Melatonin and pregnancy in the human.

The purpose of this systematic review is to access the current state of knowledge concerning the role for melatonin in human pregnancy. Melatonin is a neuroendocrine hormone secreted nightly by pineal gland and regulates biological rhythms. The nighttime serum concentration of melatonin shows an incremental change toward the end of pregnancy. This small lipophilic indoleamine crosses the placenta freely without being altered. Maternal melatonin enters the fetal circulation with ease providing photoperiodic information to the fetus. Melatonin works in a variety of ways as a circadian rhythm modulator, endocrine modulator, immunomodulator, direct free radical scavenger and indirect antioxidant and cytoprotective agent in human pregnancy, and it appears to be essential for successful pregnancy. It also seems to be involved in correcting the pathophysiology of complications during pregnancy including those due to abortion, pre-eclampsia and fetal brain damage. The scientific evidence supporting a role for melatonin in human pregnancy is summarized.

Reactive oxygen species and the hypomotility of the gall bladder as targets for the treatment of gallstones with melatonin: a review.

Free radical-mediated damage of the gall bladder epithelium predisposes to the development of both gall bladder inflammation and gallstone formation, which often coexist. Melatonin, a pineal and gut secretory product, due to its antioxidant activity along with its effect on the aging gall bladder myocytes, inhibits gallstone formation. Melatonin reduces the biliary levels of cholesterol by inhibiting cholesterol absorption across the intestinal epithelium and by increasing the conversion of cholesterol to bile acids. The incidence of gallstones is increasing and is expected to rise dramatically with the increase in the longevity and the risk factors such as obesity. The change in the prevalence of cholelithiasis is associated with a proportionate rise in the incidence of cholangiocarcinoma. In an attempt to improve the quality of life of the rapidly increasing aging population, this article reviews up-to-date information on the pathophysiology of the gall bladder function and discusses the development of new therapies with potential good patient compliance and lower cost than the current treatments.

Cardiovascular diseases: protective effects of melatonin.

This brief review considers some of the cardiac diseases and conditions where free radicals and related reactants are believed to be causative. The report also describes the beneficial actions of melatonin against oxidative cardiovascular disorders. Based on the data available, melatonin seems to have cardioprotective properties via its direct free radical scavenger and its indirect antioxidant activity. Melatonin efficiently interacts with various reactive oxygen and reactive nitrogen species (receptor independent actions) and it also upregulates antioxidant enzymes and downregulates pro-oxidant enzymes (receptor-dependent actions). Moreover, melatonin enters all cells and subcellular compartments and crosses morphophysiologic barriers. These findings have implications for the protective effects of melatonin against cardiac diseases induced by oxidative stress. Melatonin attenuates molecular and cellular damages resulting from cardiac ischemia/reperfusion in which destructive free radicals are involved. Anti-inflammatory and antioxidative properties of melatonin are also involved in the protection against a chronic vascular disease, atherosclerosis. The administration of melatonin, as a result of its antioxidant features, has been reported to reduce hypertension and cardiotoxicity induced by clinically used drugs. The results described herein help to clarify the beneficial effects of melatonin against these conditions and define the potential clinical applicability of melatonin in cardiovascular diseases.

Melatonin as a naturally occurring co-substrate of quinone reductase-2, the putative MT3 melatonin membrane receptor: hypothesis and significance.

The nature of the MT3 melatonin receptor/binding site has been a long pondered mystery for scientists. Even though it is a presumptive membrane receptor, neither its transduction cascade nor its biological consequences, after its stimulation, have been uncovered. Moreover, solid data support the idea that the MT3 melatonin binding site is an enzyme, quinone reductase 2 (QR2), rather than a membrane melatonin receptor. Based on the data available and our preliminary studies, we hypothesize that melatonin is a co-substrate of QR2. We surmise that melatonin binds to a co-substrate binding site (MT3 binding site) donating an electron to the enzyme co-factor, flavin adenine dinucleotide (FAD). FAD can be reduced to either FADH or FADH2 while melatonin is converted to N1-acetyl-N2-formyl-5-methoxykynuramine and/or cyclic 3-hydroxymelatonin. QR2 is considered to be a detoxifying and antioxidant enzyme and its behavior changes depending on available co-substrates. As a naturally occurring substance, melatonin's levels fluctuate with the light/dark cycle, with aging and with health/disease state. As a result, these alterations in melatonin production under physiological or pathological conditions would probably influence the activity of QR2.

Effect of exogenous melatonin on viability, ingestion capacity, and free-radical scavenging in heterophils from young and old ringdoves (Streptopelia risoria).

The decrease of melatonin production with aging contributes to the decline in immune function as organisms age. Treatment with the exogenously administered indoleamine restores the reduced immunological functions. Therefore, we investigated the effect of melatonin on viability, phagocyte ingestion capacity, and free radical generation levels of heterophils from young and old ringdove (Streptopelia risoria) aged 3-4 and 11-13 years, respectively. Animals received a single oral dose of melatonin 1 h before lights off for three consecutive days. Experiments were performed at the acrophases and nadirs of melatonin. Melatonin treatment significantly increased serum melatonin levels at the acrophases, but not at the nadirs of the two age groups. In both young and old animals there was increased heterophil viability at acrophases with respect to nadirs, and also increased cell resistance to oxidative stress in the old animals after the melatonin treatment. At acrophases, the index, percentage and efficiency of phagocytosis all increased significantly, and superoxide anion levels decreased significantly with respect to the nadir values of vehicle and melatonin-treated animals, the effect being greater in young than in old ringdoves. At the nadirs, no change was observed in any parameter analyzed. In both young and old animals, phagocytosis and melatonin were positively correlated, while superoxide anion levels and melatonin were negatively correlated. In conclusion, exogenous melatonin enhanced heterophil viability in old animals as well as increasing phagocytosis and free-radical scavenging in both age groups during the nocturnal period, accompanied by an increase in the levels of the indoleamine.

Melatonin and its metabolites: new findings regarding their production and their radical scavenging actions.

This review summarizes some of the recent findings concerning the long-held tenet that the enzyme, N-acetyltransferase, which is involved in the production of N-acetylserotonin, the immediate precursor of melatonin, may in fact not always control the quantity of melatonin generated. New evidence from several different laboratories indicates that hydroxyindole-O-methyltransferase, which O-methylates N-acetylserotonin to melatonin may be rate-limiting in some cases. Also, the review makes the point that melatonin's actions are uncommonly widespread in organs due to the fact that it works via membrane receptors, nuclear receptors/binding sites and receptor-independent mechanisms, i.e., the direct scavenging of free radicals. Finally, the review briefly summarizes the actions of melatonin and its metabolites in the detoxification of oxygen and nitrogen-based free radicals and related non-radical products. Via these multiple processes, melatonin is capable of influencing the metabolism of every cell in the organism.

Comparative study of the activity/rest rhythms in young and old ringdove (Streptopelia risoria): correlation with serum levels of melatonin and serotonin.

Aging is characterized by changes in the circadian rhythms of melatonin, serotonin, and sleep/wakefulness, alterations that affect sleep quality. The authors studied the circadian rhythms of serotonin and melatonin in young and old ringdoves (Streptopelia risoria) (2-3 and 10-12 yrs old, respectively), animals that are characterized by being monophasic and active by day, like humans. The aim was to correlate the indole rhythms with the animals' activity/rest periods. The animals were kept under a 12:12 h light/dark cycle, fed ad libitum, and housed in separate cages equipped for activity recording. Activity pulses were recorded with one actometer per animal (two perpendicular infrared transmitters) and were logged every 15 min by a computer program (DAS 16) throughout the experiment. Melatonin was measured by radioimmunoassay and serotonin by ELISA at intervals of 3 h (from 09:00 to 18:00 h) and 1 h (from 21:00 to 06:00 h), respectively. The results showed a reduction in nocturnal vs. diurnal activity of 89% and 61% in the young and old animals, respectively, with 100% considered to be the diurnal activity of each group. The amplitude of a cosine function fit to the melatonin concentrations of the old animals was half that of the young birds. The acrophase and nadir were at 02:00 and 14:00 h in the young and 01:00 and 13:00 h in the old animals, respectively. The amplitude of the corresponding cosine function fit to the serotonin concentrations in the old birds was one-third that of the young animals. The acrophase and nadir were at 15:00 and 03:00 h in the young and 16:00 and 04:00 h in the old animals, respectively. For both melatonin and serotonin, the concentrations in the young animals were significantly higher than in the old at most of the measurement times. There was a clear negative correlation between the circadian rhythms of activity and the serum melatonin levels in both young and old animals. The equivalent correlation for serotonin was positive, and stronger in the case of the young animals. The results suggest a possible relationship between the observed decline in the amplitude of the old animals' melatonin and serotonin rhythms and the lower percentage reduction in their nocturnal relative to diurnal activity pulses compared to the young animals. In conclusion, the circadian rhythms of melatonin and serotonin undergo alterations with age that could be involved in the changes in age-associated sleep.