Melatonin (N-acetyl-5-methoxytryptamine) is a chemical mediator produced in the pineal gland and other sites in the body. The melatonin found in the blood is derived almost exclusively from the pineal gland. Since the pineal synthesizes melatonin primarily at night, blood levels of the indole are also higher at night (5–15 fold) than during the day. Some individuals on a nightly basis produce twice as much melatonin as others of the same age. Throughout life, the melatonin rhythm gradually wanes such that, in advanced age, melatonin production is usually at a minimum. Melatonin was recently found to be a free radical scavenger and antioxidant. It has been shown, in the experimental setting, to protect against both free radical induced DNA damage and oxidative stress-mediated lipid peroxidation. Pharmacologically, melatonin has been shown to reduce oxidative damage caused by such toxins as the chemical carcinogen safrole, carbon tetrachloride, paraquat, bacterial lipopolysaccharide, kainic acid, δ-aminolevulinic and amyloid β peptide of Alzheimer’s disease as well as a model of Parkinson’s disease involving the drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Additionally, the oxidative damage caused by agents such as ionizing radiation and excessive exercise is reduced by melatonin. Since free radical-induced molecular injury may play a significant role in aging, melatonin’s ability to protect against it suggests a potential function of melatonin in deferring aging and age-related, free radical-based diseases. Besides its ability to abate oxidative damage, other beneficial features of melatonin may be important in combating the signs of aging; these include melatonin’s immune-stimulating function, its sleep-promoting ability, its function as an anti-viral agent, and general protective actions at the cellular level. Definitive tests of the specific functions of physiological levels of melatonin in processes of aging are currently being conducted.
Lower urinary melatonin levels are associated with a higher risk of breast cancer in postmenopausal women. Literature for premenopausal women is scant and inconsistent.
In a prospective case–control study we measured the concentration of 6-sulphatoxymelatonin (aMT6s), in the 12-hour overnight urine of 180 premenopausal women with incident breast cancer and 683 matched controls.
In logistic regression models, the multivariate odds ratio (OR) of invasive breast cancer for women in the highest quartile of total overnight aMT6s output compared with the lowest was 1.43 [95% confidence interval (CI) = 0.83–2.45; Ptrend = 0.03]. Among current non-smokers no association was existent (OR, 1.00, 95% CI, 0.52–1.94; Ptrend = 0.29). We observed an OR of 0.68 between overnight urinary aMT6s level and breast cancer risk in women with invasive breast cancer diagnosed >2 years after urine collection and a significant inverse association in women with a breast cancer diagnosis >8 years after urine collection (OR, 0.17, 95% CI = 0.04–0.71; Ptrend = 0.01). There were no important variations in ORs by tumor stage or hormone receptor status of breast tumors.
Overall we observed a positive association between aMT6s and risk of breast cancer. However, there was some evidence to suggest that this might be driven by the influence of subclinical disease on melatonin levels, with a possible inverse association among women diagnosed further from recruitment. Thus, the influence of lagtime on the association between melatonin and breast cancer risk needs to be evaluated in further studies.
melatonin; aMT6s; premenopausal; night work; breast cancer
Melatonin is a potent antioxidant and free radical scavenger. It has been reported that serum melatonin level is relevant to certain aging diseases. The purpose of this study was to investigate melatonin levels in age-related macular degeneration (AMD) patients by measurement of 6-sulfatoxymelatonin levels (aMT6s), the major metabolite of melatonin in urine, and compare it with a group of age- and gender-matched controls.
The first urine of the morning was collected from 43 AMD patients and 12 controls who did not have AMD. The level of aMT6s in specimens was measured by a commercial 6-sulfatoxymelatonin ELISA kit. The assay was performed by researchers, who were masked to the clinical information. To adjust for variation in the diluteness of urine, urinary creatinine level was measured and aMT6s levels were expressed as aMT6s/creatinine.
The level of urinary aMT6s/creatinine (mean±SD) in AMD (6.24±3.45 ng aMT6s/mg creatinine) was significantly lower than that of the controls (10.40±4.51, p=0.0128). After adjustment for various factors (age, smoking, cancer, and coronary heart disease) that may influence the aMT6s level, the odds-ratio of urinary aMT6s comparing AMD patients to controls was 0.65 (95% confidence interval=0.48–0.88, p=0.0036), indicating that urinary aMT6s level in AMD patients was lower than in controls even after multivariate adjustment.
Urinary aMT6s level in AMD patients was 40% lower than in age- and gender-matched controls. This difference between AMD patients and controls is present after adjustment for the factors of age, smoking, and histories of cancer and coronary heart disease. The significance of this result and the role of melatonin in the occurrence of AMD require further investigation.
Melatonin, the hormone of darkness and messenger of the photoperiod, is also well known to exhibit strong direct and indirect antioxidant properties. Melatonin has previously been demonstrated to be a powerful organ protective substance in numerous models of injury; these beneficial effects have been attributed to the hormone’s intense radical scavenging capacity. The present report reviews the hepatoprotective potential of the pineal hormone in various models of oxidative stress in vivo, and summarizes the extensive literature showing that melatonin may be a suitable experimental substance to reduce liver damage after sepsis, hemorrhagic shock, ischemia/reperfusion, and in numerous models of toxic liver injury. Melatonin’s influence on hepatic antioxidant enzymes and other potentially relevant pathways, such as nitric oxide signaling, hepatic cytokine and heat shock protein expression, are evaluated. Based on recent literature demonstrating the functional relevance of melatonin receptor activation for hepatic organ protection, this article finally suggests that melatonin receptors could mediate the hepatoprotective actions of melatonin therapy.
Antioxidant enzymes; Hemorrhagic shock; Hepatoprotection; Ischemia; Liver; Liver function; Melatonin; Melatonin receptor; Ramelteon; Reperfusion; Sepsis; Toxic liver injury
The pineal secretory product melatonin (chemically, N-acetyl-5-methoxytryptamine) acts as an effective antioxidant and free-radical scavenger and plays an important role in several physiological functions such as sleep induction, immunomodulation, cardiovascular protection, thermoregulation, neuroprotection, tumor-suppression and oncostasis. Membrane lipid-peroxidation in terms of malondialdehyde (MDA) and intracellular glutathione (GSH) is considered to be a reliable marker of oxidative stress. The present work was undertaken to study the modulating effect of melatonin on MDA and GSH in human erythrocytes during day and night. Our observation shows the modulation of these two biomarkers by melatonin, and this may have important therapeutic implications. In vitro dose-dependent effect of melatonin also showed variation during day and night. We explain our observations on the basis of melatonin's antioxidative function and its effect on the fluidity of plasma membrane of red blood cells. Rhythmic modulation of MDA and GSH contents emphasized the role of melatonin as an antioxidant and its function against oxidative stress.
Melatonin or N-acetyl-5-methoxytryptamine, is a compound derived from tryptophan that is found in all organisms from single cells to vertebrates and the human. It is one of the most evolutionarily conserved and pleiotropic hormone still active in humans and has been implicated in vital skin functions such as hair growth, fur pigmentation as well as melanoma control. Being a main secretory product of the pineal gland, melatonin regulates seasonal biorhythms, reproductive mechanisms or mammary gland metabolism. Due to its wide range endocrine properties it is also recognized to modulate numerous additional functions ranging from scavenging free radicals, immunomodulation-mediated DNA repair, wound healing, involvement in gene expression connected with circadian clocks and modulation of secondary endocrine signaling including prolactin release. Recently, apart from above mentioned entities, it was shown that melatonin suppresses ultraviolet (UV)-induced damage in human skin and human derived cell lines (e.g., keratinocytes, fibroblasts). The magnitude of UV-induced damage is mediated apparently by various molecular mechanisms related to generation of reactive oxygen species (ROS), apoptosis and mitochondrial-mediated cell death which are all counteracted or modulated by melatonin. We provide here an update of the relevant protective effects and molecular mechanisms of action of melatonin in the skin.
melatonin; skin; ultraviolet radiation; antioxidant; oxidative stress; mitochondria; apoptosis
Melatonin, a product of the pineal gland, is released from the gut mucosa in response to food ingestion. Specific receptors for melatonin have been detected in many gastrointestinal tissues including the pancreas. Melatonin as well as its precursor, L-tryptophan, attenuates the severity of acute pancreatitis and protects the pancreatic tissue from the damage caused by acute inflammation. The beneficial effect of melatonin on acute pancreatitis, which has been reported in many experimental studies and supported by clinical observations, is related to: (1) enhancement of antioxidant defense of the pancreatic tissue, through direct scavenging of toxic radical oxygen (ROS) and nitrogen (RNS) species, (2) preservation of the activity of antioxidant enzymes; such as superoxide dismutase (SOD), catalase (CAT), or glutathione peroxidase (GPx), (3) the decline of pro-inflammatory cytokine tumor necrosis α (TNFα) production, accompanied by stimulation of an anti-inflammatory IL-10, (4) improvement of pancreatic blood flow and decrease of neutrophil infiltration, (5) reduction of apoptosis and necrosis in the inflamed pancreatic tissue, (6) increased production of chaperon protein (HSP60), and (7) promotion of regenerative process in the pancreas. Conclusion. Endogenous melatonin produced from L-tryptophan could be one of the native mechanisms protecting the pancreas from acute damage and accelerating regeneration of this gland. The beneficial effects of melatonin shown in experimental studies suggest that melatonin ought to be employed in the clinical trials as a supportive therapy in acute pancreatitis and could be used in people at high risk for acute pancreatitis to prevent the development of pancreatic inflammation.
Melatonin (N-acetyl-5-methoxytryptamine) is secreted during the dark hours at night by pineal gland, and it regulates a variety of important central and peripheral actions related to circadian rhythms and reproduction. It has been believed that melatonin regulates ovarian function by the regulation of gonadotropin release in the hypothalamus-pituitary gland axis via its specific receptors. In addition to the receptor mediated action, the discovery of melatonin as a direct free radical scavenger has greatly broadened the understanding of melatonin's mechanisms which benefit reproductive physiology. Higher concentrations of melatonin have been found in human preovulatory follicular fluid compared to serum, and there is growing evidence of the direct effects of melatonin on ovarian function especially oocyte maturation and embryo development. Many scientists have focused on the direct role of melatonin on oocyte maturation and embryo development as an anti-oxidant to reduce oxidative stress induced by reactive oxygen species, which are produced during ovulation process. The beneficial effects of melatonin administration on oocyte maturation and embryo development have been confirmed by in vitro and in vivo experiments in animals. This review also discusses the first application of melatonin to the clinical treatment of infertile women and confirms that melatonin administration reduces intrafollicular oxidative damage and increase fertilization rates. This review summarizes our recent works and new findings related to the reported beneficial effects of melatonin on reproductive physiology in its role as a reducer of oxidative stress, especially on oocyte maturation and embryo development.
melatonin; oocyte; ovulation; reactive oxygen species; antioxidant
The aim of the study was to examine the role that melatonin production plays in the regulation of sleep consolidation in a population of shiftworkers working and sleeping in their natural environments.
253 locomotive engineers (249 male, 4 female, mean age = 39.7 years) participated in the study for a 2-week period whilst working their normal roster patterns. Participants recorded details for all sleep periods in a sleep diary and collected urine samples during each day's main sleep period. The samples were subsequently assayed for the metabolite of melatonin in urine, 6-sulphatoxymelatonin (aMT6s), and the rate of excretion during main sleep periods was calculated.
Separate one-way factorial ANOVAs revealed a significant effect of time of sleep onset on aMT6s excretion rate, sleep duration, and subjective sleep quality. Generally, the rate of aMT6s excretion was lower, sleep duration was shorter, and sleep quality was lower for sleeps initiated during the daytime than for sleeps initiated at night.
Combined with previous studies linking melatonin production and sleep propensity, and others demonstrating the relationship between sleep consolidation and melatonin production in forced desynchrony protocols, the current results indicate that low production of melatonin may play a role in the poor consolidation of daytime sleep in natural sleep settings.
Tryptophan (TRP) is the precursor of melatonin, the primary secretory product of the pineal gland. Hepatic heme deficiency decreases the activity of liver tryptophan pyrrolase, leading to increased plasma TRP and serotonin. As a paradox, patients with attacks of acute intermittent porphyria (AIP), exhibit low nocturnal plasma melatonin levels. This study using a rat experimental model was designed to produce a pattern of TRP and melatonin production similar to that in AIP patients. Pineal melatonin production was measured in response to: (a) a heme synthesis inhibitor, succinylacetone, (b) a heme precursor, delta-aminolevulinic acid (Ala), (c) a structural analogue of Ala, gamma-aminobutyric acid. Studies were performed in intact rats, perifused pineal glands, and pinealocyte cultures. Ala, succinylacetone, and gamma-aminobutyric acid significantly decreased plasma melatonin levels independently of blood TRP concentration. In the pineal gland, the key enzyme activities of melatonin synthesis were unchanged for hydroxyindole-O-methyltransferase and decreased for N-acetyltransferase. Our results strongly suggest that Ala overproduced by the liver acts by mimicking the effect of gamma-aminobutyric acid on pineal melatonin in AIP. They also support the view that Ala acts as a toxic element in the pathophysiology of AIP.
Melatonin, a hormone-like substance involved in the regulation of the circadian rhythm, has been demonstrated to protect cells against oxidative DNA damage and to inhibit tumorigenesis.
In the current study, we investigated the effect of melatonin on DNA strand breaks using the alkaline DNA comet assay in breast cancer (MCF-7) and colon cancer (HCT-15) cell lines. Our results demonstrated that cells pretreated with melatonin had significantly shorter Olive tail moments compared to non-melatonin treated cells upon mutagen (methyl methanesulfonate, MMS) exposure, indicating an increased DNA repair capacity after melatonin treatment. We further examined the genome-wide gene expression in melatonin pretreated MCF-7 cells upon carcinogen exposure and detected altered expression of many genes involved in multiple DNA damage responsive pathways. Genes exhibiting altered expression were further analyzed for functional interrelatedness using network- and pathway-based bioinformatics analysis. The top functional network was defined as having relevance for “DNA Replication, Recombination, and Repair, Gene Expression, [and] Cancer”.
These findings suggest that melatonin may enhance DNA repair capacity by affecting several key genes involved in DNA damage responsive pathways.
Melatonin; DNA repair; Comet assay; Genome-wide expression; Network analysis
An institutionalised 13 year old girl with psychomotor
retardation suffered from an irregular sleep-wake pattern. Multiple measurements of urinary sulphatoxymelatonin (aMT6) concentrations were abnormally low, without any significant day-night differences. Administration of exogenous melatonin (3 mg) at 18:00 resulted in
increased nocturnal urinary aMT6 concentrations and improvements in her
sleep-wake pattern. Melatonin may help disabled children suffering
from sleep disorders.
Children with autism often suffer from sleep disturbances, and compared to age-matched controls, have decreased melatonin levels, as indicated by urine levels of the primary melatonin metabolite, 6-sulfatoxymelatonin (6-SM). We therefore investigated the relationship between 6-SM levels and sleep architecture in children with autism spectrum disorders (ASD). Twenty-three children, aged 4–10 years, completed two nights of polysomnography and one overnight urine collection for measurement of urinary 6-SM excretion rate. Parents completed the Children’s Sleep Habits Questionnaire. We found that higher urinary 6-SM excretion rates were associated with increased N3 sleep, decreased N2 sleep, and decreased daytime sleepiness. The results warrant further examination to examine the effects of supplemental melatonin on sleep architecture and daytime sleepiness.
6-Sulfatoxymelatonin; 6-SM; Sleep stages; Children’s Sleep Habits Questionnaire; Parental Concerns Questionnaire; Polysomnography
Oxidative stress is a contributing factor to the development and progression of diabetic retinopathy, a leading cause of blindness in people at working age worldwide. Recent studies showed that Müller cells play key roles in diabetic retinopathy and produce vascular endothelial growth factor (VEGF) that regulates retinal vascular leakage and proliferation. Melatonin is a potent antioxidant capable of protecting variety of retinal cells from oxidative damage. In addition to the pineal gland, the retina produces melatonin. In the current study, we investigated whether melatonin protects against hyperglycemia-induced oxidative injury to Müller cells and explored the potential underlying mechanisms. Our results show that both melatonin membrane receptors, MT1 and MT2, are expressed in cultured primary Müller cells and are upregulated by elevated glucose levels. Both basal and high glucose-induced VEGF production was attenuated by melatonin treatment in a dose-dependent manner. Furthermore, we found that melatonin is a potent activator of Akt in Müller cells. Our findings suggest that in addition to functioning as a direct free radical scavenger, melatonin can elicit cellular signaling pathways that are protective against retinal injury during diabetic retinopathy.
Levels of melatonin in mammalian circulation are well documented; however, its levels in tissues and other body fluids are yet only poorly established. It is obvious that melatonin concentrations in cerebrospinal fluid (CSF) of mammals including humans are substantially higher than those in the peripheral circulation. Evidence indicates that melatonin produced in pineal gland is directly released into third ventricle via the pineal recess. In addition, brain tissue is equipped with the synthetic machinery for melatonin production and the astrocytes and glial cells have been proven to produce melatonin. These two sources of melatonin may be responsible for its high levels in CNS. The physiological significance of the high levels of melatonin in CNS presumably is to protect neurons and glia from oxidative stress. Melatonin as a potent antioxidant has been reported to be a neuroprotector in animals and in clinical studies. It seems that long term melatonin administration which elevates CSF melatonin concentrations will retard the progression of neurodegenerative disorders, for example, Alzheimer disease.
Melatonin; pineal gland; CNS; CSF; oxidative stress; neurodegenerative disease.
Oxidative DNA damage, linked pathogenically to a variety of diseases such as cancer and ageing, can be investigated by measuring specific DNA repair products in urine. Within the last decade, since it was established that such products were excreted into urine, progress in their analysis in urine has been limited. Guanine is the DNA base most prone to oxidation. We present a method for determination of the urinary 8-hydroxylated species of guanine, based on direct injection of urine onto a high-performance liquid chromatography (HPLC)–tandem mass spectrometry system. The analysis covers the 8-hydroxylated base, ribonucleoside and deoxynucleoside, and the corresponding non-oxidised species. Without pre-treatment of urine the detection limits for the nucleobases are ∼2 nM (50 fmol injected) and for the nucleosides ∼0.5 nM (12.5 fmol injected). Previously, liquid chromatography of the nucleobases has been problematic but is made possible by low-temperature reverse-phase C18 chromatography, a method that increases retention on the column. In the case of the nucleosides, retention was almost total and provides a means for on-column concentration of larger urine samples and controlled high peak gradient elution. The total excretion of 8-hydroylated guanine species was 212 nmol/24 h. The oxidised base accounted for 64%, the ribonucleoside for 23% and the deoxynucleoside for 13%, indicating substantial oxidation of RNA in humans. In rat urine, excretion of the oxidised base was more dominant, the percentages of the oxidised base, ribonucleoside and deoxynucleosides being 89, 8 and 3%. This finding is at odds with previous reports using immunoaffinity pre-purification and HPLC–electrochemical detection analysis. The developed method now makes it possible to measure oxidative nucleic acid stress to both RNA and DNA in epidemiological and intervention settings, and our findings indicate a substantial RNA oxidation in addition to DNA oxidation. The small volume needed also makes the method applicable to small experimental animals.
Melatonin is a recognized antioxidant with high potential as a protective agent in many conditions related to oxidative stress such as neurodegenerative diseases, ischemia/reperfusion syndromes, sepsis and aging. These processes may be favorably affected by melatonin through its radical scavenging properties and/or antiapoptotic activity. Also, there is increasing evidence that these effects of melatonin could be relevant in keratinocytes, the main cell population of the skin where it would contribute to protection against damage induced by ultraviolet radiation (UVR). We therefore investigated the kinetics of UVR-induced apoptosis in cultured keratinocytes characterizing the morphological and mitochondrial changes, the caspases-dependent apoptotic pathways and involvement of poly(ADP-ribose) polymerase (PARP) activation as well as the protective effects of melatonin. When irradiated with UVB radiation (50 mJ/cm2), melatonin treated, cultured keratinocytes were more confluent, showed less cell blebbing, more uniform shape and less nuclear condensation as compared to irradiated, nonmelatonin-treated controls. Preincubation with melatonin also led to normalization of the decreased UVR-induced mitochondrial membrane potential. These melatonin effects were followed by suppression of the activation of mitochondrial pathway-related initiator caspase 9 (casp-9), but not of death receptor-dependent casp-8 between 24 and 48 hr after UVR exposure. Melatonin down-regulated effector caspases (casp-3/casp-7) at 24–48 hr post-UV irradiation and reduced PARP activation at 24 hr. Thus, melatonin is particularly active in UV-irradiated keratinocytes maintaining the mitochondrial membrane potential, inhibiting the consecutive activation of the intrinsic apoptotic pathway and reducing PARP activation. In conclusion, these data provide detailed evidence for specific antiapoptotic mechanisms of melatonin in UVR-induced damage of human keratinocytes.
antioxidant; apoptosis; caspases; keratinocytes; melatonin; mitochondria; poly(ADP-ribose) polymerase; ultraviolet radiation
The pineal gland is a neuroendocrine organ of the brain. Its main task is to synthesize and secrete melatonin, a nocturnal hormone with diverse physiological functions. This review will focus on the central and pineal mechanisms in generation of mammalian pineal rhythmicity including melatonin production. In particular, this review covers the following topics: (1) local control of serotonin and melatonin rhythms; (2) neurotransmitters involved in central control of melatonin; (3) plasticity of the neural circuit controlling melatonin production; (4) role of clock genes in melatonin formation; (5) phase control of pineal rhythmicity; (6) impact of light at night on pineal rhythms; and (7) physiological function of the pineal rhythmicity.
Aminoglycosides are commonly used antibiotic agents, and they are known to generate free oxygen radicals within the inner ear and to cause vestibulo-cochlear toxicity and permanent damage to the sensory hair cells and neurons. Melatonin, a pineal secretory product, has the properties of being a powerful direct and indirect antioxidant. The aim of the present study was to prove the antioxidant effect of melatonin against gentamicin-induced ototoxicty.
The utricular maculae of Sprague-Dawley rats were prepared from postnatal day 2-4, and these maculae were were divided into 6 groups as follows: 1) control, 2) melatonin only, 3) gentamicin only, and 4), 5), and 6) gentamicin plus melatonin (10, 50, and 100 µM, respectively). To count the number of hair cells, 5 utricles from each group were stained with phalloidin-FITC on the 1st, 4th, and 7th days after drug administration. Reactive oxygen species (ROS) was assessed by using the fluorescent probe hydrofluorescent diacetate acetyl ester. The caspase-3 activity was also examined with using the fluorescent caspase-3 substrate and performing Western blotting.
The result of this study showed that gentamicin induced the loss of utricular hair cells, and this loss of hair cells was significantly attenuated by co-administration of melatonin. Melatonin reduced ROS production and caspase-3 activation in the gentamicin treated utricular hair cells.
Our findings conclusively reveal that melatonin has protective effects against gentamicin-induced hair cell loss in the utricles of rat by inhibiting both ROS production and caspase-3 activity.
Melatonin; Ototoxicity; Antioxidants; Utricle
Melatonin, originally discovered as a hormone of the pineal gland, is also produced in other organs and represents, additionally, a normal food constituent found in yeast and plant material, which can influence the level in the circulation. Compared to the pineal, the gastrointestinal tract contains several hundred times more melatonin, which can be released into the blood in response to food intake and stimuli by nutrients, especially tryptophan. Apart from its use as a commercial food additive, supraphysiological doses have been applied in medical trials and pure preparations are well tolerated by patients. Owing to its amphiphilicity, melatonin can enter any body fluid, cell or cell compartment. Its properties as an antioxidant agent are based on several, highly diverse effects. Apart from direct radical scavenging, it plays a role in upregulation of antioxidant and downregulation of prooxidant enzymes, and damage by free radicals can be reduced by its antiexcitatory actions, and presumably by contributions to appropriate internal circadian phasing, and by its improvement of mitochondrial metabolism, in terms of avoiding electron leakage and enhancing complex I and complex IV activities. Melatonin was shown to potentiate effects of other antioxidants, such as ascorbate and Trolox. Under physiological conditions, direct radical scavenging may only contribute to a minor extent to overall radical detoxification, although melatonin can eliminate several of them in scavenger cascades and potentiates the efficacy of antioxidant vitamins. Melatonin oxidation seems rather important for the production of other biologically active metabolites such as N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), which have been shown to also dispose of protective properties. Thus, melatonin may be regarded as a prodrug, too. AMK interacts with reactive oxygen and nitrogen species, conveys protection to mitochondria, inhibits and downregulates cyclooxygenase 2.
Melatonin (MT) release from the pineal gland has been used as a marker for central noradrenergic function in major depression. Norepinephrine acts at both alpha and beta adrenergic receptors on the pinealocyte membrane to mediate nocturnal MT release, but in humans the contribution of each receptor class is unclear. In order to explore the effect of alpha 2 receptors on MT release, 10 female subjects were given oral challenges, in separate placebo-controlled trials, of either 10.8 mg of yohimbine, an alpha 2 adrenergic antagonist, or clonidine, a partial alpha 2 adrenergic agonist, at doses of either 200 micrograms or 300 micrograms. Post-challenge serum melatonin was measured from 18:00 h to 22:00 h in both studies as was urinary 6-sulphatoxy-melatonin (aMT6s), the major metabolite of MT (from 18:00 h to 22:00 h, and from 22:00 h to 10:00 h). Growth hormone (GH) was also assayed following the clonidine challenge, and blood pressure, pulse rate, and side effects were monitored after both challenges. Neither yohimbine nor clonidine significantly altered nocturnal serum MT levels compared to placebo. However, there was a significant increase in urinary aMT6s between 18:00 h and 22:00 h following yohimbine ingestion. Yohimbine ingestion produced significant rises in pulse rate and the urge to urinate compared to placebo. Both doses of clonidine resulted in a significant reduction in pulse rate, systolic and diastolic blood pressure, and significant increases in drowsiness and other measures of sedation following ingestion. Only clonidine 300 micrograms produced a significant elevation in GH release. This study highlights the limitations of oral neuroendocrine challenge studies.
Alzheimer disease (AD) is an age-related neurodegenerative disorder characterized by the presence of senile plaques, neurofibrillary tangles and neuronal loss. Amyloid-β protein (Aβ) deposition plays a critical role in the development of AD. It is now generally accepted that massive neuronal death due to apoptosis is a common characteristic in the brains of patients suffering from neurodegenerative diseases, and apoptotic cell death has been found in neurons and glial cells in AD. Melatonin is a secretory product of the pineal gland; melatonin is a potent antioxidant and free radical scavenger and may play an important role in aging and AD. Melatonin decreases during aging and patients with AD have a more profound reduction of this indoleamine. Additionally, the antioxidant properties, the anti-amyloidogenic properties and anti-apoptotic properties of melatonin in AD models have been studied. In this article, we review the anti-amyloidogenic and anti-apoptotic role of melatonin in AD
Alzheimer disease; neurodegeneration; neuroprotection; melatonin; amyloid beta-protein; amyloid precursor protein; apoptosis; mitochondria.
The 8-oxo-7,8-dihydrodeoxyguanosine (8oxoG), a major mutagenic DNA lesion, results either from direct oxidation of guanines or misincorporation of 8oxodGTP by DNA polymerases. At present, little is known about the mechanisms preventing the mutagenic action of 8oxodGTP in Saccharomyces cerevisiae. Herein, we report for the first time the identification of an alternative repair pathway for 8oxoG residues initiated by S. cerevisiae AP endonuclease Apn1, which is endowed with a robust progressive 3′→5′ exonuclease activity towards duplex DNA. We show that yeast cell extracts, as well as purified Apn1, excise misincorporated 8oxoG, providing a damage-cleansing function to DNA synthesis. Consistent with these results, deletion of both OGG1 encoding 8oxoG-DNA glycosylase and APN1 causes nearly 46-fold synergistic increase in the spontaneous mutation rate, and this enhanced mutagenesis is primarily due to G · C to T · A transversions. Expression of the bacterial 8oxodGTP triphosphotase MutT in the apn1Δ ogg1Δ mutant reduces the mutagenesis. Taken together, our results indicate that Apn1 is involved in an S. cerevisiae 8-oxoguanine-DNA glycosylase (Ogg1)-independent repair pathway for 8oxoG residues. Interestingly, the human major AP endonuclease, Ape1, also exhibits similar exonuclease activity towards 8oxoG residues, raising the possibility that this enzyme could participate in the prevention of mutations that would otherwise result from the incorporation of 8oxodGTP.
Hydroxyl radicals predominantly react with the C8 of purines forming 7,8-dihydro-8-oxoguanine (8oxoG) and 7,8-dihydro-8-oxoadenine (8oxoA) adducts, which are highly mutagenic in mammalian cells. The majority of oxidized DNA bases are removed by DNA glycosylases in the base excision repair pathway. Here, we report for the first time that human thymine-DNA glycosylase (hTDG) and Escherichia coli mismatch-specific uracil-DNA glycosylase (MUG) can remove 8oxoA from 8oxoA•T, 8oxoA•G and 8oxoA•C pairs. Comparison of the kinetic parameters of the reaction indicates that full-length hTDG excises 8oxoA, 3,N4-ethenocytosine (εC) and T with similar efficiency (kmax = 0.35, 0.36 and 0.16 min−1, respectively) and is more proficient as compared with its bacterial homologue MUG. The N-terminal domain of the hTDG protein is essential for 8oxoA–DNA glycosylase activity, but not for εC repair. Interestingly, the TDG status had little or no effect on the proliferation rate of mouse embryonic fibroblasts after exposure to γ-irradiation. Nevertheless, using whole cell-free extracts from the DNA glycosylase-deficient murine embryonic fibroblasts and E. coli, we demonstrate that the excision of 8oxoA from 8oxoA•T and 8oxoA•G has an absolute requirement for TDG and MUG, respectively. The data establish that MUG and TDG can counteract the genotoxic effects of 8oxoA residues in vivo.
Administered in supra-physiologic doses, the hormone melatonin may reduce blood pressure, particularly nocturnal blood pressure. However, whether lower physiologic levels of melatonin are an independent risk factor for the development of hypertension has never been reported.
We examined the association between first morning urine melatonin levels and the risk of developing hypertension among 554 young women without baseline hypertension who were followed for 8 years. Cox proportional hazards models were adjusted for age, body mass index, physical activity, alcohol intake, smoking status, urinary creatinine, and family history of hypertension.
During 8 years of follow-up, a total of 125 women developed hypertension. The relative risk for incident hypertension among women in the highest quartile of urinary melatonin (>27.0 ng per mg creatinine) compared to the lowest quartile (<10.1 ng per mg creatinine) was 0.49 (95% confidence intervals, 0.28-0.85; p-trend<0.001).
First morning melatonin levels are independently and inversely associated with incident hypertension; low melatonin production may be a pathophysiologic factor in the development of hypertension.
risk factors; hypertension; epidemiology; melatonin