CiteULike: Tag melatonin

Prophylactic action of melatonin against cyclophosphamide-induced oxidative stress in mice.

K Manda — 2007-05-31T20:48:13-00:00

Cell Biol Toxicol, Vol. 19, No. 6. (November 2003), pp. 367-372.

The present study investigated the prophylactic influence of melatonin against cyclophosphamide-induced oxidative stress in mouse tissues. Lipid peroxidation, reduced glutathione (GSH), glutathione disulphide (GSSG), glutathione peroxidase (GSH-Px) and serum phosphatase levels were analyzed in brain, spleen liver, lungs, kidney and testes. Fifteen days oral administration with melatonin (0.1 mg/kg bw per day) before treatment checked the augmentation of the level of lipid peroxidation, blood GSSG and acid phosphatase caused by an acute treatment with a radiomimetic drug, cyclophosphamide (75 mg/kg bw). Cyclophosphamide-induced depletion in the level of GSH, GSH-Px and alkaline phosphatase was made up statistically significant by chronic melatonin administration given orally. The results indicate the antioxidative properties of melatonin resulting into its prophylactic property against the cyclophosphamide-induced biochemical alterations. The finding support the idea that melatonin is a potent free-radical scavenger and antioxidant.

Circadian clock in cell culture: I. Oscillation of melatonin release from dissociated chick pineal cells in flow-through microcarrier culture

Lm Robertson — 2007-09-13T16:42:00-00:00

J. Neurosci., Vol. 8, No. 1. (1 January 1988), pp. 12-21.

Alpha-2 adrenergic regulation of melatonin release in chick pineal cell cultures

Bl Pratt — 2007-09-13T16:37:11-00:00

J. Neurosci., Vol. 7, No. 11. (1 November 1987), pp. 3665-3674.

Circadian Disruption, Shift Work and the Risk of Cancer: A Summary of the Evidence and Studies in Seattle

Scott Davis — 2006-04-12T04:08:22-00:00

Cancer Causes and Control, Vol. 17, No. 4. (May 2006), pp. 539-545.

Melatonin, environmental light, and breast cancer

V Srinivasan — 2008-05-10T01:58:41-00:00

Breast Cancer Research and Treatment, Vol. 108, No. 3. (20 April 2008), pp. 339-350.

Abstract Although many factors have been suggested as causes for breast cancer, the increased incidence of the disease seen in women working in night shifts led to the hypothesis that the suppression of melatonin by light or melatonin deficiency plays a major role in cancer development. Studies on the 7,12-dimethylbenz[a]anthracene and N-methyl-N-nitrosourea experimental models of human breast cancer indicate that melatonin is effective in reducing cancer development. In vitro studies in MCF-7 human breast cancer cell line have shown that melatonin exerts its anticarcinogenic actions through a variety of mechanisms, and that it is most effective in estrogen receptor (ER) α-positive breast cancer cells. Melatonin suppresses ER gene, modulates several estrogen dependent regulatory proteins and pro-oncogenes, inhibits cell proliferation, and impairs the metastatic capacity of MCF-7 human breast cancer cells. The anticarcinogenic action on MCF-7 cells has been demonstrated at the physiological concentrations of melatonin attained at night, suggesting thereby that melatonin acts like an endogenous antiestrogen. Melatonin also decreases the formation of estrogens from androgens via aromatase inhibition. Circulating melatonin levels are abnormally low in ER-positive breast cancer patients thereby supporting the melatonin hypothesis for breast cancer in shift working women. It has been postulated that enhanced endogenous melatonin secretion is responsible for the beneficial effects of meditation as a form of psychosocial intervention that helps breast cancer patients.

Sleep-anticipating effects of melatonin in the human brain

Tali Gorfine — 2008-04-24T19:05:23-00:00

NeuroImage, Vol. 31, No. 1. (15 May 2006), pp. 410-418.

Melatonin, the hormone produced nocturnally by the pineal gland, is an endogenous regulator of the sleep-wake cycle. The effects of melatonin on brain activities and their relation to induction of sleepiness were studied in a randomized, double-blind, placebo controlled functional magnetic resonance imaging (fMRI) study. Melatonin, but not placebo, reduced task-related activity in the rostro-medial aspect of the occipital cortex during a visual-search task and in the auditory cortex during a music task. These effects correlated with subjective measurements of fatigue. In addition, melatonin enhanced the activation in the left parahippocampus in an autobiographic memory task. Results demonstrate that melatonin modulates brain activity in a manner resembling actual sleep although subjects are fully awake. Furthermore, the fatigue inducing effect of melatonin on brain activity is essentially different from that of sleep deprivation thus revealing differences between fatigues related to the circadian sleep regulation as opposed to increased homeostatic sleep need. Our findings highlight the role of melatonin in priming sleep-associated brain activation patterns in anticipation of sleep.

Neither functional rod photoreceptors nor rod or cone outer segments are required for the photic inhibition of pineal melatonin.

RJ Lucas — 2006-06-21T18:07:23-00:00

Endocrinology, Vol. 140, No. 4. (April 1999), pp. 1520-1524.

Pineal melatonin production is rapidly suppressed by light. In mammals, the photoreceptors mediating this response are ocular; however, definitive information regarding their nature and precise location is absent. In an attempt to define these photoreceptors, we examined the sensitivity of pineal melatonin production to inhibition by controlled irradiance monochromatic green light (lambda max 509 nm) in C3H mice bearing either of two mutations affecting the retina: retinal degeneration (rd), a disruption of rod phototransduction, and retinal degeneration slow (rds), an ablation of photoreceptor outer segments. Diurnal profiles of pineal melatonin content were similar in both mutant genotypes and in wild-type mice; melatonin peaked between 3-5 h before lights on. All three genotypes exhibited irradiance dependent inhibition of pineal melatonin content; 2.6 x 10(-2) microwatts/cm2 509 nm light induced complete suppression in all three genotypes, whereas lower irradiances were ineffective in all cases. Bilateral enucleation abolished responses even to 6 microwatts/cm2 509 nm light. These results demonstrate that the process of irradiance detection for pineal melatonin inhibition is buffered against considerable loss of photoreceptive capacity and that neither rod photoreceptors nor rod or cone outer segments are required for mediating this response in mice.

Immunocytochemical demonstration of day/night changes of clock gene protein levels in the murine adrenal gland: differences between melatonin-proficient (C3H) and melatonin-deficient (C57BL) mice

Claudia Torres-Farfan — 2005-11-30T14:49:13-00:00

Journal of Pineal Research, Vol. 40, No. 1. (January 2006), pp. 64-70.

Chromophore regeneration: Melanopsin does its own thing.

RJ Lucas — 2006-07-25T15:56:13-00:00

Proc Natl Acad Sci U S A, Vol. 103, No. 27. (5 July 2006), pp. 10153-10154.

Photic and circadian regulation of retinal melatonin in mammals.

G Tosini — 2006-06-21T18:17:20-00:00

J Neuroendocrinol, Vol. 15, No. 4. (April 2003), pp. 364-369.

Several studies have established that melatonin synthesis occurs in the retina of vertebrates, including mammals. In mammals, a subpopulation of photoreceptors (probably the cones) synthesize melatonin. Melatonin synthesis in the retina is elevated at night and reduced during the day in a fashion similar to events in the pineal gland. Both the MT1 and MT2 melatonin receptors are present in the retina and retinal melatonin does not contribute to circulating levels, suggesting that retinal melatonin acts locally as a neurohormone and/or neuromodulator. Melatonin synthesis in the retina of mammals is under the control of a circadian oscillator, and circadian rhythms in melatonin synthesis and/or release have been described for several species of mammals. These rhythms are present in vivo, persist in vitro, are entrained by light and are temperature compensated. The cloning of the gene responsible for the synthesis of the enzyme arylalkylamine N-acetyltransferase (the key enzyme in the melatonin biosynthetic pathway) has allowed studies of the molecular mechanisms responsible for the generation of retinal melatonin rhythmicity. The present review focuses on the cellular and molecular mechanisms that regulate melatonin synthesis. In particular, we discuss how the photic environment and the circadian clock interact in determining melatonin levels, in addition to the role that melatonin plays in retinal physiology.

Natural melatonin 'knockdown' in C57BL/6J mice: rare mechanism truncates serotonin N-acetyltransferase.

PH Roseboom — 2007-08-17T12:59:30-00:00

Brain Res Mol Brain Res, Vol. 63, No. 1. (10 December 1998), pp. 189-197.

Pineal melatonin synthesis (serotonin --> N-acetylserotonin --> melatonin) is severely compromised in most inbred strains of mice, in many cases because serotonin is not acetylated by serotonin N-acetyltransferase (arylalkylamine N-acetyltransferase, AANAT). We have found that in the C57BL/6J strain, AANAT mRNA encodes a severely truncated AANAT protein, because a pseudo-exon containing a stop codon is spliced in. This is the first identification of a natural mutation which knocks down melatonin synthesis. The decrease in melatonin signaling may have been a selective factor in the development of laboratory strains of mice because melatonin can inhibit reproduction and modify circadian rhythmicity.

Melatonin receptors and their regulation: biochemical and structural mechanisms

Paula Witt-Enderby — 2006-05-28T20:08:04-00:00

Life Sciences, Vol. 72, No. 20. (4 April 2003), pp. 2183-2198.

There is growing evidence demonstrating the complexity of melatonin's role in modulating a diverse number of physiological processes. This complexity could be attributed to the fact that melatonin receptors belong to two distinct classes of proteins, that is, the G-protein coupled receptor superfamily (MT1, MT2) and the quinone reductase enzyme family (MT3) which makes them unique at the molecular level. Also, within the G-protein coupled receptor family of proteins, the MT1 and MT2 receptors can couple to multiple and distinct signal transduction cascades whose activation can lead to unique cellular responses. Also, throughout the 24-hour cycle, the receptors' sensitivity to specific cues fluctuates and this sensitivity can be modulated in a homologous fashion, that is, by melatonin itself, and in a heterologous manner, that is, by other cues including the photoperiod or estrogen. This sensitivity of response may reflect changes in melatonin receptor density that also occurs throughout the 24-hour light/dark cycle but out of phase with circulating melatonin levels. The mechanisms that underlie the changes in melatonin receptor density and function are still not well-understood, but data is beginning to show that transcriptional events and G-protein uncoupling may be involved. Even though this area of research is still in its infancy, great strides are being made everyday in elucidating the mechanisms that underlie melatonin receptor function and regulation. The focus of this review is to highlight some of these discoveries in an attempt to reveal the uniqueness of the melatonin receptor family while at the same time provide thought-provoking ideas to further advance this area of research. Thus, a brief overview of each of the mammalian melatonin receptor subtypes and the signal transduction cascades to which they couple will be discussed with a greater emphasis placed on the mechanisms underlying their regulation and the domains within the receptors essential for proper signaling.

Daily exercise facilitates phase delays of circadian melatonin rhythm in very dim light.

LK Barger — 2006-01-11T01:54:37-00:00

Am J Physiol Regul Integr Comp Physiol, Vol. 286, No. 6. (June 2004)

Shift workers and transmeridian travelers are exposed to abnormal work-rest cycles, inducing a change in the phase relationship between the sleep-wake cycle and the endogenous circadian timing system. Misalignment of circadian phase is associated with sleep disruption and deterioration of alertness and cognitive performance. Exercise has been investigated as a behavioral countermeasure to facilitate circadian adaptation. In contrast to previous studies where results might have been confounded by ambient light exposure, this investigation was conducted under strictly controlled very dim light (standing approximately 0.65 lux; angle of gaze) conditions to minimize the phase-resetting effects of light. Eighteen young, fit males completed a 15-day randomized clinical trial in which circadian phase was measured in a constant routine before and after exposure to a week of nightly bouts of exercise or a nonexercise control condition after a 9-h delay in the sleep-wake schedule. Plasma samples collected every 30-60 min were analyzed for melatonin to determine circadian phase. Subjects who completed three 45-min bouts of cycle ergometry each night showed a significantly greater shift in the dim light melatonin onset (DLMO(25%)), dim light melatonin offset, and midpoint of the melatonin profile compared with nonexercising controls (Student t-test; P < 0.05). The magnitude of phase delay induced by the exercise intervention was significantly dependent on the relative timing of the exercise after the preintervention DLMO(25%) (r = -0.73, P < 0.05) such that the closer to the DLMO(25%), the greater the phase shift. These data suggest that exercise may help to facilitate circadian adaptation to schedules requiring a delay in the sleep-wake cycle.

The in vivo effect of melatonin on cellular activation processes in human blood during strenuous physical exercise

Paul Johe — 2005-09-18T01:58:23-00:00

Journal of Pineal Research, Vol. 39, No. 3. (October 2005), pp. 324-330.

Effects of melatonin and Vitamin E on oxidative-antioxidative status in rats exposed to irradiation.

Seval Yilmaz — 2006-04-17T01:17:14-00:00

Toxicology (6 March 2006)

Bone marrow is known to be particularly susceptible to radiation. In this study, the effects of treatment with Vitamin E and melatonin and irradiation-induced lipid peroxidation and its association with antioxidant enzymes in the total bone (bone and bone marrow) and skeletal muscle of rats subjected to total body irradiation was investigated. Wistar-Albino rats were intraperitoneally treated with 100mg/kg Vitamin E or melatonin before exposure to 720cGy irradiation. Control, irradiation, Vitamin E plus irradiation, melatonin plus irradiation groups were sacrificed by decapitation under ether anaesthesia on the 10th day after irradiation exposure. Application of total body irradiation elevated malondialdehyde (MDA) levels in rat skeletal muscle (p<0.001), but glutathione peroxidase (GSH-Px) and catalase activities remained unchanged. Application of Vitamin E with irradiation or melatonin decreased the MDA levels in skeletal muscle (p<0.01), but did not affect the GSH-Px and catalase activity. MDA levels were found elevated in total bone (p<0.001), GSH-Px activity decreased (p<0.001) and catalase activity remained unchanged in the group treated with irradiation. Application of Vitamin E with irradiation increased the GSH-Px activity in total bone (p<0.01), but the activity of MDA and catalase remained unchanged. Treatment of the animals with melatonin concurrent with total body irradiation reduced the degree of lipid peroxidation and elevation in antioxidant enzymes in total bone (p<0.01). We conclude that melatonin may protect the total bone from the damaging effects of irradiation exposure, and its actions protect total bone from oxidative stress. However, protective effects of Vitamin E were not observed in this study.

Effects of daytime ingestion of melatonin on short-term athletic performance.

G Atkinson — 2006-01-11T01:45:21-00:00

Ergonomics, Vol. 48, No. 11. (v 2005), pp. 1512-1522.

The immediate effects of ingesting melatonin in the daytime include decreased alertness and body temperature. To date, no researcher has examined whether daytime ingestion of melatonin leads to impairments in variables relevant to short-term (<10 min) athletic performance. Twelve physically active participants (mean +/- s age = 25.2 +/- 5.0 years, body mass = 81.4 +/- 12.1 kg and chronotype = 33.8 +/- 6.3 units) ingested 5 mg of melatonin or placebo at 11:45 hours in a double-blind experiment. At 13:00 and 17:00 hours, subjective alertness was measured, together with intra-aural temperature, reaction time (two-, four- and eight-choice), short-term memory recall and grip strength. Performance, ratings of perceived exertion (RPE) and heart rate were also recorded during a 4-km cycling time trial. At 13:00 hours, the mean +/- s intra-aural temperature was 0.49 +/- 0.79 degrees C lower after ingestion of melatonin than after placebo (p = 0.015), but this difference was not apparent at 17:00 hours. At both 13:00 and 17:00 hours, melatonin reduced (p < 0.05) alertness, short-term memory and exercise heart rate by 1.5 +/- 1.8 units, 1 +/- 1 digits and 6 +/- 9 beats.min(-1), respectively (mean +/- s). Eight-choice reaction time was also slower at both times of day after ingesting melatonin. Melatonin did not influence time trial performance or RPE (p > 0.05). The effects of 5 mg of melatonin seem more pronounced for mental rather than physical components of short-term athletic performance, although the cardiovascular responses to exercise are affected. Some effects of melatonin were apparent 5 h after ingestion when the hypothermic effects of melatonin had dissipated.

Regulation of antioxidant enzymes: a significant role for melatonin.

C Rodriguez — 2005-10-17T15:22:20-00:00

J Pineal Res, Vol. 36, No. 1. (January 2004), pp. 1-9.

Antioxidant enzymes form the first line of defense against free radicals in organisms. Their regulation depends mainly on the oxidant status of the cell, given that oxidants are their principal modulators. However, other factors have been reported to increase antioxidant enzyme activity and/or gene expression. During the last decade, the antioxidant melatonin has been shown to possess genomic actions, regulating the expression of several genes. Melatonin also influences both antioxidant enzyme activity and cellular mRNA levels for these enzymes. In the present report, we review the studies which document the influence of melatonin on the activity and expression of the antioxidative enzymes glutathione peroxidase, superoxide dismutases and catalase both under physiological and under conditions of elevated oxidative stress. We also analyze the possible mechanisms by which melatonin regulates these enzymes.

Melatonin madness.

SM Reppert — 2006-06-14T18:59:31-00:00

Cell, Vol. 83, No. 7. (29 December 1995), pp. 1059-1062.

Sleep protects excitatory cortical circuits against oxidative damage.

G Schulze — 2006-06-15T00:51:10-00:00

Med Hypotheses, Vol. 63, No. 2. (2004), pp. 203-207.

Activity in excitatory cortical pathways increases the oxidative metabolism of the brain and the risk of oxidative damage. Oxyradicals formed during periods of activity are mopped up by neural pools of nuclear factor kappa-B resulting in their activation and translocation to cell nuclei. During waking hours, glucocorticoids inhibit transactivation by nuclear factor kappa-B, increase central norepinephrine release, and elevate expression of prostaglandin D2. The build-up of nuclear factor kappa-B and prostaglandin D2 produces sleep pressures leading to sleep onset, normally gated by circadian melatonin release. During slow wave sleep nuclear factor kappa-B induces transcription of synaptogenic and antioxidant products and synaptic remodeling follows. Synaptically remodeled neural circuits have modified conductivity patterns and timescales and need to be resynchronized with existing unmodified neural circuits. The resynchronization process, mediated by theta rhythm, occurs during rapid eye movement sleep and is orchestrated from pontine centers. Resynchronization of remodeled neural circuits produces dreams. The waking state results upon successful resynchronization. Rapid eye movement sleep deprivation results in a lack of resynchronization and leads to cognitive inefficiencies. The model presented here proposes that the primary purpose of sleep is to protect cortical circuits against oxidative damage by reducing cortical activity and by remodeling and resynchronizing cortical circuits during this period of reduced activity to sustain new patterns of activation more effectively.

The rotational origin and state of the whole: its relation to growth, fertility, aging, death, and diseases.

W Pierpaoli — 2006-06-16T04:23:07-00:00

Ann N Y Acad Sci, Vol. 1057 (December 2005), pp. 1-15.

The purpose of my report is to synthetically summarize the concept of the rotatory essence of the Whole and to bring evidence that while aging responds to a precise inner "program" of the mammalian and any other species' "brain," acceleration of aging and all diseases are simply the direct outcome of a desynchronization of our inner "clock" with respect to the precise periodicity and hormone-integrated rhythmicity of the solar system. Those neuroendocrine, hormonal derangements of our inner clock are easily detectable and inevitably anticipate even by decades the onset of all diseases (autoimmune, cardiovascular, neurodegenerative, neoplastic). I will introduce those interventions capable of detecting early alterations and of restoring hormonal rhythmicity, which will consequently restore immunological surveillance in a positive cascade sequence.

Melatonin prevents oxidative stress and inhibits reactive gliosis induced by hyperhomocysteinemia in rats.

G Baydas — 2006-06-15T00:48:39-00:00

Biochemistry (Mosc), Vol. 71 Suppl 1 (2006)

Homocysteine (Hcy), an independent risk factor for atherosclerosis, undergoes auto-oxidation and generates reactive oxygen species, which are thought to be main cause of Hcy neurotoxicity. However, the mechanisms leading to neurodegenerative disorders are poorly understood because studies that have investigated the potential neurotoxicity of hyperhomocysteinemia in vivo are scarce. The purpose of this study was to test whether daily administration of methionine, which induces hyperhomocysteinemia, causes glial hyperactivity, and also to investigate the protective effects of melatonin on the brain tissue against oxidative stress of Hcy in rats. There was a significant development of oxidative stress as indicated by an increase in malondialdehyde + 4-hydroxyalkenals in hippocampus and cortex of hyperhomocysteinemic rats, whereas significant reduction was found in the activity of glutathione peroxidase (GSH-Px). Co-treatment with melatonin inhibited the elevation of lipid peroxidation and significantly increased GSH-Px activity in the brain regions studied. Western blot analysis revealed an increase in glial fibrillary acidic protein (GFAP) contents both in hippocampus and frontal cortex (p < 0.001) of hyperhomocysteinemic rats compared to the controls. Administration of melatonin significantly decreased GFAP contents in hippocampus and cortex (p < 0.05). S100B contents increased only in frontal cortex in hyperhomocysteinemic rats compared to the control (p < 0.01) and was inhibited by melatonin treatment (p < 0.01). The present findings show that Hcy can sensitize glial cells, a mechanism which might contribute to the pathogenesis of neurodegenerative disorders, and further suggest that melatonin can be involved in protecting against the toxicity of Hcy by inhibiting free radical generation and stabilizing glial cell activity.

Light and exercise and melatonin production in women.

JA Knight — 2006-05-10T16:35:48-00:00

Am J Epidemiol, Vol. 162, No. 11. (1 December 2005), pp. 1114-1122.

Melatonin may protect against breast cancer. Light and other factors influence melatonin, but the evidence is limited. The authors conducted a study to determine factors related to melatonin. Women volunteers recruited in Toronto, Canada, from 2002 to 2004 collected urine for three nights (winter and summer), took periodic light measurements, and recorded exposures in a diary. The relation of each variable to log-transformed creatinine-corrected 6-sulfatoxymelatonin in overnight urine was determined by use of generalized estimating equation linear regression. The final model was based on 1,054 measurement days from 213 participating women. None of the light variables was related to the log of 6-sulfatoxymelatonin. A significant interaction between season and day length was included in the final model. The most significant factor was duration of exercise (beta = 0.072; p = 0.004, two-tailed), which increased the amount of melatonin produced. Exercise duration later in the day was more significant (beta = 0.108; p = 0.0009, two-tailed). There was no difference between moderate or strenuous exercise. The failure to find a relation between light brightness and melatonin may be due to the difficulty of measuring this, as well as the importance of the light spectrum, which could not be measured. It is possible that the protective effect of exercise with respect to breast cancer may operate in part through an effect on melatonin.

Circadian rhythms, oxidative stress, and antioxidative defense mechanisms.

R Hardeland — 2005-10-16T19:35:10-00:00

Chronobiol Int, Vol. 20, No. 6. (November 2003), pp. 921-962.

Endogenous circadian and exogenously driven daily rhythms of antioxidative enzyme activities and of low molecular weight antioxidants (LMWAs) are described in various phylogenetically distant organisms. Substantial amplitudes are detected in several cases, suggesting the significance of rhythmicity in avoiding excessive oxidative stress. Mammalian and/or avian glutathione peroxidase and, as a consequence, glutathione reductase activities follow the rhythm of melatonin. Another hint for an involvement of melatonin in the control of redox processes is seen in its high-affinity binding to cytosolic quinone reductase 2, previously believed to be a melatonin receptor. Although antioxidative protection by pharmacological doses of melatonin is repeatedly reported, explanations of these findings are still insufficient and their physiological and chronobiological relevance is not yet settled. Recent data indicate a role of melatonin in the avoidance of mitochondrial radical formation, a function which may prevail over direct scavenging. Rhythmic changes in oxidative damage of protein and lipid molecules are also reported. Enhanced oxidative protein modification accompanied by a marked increase in the circadian amplitude of this parameter is detected in the Drosophila mutant rosy, which is deficient in the LMWA urate. Preliminary evidence for the significance of circadian rhythmicity in diminishing oxidative stress comes from clock mutants. In Drosophila, moderately enhanced protein damage is described for the arrhythmic and melatonin null mutant per0, but even more elevated, periodic damage is found in the short-period mutant per(s), synchronized to LD 12:12. Remarkably large increases in oxidative protein damage, along with impairment of tissue integrity and--obviously insufficient--compensatory elevations in protective enzymes are observed in a particularly vulnerable organ, the Harderian gland, of another short-period mutant tau, in the Syrian hamster. Mice deficient in the per2 gene homolog are reported to be cancer-prone, a finding which might also relate to oxidative stress. In the dinoflagellate Lingulodinium polyedrum [Gonyaulax polyedra], various treatments that cause oxidative stress result in strong suppressions of melatonin and its metabolite 5-methoxytryptamine (5-MT) and to secondary effects on overt rhythmicity. The glow maximum, depending on the presence of elevated 5-MT at the end of subjective night, decreases in a dose-dependent manner already under moderate, non-lethal oxidative stress, but is restored by replenishing melatonin. Therefore, a general effect of oxidative stress may consist in declines of easily oxidizable signaling molecules such as melatonin, and this can have consequences on the circadian intraorganismal organization and expression of overt rhythms. Recent findings on a redox-sensitive input into the core oscillator via modulation of NPAS2/BMAL1 or CLK/BMAL1 heterodimer binding to DNA indicate a direct influence of cellular redox balance, including oxidative stress, on the circadian clock.

Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance.

R Hardeland — 2005-10-16T19:08:41-00:00

Endocrine, Vol. 27, No. 2. (July 2005), pp. 119-130.

Melatonin has been shown to protect against oxidative stress in various, highly divergent experimental systems. There are many reasons for its remarkable protective potential. Signaling effects comprise the upregulation of antioxidant enzymes, such as superoxide dismutases, peroxidases, and enzymes of glutathione supply, down-regulation of prooxidant enzymes, such as nitric oxide synthases and lipoxygenases, and presumably also the control of quinone reductase 2. Other mechanisms are based on direct interactions with several reactive oxygen and nitrogen species. Among these reactions, the capacity of easily undergoing single-electron transfer reactions is of particular importance. Electron donation by melatonin is not only an aspect of direct radical scavenging, but additionally represents the basis for formation of the protective metabolites AFMK (N1-ace-tyl-N2-formyl-5-methoxykynuramine) and AMK (N1-acetyl-5-methoxykynuramine). Recent investigations on mitochondrial metabolism indicate that melatonin as well as AMK are capable of supporting the electron flux through the respiratory chain, of preventing the breakdown of the mitochondrial membrane potential, and of decreasing electron leakage, thereby reducing the formation of superoxide anions. Radical avoidance is a new line of investigation, which exceeds mitochondrial actions and also comprises antiexcitatory effects and contributions to the maintenance of internal circadian phase relationships.

Melatonin as antioxidant, geroprotector and anticarcinogen.

Vladimir N Anisimov — 2006-05-23T20:57:58-00:00

Biochim Biophys Acta (17 April 2006)

The effect of the pineal indole hormone melatonin on the life span of mice, rats and fruit flies has been studied using various approaches. It has been observed that in female CBA, SHR, SAM and transgenic HER-2/neu mice long-term administration of melatonin was followed by an increase in the mean life span. In rats, melatonin treatment increased survival of male and female rats. In D. melanogaster, supplementation of melatonin to nutrient medium during developmental stages produced contradictory results, but and increase in the longevity of fruit flies has been observed when melatonin was added to food throughout the life span. In mice and rats, melatonin is a potent antioxidant both in vitro and in vivo. Melatonin alone turned out neither toxic nor mutagenic in the Ames test and revealed clastogenic activity at high concentration in the COMET assay. Melatonin has inhibited mutagenesis and clastogenic effect of a number of indirect chemical mutagens. Melatonin inhibits the development of spontaneous and 7-12-dimethlbenz(a)anthracene (DMBA)- or N-nitrosomethylurea-induced mammary carcinogenesis in rodents; colon carcinogenesis induced by 1,2-dimethylhydrazine in rats, N-diethylnitrosamine-induced hepatocarcinogenesis in rats, DMBA-induced carcinogenesis of the uterine cervix and vagina in mice; benzo(a)pyrene-induced soft tissue carcinogenesis and lung carcinogenesis induced by urethan in mice. To identify molecular events regulated by melatonin, gene expression profiles were studied in the heart and brain of melatonin-treated CBA mice using cDNA gene expression arrays (15,247 and 16,897 cDNA clone sets, respectively). It was shown that genes controlling the cell cycle, cell/organism defense, protein expression and transport are the primary effectors for melatonin. Melatonin also increased the expression of some mitochondrial genes (16S, cytochrome c oxidases 1 and 3 (COX1 and COX3), and NADH dehydrogenases 1 and 4 (ND1 and ND4)), which agrees with its ability to inhibit free radical processes. Of great interest is the effect of melatonin upon the expression of a large number of genes related to calcium exchange, such as Cul5, Dcamkl1 and Kcnn4; a significant effect of melatonin on the expression of some oncogenesis-related genes was also detected. Thus, we believe that melatonin may be used for the prevention of premature aging and carcinogenesis.

Effect of melatonin treatment on oxygen consumption by rat liver mitochondria.

C F Reyes-Toso — 2006-05-23T23:58:40-00:00

Amino Acids (24 March 2006)

The objective of this study was to examine the in vivo effect of melatonin on rat mitochondrial liver respiration. Two experiments were performed: For experiment 1, adult male rats received melatonin in the drinking water (16 or 50 microg/ml) or vehicle during 45 days. For experiment 2, rats received melatonin in the drinking water (50 microg/ml) for 45 days, or the same amount for 30 days followed by a 15 day-withdrawal period. At sacrifice, a liver mitochondrial fraction was prepared and oxygen consumption was measured polarographically in the presence of excess concentration of DL-3-beta-hydroxybutyrate or L-succinate. Melatonin treatment decreased Krebs' cycle substrate-induced respiration significantly at both examined doses. The stimulation of mitochondrial respiration caused by excess concentration of substrate recovered after melatonin withdrawal. Basal state 4 respiration was not modified by melatonin. Melatonin, by curtailing overstimulation of cellular respiration caused by excess Krebs' cycle substrates, can protect the mitochondria from oxidative damage.

Melatonin and mitochondrial function.

J Leon — 2005-12-21T18:51:01-00:00

Life Sci, Vol. 75, No. 7. (2 July 2004), pp. 765-790.

Melatonin is a natural occurring compound with well-known antioxidant properties. In the last decade a new effect of melatonin on mitochondrial homeostasis has been discovered and, although the exact molecular mechanism for this effect remains unknown, it may explain, at least in part, the protective properties found for the indoleamine in degenerative conditions such as aging as well as Parkinson's disease, Alzheimer's disease, epilepsy, sepsis and other injuries such as ischemia-reperfusion. A common feature in these diseases is the existence of mitochondrial damage due to oxidative stress, which may lead to a decrease in the activities of mitochondrial complexes and ATP production, and, as a consequence, a further increase in free radical generation. A vicious cycle thus results under these conditions of oxidative stress with the final consequence being cell death by necrosis or apoptosis. Melatonin is able of directly scavenging a variety of toxic oxygen and nitrogen-based reactants, stimulates antioxidative enzymes, increases the efficiency of the electron transport chain thereby limiting electron leakage and free radical generation, and promotes ATP synthesis. Via these actions, melatonin preserves the integrity of the mitochondria and helps to maintain cell functions and survival.

Effect of orally administered L-tryptophan on serotonin, melatonin, and the innate immune response in the rat.

S Esteban — 2005-09-17T22:47:20-00:00

Mol Cell Biochem, Vol. 267, No. 1-2. (December 2004), pp. 39-46.

To assess the effects of external administration of L-tryptophan on the synthesis of serotonin and melatonin as well as on the immune function of Wistar rats, 300 mg of the amino acid were administered through an oral cannula either during daylight (08:00) or at night (20:00) for 5 days. Brain, plasma, and peritoneal macrophage samples were collected 4 h after the administration. The accumulation of 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition was used to measure the rate of tryptophan hydroxylation in vivo. Circulating melatonin levels were determined by radioimmunoassay, and the phagocytic activity of macrophages was measured by counting, under oil-immersion phase-contrast microscopy, the number of particles ingested. The results showed a diurnal increase (p < 0.05) in the brain 5-HTP, serotonin (5-hydroxytryptamine, 5-HT), and 5-hydroxyindolacetic acid (5-HIAA) of the animals which had received tryptophan at 08:00 and were killed 4 h later. In the animals which received tryptophan during the dark period, the 5-HT declined but the 5-HT/5-HIAA ratio remained unchanged. There was also a significant increase (p < 0.05) in nocturnal circulating melatonin levels and in the innate immune response of the peritoneal macrophages in the animals which had received tryptophan at 20:00. The results indicated that the synthesis of serotonin and melatonin, as well as the innate immune response, can be modulated by oral ingestion of tryptophan.

Administration of melatonin and related indoles prevents exercise-induced cellular oxidative changes in rats.

M Hara — 2005-11-08T16:56:16-00:00

Biol Signals, Vol. 6, No. 2. (r 1997), pp. 90-100.

In an attempt to define the role of the pineal hormone melatonin and two analogues (5-methoxytryptamine, 5MT, and 6-hydroxymelatonin, 6HM) in limiting oxidative stress, the present study investigated the changes in glutathione, lipid peroxidation, and the activity of the antioxidant enzyme glutathione peroxidase after exercise (swimming for 60 min) with or without treatment with the indolamines mentioned. Lipid peroxidation was measured by estimating tissue levels of malondialdehyde and 4-hydroxyalkenals; the experimental animals in these studies were male Sprague-Dawley rats. In the liver, swimming exercise increased the levels of reduced glutathione (GSH) and also significantly increasing oxidized glutathione (GSSG), while decreasing the GSH/GSSG ratio, an index directly related to oxidative stress. When the animals were treated with melatonin, the concentrations of GSH and GSSG were also increased after swimming; however, no reduction in the GSH/GSSG ratio appeared. In the animals treated with 6HM the changes were the same as in those treated with melatonin. In muscle as well, the concentration of GSH and the GSH/GSSG ratio were decreased following 60 min of swimming. Pretreatment of the rats with melatonin prevented these effects. Pretreatment of the rats with both 5MT and 6HM also prevented the changes. Brain GSH/GSSG ratio was not affected by either exercise or indolamine administration. Swimming enhanced lipid peroxidation in the liver, muscle and brain; however, this was prevented in animals treated with melatonin or 6HM before swimming. Glutathione peroxidase was significantly elevated after exercise in the brain but not in the liver and muscle. It is concluded that swimming imposes a severe oxidative stress and suggests that melatonin and, to a lesser degree, 5MT and 6HM confer protection against the oxidative damage associated with swimming for 60 min. This mechanism may be reasonably attributed to their indole structure, which possibly allows these molecules to act as free-radical scavengers.

Melatonin mitigates mitochondrial malfunction

Josefa Leon — 2004-12-28T16:44:06-00:00

Journal of Pineal Research, Vol. 38, No. 1., 1.

Interactions between melatonin and nicotinamide nucleotide: NADH preservation in cells and in cell-free systems by melatonin

Dun-Xian Tan — 2005-07-31T11:48:30-00:00

Journal of Pineal Research, Vol. 39, No. 2. (September 2005), pp. 185-194.

Melatonin and ulcerative colitis: Evidence, biological mechanisms, and future research

Paul Terry — 2008-07-17T10:49:51-00:00

Inflammatory Bowel Diseases, Vol. 9999, No. 9999. (2008), NA.

Ulcerative colitis (UC) is an inflammatory bowel disease that afflicts up to 1 million people in the US. Current treatments for UC are mostly nonspecific, not always effective, and often accompanied by serious side effects. Therefore, there is considerable interest in finding alternative and more tolerable treatments for this disease. Physiologic data suggest that melatonin is an important regulator of both inflammation and motility in the gastrointestinal tract, and data from in vitro studies, animal experiments, and limited studies in humans suggest that supplemental melatonin may have an ameliorative effect on colitis. In this review we summarize the evidence regarding melatonin as a possible therapeutic agent in UC and discuss possible biological mechanisms and directions for future research.(Inflamm Bowel Dis 2008)

Melatonin signaling dysfunction in adolescent idiopathic scoliosis.

A Moreau — 2007-01-03T19:41:56-00:00

Spine, Vol. 29, No. 16. (15 August 2004), pp. 1772-1781.

STUDY DESIGN: In vitro assays were performed with bone-forming cells isolated from 41 patients with adolescent idiopathic scoliosis and 17 control patients exhibiting another type of scoliosis or none. OBJECTIVE: To determine whether a dysfunction of the melatonin-signaling pathway in tissues targeted by this hormone is involved in adolescent idiopathic scoliosis. SUMMARY OF BACKGROUND DATA: Pinealectomy in chicken has led to the formation of a scoliotic deformity, thereby suggesting that a melatonin deficiency may be at the source of adolescent idiopathic scoliosis. However, the relevance of melatonin in the etiopathogenesis of that condition is controversial because most studies have reported no significant change in circulating levels of melatonin in patients with adolescent idiopathic scoliosis. METHODS: Primary osteoblast cultures prepared from bone specimens obtained intraoperatively during spine surgeries were used to test the ability of melatonin and Gpp(NH)p, a GTP analogue, to block cAMP accumulation induced by forskolin. In parallel, melatonin receptor and Gi protein functions were evaluated by immunohistochemistry and by coimmunoprecipitation experiments. RESULTS: The cAMP assays demonstrated that melatonin signaling was impaired in osteoblasts isolated from adolescent idiopathic scoliosis patients to different degrees allowing their classification in 3 distinct groups based on their responsiveness to melatonin or Gpp(NH)p. CONCLUSION: Melatonin signaling is clearly impaired in osteoblasts of all patients with adolescent idiopathic scoliosis tested. Classification of patients with adolescent idiopathic scoliosis in 3 groups based on functional in vitro assays suggests the presence of distinct mutations interfering with the melatonin signal transduction. Posttranslational modifications affecting Gi protein function, such as serine residues phosphorylation, should be considered as one possible mechanism in the etiopathogenesis of AIS.

Melatonin Suppresses Nighttime Memory Formation in Zebrafish

Oliver Rawashdeh — 2007-11-16T13:39:49-00:00

Science, Vol. 318, No. 5853. (16 November 2007), pp. 1144-1146.

Memory processes are modulated by the biological clock, although the mechanisms are unknown. Here, we report that in the diurnal zebrafish both learning and memory formation of an operant conditioning paradigm occur better during the day than during the night. Melatonin treatment during the day mimics the nighttime suppression of memory formation. Training in constant light improves nighttime memory formation while reducing endogenous melatonin concentrations. Treatment with melatonin receptor antagonists at night dramatically improves memory. Pinealectomy also significantly improves nighttime memory formation. We adduce that melatonin is both sufficient and necessary for poor memory formation during the night. 10.1126/science.1148564

Human malarial parasite, Plasmodium falciparum, displays capacitative calcium entry: 2-aminoethyl diphenylborinate blocks the signal transduction pathway of melatonin action on the P. falciparum cell cycle

Beraldo — 2007-10-11T19:33:24-00:00

Journal of Pineal Research, Vol. 43, No. 4. (November 2007), pp. 360-364.

mt1 Melatonin Receptor in the Primate Adrenal Gland: Inhibition of Adrenocorticotropin-Stimulated Cortisol Production by Melatonin

Claudia Torres-Farfan — 2006-09-05T21:28:13-00:00

J Clin Endocrinol Metab, Vol. 88, No. 1. (1 January 2003), pp. 450-458.

The pineal hormone melatonin participates in circadian, seasonal, and reproductive physiology. The presence of melatonin binding sites in human brain and peripheral tissues is well documented. However, in the mammalian adrenal gland, low-affinity melatonin binding sites have been detected only in the rat by some but not all authors. Conflicting evidence for a regulatory role of melatonin on adrenal cortisol production, prompted us to investigate this possibility in a New World primate, the capuchin monkey. Expression of melatonin receptors in the adrenal cortex was demonstrated through pharmacological characterization and autoradiographic localization of 2-[125I]iodomelatonin binding sites (dissociation constant = 96.9 +/- 15 pM; maximal binding capacity = 3.8 +/- 0.4 fmol/mg protein). The mt1 identity of these receptors was established by cDNA sequencing. Melatonin treatment of dispersed cells and explants from adrenal gland did not affect basal cortisol production. However, cortisol production stimulated by 100 nM ACTH was significantly inhibited by low melatonin concentrations (0.1-100 nM); this inhibitory effect was reversed by the mt1/MT2 melatonin antagonist luzindole. Melatonin also inhibited dibutyril-cAMP-stimulated cortisol production, suggesting that melatonin acts through a cAMP-independent signaling pathway. The present data demonstrate that the primate adrenal gland cortex expresses functional mt1 melatonin receptors and shows that melatonin inhibits ACTH-stimulated cortisol production. 10.1210/jc.2002-021048

Circadian melatonin and cortisol levels in rheumatoid arthritis patients in winter time: a north and south Europe comparison.

M Cutolo — 2005-06-03T17:25:05-00:00

Ann Rheum Dis, Vol. 64, No. 2. (February 2005), pp. 212-216.

BACKGROUND: Altered functioning of the hypothalamic-pituitary-adrenal axis and altered melatonin production might modulate the circadian symptoms in patients with rheumatoid arthritis. OBJECTIVE: To investigate the influence of different winter photoperiods on the circadian rhythms of serum melatonin, cortisol, tumour necrosis factor alpha (TNFalpha), and interleukin 6 (IL6) in patients with rheumatoid arthritis from a north Europe country (Estonia) and a south Europe country (Italy). METHODS: The patients from Estonia (n = 19) and Italy (n = 7) had similar disease severity and duration and were compared with healthy age and sex matched controls in the two countries. Blood samples were collected during the period January to February at 8 pm, 10 pm, midnight, 2 am, 4 am, 6 am, 8 am, and 3 pm. Melatonin was measured by radioimmunoassay using (125)I-melatonin. Serum cortisol, TNFalpha, and IL6 cytokines were assayed by standard methods. RESULTS: Higher circadian melatonin concentrations from 10 pm and an earlier peak were observed in Estonian patients than in their age and sex matched controls (p<0.01). Starting from midnight, melatonin concentrations were significantly higher in the Estonian patients than in the Italian patients. No significant differences were observed for serum cortisol. Serum TNFalpha was higher (p<0.05) in Estonian patients than in their controls and was correlated with the melatonin levels. CONCLUSIONS: In a north European country (Estonia), the circadian rhythm of serum concentrations of melatonin and TNFalpha in patients with rheumatoid arthritis were significantly higher than in matched controls or in rheumatoid patients from a south Europe country (Italy).

Effect of a synthetic pineal tetrapeptide (Ala-Glu-Asp-GLy) on melatonin secretion by the pineal gland of young and old rats.

Y Djeridane — 2005-06-22T00:15:58-00:00

J Endocrinol Invest, Vol. 26, No. 3. (March 2003), pp. 211-215.

The pineal gland contains many peptides known to be implicated in melatonin production. We examined the effects of a synthetic pineal tetrapeptide Ala-Glu-Asp-Gly on melatonin secretion by the pineal gland. The tetrapeptide effects on pineal gland melatonin secretion were studied in young (9 weeks) and old (27 months) male Wistar rats using a perifusion device. Pineal tetrapeptide at the concentrations used (10(-4) to 10(-6) M) had no significant effect upon melatonin secretion whatever the age of the animals, young or old. We also looked at the effect of the tetrapeptide on pineal melatonin stimulated by a beta-adrenergic agonist, isoproterenol. We found that isoproterenol-induced melatonin increase was not modified by the tetrapeptide. Our results suggest that the pineal tetrapeptide Ala-Glu-Asp-Gly, does not seem to play a role, at least in vitro, in the control of melatonin secretion by the rat pineal gland.

Regulatory effect of Epithalon on production of melatonin and cortisol in old monkeys.

ND Goncharova — 2005-06-22T00:44:34-00:00

Bull Exp Biol Med, Vol. 131, No. 4. (April 2001), pp. 394-396.

The effect of Epithalon on melatonin and cortisol secretion in female rhesus monkeys of various ages was evaluated by enzyme immunoassay. Epithalon stimulated evening melatonin production and normalized circadian rhythms of cortisol production in old monkeys.

Effect of peptide preparation epithalamin on circadian rhythm of epiphyseal melatonin-producing function in elderly people.

OV Korkushko — 2005-06-21T23:55:48-00:00

Bull Exp Biol Med, Vol. 137, No. 4. (April 2004), pp. 389-391.

Circadian rhythm of plasma melatonin concentrations in healthy elderly subjects was studied before and after a course treatment with Epithalamin (peptide preparation from the pineal gland). Epithalamin modulated the melatonin-producing function of the pineal gland. During the dark period plasma melatonin concentration increased in subjects with initially lowered activity of the pineal gland, while in subjects with normal epiphyseal function plasma melatonin concentration tended to decrease.

Effect of pineal peptide preparation (epithalamin) on life span and pineal and serum melatonin level in old rats.

VN Anisimov — 2005-06-22T21:28:21-00:00

Ann N Y Acad Sci, Vol. 673 (26 December 1992), pp. 53-57.

Effect of epithalamin on circadian relationship between the endocrine function of the thymus and melatonin-producing function of the pineal gland in elderly people.

IF Labunets — 2005-06-21T23:50:50-00:00

Bull Exp Biol Med, Vol. 137, No. 5. (May 2004), pp. 507-509.

The effect of epithalamin on circadian rhythms of thymic serum factor titers and melatonin concentrations in the blood of elderly people was studied. Course treatment with epithalamin modulated the rhythm of the thymic endocrine function. The increase in the titer of thymic serum factor at night coincided with the increase in blood melatonin concentration and shift of its acrophase to 3.00, which was characteristic of young people. In elderly people with preserved nocturnal peak of the thymic serum factor titer before therapy the nocturnal (3.00) concentration of melatonin was high and did not change after drug therapy. The correlation between melatonin concentration and titer of thymic serum factor increased after epithalamin treatment.

Effect of melatonin and tetrapeptide on gene expression in mouse brain.

SV Anisimov — 2005-06-21T23:28:59-00:00

Bull Exp Biol Med, Vol. 138, No. 5. (November 2004), pp. 504-509.

A microchip technique was used to study expression of 16,897 clones from a cDNA library in the brain of mice receiving melatonin or tetrapeptide Epithalon (Ala-Glu-Asp-Gly). Expression of 53 transcripts in mouse brain underwent significant changes after treatment with the preparations. Melatonin and Epithalon modified expression of 38 and 22 transcripts, respectively. These preparations produced similar changes in the expression of 6 transcripts. Expression of 1 transcript (Rp119) was inhibited by melatonin, but induced by Epithalon. The target genes are physiologically related to the cell cycle, apoptosis, biosynthesis, processing, and transport of nucleic acids. Comparative study of gene expression in the brain and heart of CBA mice receiving melatonin and Epithalon suggest that these preparations have a tissue-specific biological effect.

[Comparison of the anti-tumor activity of extracts of the epiphysis and hypothalamus, melatonin and sigetin in mice with transplanted mammary gland cancer]

VN Anisimov — 2005-06-23T09:57:52-00:00

Vopr Onkol, Vol. 19, No. 10. (1973), pp. 99-101.

[The effect of melatonin on the indices of biological age, on longevity and on the development of spontaneous tumors in mice]

VN Anisimov — 2005-06-22T01:03:59-00:00

Vopr Onkol, Vol. 46, No. 3. (2000), pp. 311-319.

Fifty female CBA mice were given melatonin with drinking water (20 mg/l) for 5 consecutive days monthly, beginning from the age of 6 months, until natural death. Another 50 intact mice were used as controls. Melatonin failed to significantly influence body weight or food consumption. Age-related switching-off of estrus function was delayed, body temperature decreased. Somewhat decreased motor activity did not affect physical one or endurance. Increase in life span led to higher spontaneous tumor incidence. Another experiment using 20 animals of the same line showed melatonin to inhibit free-radical processes. A conclusion was drawn that caution should be exercised before melatonin is recommended for long-term administration as a geroprotector.

[Melatonin and epithalamin inhibit the process of free radical oxidation in rats]

VN Anisimov — 2005-06-22T20:50:05-00:00

Dokl Akad Nauk, Vol. 343, No. 4. (August 1995), pp. 557-559.

[Melatonin and epithalamin extinguishes the lipid peroxidation process in rats]

VN Anisimov — 2005-06-22T20:49:38-00:00

Dokl Akad Nauk, Vol. 348, No. 2. (May 1996), pp. 265-267.

[Effect of melatonin and epithalamin on life span and lipid peroxidation in Drosophila melanogaster]

VN Anisimov — 2005-06-22T20:47:11-00:00

Dokl Akad Nauk, Vol. 352, No. 5. (February 1997), pp. 704-707.

[Effect of melatonin and epithalamin on the antioxidant defense system activity in rats]

VM Anisimov — 2005-06-22T20:46:48-00:00

Dokl Akad Nauk, Vol. 352, No. 6. (February 1997), pp. 831-833.

Effect of melatonin and pineal peptide preparation epithalamin on life span and free radical oxidation in Drosophila melanogaster.

VN Anisimov — 2005-06-22T20:46:02-00:00

Mech Ageing Dev, Vol. 97, No. 2. (August 1997), pp. 81-91.

It was shown previously that epithalamin delays age-related changes in reproductive and immune systems and increases the life span of mice and rats. These effects could be mediated by stimulating influences of epithalamin on synthesis and secretion of melatonin and on free radical processes. A comparative study on the effect of epithalamin and melatonin on both the life span of Drosophila melanogaster (strain HEM) and on the intensity of lipid peroxidation and activity of antioxidative enzymes in their tissues was the main aim of this work. Melatonin and epithalamin was added to the nutrition medium (100 micrograms/ml) during 2-3rd age of larvas. For survival analysis the flies were passed (five coupes per vessel) each 3-7 days. Lipid peroxidation was evaluated as the level of ketodienes (KD) and conjugated hydroperoxides (CHP) in fly tissues at the age of 11 days. Activity of Cu, Zn-superoxide dismuatse (SOD) and catalase was evaluated as well. The mean, median and maximum life span (MLS) were estimated. Mortality rate (MR) was calculated as alpha in the Gompertz equation (R = Ro (exp alpha t) and mortality rate doubling time (MRDT) as in 2/alpha. These parameters in groups of male and female flies exposed to melatonin and in male flies exposed to epithalamin were no different from the parameters for controls. However, exposure to epithalamin was followed in females by a significant increase in mean life span (by 17%, P < 0.02), of median (by 26%), of MLS by 14% and by a 2.12 times decrease of MR (P < 0.01) and MRDT (by 32%) compared with female controls. The level of CHP and KD in the tissues of male control flies was 40 and 49% less than that in females and indirectly correlates with male life span. Exposure to melatonin was followed by a decrease in the level of CHP and KD in females and the deletion of sex differences in them. Exposure to epithalamin significantly decreased the level of CHP and KD in female flies compared to controls (2.3 and 3.4 times, respectively, P < 0.001). Exposure to melatonin failed to influence the activity of catalase in males but increased it in females by 24% (P < 0.02) and failed to influence SOD activity both in males and females. Exposure to epithalamin was followed by a significant increase in activity of catalse, 20% in males and 7% in females and by an increase in SOD activity in males (41%). Thus, it was shown that exposure to epithalamin significantly increases the mean life span and MLS of female D.melanogaster and slowed down their aging rate by 2.12 times. This effect is in good agreement with the inhibiting effect of epithalamin in lipid peroxidation processes in fly tissues.