Showing papers in "Journal of Pineal Research in 2003"
TL;DR: This review focuses on the direct radical scavenging activity of melatonin and provides a summary of the mechanisms of the reactions between the indoleamine and reactive species in pure chemical solutions.
Abstract: Melatonin has been shown to be an effective antioxidant in a number of experimental models both in vitro and in vivo. Considering the data available, it is now clear that the indoleamine is involved in antioxidative mechanisms more complex than originally envisaged. These range from the direct radical scavenging of a variety of radicals and reactive species to the control and/or modulation of a number of processes which may trigger a redox imbalance between antioxidant and prooxidant species. This review focuses on the direct radical scavenging activity of melatonin and provides a summary of the mechanisms of the reactions between the indoleamine and reactive species in pure chemical solutions. These actions likely account for at least some of the protective actions of melatonin under conditions of high oxidative stress.
705 citations
TL;DR: It seems likely that melatonin initially evolved as an antioxidant, becoming a vitamin in the food chain, and in multicellular organisms, where it is produced, it has acquired autocoid, paracoid and hormonal properties.
Abstract: Melatonin, a derivative of an essential amino acid, tryptophan, was first identified in bovine pineal tissue and subsequently it has been portrayed exclusively as a hormone. Recently accumulated evidence has challenged this concept. Melatonin is present in the earliest life forms and is found in all organisms including bacteria, algae, fungi, plants, insects, and vertebrates including humans. Several characteristics of melatonin distinguish it from a classic hormone such as its direct, non-receptor-mediated free radical scavenging activity. As melatonin is also ingested in foodstuffs such as vegetables, fruits, rice, wheat and herbal medicines, from the nutritional point of view, melatonin can also be classified as a vitamin. It seems likely that melatonin initially evolved as an antioxidant, becoming a vitamin in the food chain, and in multicellular organisms, where it is produced, it has acquired autocoid, paracoid and hormonal properties.
505 citations
TL;DR: Melatonin has been detected in bacteria, eukaryotic unicells, macroalgae, plants, fungi and various taxa of invertebrates, findings with possible implications in ecophysiology as well as for human nutrition and, with regard to high levels in medicinal plants, also in pharmacology.
Abstract: Melatonin has been detected in bacteria, eukaryotic unicells, macroalgae, plants, fungi and various taxa of invertebrates Although precise determinations are missing in many of these organisms and the roles of melatonin are still unknown, investigations in some species allow more detailed conclusions Non-vertebrate melatonin is not necessarily circadian, and if so, not always peaking at night, although nocturnal maxima are frequently found In the cases under study, the major biosynthetic pathway is identical with that of vertebrates Mimicking of photoperiodic responses and concentration changes upon temperature decreases have been studied in more detail only in dinoflagellates In plants, an involvement in photoperiodism seems conceivable but requires further support No stimulation of flowering has been demonstrated to date A participation in antioxidative protection might be possible in many aerobic non-vertebrates, although evidence for a contribution at physiological levels is mostly missing Protection from stress by oxidotoxins or/and extensions of lifespan have been shown in very different organisms, such as the dinoflagellate Lingulodinium, the ciliate Paramecium, the rotifer Philodina and Drosophila Melatonin can be taken up from the food, findings with possible implications in ecophysiology as well as for human nutrition and, with regard to high levels in medicinal plants, also in pharmacology
324 citations
TL;DR: It is demonstrated for the first time that CSF melatonin levels were significantly decreased in the aged individuals with early neuropathological changes in the temporal cortex, where the AD process starts, suggesting that the decrease in CSFmelatonin levels may be an early event in the development of AD possibly occurring even before the clinical symptoms.
Abstract: Neuropathology is the most reliable criterion for diagnosing Alzheimer's disease (AD). A well-established system for staging the spread of neuropathological changes in AD is available. The clinical use of a biomarker that reflects the neuropathological change occurring in brain tissue has not yet been established. Melatonin is a product that plays not only a major role in the regulation of the circadian rhythms but may also exert neuroprotective effects in AD. Melatonin levels were determined in ventricular postmortem cerebrospinal fluid (CSF) of 121 subjects. Braak staging and a modified Braak staging for cortex (MBSC) were used to evaluate the severity of AD neuropathology. The present study revealed that not only the Braak stages of AD, but also the MBSC were negatively correlated with CSF melatonin levels. By using MBSC, we now demonstrate for the first time that CSF melatonin levels were significantly decreased in the aged individuals with early neuropathological changes in the temporal cortex, where the AD process starts. Those individuals that did not have any neurofibrillary tangle (NFT) or neuritic plaque (NP) in the temporal cortex, had much higher melatonin levels (287 +/- 68 and 280 +/- 64 pg/mL, respectively) than those individuals that had a few NFTs and NPs (82 +/- 4 and 39 +/- 8 pg/mL, respectively) in the temporal cortex. These results suggest that the decrease in CSF melatonin levels may be an early event in the development of AD possibly occurring even before the clinical symptoms.
242 citations
TL;DR: The present study suggests that melatonin may be of therapeutic benefit when used with MTX and elucidates the role of free radicals in MTX‐induced toxicity and the protection by melatonin.
Abstract: Regarding the mechanisms of methotrexate (MTX) hepatotoxicity and nephrotoxicity, several hypotheses have been put forward, among which oxidative stress (including depletion of glutathione) is likely. This investigation elucidates the role of free radicals in MTX-induced toxicity and the protection by melatonin. Wistar albino rats were injected with MTX intraperitoneally. Following a single dose of MTX (20 mg/kg), either saline (MTX group) or melatonin (10 mg/kg, MTX + Mel group) was administered for 5 days. In other rats, physiologic saline (control group) or melatonin (10 mg/kg, Mel group) was injected for 5 days, following a single injection of saline. On the sixth day, rats were killed to obtain blood, liver, and kidney tissue samples. Malondialdehyde (MDA), an end product of lipid peroxidation, and glutathione (GSH), a key antioxidant, levels were evaluated in blood and tissue homogenates. Reactive oxygen metabolite-induced inflammatory changes in kidney and liver tissues were evaluated by measuring myeloperoxidase (MPO) activity, an index of neutrophil infiltration. MTX administration resulted in increased MDA levels and MPO activity and decreased GSH levels in the blood, liver, and kidney whereas melatonin reversed these effects. When melatonin was administered alone, no significant changes in biochemical parameters were noted. In conclusion, the present study suggests that melatonin may be of therapeutic benefit when used with MTX.
237 citations
TL;DR: Early studies on melatonin–bone relationships and recent data that suggest a direct effect of melatonin on bone suggest that melatonin may impair development of osteopenia associated with senescence by improving non‐rapid eye movement sleep and restoring GH secretion.
Abstract: Bone formation proceeds through a remodeling process that runs continuously, involving the resorption of old bone by osteoclasts, and the subsequent formation of new bone by osteoblasts. This is controlled by growth factors and cytokines produced in bone marrow microenvironment and by the action of systemic hormones, like parathyroid hormone, estradiol or growth hormone (GH). One candidate for hormonal modulation of osteoblast and osteoclast formation is melatonin. Because circulating melatonin declines with age, its possible involvement in post-menopausal and senescence osteoporosis is considered. This review article discusses early studies on melatonin-bone relationships and recent data that suggest a direct effect of melatonin on bone. Melatonin could act as an autacoid in bone cells as it is present in high quantities in bone marrow, where precursors of bone cells are located. Melatonin dose-dependently augmented proteins that are incorporated into the bone matrix, like procollagen type I c-peptide. Osteoprotegerin, an osteoblastic protein that inhibits the differentiation of osteoclasts is also augmented by melatonin in vitro. Another possible target cell for melatonin is the osteoclast, which degrades bone partly by generating free radicals. Melatonin through its free radical scavenger and antioxidant properties may impair osteoclast activity and bone resorption. At least in one study melatonin was both inhibitory to osteoclastic and osteoblastic cells. Therefore, the documented bone-protecting effect of melatonin in ovariectomized rats can depend in part on the free radical scavenging properties of melatonin. Additionally, melatonin may impair development of osteopenia associated with senescence by improving non-rapid eye movement sleep and restoring GH secretion. Whether melatonin can be used as a novel mode of therapy for augmenting bone mass in diseases deserves to be studied.
222 citations
TL;DR: In terms of scavenging ABTSb+, melatonin exhibits a different profile than that of the classic antioxidants as mentioned in this paper, while classic antioxidants scavenge one or less ABTS b+ while each melatonin molecule can scavenge more than one ABTSc+ with a maximum of four.
Abstract: Melatonin and classic antioxidants possess the capacity to scavenge ABTSb+ with IC50s of 4, 11, 15.5, 15.5, 17 and 21 microm for melatonin, glutathione, vitamin C, trolox, NADH and NADPH, respectively. In terms of scavenging ABTSb+, melatonin exhibits a different profile than that of the classic antioxidants. Classic antioxidants scavenge one or less ABTSb+, while each melatonin molecule can scavenge more than one ABTSb+, probably with a maximum of four. Classic antioxidants do not synergize when combined in terms of scavenging ABTSb+. However, a synergistic action is observed when melatonin is combined with any of the classic antioxidants. Cyclic voltammetry indicates that melatonin donates an electron at the potential of 715 mV. The scavenging mechanism of melatonin on ABTSb+ may involve multiple-electron donations via intermediates through a stepwise process. Intermediates including the melatoninyl cation radical, the melatoninyl neutral radical and cyclic 3-hydroxymelatonin (cyclic 3-OHM) and N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) seem to participate in these reactions. More interestingly, the pH of the solution dramatically modifies the ABTSb+ scavenging capacity of melatonin while pH changes have no measurable influence on the scavenging activity of classic antioxidants. An acidic pH markedly reduces the ABTSb+ scavenging capacity of melatonin while an increased pH promotes the interaction of melatonin and ABTSb+. The major melatonin metabolites that develop when melatonin interacts with ABTSb+ are cyclic 3-OHM and AFMK. Cyclic 3-OHM is the intermediate between melatonin and AFMK, and cyclic 3-OHM also has the ability to scavenge ABTSb+. Melatonin and the metabolites which are generated via the interaction of melatonin with ABTSb+, i.e. the melatoninyl cation radical, melatoninyl neutral radical and cyclic 3-OHM, all scavenge ABTSb+. This unique cascade action of melatonin, in terms of scavenging, increases its efficiency to neutralized ABTSb+; this contrasts with the effects of the classic antioxidants.
187 citations
TL;DR: Assessment of the 5‐year survival results in metastatic non‐small cell lung cancer patients obtained with a chemotherapeutic regimen consisting of cisplatin and etoposide, with or without the concomitant administration of melatonin suggests a new biochemotherAPEutic strategy in the treatment of human neoplasms.
Abstract: Numerous experimental data have documented the oncostatic properties of melatonin. In addition to its potential direct antitumor activity, melatonin has proved to modulate the effects of cancer chemotherapy, by enhancing its therapeutic efficacy and reducing its toxicity. The increase in chemotherapeutic efficacy by melatonin may depend on two main mechanisms, namely prevention of chemotherapy-induced lymphocyte damage and its antioxidant effect, which has been proved to amplify cytotoxic actions of the chemotherapeutic agents against cancer cells. However, the clinical results available at present with melatonin and chemotherapy in the treatment of human neoplasms are generally limited to the evaluation of 1-year survival in patients with very advanced disease. Thus, the present study was performed to assess the 5-year survival results in metastatic non-small cell lung cancer patients obtained with a chemotherapeutic regimen consisting of cisplatin and etoposide, with or without the concomitant administration of melatonin (20 mg/day orally in the evening). The study included 100 consecutive patients who were randomized to receive chemotherapy alone or chemotherapy and melatonin. Both the overall tumor regression rate and the 5-year survival results were significantly higher in patients concomitantly treated with melatonin. In particular, no patient treated with chemotherapy alone was alive after 2 years, whereas a 5-year survival was achieved in three of 49 (6%) patients treated with chemotherapy and melatonin. Moreover, chemotherapy was better tolerated in patients treated with melatonin. This study confirms, in a considerable number of patients and for a long follow-up period, the possibility to improve the efficacy of chemotherapy in terms of both survival and quality of life by a concomitant administration of melatonin. This suggests a new biochemotherapeutic strategy in the treatment of human neoplasms.
183 citations
TL;DR: In this paper, the metal chelating and scavenging activity of melatonin was evaluated and it was concluded that melatonin is an effective metal chelator and scavenger of H2O2.
Abstract: Antioxidant activity of a molecule is attributed to various mechanisms such as prevention of chain initiation, binding of transition metal ion catalysts and decomposition of peroxides This study was aimed at evaluating the metal chelating and hydrogen peroxide (H2O2) scavenging activity of melatonin The metal chelating and H2O2 scavenging activity increased with increasing concentrations of melatonin (20-60 micro g/mL) alpha-Tocopherol, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT) were used as standards Sixty micrograms per milliliter concentration of melatonin exhibited 95% chelating effect on ferrous ions and scavenged 83% of H2O2 On the other hand, the same concentration of alpha-tocopherol, BHA, and BHT exhibited 58, 61, and 72% inhibition, respectively, of the formation of the Fe2+-ferrozine complex and scavenged 48, 20, and 23%, respectively, of H2O2 Based on these results, it is concluded that melatonin is an effective metal chelating agent and scavenger of H2O2 These properties may be major reasons for the melatonin's ability to inhibit lipid peroxidation
163 citations
TL;DR: In vivo and in vitro evidence that melatonin protects against ischemia/reperfusion injury is summarized and interested clinical scientists should consider planning phase II and III studies to confirm the benefit of melatonin as an acute stroke treatment or a preventive measure for stroke patients.
Abstract: The brain is highly susceptible to focal or global ischemia. Unless ischemia is promptly reversed, reperfusion produces further cerebral damage. Acute thrombolysis or defibrinogenation is effective only in selective patients with ischemic stroke and carries a significant risk of bleeding complications. Whereas numerous neuroprotectants were shown to be effective in experimental studies, none of them have been shown to work in clinical trials. The major pathogenetic mechanisms of ischemia/reperfusion injury include excitotoxicity, disturbed calcium ion homeostasis, overproduction of nitric oxide and other free radicals, inflammation, and apoptosis. Nitric oxide and other free radicals, the key mediators of excitotoxicity and disturbed calcium ion homeostasis, cause direct injury and also indirectly damage via inflammation and apoptosis. Melatonin is a potent free radical scavenger and an indirect antioxidant. This mini review summarizes the in vivo and in vitro evidence that melatonin protects against ischemia/reperfusion injury. There is convincing evidence from the literature that melatonin treatment is highly effective in different in vivo and in vitro models of excitotoxicity or ischemia/reperfusion in multiple animal species. Melatonin is safe and non-toxic in humans, and its administration via the oral route or intravenous injection is convenient. While more experimental studies should be conducted to further explore the neuroprotective mechanisms and to document any synergistic or additive protection from combining melatonin with thrombolysis, defibrinogenation or other neuroprotectants, interested clinical scientists should consider planning phase II and III studies to confirm the benefit of melatonin as an acute stroke treatment or a preventive measure for stroke patients.
156 citations
TL;DR: Melatonin is potentially useful in the treatment of acute brain pathologies associated with oxidative stress‐induced neuronal damage such as epilepsy, stroke, and traumatic brain injury and a possible mechanism for melatonin‐mediated neuroprotection involves its antioxidant and anti‐inflammatory actions.
Abstract: The antioxidant and anti-inflammatory effects of melatonin on kainic acid (KA)-induced neurodegeneration in the hippocampus were evaluated in vivo. It has been suggested that the pineal secretory product, melatonin, protects neurons in vitro from excitotoxicity mediated by kainate-sensitive glutamate receptors, and from oxidative stress-induced DNA damage and apoptosis. In this study, we injected 10 mg/kg kainate intraperitoneally (i.p.) into adult male Sprague-Dawley rats. This results in selective neuronal degeneration accompanied by intense microglial activation and triggers DNA damage in the hippocampus. We tested the in vivo efficacy of melatonin in preventing KA-induced neurodegeneration, oxidative stress and neuroinflammation in the hippocampus. Melatonin (2.5 mg/kg, i.p.) was given 20 min before, immediately after, and 1 and 2 hr after KA administration. Rats were killed 72 hr later and their hippocampi were examined for evidence of DNA damage (in situ dUTP end-labeling, i.e. TUNEL staining), cell viability (hematoxylin and eosin staining), and microglial (isolectin-B4 histochemistry) and astroglial responses (glial fibrillary acidic protein immunohistochemistry), as well as lipid peroxidation (4-hydroxynonenal immunohistochemistry). A cumulative dose of 10 mg/kg melatonin attenuates KA-induced neuronal death, lipid peroxidation, and microglial activation, and reduces the number of DNA breaks. A possible mechanism for melatonin-mediated neuroprotection involves its antioxidant and anti-inflammatory actions. The present data suggest that melatonin is potentially useful in the treatment of acute brain pathologies associated with oxidative stress-induced neuronal damage such as epilepsy, stroke, and traumatic brain injury.
TL;DR: The data show that melatonin reduces liver damage inflicted by irradiation when given prior to the exposure to ionizing radiation, suggesting that the radioprotective effect of melatonin is likely achieved by its ability to function as a scavenger for free radicals generated by ionizing Radiation.
Abstract: Radiation therapy is a popular and useful tool in the treatment of cancer. Melatonin participates in the regulation of a number of important physiological and pathological processes. Melatonin, a powerful endogenous antioxidant, plays a role in the reduction of oxidative damage. Thirty adult rats were divided into five equal groups. On the day of the experiment, groups I and II were injected with 5 or 10 mg/kg melatonin, respectively, while group III received isotonic NaCl solution. Thirty minutes later, groups I, II and III were exposed to 6.0 Gy whole body ionizing radiation in a single fraction. Group IV was injected with 5 mg/kg melatonin but was not irradiated. The final group was reserved as sham treated. Liver malondialdehyde (MDA) and nitric oxide (NOċ) levels were measured in all groups. Whole body irradiation caused a significant increase in liver MDA and NOċ levels. Hepatic MDA and NOċ levels in irradiated rats that were pretreated with melatonin (5 or 10 mg/kg) were significantly decreased. Malondialdehyde and NOċ levels were reduced in a dose-related manner by melatonin. The data show that melatonin reduces liver damage inflicted by irradiation when given prior to the exposure to ionizing radiation. The radioprotective effect of melatonin is likely achieved by its ability to function as a scavenger for free radicals generated by ionizing radiation.
TL;DR: Melatonin influences telomerase both in vivo and in vitro, decreasing its activity in the tumors of nude mice and the mRNA expression of the TERT and TR subunits, essential factors for the proper function of the telomere elongation enzyme.
Abstract: In this study for the first time the relationship between melatonin and telomerase activity was investigated. Melatonin exhibits oncostatic properties, but the actual mechanism of action by which the indole reduces tumor cell activity is not clear. Telomerase is an enzyme responsible of telomere elongation and is activated in most human cancers. In the current in vivo study, eight nude mice received a MCF-7 xenograft and thereafter they were treated for 5 weeks with 0.1 mg/mL of melatonin in the drinking water. Melatonin treatment caused a significant reduction in the weight of tumors and reduced metastases when compared with the control group. As indicated by the Telomerase Repeats Amplification Protocol (TRAP) assay, a significant decrease in telomerase activity was observed in the group treated with melatonin. In related in vitro studies, cultured MCF-7 cells were treated with three different concentrations of melatonin and a control without indole treatment. A significant dose-dependent decrease in Telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase, mRNA expression was observed in the melatonin-treated cells. We also observed a significant reduction in TR, the RNA telomerase subunit, mRNA expression at physiological concentrations of melatonin (1 nm). Significant differences in TEP1, an associated telomerase protein, mRNA expression were also observed. In conclusion, melatonin influences telomerase both in vivo and in vitro, decreasing its activity in the tumors of nude mice and the mRNA expression of the TERT and TR subunits, essential factors for the proper function of the telomerase enzyme.
TL;DR: Vitamin E was the least efficient agent in reversing AA toxicity while melatonin, considering it was given as at lower dose than either vitamin E or NAC, was the most effective.
Abstract: Acetaminophen (AA) is a commonly used analgesic and antipyretic drug; however, when used in high doses, it causes fulminant hepatic necrosis and nephrotoxic effects in both humans and experimental animals. It has been reported that the toxic effects of AA are the result of oxidative reactions that take place during its metabolism. In this study we investigated if melatonin, vitamin E or N-acetylcysteine (NAC) are protective against AA toxicity in mice. The doses of the antioxidants used were as follows: melatonin (10 mg/kg), vitamin E (30 mg/kg) and NAC (150 mg/kg). Blood urea nitrogen (BUN), serum creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels in blood, and glutathione (GSH), malondialdehyde (MDA), oxidized protein levels and myeloperoxidase (MPO) activity in liver and kidney tissues were measured. BUN and serum creatinine, ALT and AST levels which were increased significantly following AA treatment decreased significantly after pretreatment with either vitamin E, melatonin or NAC; however, they were not reduced to control levels. ALT and AST levels were significantly higher at 4 hr compared with the 24 hr levels after AA administration. However, BUN and creatinine levels were significantly elevated only at 24 hr. GSH levels were reduced while MDA, MPO and oxidized protein levels were increased significantly following AA administration. These changes were reversed by pretreatment with either melatonin, vitamin E or NAC. Liver toxicity was higher at 4 hr, whereas nephrotoxicity appeared to be more severe 24 hr after treatment with AA. Vitamin E was the least efficient agent in reversing AA toxicity while melatonin, considering it was given as at lower dose than either vitamin E or NAC, was the most effective. This may be the result of the higher efficacy of melatonin in scavenging various free radicals and also because of its ability in stimulating the antioxidant enzymes.
TL;DR: Melatonin was the most effective of these antioxidants tested, and reversed the pro‐oxidant effect of resveratrol and vitamin C, and exhibited synergism in combination with vitamin C and with LA (5 μM).
Abstract: DNA damage generated by oxygen-derived free radicals is related to mutagenesis, carcinogenesis and aging. In the last several years, hundreds of publications have confirmed that melatonin is a potent endogenous free radical scavenger. In the present in vitro study, we have examined the efficacy of three polyphenolic antioxidants, i.e. xanthurenic acid, resveratrol (3,4',5-trihydroxy-trans-stilbene) and (-)-epigallocatechin-3-gallate (EGCG) and two classical non-polyphenolic antioxidants, i.e. vitamin C (ascorbic acid) and alpha-lipoic acid (LA, 1,2-dithiolane-3-pentanoic acid) in inhibiting *OH-induced oxidative DNA damage. We compared the efficacy of these five antioxidants with the effectiveness of melatonin (N-acetyl-5-methoxytryptamine) and we also investigated the possible synergistic effects of melatonin with the other five molecules. Using high performance liquid chromatography (HPLC), the formation of 8-hydroxy-2-deoxyguanosine (8-OH-dG) in purified calf thymus DNA treated with the Fenton reagents, chromium(III) (as CrCl3) plus hydrogen peroxide (H2O2) (Cr(III)/H2O2), was measured in the presence or absence of the antioxidants alone or in combination with melatonin. 8-OH-dG is considered a biomarker of oxidative DNA damage. Among the antioxidants tested, melatonin was the most effective of these with an IC50 = 3.6 +/- 0.1 micro m. For the other antioxidants the IC50 values were as follows: xanthurenic acid (IC50 = 7.9 +/- 0.3), resveratrol (IC50 = 10.9 +/- 0.3), EGCG (IC50 = 5.7 +/- 0.3), vitamin C (IC50 = 16.9 +/- 0.5) and LA (IC50 = 38.8 +/- 0.7). These values differ from that of melatonin with a P < 0.01. Melatonin (1 micro M) reversed the pro-oxidant effect of resveratrol (0.5 micro M) and vitamin C (0.5 micro M), had an antagonistic effect when used in combination with EGCG (1 micro M) and it exhibited synergism in combination with vitamin C (0.5 micro M) and with LA (5 micro M).
TL;DR: Melatonin concentrations differ in different body fluids, in different cells, inDifferent subcellular organelles and in different organisms, hereinafter when the term physiological is used to describe a concentration of melatonin, it must be defined in reference to a specific compartment in multicellular organisms or for a given specie.
Abstract: There seems to be a considerable amount of confusion as to what constitutes a physiological concentration of melatonin in organisms. A frequently made and often-propagated error is the assumption that melatonin concentrations throughout the body are the same as in the blood. Thus, in many reports the authors state, regardless of the fluid, tissue or organism with which they are working, that the physiological levels of melatonin are in the picomolar and low nanomolar range. A search of the literature, however, shows that melatonin in other body fluids and cells is not necessarily in equilibrium with those in the blood. This was dramatically emphasized when it was shown that in the bile [1] and the cerebrospinal fluid of the third ventricle [2, 3] melatonin concentrations are orders of magnitude higher than in the blood. These high levels are, in fact, the physiological concentrations of melatonin for these fluids. There is also evidence that melatonin levels in the follicular fluid of the human Graffian follicule [4] exceed those in the serum. Tissue concentrations also may not depend exclusively on those in the blood. While this is obviously true for cells that produce melatonin, e.g. cells of the pineal gland and retinas [5], it may also be the case with other cells. For example, some bone marrow cells contain high concentrations of melatonin [6] and there is evidence that these elements have the synthetic machinery to produce the indole [7]. Cells in the gastrointestinal tract also contain melatonin in seemingly high concentrations [8, 9]. Beyond this, a number of other tissues are now included in the list of organs that may have the potential to generate melatonin (for example, cochlea [10]; lens [11]; skin [12]; etc), and, therefore, these cells may have elevated concentrations of the indole relative to levels in the blood. Finally, if the findings of Stefulj et al. [13] are confirmed and extended with a documentation of the ability of many cells to produce melatonin, the concept of what constitutes a physiological level of the indole may again have to be revised. Within subcellular organelles as well, the concentrations of melatonin may vary. For example, Martin et al. [14] report that the levels of this indole in the mitochondria may significantly exceed those in the serum. Physiological levels vary according to the organism in which measurements are made. In the unicell Gonyaulax polyedra [15] and in yeast Saccharomyces cerevisiae [16], for example, melatonin concentrations can be exceptionally high but, nevertheless, physiological. There may be many other organisms and/or cells that, for various reasons, contain higher concentrations of melatonin than are normally found in the blood of mammals. In the published literature, it is often mentioned that, if melatonin levels exceed the picomolar or low nanomolar range, the concentrations are pharmacological. This is obviously not the case since, as summarized herein, melatonin concentrations differ in different body fluids, in different cells, in different subcellular organelles and in different organisms. This being so, hereinafter when the term physiological is used to describe a concentration of melatonin, it must be defined in reference to a specific compartment in multicellular organisms or for a given specie.
TL;DR: Melatonin exhibited a superior capacity to reduce the pro‐inflammatory response induced by fAβ, and was found to have immunomodulatory functions.
Abstract: To determine the efficacy of antioxidants in reducing amyloid-beta-induced oxidative stress, and the neuroinflammatory response in the central nervous system (CNS) in vivo, three injections of fibrillar amyloid-beta (fAbeta) or artificial cerebrospinal fluid (aCSF) into the CA1 region of the hippocampus of the rat were made. Concomitantly, one of the three free radical scavengers, i.e. melatonin, vitamin C, or vitamin E was also administered. Besides being a free radical scavenger, melatonin also has immunomodulatory functions. Antioxidant treatment reduced significantly oxidative stress and pro-inflammatory cytokines. There were no marked differences between melatonin, vitamin C, and vitamin E regarding their capacity to reduce nitrites and lipoperoxides. However, melatonin exhibited a superior capacity to reduce the pro-inflammatory response induced by fAbeta.
TL;DR: Both site‐directed and chimaeric receptor mutagenesis studies have been performed which have provided some insight into the structure–function relationships of the melatonin receptors, and these studies may lead to the identification of the ligand for the orphan MRR.
Abstract: The melatonin receptor family is a small group of receptors within the G protein-coupled receptor (GPCR) superfamily. The group comprises of three subtypes which bind melatonin and one member, the melatonin related receptor (MRR), that shares >40% sequence identity with the other melatonin receptors but does not bind melatonin. Identification of two subtypes expressed in the mouse suprachiasmatic nucleus, one of which (MT1) inhibits neuronal firing and the other (MT2) mediating the phase advancing properties of melatonin has given renewed interest to the development of subtype specific compounds for each of the mammalian melatonin receptors. Towards this goal site-directed and chimaeric receptor mutagenesis studies have been performed which have provided some insight into the structure-function relationships of the melatonin receptors. Furthermore, these studies may lead to the identification of the ligand for the orphan MRR.
TL;DR: It is suggested that in coronary heart disease MT2‐receptor expression is altered and there is evidence for heterogeneous MT2 expression patterns in individual patients.
Abstract: We showed that the melatonin receptor subtype, MT1, is expressed in healthy and diseased human coronary arteries. As studies in experimental animals suggest that the MT2 melatonin receptor subtype is also present in the vasculature, we investigated whether the MT2 is expressed in human aorta and coronary arteries. Additionally, MT2 expression in human ventricular specimens was analysed, as melatonin was shown to affect myocyte function. Expression of the MT2-receptor was studied in sections of isolated coronary arteries, aorta and left ventricular specimens from healthy heart donors (control) and patients with dilated or ischemic cardiomyopathy. MT2 expression was found by reverse transcriptase (RT)-nested-polymerase chain reaction (PCR) in all of the specimens (aorta, left ventricle and coronary arteries) derived from controls. Also, visible evidence for receptor expression was found in 12 of 15 samples from cardiomyopathy patients and 10 of 15 of coronary heart disease patients. Additionally, the expression of MT2-receptor between aorta, left ventricle and coronary arteries varied among the individuals, some of them showing highest expression in the aorta while in others principal expression sites were coronary arteries or left ventricles. In conclusion, the MT2-receptor subtype is present in human arteries and left ventricles and it is suggested that in coronary heart disease MT2-receptor expression is altered. Furthermore, there is evidence for heterogeneous MT2 expression patterns in individual patients.
TL;DR: The present study showed that salivary melatonin measurement is a reliable, sensitive and easy method to monitor changes in the circadian rhythms of melatonin during the course of aging.
Abstract: To investigate whether free melatonin may be better suited to reveal age-related changes, we studied the circadian rhythm alterations in saliva melatonin levels during aging. Special attention was paid to the question as to how the free melatonin rhythms change in aging and when such changes take place. A total of 52 healthy volunteers participated in the study consisting of young, middle-aged, old and the oldest groups. In each subject, a total of 12 time-point salivary melatonin samples was taken over 24 hr. Of the 52 data sets, 51 exhibited significant circadian rhythm over 24 hr by using the base cosine function analysis to fit the data. A clear circadian rhythm of salivary melatonin was present in all age groups. The decline in nocturnal peak levels (amplitude) in salivary melatonin was found in old and the oldest subjects. Both the old and the oldest subjects showed an increased daytime (baseline) melatonin levels. The off-set melatonin levels were more than two times higher in the oldest group than that in the other groups indicating a delayed phase of salivary melatonin. Most strikingly, we found that a step-wise decrease in the circadian rhythms of saliva melatonin occurred early in life, around 40 yr of ages. The middle-aged subjects had only 60% of the amplitude of the young subjects. In addition, the middle-aged subjects showed the longest peak levels duration and the lowest daytime melatonin levels. The present study showed that the alterations in the circadian rhythms of salivary melatonin begin during middle-age. Our results showed that salivary melatonin measurement is a reliable, sensitive and easy method to monitor changes in the circadian rhythms of melatonin during the course of aging.
TL;DR: It is concluded that exogenous melatonin, and that produced from l‐tryptophan, attenuates pancreatic damage induced by CIP or by I/R and this effect may be attributable to the reduction in lipid peroxidation and TNFα release combined with an increase of plasma anti‐inflammatory IL‐10 in rats with acute pancreatitis.
Abstract: Melatonin, a pineal secretory product, synthesized from l-tryptophan, has received increased attention because of its antioxidative and immunomodulatory properties. It has been detected in the gut and shown to protect the gastric mucosa, and liver from acute damage, but the role of melatonin in the protection of the pancreas against acute inflammation is not clear. The aim of this study was to investigate the effects of melatonin and its precursor, l-tryptophan, on caerulein-induced pancreatitis (CIP) and on ischemia/reperfusion (I/R)-provoked pancreatitis in rats. CIP was induced by subcutaneous infusion of caerulein to the rats (25 microg/kg). I/R was induced by clamping of the inferior splenic artery for 30 min followed by 2 hr of reperfusion. Melatonin (10, 25 or 50 mg/hr) or l-tryptophan (50, 100 or 250 mg/kg) was given as a bolus intraperitoneal (i.p.) injection 30 min prior to the onset of pancreatitis. CIP and I/R were confirmed by histologic examination and manifested by typical pancreatic edema, by an increase of plasma levels of amylase (by 500% in CIP and by 40% in I/R) and the pro-inflammatory tumor necrosis factor alpha (TNFalpha) (by 500%). Lipid peroxidation products such as malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE), were increased several fold in the pancreas CIP and I/R, whereas pancreatic blood flow (PBF) was significantly reduced in these animals. Pretreatment of rats subjected to CIP or to I/R with melatonin (25 or 50 mg/kg i.p.) or l-tryptophan (100 or 250 mg/kg i.p.) significantly reduced pancreatic edema, plasma levels of amylase and TNFalpha and diminished pancreatic MDA + 4-HNE contents, while enhancing PBF, pancreatic integrity and plasma levels of the anti-inflammatory interleukin 10 (IL-10). This was accompanied by a marked and dose-dependent rise of plasma melatonin immunoreactivity. Gene expression of N-acetyl transferase, an enzyme involved in melatonin biosynthesis, was detected in the pancreas of normal rats and was significantly enhanced in the rats with CIP. We conclude that exogenous melatonin, and that produced from l-tryptophan, attenuates pancreatic damage induced by CIP or by I/R and this effect may be attributable to the reduction in lipid peroxidation and TNFalpha release combined with an increase of plasma anti-inflammatory IL-10 in rats with acute pancreatitis.
TL;DR: It is demonstrated that luminal melatonin is a potent stimulant of duodenal HCO secretion and, furthermore, strongly suggests melatonin as an important mediator of acid‐induced secretion.
Abstract: Melatonin, originating from intestinal enterochromaffin cells, mediates vagal and sympathetic neural stimulation of the HCO secretion by the duodenal mucosa. This alkaline secretion is considered the first line of mucosal defense against hydrochloric acid discharged from the stomach. We have studied whether luminally applied melatonin stimulates the protective secretion and whether a melatonin pathway is involved in acid-induced stimulation of the secretion. Rats were anaesthetized (Inactin) and a 12-mm segment of proximal duodenum with an intact blood supply was cannulated in situ. Mucosal HCO secretion (pH-stat) and the mean arterial blood pressure were continuously recorded. Luminal melatonin at a concentration of 1.0 micro m increased (P < 0.05) the secretion from 7.20 +/- 1.35 to 13.20 +/- 1.51 micro Eq/cm/hr. The MT2 selective antagonist luzindole (600 nmol/kg, i.v.) had no effect on basal HCO secretion, but inhibited (P < 0.05) secretion stimulated by luminal melatonin. Hexamethonium (10 mg/kg i.v. followed by continuous i.v. infusion at a rate of 10 mg/kg/hr), abolishes neurally mediated rises in secretion and also inhibited (P < 0.05) the stimulation by luminal melatonin. Exposure of the lumen to acid containing perfusate (pH 2.0) for 5 min increased (P < 0.05) the HCO secretion from 5.85 +/- 0.82 to 12.35 +/- 1.51 micro Eq/cm/hr, and luzindole significantly inhibited (P < 0.05) this rise in secretion. The study thus demonstrates that luminal melatonin is a potent stimulant of duodenal HCO secretion and, furthermore, strongly suggests melatonin as an important mediator of acid-induced secretion.
TL;DR: Pinealectomy causes severe hyperinsulinemia and accumulation of triglycerides in the liver, probably owing to the loss of the nocturnal melatonin surge, in type 2 diabetic Otsuka Long‐Evans Tokushima Fatty rats.
Abstract: We previously reported that pharmacological melatonin administration to type 2 diabetic rats reduces hyperinsulinemia and improves the altered fatty-acid metabolism. To determine whether melatonin deficiency exacerbates diabetes-associated conditions, we investigated the effect of pinealectomy (i.e. melatonin-deficiency) on plasma hormone levels and lipid metabolism in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats. We compared levels of insulin and leptin, and hepatic lipids in pinealectomized OLETF (PO) rats, sham-operated OLETF (SO) rats and sham-operated healthy Long-Evans Tokushima Otsuka (LETO) (SL) rats 16 and 30 wk after the operation. Plasma glucose and triglycerides were increased in SO and PO rats 30 wk after operation compared with age-matched SL rats. Pinealectomy caused an increase in free cholesterol among the plasma lipids, as compared with SO rats. Sixteen weeks after pinealectomy, typical hyperinsulinemia was observed in PO rats (3.47-fold increase, P < 0.01) as compared with SL rats, whereas at 30 wk, the plasma levels of insulin in PO and SO rats had decreased and there was no significant difference among the three groups. Hepatic triglycerides were increased (1.54-fold, P < 0.005) in PO rats, compared with SO rats. Hepatic acyl-CoA synthetase (ACS) activity was significantly augmented in PO rats at 30 wk (10%, P < 0.01 versus SO group), while microsomal triglyceride transfer protein (MTP) decreased (-27% versus SO, P < 0.05); thus, the increased ACS activity and decreased MTP might have a role in the accumulation of hepatic triglycerides in PO rats. In summary, pinealectomy causes severe hyperinsulinemia and accumulation of triglycerides in the liver, probably owing to the loss of the nocturnal melatonin surge.
TL;DR: Melatonin treatment restrained bone remodelling after ovariectomy; the effect of melatonin required adequate concentrations of oestradiol; and a counter‐regulation by melatonin of the increase in body fat caused by ovariectomized rats was uncovered.
Abstract: To assess the effect of melatonin on bone metabolism in ovariectomized rats, receiving oestradiol therapy or not, melatonin was administered in the drinking water (25 microg/mL water) and oestradiol (10 microg/kg body weight) or vehicle was given subcutaneously 5 days/week for up to 60 days after surgery. Urinary deoxypyridinoline (a marker of bone resorption) and circulating levels of bone alkaline phosphatase activity (a marker of bone formation), as well as serum calcium and phosphorus levels, were measured every 15 days. Bone area (BA), bone mineral content (BMC), bone mineral density (BMD) and total body fat (expressed as 100 g body weight) were measured by dual-energy X-ray absorptiometry at the end of the experiment. Body weight and total body fat were augmented after ovariectomy, and decreased after melatonin or oestradiol treatment. The effect of melatonin on body weight was seen in sham-operated rats only. Ovariectomy augmented, and melatonin or oestradiol lowered, urinary deoxypyridinoline excretion. This effect of melatonin and oestradiol was seen mainly in ovariectomized rats. The efficacy of oestradiol to counteract ovariectomy-induced bone resorption was increased by melatonin. Melatonin or oestradiol lowered serum bone alkaline phosphatase activity. Melatonin inhibition was seen mainly on the increase of bone alkaline phosphatase activity that followed ovariectomy. Serum phosphorus levels decreased after melatonin administration and were augmented after oestradiol injection; overall, melatonin impaired the increase of serum phosphorus caused by oestradiol. Ovariectomy decreased, and oestradiol increased, serum calcium levels while melatonin augmented serum calcium in sham-operated rats only. On day 60 after surgery, BMD and content decreased after ovariectomy and were increased after oestradiol injection. Melatonin augmented BA of spine and BMC of whole of the skeleton and tibia. The highest values observed were those of rats treated concurrently with oestradiol and melatonin. The present results indicate that: (i) melatonin treatment restrained bone remodelling after ovariectomy; (ii) the effect of melatonin required adequate concentrations of oestradiol; (iii) melatonin augmented oestradiol effects on bone in ovariectomized rats; (iv) a counter-regulation by melatonin of the increase in body fat caused by ovariectomy was uncovered. The melatonin doses employed were pharmacological in terms of circulating melatonin levels but not necessarily for some other fluids or tissues.
TL;DR: Melatonin's capability of scavenging CO may contribute to its protective potency, and Tiron, a scavenger of superoxide anions, strongly and almost instantaneously inhibited chemiluminescence, in accordance to the requirement of this reactive oxygen species for AFMK formation and its involvement in ‐radical formation.
Abstract: Oxidation of melatonin was followed by measuring chemiluminescence emitted during pyrrole ring cleavage, a process leading to the main oxidation product of this indoleamine, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK). Radical reactions of melatonin were studied in two variants of a moderately alkaline (pH 8) H2O2 system, one of which contained hemin as a catalyst. In both systems, light emission from melatonin oxidation lasted several hours. Time courses and turnover rates depended on the presence or absence of hemin; the catalyst enhanced light emission many-fold. In the two reaction systems, the presence of hydrogen carbonate (HCO)(3)(-) enhanced chemiluminescence by more than 10-fold, indicating scavenging of carbonate radicals. In the presence of 10% dimethylsulfoxide (DMSO) or 1 m mannitol, HCO(3)(-)-dependent as well as independent light emissions were only partially inhibited. With regard to the stimulatory effect of HCO(3)(-), this implies a formation of carbonate radicals (CO)(3)(-) independent of hydroxyl (OH) radicals, presumably involving superoxide anions abundantly present in the system. Tiron, a scavenger of superoxide anions, strongly and almost instantaneously inhibited chemiluminescence, in accordance to the requirement of this reactive oxygen species for AFMK formation and its involvement in -radical formation. Melatonin's capability of scavenging CO(3)(-) may contribute to its protective potency.
TL;DR: The results show that pinealectomy, for lack of melatonin, decreased insulin sensitivity as well as GLUT4 gene expression, and calorie restriction improved insulin sensitivity in Pinx rats, and this was related to increased GLUT 4 gene expression and insulin‐inducedGLUT4 translocation to the plasma membrane in WAT.
Abstract: The present study aimed to investigate insulin sensitivity and GLUT4 expression protein in pinealectomized rats, as well as to determining the effects of melatonin and calorie restriction on the changes induced by pinealectomy. Wistar rats were pinealectomized (Pinx) or sham operated (Sham), and studied 30 days later. Melatonin replacement treatment (50 g/100 g body weight) was continued for 30 days after pinealectomy. Calorie restriction was performed by offering 60% of the standard food intake. In vivo insulin sensitivity was evaluated using the glucose disappearance constant (kITT) during an insulin tolerance test, and GLUT4 mRNA and protein were assessed by Northern and Western blotting, respectively. The in vitro effect of melatonin on GLUT4 protein content in plasma membrane was investigated in adipocytes isolated from intact rats. Compared with Sham rats, Pinx rats showed decreased kITT (40%), GLUT4 expression in white adipose tissue (WAT, approximately 70%), and unchanged GLUT4 expression in skeletal muscle. Melatonin treatment in Pinx rats restored the kITT and GLUT4 protein to control values. No in vitro effects of melatonin (10-9 m) upon GLUT4 protein were observed. Calorie restriction of Pinx rats increased their kITT value ( approximately 40%), total GLUT4 protein content ( approximately 240%) and its translocation to the plasma membrane ( approximately 80%) in WAT. The results show that pinealectomy, for lack of melatonin, decreased insulin sensitivity as well as GLUT4 gene expression. Calorie restriction improved insulin sensitivity in Pinx rats, and this was related to increased GLUT4 gene expression and insulin-induced GLUT4 translocation to the plasma membrane in WAT.
TL;DR: Results show that physiologic melatonin concentrations are important in reducing AK‐induced renal damage, while pharmacologic concentrations of melatonin did not add to the beneficial effect.
Abstract: It is well established that some agents such as aminoglycosides generate free oxygen radicals, leading to an increased oxireductase production, which in turn increases tissue toxicity. The aim of this study is to test whether melatonin, the chief secretory product of the pineal gland and a highly effective antioxidant and free radical scavenger, reduces the nephrotoxicity caused by amikacin (AK). Herein, we investigated the physiologic and pharmacological role of melatonin in influencing AK-induced nephrotoxicity. For this, pinealectomized (Px) and sham operated (non-Px) rats were used. Both AK and melatonin were administered to all groups. We investigated the effects of melatonin on AK-induced changes in levels of malondialdehyde (MDA), a lipid peroxidation product, glutathione (GSH), an antioxidant whose levels are influenced by oxidative stress, and blood urea nitrogen (BUN) and serum creatine (Cr) levels. Morphologic changes in the kidney were also examined by using light microscopy. MDA levels were found to be higher in Px than in non-Px AK-treated animals. Melatonin administration to Px rats reduced MDA levels. In relative to non-Px rats, Px animals treated with AK had significantly lower GSH concentrations while melatonin administration elevated GSH levels in the kidney; however, this stimulatory effect of melatonin was not observed in non-Px AK-treated rats. Treatment with AK alone resulted in significantly higher plasma Cr and BUN levels. Repeated administration of melatonin prevented the AK-induced elevation of plasma Cr and BUN levels. Morphologic damage to renal tubules as a result of AK was more severe in the renal cortex than in the medulla. The damage to the kidney induced by AK was reversed by melatonin in the Px rats. In conclusion, these results show that physiologic melatonin concentrations are important in reducing AK-induced renal damage, while pharmacologic concentrations of melatonin did not add to the beneficial effect.
TL;DR: Melatonin showed a weak effect as a nitrogen monoxide (NO) scavenger in the presence of sodium nitroprusside (NO donor) and low reactivity with 1,1–diphenyl‐2‐picryl hydrazyl (DPPH).
Abstract: We have investigated the action of melatonin against lipid peroxidation in membranes including brain homogenates (BH), brain and liver microsomes (MIC), and phosphatidylcholine (PC) liposomes, as well as its effect on the activity of pro-oxidant enzymes such as constitutive neuronal nitric oxide synthase (cnNOS), xanthine oxidase (XO) and myeloperoxidase (MPO). The liposomes were reconstituted by a dialysis method, lipid peroxidation was monitored using the thiobarbituric reactive substances (TBARS) method and enzyme activities were measured spectrophotometrically. The ascorbyl and hydroxyl free radicals were generated by the reaction of ascorbic acid + FeSO4 and H2O2 + FeCl2, respectively, and peroxynitrite using a mixture of NaNO2 in an alkaline medium. Melatonin protected against lipid peroxidation induced by distinct reactive oxygen species (ROS) in all membranes tested although with different potency, in the following order BH < MIC < PC. The K0.5 for enzyme inhibition by melatonin was determined for nNOS (2.0 +/- 0.1 mm), for XO (0.8 +/- 0.1 mm) and for MPO (0.063 +/- 0.003 mm), the latter one with high affinity. Melatonin showed a weak effect as a nitrogen monoxide (NO) scavenger in the presence of sodium nitroprusside (NO donor) and low reactivity with 1,1-diphenyl-2-picryl hydrazyl (DPPH). These results demonstrate the antioxidant action of melatonin, principally that related to the activity of pro-oxidant enzymes such as XO and MPO.
TL;DR: In this article, the effects of melatonin as an antioxidant, on prevention and treatment of streptozotocin (STZ)-induced diabetic renal injury in rats were investigated.
Abstract: The aim of this study was to investigate the effects of melatonin as an antioxidant, on prevention and treatment of streptozotocin (STZ)-induced diabetic renal injury in rats. Male Wistar rats were divided into four groups: (1) untreated, (2) melatonin-treated, (3) untreated diabetic (UD), (4) melatonin-treated diabetic (MD). Experimental diabetes was induced by single dose (60 mg/kg, i.p.) STZ injection. For 3 days prior to administration of STZ, melatonin was injected (200 microg/kg/day, i.p.); these injections were continued until the end of the study (4 weeks). Malondialdehyde (MDA) levels as a marker of lipid peroxidation were significantly increased in the renal homogenates of UD animals and decreased after melatonin administration. The activity of the antioxidative enzyme glutathione peroxidase (GSH-Px) was significantly reduced in UD rats. Melatonin treatment reversed STZ-induced reduction of GSH-Px activity without having an effect on blood glucose. Upon histopathological examination, it was observed that the melatonin treatment prevented the renal morphological damage caused by diabetes. Upon immunohistochemical investigation, glomerular anti-laminin beta1 staining decreased in MD rats. Additionally, no tubular anti-IGF-1 staining was observed in melatonin-treated rats. In conclusion, chronically administered melatonin reduced renal injury in STZ-induced diabetic rats and thus it may provide a useful therapeutic option in humans to reduce oxidative stress and the associated renal injury in patients with diabetes mellitus.
TL;DR: The biochemical changes observed in neural tissues show that Al acts as pro‐oxidant, while melatonin exerts an antioxidant action in Al‐treated animals, making melatonin worthy of investigation as a potential supplement to be included in the treatment of neurological disorders in which the oxidative effects must be minimized.
Abstract: In recent years, it has been suggested that oxidative stress is a feature of Alzheimer's disease in which aluminum (Al) could exacerbate oxidative events. The goal of the present study was to assess in rats the pro-oxidant effects induced by Al exposure, as well as the protective role of exogenous melatonin. Two groups of male rats were intraperitoneally injected with Al only or melatonin only, at doses of 5 and 10 mg/kg/day, respectively for 8 wk. During this period, a third group of animals received Al (5 mg/kg/day) and melatonin (10 mg/kg/day). At the end of the treatment period, rats were anesthesized and arterial blood was obtained. Thereafter, animals were killed and liver and brain (cortex, hippocampus and cerebellum) were removed. These tissues were processed to examine oxidative stress markers: glutathione transferase (GST), reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), thiobarbituric acid reactive substances (TBARS), as well as protein content. Samples of these tissues were also used to determine Al, Fe, Mn, Cu and Zn concentrations. The results show that Al exposure promotes oxidative stress in different neural areas, including those in which Al concentrations were not significantly increased. The biochemical changes observed in neural tissues show that Al acts as pro-oxidant, while melatonin exerts an antioxidant action in Al-treated animals. The protective effects of melatonin against cellular damage caused by Al-induced oxidative stress, together with its low toxicity, make melatonin worthy of investigation as a potential supplement to be included in the treatment of neurological disorders in which the oxidative effects must be minimized.