perumal SR, Trakht I, Cardinali DP. Therapeutic actions of melatonin in cancer: Possible mechanisms. Integrative Cancer Therapies. 2008;7(3):189-203
  135. 135. Jung B, Ahmad N. Melatonin in cancer management: Progress and promise. Cancer Research. 2006;66(20):9789-9793
  136. 136. Reiter RJ, Rosales-Corral SA, Tan DX, Acuna-Castroviejo D, Qin L, Yang SF, Xu K. Melatonin, a full service anti-cancer agent: Inhibition of initiation, progression and metastasis. International Journal of Molecular Sciences. 2017;18(4):1-47
  137. 137. Li Y, Li S, Zhou Y, Meng X, Zhang JJ, Xu DP, Li HB. Melatonin for the prevention and treatment of cancer. Oncotarget. 2017;8(24):39896-39921
  138. 138. Chojnacki C, Walecka-Kapica E, Romanowski M, Chojnacki J, Klupinska G. Protective role of melatonin in liver damage. Current Pharmaceutical Design. 2014;20(30):4828-4833
  139. 139. Lebda MA, Sadek KM, Abouzed TK, Tohamy HG, El-Sayed YS. Melatonin mitigates thioacetamide-induced hepatic fibrosis via antioxidant activity and modulation of proinflammatory cytokines and fibrogenic genes. Life Sciences. 2018;192:136-143
  140. 140. Das N, Mandala A Naaz S, Giri S, Jain M, Bandyopadhyay D, Reiter RJ, Roy SS. Melatonin protects against lipid-induced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice. Journal of Pineal Research. 2017;62(4):1-21. DOI: 10.1111/jpi.12404
  141. 141. Hacışevki A, Baba B, Sezer S, Özkan Y. Increased kynurenine/tryptophan and neopterin levels in hemodialysis. Oxidation Communications. 2013;36(1):246-253
  142. 142. Hacışevki A, Gönenç A, Sezer S, Karakan Ş, Şimşek B, Torun M. Accumulation of an endogenous inhibitor of nitric oxide synthesis and oxidative DNA damage in end-stage renal disease. Clinical Laboratory. 2013;59:1353-1361
  143. 143. Dehdashtian E, Mehrzadi S, Yousefi B, Hosseinzadeh A, Reiter RJ, Safa M, Ghaznavi H, Naseripour M. Diabetic retinopathy pathogenesis and the ameliorating effects of melatonin; involvement of autophagy, inflammation and oxidative stress. Life Sciences. 2018;193:20-33
  144. 144. Zephy D, Ahmad J. Type 2 diabetes mellitus: Role of melatonin and oxidative stress. Diabetes and Metabolic Syndrome: Clinical Research and Reviews. 2015;9(2):127-131

Written By

Aysun Hacışevki and Burcu Baba

Submitted: March 1st, 2018 Reviewed: June 11th, 2018 Published: November 5th, 2018