YOU ARE NOW CONNECTED TO THE TOXLINE (1981 FORWARD, NON-ROYALTY) FILE. ==MELATONIN AND AGING, JET LAG OR SLEEP== 13 AUTHOR Redfern PH TITLE Can pharmacological agents be used effectively in the alleviation of jet-lag? SOURCE Drugs; VOL 43 ISS Feb 1992, P146-153, (REF 59) ABSTRACT IPA COPYRIGHT: ASHP A review is presented of the physiology of jet lag, theoretical considerations for pharmacological intervention, sites of drug action, and the effects of benzodiazepines and melatonin. 17 AUTHOR Petrie K AUTHOR Conaglen JV AUTHOR Thompson L AUTHOR Chamberlain K TITLE Effect of melatonin on jet lag after long haul flights SOURCE Br. Med. J.; VOL 298 ISS Mar 18 1989, P705-707, (REF 9) ABSTRACT IPA COPYRIGHT: ASHP The prevention of jet lag in 20 subjects, aged 28-68 yr, of whom 10 were treated with melatonin (I), 5 mg between 10 am and 12 noon for 3 days before a 26 h airplane flight, once during the trip, and once a day between 10 pm and 12 midnight for 3 days after arrival, is reported in a double blind, placebo controlled study. Feelings of jet lag were less for subjects given I, and for all subjects jet lag was more severe on the return trip westward than on the outward journey eastward. 14 AUTHOR Samel A AUTHOR Wegmann H-M AUTHOR Vejvoda M AUTHOR Maab H AUTHOR Gundel A AUTHOR Schutz M TITLE Influence of Melatonin Treatment on Human Circadian Rhythmicity before and after a Simulated 9-Hr Time Shift SOURCE Journal of Biological Rhythms, Vol. 6, No. 3, pages 235-248, 39 references, 1991 ABSTRACT Melatonin (73314) treatment for the effects of jet lag were explored through controlled laboratory experimentation. Eight male subjects experienced a 9 hour advance shift in an isolation facility during two 15 day periods. During the initial period, four of the subjects received 5 milligrams melatonin and four received placebos; in the second period this administration was reversed. The time shift was simulated on days seven and eight by shortening the sleep period by 6 hours and the following wake period by 3 hours. Body temperatures were recorded every 90 minutes and urine samples were collected at 3 hour intervals around the clock. The subjects were also evaluated with respect to reaction times, error assessment, tenseness, alertness, and fatigue. Melatonin treatment resulted in the resynchronization of some hormone and excretion rates. Temperature rhythm adaptation speed was significantly increased during one postshift day and had a higher amplitude with treatment than without. The placebo group exhibited both advance and delay shifts in the rhythm of 6-hydroxymelatoninsulfate excretion; alteration was not greater than half that expected within 8 days. The treated group, in contrast, exhibited significantly different adjustment, with seven subjects experiencing an advance shift of 9 hours in 8 days. The authors conclude that, while melatonin treatment can facilitate resynchronization of the melatonin excretion rhythm after simulated transition to the eastern time zone, the degree of improvement is not sufficient for the treatment of jet lag. 2 AUTHOR Reiter RJ TITLE Oxygen radical detoxification processes during aging: the functional importance of melatonin. SOURCE Aging (Milano); VOL 7, ISS 5, 1995, P340-51 (REF: 98) ABSTRACT That free radical destruction of macromolecules is a basis of aging and age-related diseases has considerable experimental support. Melatonin, a hormone produced in organisms as diverse as algae and humans, is believed to have evolved coincident with aerobic metabolism. In all organisms melatonin is produced primarily during the daily period of darkness, with only small amounts being synthesized during the day. In mammals including man, melatonin is produced by and secreted from the pineal gland during the night; however, the night-time production of melatonin falls markedly with aging such that in senescent animals a night-time melatonin rise is barely measurable. This may be significant in terms of aging in the light of recent observations which show that melatonin is a highly efficient free radical scavenger and antioxidant both in vitro and in vivo. In vitro, melatonin has been shown to directly scavenge both the hydroxyl and peroxyl radical, and it does so more efficiently than other known antioxidants. Furthermore, melatonin greatly potentiates the efficiency of previously-discovered endogenous and exogenous antioxidants. In vivo, both physiological and pharmacological levels of melatonin reportedly counteract the devastatingly destructive actions of free radical generating chemicals. For example, melatonin effectively combats DNA damage in rats given massive doses of the chemical carcinogen safrole, and the indole overcomes much of the genomic damage inflicted by ionizing radiation. Also, lipid peroxidation induced by either paraquat, bacterial lipopolysaccharide or H2O2 is highly significantly reduced by concurrent melatonin administration. Finally, cataracts produced in newborn rats by the depletion of the endogenous antioxidant glutathione are prevented by melatonin. These findings provide evidence that melatonin is operative in the cell nucleus, in the aqueous cytosol and in lipid-rich cellular membranes as an antioxidant. Considering this, the loss of this potent antioxidant during aging may be consequential in terms of cellular and organismal aging as well as the onset of age-related diseases. These experimental results from a variety of sources suggest that a more determined approach to the study of melatonin as an anti-aging factor is warranted. 5 AUTHOR Kancheva RL AUTHOR Zofkova I TITLE [Melatonin--the hormone of darkness] SOURCE Cas Lek Cesk; VOL 135, ISS 8, 1996, P231-5 (REF: 43) ABSTRACT Melatonin is a hormone produced mainly by the pineal gland during the dark phase of the circadian cycle with typical circadian rhythm with maximal secretion at night and depression during the day. The indoleamine has wide regulatory and integrative functions. Perhaps there is no organ and system which can escape the influence of epiphysis, incl. reproductive, cardiovascular gastrointestinal, respiratory as well as renal system and water and mineral metabolism. Melatonin regulates not only neuroendocrine functions but also has immunoenhancing and antitumor effects. That is why there are trials/attempts these properties to be utilized in the treatment of malignancies and AIDS patients. The hormone plays a certain role in temperature regulation in mammals as well as in the onset of puberty and senescence. Attention has been paid to its role as a scavenger of toxic free radicals and it is believed that melatonin is the most effective lipophilic antioxidant. However, the exact mechanism of action of this high active hormone remains to be elucidated. Further studies are also necessary for discovering the next its properties and functions. 6 AUTHOR Reiter RJ TITLE The role of the neurohormone melatonin as a buffer against macromolecular oxidative damage. SOURCE Neurochem Int; VOL 27, ISS 6, 1995, P453-60 (REF: 54) ABSTRACT This paper summarizes the recent findings which show that the neural hormone melatonin is a free radical scavenger and general antioxidant. When compared with other antioxidants melatonin seems to have greater efficacy in protecting against cellular oxidative stress. These findings illustrate that melatonin preserves macromolecules including DNA, protein and lipid from oxidative damage following the administration of the chemical carcinogen, safrole, after exposure to ionizing radiation, following glutathione depletion, and after administration of the free radical generating herbicide, paraquat. In vitro evidence shows that melatonin is a potent scavenger of the highly toxic hydroxyl radical and in vitro evidence suggests that melatonin is an important and powerful antioxidant. Considering its high lipophilicity and its non-toxic nature as well as its ability to readily cross the blood-brain barrier, the neurohormone melatonin may prove to be an effective and important molecule in the antioxidative defense system, especially in the central nervous system. Besides the ease with which melatonin enters the brain, neurons seem to accumulate readily this hormone. 7 AUTHOR Reiter RJ TITLE Functional pleiotropy of the neurohormone melatonin: antioxidant protection and neuroendocrine regulation. SOURCE Front Neuroendocrinol; VOL 16, ISS 4, 1995, P383-415 (REF: 133) ABSTRACT The pineal hormone melatonin exhibits remarkable functional versatility. Shortly after its discovery, melatonin was functionally linked to the regulation of the neuroendocrine axis, particularly to the reproductive system. However, judging from the wide variety of cellular changes that occurred following either pinealectomy, to remove the primary source of melatonin, or the exogenous administration of the indole, it was obvious that the activity of melatonin far transcended its actions on the hypothalamo-pituitary-gonadal system. Roughly 30 months ago it was discovered that melatonin is a highly efficient free radical scavenger and general antioxidant. This implied that melatonin, which is both lipophilic and hydrophilic, has effects not only in every cell but also within every subcellular compartment. These intracellular actions of melatonin, some of which are independent of any receptor interaction and some of which are mediated by nuclear receptors, have become the focus of much of the current investigation. As an antioxidant, melatonin has been shown in vitro to be a highly efficient scavenger of the very reactive and toxic hydroxyl radical. Indeed, on an equimolar basis melatonin proved significantly more efficient in neutralizing the hydroxyl radical than did the two well-known scavengers, glutathione and mannitol. Likewise, melatonin was found to also scavenge the peroxyl radical which is generated during lipid peroxidation; in this regard it was roughly twice as effective as vitamin E (alpha-tocopherol). The antioxidant activities of melatonin have been well documented in tissue homogenates and organisms as well. When rats are treated with the chemical carcinogen safrole, this agent induces the generation of free radicals which in turn extensively damage nuclear DNA; this damage is almost totally eliminated if the animals are cotreated with melatonin. Also, damage to DNA in human lymphocytes due to ionizing radiation, another treatment which is known to induce free radical formation, is greatly reduced if the cells are treated with melatonin prior to radiation. Cytosolic protein seems also to be protected from free radical damage when melatonin is present. When newborn rats are treated with a glutathione-depleting drug at birth, by 2 weeks of age the animals have cataracts. Cataracts form because oxidants damage protein in the presence of low intracellular levels of glutathione. Cataracts induced by this means are essentially prevented if the glutathione-depleted rats are supplemented with melatonin. Finally, membrane lipid peroxidation, induced either in vivo or in vitro by any of several means, all of which involve free radicals, is drastically attenuated in the presence of melatonin. Considering melatonin's ability to cross all morphophysiological barriers and to enter every cell, and all subcellular compartments, the implication is that this indole may play a very important role in the antioxidative defense system of the organism. These findings potentially have important implications for a wide variety of age-related diseases and to aging itself. Melatonin's control of reproductive physiology in photoperiodic mammals is well documented. However, the site of interaction of melatonin with the neuroendocrine axis has been especially difficult to determine. The discovery and cloning of a membrane melatonin receptor on neurosecretory cells in the hypothalamus and on hormone secreting cells of the anterior pituitary gland stimulated a great deal of investigation which has failed to prove the involvement of these receptors in the processes by which melatonin influences reproductive physiology. The recent identification of nuclear melatonin receptors as well as the nonreceptor-mediated actions of the indole are currently being examined as to their association with reproductive function. 8 AUTHOR Reiter RJ TITLE The pineal gland and melatonin in relation to aging: a summary of the theories and of the data. SOURCE Exp Gerontol; VOL 30, ISS 3-4, 1995, P199-212 (REF: 73) ABSTRACT Within recent years, many investigators have implicated the pineal gland and melatonin in the processes of both aging and age-related diseases. These theories stem from the importance of melatonin in a number of biological functions and the fact that melatonin production in the organism is gradually lost throughout life, such that in very old individuals of any species the circadian melatonin rhythm is bearly discernible. In most species, from algae to humans, where it has been investigated, melatonin has been shown to exhibit a strong circadian rhythm in production and secretion, with high levels of the indole always being associated with the dark period of the light:dark cycle. One theory states that when the melatonin rhythm deteriorates during aging, other circadian rhythms are likewise weakened and rhythms become dysynchronized. This dysynchronization is believed to contribute significantly to aging and to render animals more susceptible to age-related diseases. Another theory assumes that the waning melatonin cycle provides an important switch for genetically programmed aging at the cellular level; furthermore, because all cells in the organism are exposed to the same gradually dampening melatonin signal throughout life, all cells age more or less at the same rate. In this theory, it is presumed to be the duration of the nocturnally elevated melatonin (which, like the amplitude, is reduced during aging), which, when coupled to a time-gating signal, is consequential in determining the rate of aging. Another compelling argument that the reduction in melatonin with age may be contributory to aging and the onset of age-related diseases is based on the recent observation that melatonin is the most potent hydroxyl radical scavenger thus far discovered. A prominent theory of aging attributes the rate of aging to accumulated free radical damage. Inasmuch as melatonin can markedly protect macromolecules, especially DNA, against free radical attack, it could, indeed, be a major factor in determining the rate at which organisms age. Besides its ability to directly scavenge the highly toxic hydroxyl radical, melatonin also promotes the activity of the antioxidative enzyme glutathione peroxidase, thereby further reducing oxidative damage. These actions may be manifested more obviously in the central nervous system, which is highly susceptible to damage by oxygen-based radicals and, because of its inability to regenerate and its high vulnerability to oxidative attack, its deterioration may be especially important in aging.(ABSTRACT TRUNCATED AT 400 WORDS) 9 AUTHOR Reiter RJ AUTHOR Melchiorri D AUTHOR Sewerynek E AUTHOR Poeggeler B AUTHOR Barlow-Walden L AUTHOR Chuang J AUTHOR Ortiz GG AUTHOR Acuna-Castroviejo D TITLE A review of the evidence supporting melatonin's role as an antioxidant. SOURCE J Pineal Res; VOL 18, ISS 1, 1995, P1-11 (REF: 85) ABSTRACT This survey summarizes the findings, accumulated within the last 2 years, concerning melatonin's role in defending against toxic free radicals. Free radicals are chemical constituents that have an unpaired electron in their outer orbital and, because of this feature, are highly reactive. Inspired oxygen, which sustains life, also is harmful because up to 5% of the oxygen (O2) taken in is converted to oxygen-free radicals. The addition of a single electron to O2 produces the superoxide anion radical (O2-.); O2-. is catalytic-reduced by superoxide dismutase, to hydrogen peroxide (H2O2). Although H2O2 is not itself a free radical, it can be toxic at high concentrations and, more importantly, it can be reduced to the hydroxyl radical (.OH). The .OH is the most toxic of the oxygen-based radicals and it wreaks havoc within cells, particularly with macromolecules. In recent in vitro studies, melatonin was shown to be a very efficient neutralizer of the .OH; indeed, in the system used to test its free radical scavenging ability it was found to be significantly more effective than the well known antioxidant, glutathione (GSH), in doing so. Likewise, melatonin has been shown to stimulate glutathione peroxidase (GSH-Px) activity in neural tissue; GSH-PX metabolizes reduced glutathione to its oxidized form and in doing so it converts H2O2 to H2O, thereby reducing generation of the .OH by eliminating its precursor. More recent studies have shown that melatonin is also a more efficient scavenger of the peroxyl radical than is vitamin E. The peroxyl radical is generated during lipid peroxidation and propagates the chain reaction that leads to massive lipid destruction in cell membranes. In vivo studies have demonstrated that melatonin is remarkably potent in protecting against free radical damage induced by a variety of means. Thus, DNA damage resulting from either the exposure of animals to the chemical carcinogen safrole or to ionizing radiation is markedly reduced when melatonin is co-administered. Likewise, the induction of cataracts, generally accepted as being a consequence of free radical attack on lenticular macromolecules, in newborn rats injected with a GSH-depleting drug are prevented when the animals are given daily melatonin injections. Also, paraquat-induced lipid peroxidation in the lungs of rats is overcome when they also receive melatonin during the exposure period. Paraquat is a highly toxic herbicide that inflicts at least part of its damage by generating free radicals.(ABSTRACT TRUNCATED AT 400 WORDS) 22 AUTHOR Sandyk R AUTHOR Kay SR TITLE Pineal melatonin in schizophrenia: a review and hypothesis. SOURCE Schizophr Bull; VOL 16, ISS 4, 1990, P653-62 (REF: 120) ABSTRACT It has long been suggested that abnormal functions of the pineal gland may be implicated in the pathophysiology of schizophrenia. We present evidence proposing that diminished melatonin secretion may be associated with the pathophysiology of a subgroup of schizophrenic patients characterized by cerebral atrophy and ventricular enlargement, negative symptoms, impaired cognitive and psychosexual development, onset at pubescence, poor response to neuroleptic medication, and possible increased risk of extrapyramidal symptoms. This view holds that a subnormal plasma melatonin level may be a marker of a subgroup of schizophrenia and may also denote a specific genetic susceptibility. 26 AUTHOR Kvetnoi IM AUTHOR Levin IM TITLE [Melatonin and tumor growth] SOURCE Eksp Onkol; VOL 8, ISS 4, 1986, P11-5 (REF: 64) ABSTRACT The role of melatonin in the process of oncogenesis is reviewed. The problems connected with functional state of the epiphysis and other melatonin-producing cells in cancer, as well as the influence of melatonin on experimental tumours and melatonin level changes in blood and urine in patients with malignant tumours are discussed. A probable mechanism of melatonin level changes in cancer is considered taking into account its extra-pineal synthesis. 14 AUTHOR Hardeland R AUTHOR Reiter RJ AUTHOR Poeggeler B AUTHOR Tan DX TITLE The significance of the metabolism of the neurohormone melatonin: antioxidative protection and formation of bioactive substances. SOURCE Neurosci Biobehav Rev; VOL 17, ISS 3, 1993, P347-57 (REF: 143) ABSTRACT Recent findings suggest that the ability of melatonin to enter all body tissues and to be metabolized, enzymatically or nonenzymatically, in any of them results in a spectrum of effects, which exceed substantially those transduced by membrane receptors. These actions comprise the formation of various bioactive compounds such as N-acetylserotonin, 5-methoxytryptamine, N,N-dimethyl-5-methoxytryptamine, 5-methoxytryptophol, cyclic 2-hydroxymelatonin, pinoline, and 5-methoxylated kynuramines. Apart from enzymatic metabolism, nonenzymatic reactions with free radicals, in particular the superoxide anion and the hydroxyl radical, represent a new and significant aspect of melatonin's biological role. Melatonin represents the most potent physiological scavenger of hydroxyl radicals found to date, and recent findings suggest an essential role of this indoleamine for protection from hydroxyl radical-induced carcinogenesis and neurodegeneration.