Melatonin (<em>5</em>-methoxy-<em>N</em>-<em>acetyl</em>tryptamine) at picomolar concentrations (IC<em>5</em>0, 40 pM) inhibited the calcium-dependent release of [3H]dopamine elicited at 3 Hz (2 min, 20 mA, 2 msec) from rabbit retina through activation of a site possessing the pharmacological and functional characteristics of a receptor. The effect of melatonin shows biological specificity as this hormone does not modify [3H]dopamine release from striatum or olfactory tubercle. This paper describes the effects of small modifications of the melatonin structure on the inhibition of calcium-dependent release of [3H]dopamine from retina. The more active melatonin analogs were those possessing a <em>5</em>-methoxy group on carbon <em>5</em> of the indole nucleus and an <em>N</em>-<em>acetyl</em> group on the same position as in melatonin. The potencies of <em>5</em>-methoxy indoles compounds was as follows (IC<em>5</em>0): melatonin (40 pM) = 6-chloromelatonin (40 pM) greater than 6-hydroxymelatonin (1.6 nM) greater than or equal to 6-methoxymelatonin (2 nM) greater than <em>5</em>-<em>methoxytryptamine</em> (63 nM) greater than <em>5</em>-methoxy-<em>N</em>,<em>N</em>-di-methyltryptamine (200 nM) much greater than <em>5</em>-methoxytryptophol (4 microM). The structure activity relationships of melatonin and related indoles indicated that the efficacy of melatonin is determined by the moiety substituted on carbon <em>5</em> (i.e., <em>5</em>-methoxy group), whereas the affinity for the receptor is determined primarily by the moiety substituted on carbon 3 (i.e., ethyl <em>N</em>-<em>acetyl</em> group) of the indole nucleus. <em>N</em>-<em>acetyl</em>tryptamine competitively antagonized the inhibitory effect of melatonin in the chicken retina and appears to be a partial agonist in the rabbit retina.(ABSTRACT TRU<em>N</em>CATED AT 2<em>5</em>0 WORDS)

Several tryptophan derivatives function as free radical scavengers and antioxidants. The molecule that has been most widely investigated in this regard is <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em> (melatonin); however, pinoline (6-methoxy-1,2,3,4-tetrahydro-beta-carboline) and <em>N</em>-<em>acetyl</em>serotonin also possess free radical scavenging activity. Experimental studies have shown that melatonin directly scavenges the hydroxy radical, peroxyl radical, peroxynitrite anion, and singlet oxygen. Furthermore, this tryptophan derivative stimulates a number of antioxidative enzymes and stabilizes cell membranes; this latter action helps membranes to resist free radical damage. While the antioxidative actions of most molecules are limited by their specific intracellular distribution, e.g., vitamin E in lipid-rich membranes, melatonin's antioxidative actions include the protection of lipids in the cell membrane, proteins in the cytosol, and D<em>N</em>A in the nucleus. Furthermore, melatonin crosses all morphophysiological barriers and enters equally well all cells in the organism.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is an endogenously produced indoleamine secreted by the pineal gland and the secretion is suppressed by light. Melatonin is a highly effective antioxidant, free radical scavenger, and has anti-inflammatory effect. Plenty of evidence supports the utility of melatonin in adults for cancer, neurodegenerative disorders, and aging. In children and neonates, melatonin has been used widely, including for respiratory distress syndrome, bronchopulmonary dysplasia, periventricular leukomalacia (PVL), hypoxia-ischemia encephalopathy and sepsis. In addition, melatonin can be used in childhood sleep and seizure disorders, and in neonates and children receiving surgery. This review article discusses the utility of melatonin in neonates and children.

Melatonin ( <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>, aMT) is an indoleamine produced by several organs and tissues including the pineal gland. Melatonin (aMT) modulates the activity of the brain, mainly acting on both GABA and glutamate receptors. Previous studies have shown the participation of melatonin in the control of convulsive crises, suggesting that aMT concentration increases during seizures, and that patients with seizures of diverse origins show an alteration of the aMT rhythm. However, what is not known is the duration of the aMT response to seizures, and whether aMT changes during seizures could be a marker of the disease. For this reason, the serum levels of aMT in <em>5</em>4 children with a convulsive crisis, febrile and epileptic, were analyzed during the crisis, as well as at 1 h and 24 hours after the seizure. The results show that aMT significantly increases during the seizure (Day group, 7<em>5</em>.64+/-4<em>5</em>.91 and <em>N</em>ight group, 90.69+/-<em>5</em>1.8<em>5</em> pg/mL), with normal values being recovered 1 h later (Day group, 26.33+/-10.1<em>5</em> and <em>N</em>ight group, 27.78+/-7.82 pg/mL) and maintained for up to 24 hours, when the circadian variation of aMT returns to the normal acrophase. Due to the interindividual variation of aMT levels among healthy people, a single determination of the indoleamine concentration is not a suitable marker of the existence of a convulsive crisis unless the circadian profile of aMT secretion in the patient is known. The results obtained also support the view that the stimulation of aMT production by the convulsive crisis may participate in the response of the organism against the seizures.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is an interesting molecule with well-known functions in vertebrates. Since its discovery in plants in 199<em>5</em>, many data indicate that its role as a cellular antioxidant is very relevant. Agents that induce stress cause increased melatonin levels in plant organs and melatonin levels fluctuate over the light:dark cycle; there are also conflicting data on the influence of environmental conditions on the melatonin content of plants. In this contribution we describe how cultivation conditions decisively influence melatonin levels in roots, stems and leaves of tomato plants, and we establish some guidelines for interpreting data with the intention of opening up new discussion options, given the lack of data on the place/s of melatonin biosynthesis and its mode of action in plant cells as an antioxidant.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is a neurohormone that maintains circadian rhythms¹ by synchronization to environmental cues and is involved in diverse physiological processes² such as the regulation of blood pressure and core body temperature, oncogenesis, and immune function³. Melatonin is formed in the pineal gland in a light-regulated manner⁴ by enzymatic conversion from <em>5</em>-hydroxytryptamine (<em>5</em>-HT or serotonin), and modulates sleep and wakefulness^<em>5</em> by activating two high-affinity G-protein-coupled receptors, type 1A (MT₁) and type 1B (MT₂)^3,6. Shift work, travel, and ubiquitous artificial lighting can disrupt natural circadian rhythms; as a result, sleep disorders affect a substantial population in modern society and pose a considerable economic burden⁷. Over-the-counter melatonin is widely used to alleviate jet lag and as a safer alternative to benzodiazepines and other sleeping aids^8,9, and is one of the most popular supplements in the United States¹⁰. Here, we present high-resolution room-temperature X-ray free electron laser (XFEL) structures of MT₁ in complex with four agonists: the insomnia drug ramelteon¹¹, two melatonin analogues, and the mixed melatonin-serotonin antidepressant agomelatine^12,13. The structure of MT₂ is described in an accompanying paper¹⁴. Although the MT₁ and <em>5</em>-HT receptors have similar endogenous ligands, and agomelatine acts on both receptors, the receptors differ markedly in the structure and composition of their ligand pockets; in MT₁, access to the ligand pocket is tightly sealed from solvent by extracellular loop 2, leaving only a narrow channel between transmembrane helices IV and V that connects it to the lipid bilayer. The binding site is extremely compact, and ligands interact with MT₁ mainly by strong aromatic stacking with Phe179 and auxiliary hydrogen bonds with Asn162 and Gln181. Our structures provide an unexpected example of atypical ligand entry for a non-lipid receptor, lay the molecular foundation of ligand recognition by melatonin receptors, and will facilitate the design of future tool compounds and therapeutic agents, while their comparison to <em>5</em>-HT receptors yields insights into the evolution and polypharmacology of G-protein-coupled receptors.

In this randomized, double-blind human study, the short-term photoprotective effects of different antioxidants and their combinations were evaluated in vivo. Vitamin C (ascorbic acid), vitamin E (alpha-tocopherol) and melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) were topically applied, alone or in combination, 30 min before ultraviolet-irradiation of the skin. The erythemal reaction was evaluated visually and non-invasively using different bioengineering methods (skin colour and skin blood flow). The results showed a modest protective effect of the vitamins when applied alone and a dose-dependent photoprotective effect of melatonin. Topical application of combinations of both vitamins, or of melatonin with vitamins, enhanced the photoprotective response. Better protection was obtained by using the combination of melatonin with both vitamins. The role of reactive oxygen species and oxygen-derived free radicals, as well as potential sunscreening properties of the employed antioxidants, are discussed in view of possible mechanisms to explain this elevated photoprotective effect.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is an indoleamine originally identified in the pineal gland, where it is synthesised enzymatically from serotonin (<em>5</em>-hydroxytryptamine) by the sequential action of arylalkylamine <em>N</em>-<em>acetyl</em>transferase (AA<em>N</em>AT) and <em>acetyl</em>serotonin O-methyltransferase (ASMT; also known as hydroxyindole O-methyltransferase). Melatonin directly affects ovarian functions and previous studies have suggested that melatonin is synthesised in the ovary. In the present study, we examined whether AA<em>N</em>AT and ASMT are expressed in the adult rat ovary. Reverse transcription-polymerase chain reaction analyses demonstrated that both AA<em>N</em>AT and ASMT mR<em>N</em>As are expressed in the ovary. Western blotting for AA<em>N</em>AT protein showed that the ovary, like the pineal gland, contains this enzymatic protein with a molecular mass of 24kDa. Immunohistochemistry revealed that the AA<em>N</em>AT protein is localised to the oocyte, corpus luteum and medulla, including mast cells. AA<em>N</em>AT protein was found in oocytes at all stages of follicular development, and its levels in oocytes increased progressively throughout follicular development. Furthermore, isolated oocytes metabolised exogenous serotonin to melatonin. These findings demonstrate that melatonin is synthesised from serotonin in oocytes. Melatonin synthesised in the oocyte may be implicated in its own growth or maturation, for example, by acting as a calmodulin antagonist or an antioxidant.

The attenuated nitric oxide (<em>N</em>O) formation and/or elevated production of reactive oxygen species are often found in experimental and human hypertension. We aimed to determine possible effects of <em>N</em>-<em>acetyl</em>cysteine (1.<em>5</em> g/kg/day) and <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em> (melatonin, 10 mg/kg/day) in adult spontaneously hypertensive rats (SHR) with established hypertension. After a six-week-treatment, blood pressure was measured and <em>N</em>O synthase (<em>N</em>OS) activity, concentration of conjugated dienes, protein expression of endothelial <em>N</em>OS, inducible <em>N</em>OS and nuclear factor-kappaB (<em>N</em>F-kappaB) in the left ventricle were determined. Both treatments improved the <em>N</em>O pathway by means of enhanced <em>N</em>OS activity and reduced reactive oxygen species level as indicated by decreased conjugated diene concentrations and lowered <em>N</em>F-kappaB expression. <em>N</em>-<em>acetyl</em>cysteine (but not melatonin) also increased the endothelial <em>N</em>OS protein expression. However, only melatonin was able to reduce blood pressure significantly. Subsequent in vitro study revealed that both <em>N</em>-<em>acetyl</em>cysteine and melatonin lowered the tone of phenylephrine-precontracted femoral artery via <em>N</em>O-dependent relaxation. <em>N</em>evertheless, melatonin-induced relaxation also involved <em>N</em>O-independent component which was preserved even after the blockade of soluble guanylate cyclase by oxadiazolo[4,3-a]quinoxalin-1-one. In conclusion, both <em>N</em>-<em>acetyl</em>cysteine and melatonin were able to improve the <em>N</em>O/reactive oxygen species balance in adult SHR, but blood pressure was significantly lowered by melatonin only. This implies that a partial restoration of <em>N</em>O/reactive oxygen species balance achieved by the antioxidants such as <em>N</em>-<em>acetyl</em>cysteine has no therapeutic effect in adult rats with established hypertension. The observed antihypertensive effect of melatonin is thus mediated by additional mechanisms independent of <em>N</em>O pathway.

Gastric mucosal damage is directly associated with extracellular matrix degradation in which matrix metalloproteinases (MMPs) play a crucial role. Remodeling of connective tissues and loss of tissue integrity due to the action of MMPs are reported in several inflammatory diseases, including gastric ulcer. Indomethacin-induced gastric ulceration involves the generation of reactive oxygen species (ROS) and a reduction in MMP-2 transcription and translation. Our aim was to identify the mechanism for suppression of MMP-2 activity by ROS during acute ulceration and further to examine the possible actions of antioxidants, especially melatonin, during healing. Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) blocked hydroxyl radical and nitrite anion generation, protein oxidation, mucosal cell disruption, and MMP-2 downregulation. In addition, suppression of MMP-2 activity by H2O2 in a dose- and time-dependent manner in vitro is blocked by melatonin, omeprazole, and curcumin. We observed that melatonin and other antioxidants (e.g., curcumin and omeprazole) offered gastroprotection in vivo by upregulation of suppressed MMP-2 expression and activity at the level of secretion and synthesis. Moreover, antioxidants reversed the suppression of MMP-2 expression by upregulation of MT1-MMP and downregulation of TIMP-2. Hence, we hypothesize that antioxidants exerted protection against H2O2-mediated inactivation and downregulation of MMP-2 expression during onset of indomethacin-induced ulceration.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is secreted during the dark hours at night by the pineal gland. After entering the circulation, melatonin acts as an endocrine factor and a chemical messenger of light and darkness. It regulates a variety of important central and peripheral actions related to circadian rhythms and reproduction. It also affects the brain, immune, gastrointestinal, cardiovascular, renal, bone and endocrine functions and acts as an oncostatic and anti-aging molecule. Many of melatonin's actions are mediated through interactions with specific membrane-bound receptors expressed not only in the central nervous system, but also in peripheral tissues. Melatonin also acts through non-receptor-mediated mechanisms, for example serving as a scavenger for reactive oxygen species and reactive nitrogen species. At both physiological and pharmacological concentrations, melatonin attenuates and counteracts oxidative stress and regulates cellular metabolism. Growing scientific evidence of reproductive physiology supports the role of melatonin in human reproduction. This review was conducted to investigate the effects of melatonin on female reproduction and to summarize our findings in this field.

Irritable bowel syndrome (IBS) is a common disorder characterized by recurrent abdominal pain or discomfort, in combination with disturbed bowel habits in the absence of identifiable organic cause. Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is a hormone produced by the pineal gland and also large number by enterochromaffin cells of the digestive mucosa. Melatonin plays an important part in gastrointestinal physiology which includes regulation of gastrointestinal motility, local anti-inflammatory reaction as well as moderation of visceral sensation. Melatonin is commonly given orally. It is categorized by the United States Food and Drug Administration as a dietary supplement. Melatonin treatment has an extremely wide margin of safety though it may cause minor adverse effects, such as headache, rash and nightmares. Melatonin was touted as a potential effective candidate for IBS treatment. Putative role of melatonin in IBS treatment include analgesic effects, regulator of gastrointestinal motility and sensation to sleep promoter. Placebo-controlled studies in melatonin suffered from heterogeneity in methodology. Most studies utilized 3 mg at bedtime as the standard dose of trial. However, all studies had consistently showed improvement in abdominal pain, some showed improvement in quality of life of IBS patients. Melatonin is a relatively safe drug that possesses potential in treating IBS. Future studies should focus on melatonin effect on gut mobility as well as its central nervous system effect to elucidate its role in IBS patients.

BACKGROUND

There are a number of studies that suggest a relationship between decline of melatonin function and the symptoms of dementia.

OBJECTIVE

The review assessed the evidence of clinical efficacy and safety of melatonin in the treatment of manifestations of dementia or cognitive impairment (CI).

METHODS

The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched for trials involving melatonin on <em>5</em> October 200<em>5</em>. The search terms used were MELATO<em>N</em>I<em>N</em>, and <em>N</em>-<em>ACETYL</em>-<em>5</em>-<em>METHOXYTRYPTAMINE</em>. This Register contains records from all major health care databases as well as many ongoing trials databases and is updated regularly.

METHODS

All relevant, randomized controlled trials in which orally administered melatonin in any dosage was compared with a control group for the effect on managing cognitive, behavioural (excluding sleep), and/or affective disturbances of people with dementia of any degree of severity.

METHODS

Two to three reviewers independently assessed the retrieved articles for relevance and methodological quality, and extracted data from the selected studies. Statistically significant differences in changes in outcomes from baseline to end of treatment between the melatonin and control groups were examined. Each study was summarized using a measure of effect (e.g. mean difference) and meta-analyses were conducted when appropriate.

RESULTS

Three studies met the inclusion criteria. This review revealed non-significant effects from the pooled estimates of MMSE cognitive, and ADAS-cognitive change scores. Individual study estimates for treatment effect demonstrated a significant improvement for melatonin compared with placebo in behavioural and affective symptoms as measured by the ADAS non-cognitive scale in a study of 20 patients, and the <em>N</em>europsychiatric Inventory (<em>N</em>PI) following treatment with 2.<em>5</em> mg/day (SR) melatonin, but not with 10mg/day (IR) melatonin in a larger study of 1<em>5</em>7 patients. The remainder of the treatment effects for affect, behaviour and activities of daily living were non-significant.

CONCLUSIONS

There is insufficient evidence to support the effectiveness of melatonin in managing the cognitive and non-cognitive sequelae of dementia.

This study was undertaken to determine whether melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em> <em>methoxytryptamine</em>) is effective in helping emergency medical services (EMS) personnel who work rotating night shifts reset their biological clocks and minimize circadian rhythm disruption. A double-blinded, randomized, crossover study was performed using 22 volunteers. Participants were working a span of consecutive night (2300 to 0700 hours) shifts and received either a melatonin capsule (6 mg) or placebo to be taken before each of the consecutive day sleeps. Each participant completed a total of 4 spans of consecutive night shifts (2 melatonin, 2 placebo). Collected data included daily sleep diaries, quantification of alcohol/caffeine consumed, and drug side effects. Assessment of sleep quality, posttreatment mood, and workload ratings were measured daily by 10-cm visual analog scale (VAS). Analysis of sleep diaries found no significant difference (P>> .0<em>5</em>) between the two treatments with respect to mean sleep latency, duration, and efficiency, and subjectively rated sleep quality. Similarly, no significant benefits were noted between the median VAS scores for daily posttreatment mood or workload ratings. Adverse effects were rare; one patient taking melatonin reported a prolonged sedative effect. Despite recent interest in melatonin for treatment of circadian-based sleep disorders, no clinical benefits were noted in EMS personnel working rotating night shifts.

Matrix metalloproteinases (MMPs) play an important role in degradation of gastric extracellular matrix proteins. However, no reports are available on the relationship between the activity of MMPs and gastric ulceration induced by alcohol. Our objective was to investigate the effect of melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) on the regulation of MMP-9 and MMP-2 activities during prevention of ethanol-induced gastric ulcer. Biochemical and zymographic methods were used to analyze MMP-9 and -2 activities in gastric tissues of Balb/c mice following induction of gastric ulcer by ethanol. Our studies reveal that melatonin arrested cell injury, protein carbonyl formation, and lipid peroxidation in mice during gastroprotection. Melatonin dose-dependently reduced proMMP-9 activity that was induced ( approximately 2<em>5</em>-fold) during ethanol-induced gastric ulceration. Severity of gastric ulcers were correlated proportionately with increased dose of ethanol and elevated activity of proMMP-9 and -2. The reduced activities of MMP-9 and -2 were associated with reduced expression of T<em>N</em>F-alpha and increased expression of tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2). We conclude that melatonin's ability to prevent ethanol-induced gastric ulceration in mice is related to a reduction in proMMP-9 activity and expression.

Major environmental variables such as daily and seasonal changes of light and temperature regulate the daily circadian variations of synthesis and release of the pineal neurohormone <em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em> (melatonin). Melatonin has now been shown to be a potent immunoregulatory agent, and to be able to antagonize the immunosuppressive effects of acute anxiety stress in mice, as measured by antibody production, by thymus weight, and by the capacity of stressed- and evening-melatonin-treated mice to react against a lethal virus. Both psychogenic factors and infectious agents such as viruses can act as "stressors" and induce an immunosuppression. Their combination is a determinant for the course of infectious diseases and, perhaps, cancer. Circadian (evening) melatonin possesses thus the singular ability to up-regulate the immunosuppression of stressed mice. This effect of melatonin is not exerted directly on immunocompetent cells, but mediated via the endogenous opioid system upon antigen-activation of T cells. Melatonin being a short-lived hormone with negligible side-effects which is rapidly degraded and eliminated by the body, the use of melatonin offers a new approach to the physiological control of stress and stress-related infectious diseases. In addition, melatonin could be used for the potentiation of primary immunization (vaccination) against antigens of the most varied nature which do not evoke a robust or longlasting secondary (memory) response. The regulatory function of pineal melatonin is discussed also in relation to hematopoiesis, to its oncostatic effects, and to its possible dual role in reproduction physiology and generation of immunocompetence and tolerance during ontogeny.

As a widely known hormone in animals, melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) has been more and more popular research topic in various aspects of plants. To summarize the these recent advances, this review focuses on the regulatory effects of melatonin in plant response to multiple abiotic stresses including salt, drought, cold, heat and oxidative stresses and biotic stress such as pathogen infection. We highlight the changes of endogenous melatonin levels under stress conditions, and the extensive metabolome, transcriptome, and proteome reprogramming by exogenous melatonin application. Moreover, melatonin-mediated stress signaling and underlying mechanism in plants are extensively discussed. Much more is needed to further study in detail the mechanisms of melatonin-mediated stress signaling in plants.

Oxygen-centred free radicals play an important role in the pathogenesis of acute and chronic UV-induced skin damage as well as in skin aging. In this double-blind randomized study the efficacy of topically applied melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>), a potent free radical scavenger, in the suppression of UV-induced erythema was assessed. A group of 20 healthy volunteers were irradiated with 0.099 J/cm2 UVB on four <em>5</em>-cm2 areas on the lower back and topically treated with various concentrations of melatonin (0.0<em>5</em>, 0.1, 0.<em>5</em>%) in a nanocolloid gel as carrier or with carrier alone. The UV-induced erythema was examined 8 and 24 h after irradiation by visual scoring and chromametry. A distinct dose response relationship was observed between the topical dose of melatonin and the degree of UV-induced erythema. Significant differences (P < 0.0<em>5</em>) were found in redness (chromameter a-value and visual scoring) 8 h after irradiation between the areas treated with melatonin at 0.<em>5</em>% and those treated with melatonin at 0.0<em>5</em>% or with the carrier. These results might open a new approach in the prevention and control of free radical-influenced skin diseases.

Melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) is a multifunctional signaling molecule that has a variety of important functions. <em>N</em>umerous clinical trials have examined the therapeutic usefulness of melatonin in different fields of medicine. Clinical trials have shown that melatonin is efficient in preventing cell damage under acute (sepsis, asphyxia in newborns) and chronic states (metabolic and neurodegenerative diseases, cancer, inflammation, aging). The beneficial effects of melatonin can be explained by its properties as a potent antioxidant and antioxidant enzyme inducer, a regulator of apoptosis and a stimulator of immune functions. These effects support the use of melatonin in viral infections, which are often associated with inflammatory injury and increases in oxidative stress. In fact, melatonin has been used recently to treat several viral infections, which are summarized in this review. The role of melatonin in infections is also discussed herein.

Cyclooxygenase-2(COX-2) overexpression promotes inflammation and tumorigenesis. COX-2 expression in response to diverse stimuli is tightly controlled to avoid persistent overexpression. <em>5</em>-methoxyindole metabolites of L-tryptophan represent a new class of compounds that control COX-2 expression at the transcriptional level. Two of the metabolites, the newly discovered <em>5</em>-methoxytryptophan (<em>5</em>-MTP, also known as cytoguardin) and <em>N</em>-<em>acetyl</em> <em>5</em>-<em>methoxytryptamine</em> (melatonin) are the focus of this review. <em>5</em>-MTP is produced by mesenchymal cells such as fibroblasts via <em>5</em>-hydroxytryptophan (<em>5</em>-HTP). It inhibits COX-2 transcriptional activation induced by diverse proinflammatory and mitogenic factors. Cancer cells are deficient in cytoguardin production which contributes to COX-2 overexpression. Fibroblast-generated <em>5</em>-MTP is capable of restoring the control of COX-2 overexpression in cancer cells. <em>5</em>-MTP blocks cancer cell migration and invasion in vitro and inhibits tumor growth and cancer metastasis in a xenograft model. Melatonin possesses similar COX-2 suppressing and anti-cancer properties albeit at supra-pharmacological concentrations. By contrast, <em>5</em>-hydroxyindole metabolites of L-tryptophan such as <em>5</em>-hydroxytryptamine (serotonin), <em>5</em>-hydroxytryptophol and other serotonin catabolites do not control COX-2 expression. <em>5</em>-hydroxytryptophan inhibits COX-2 expression through conversion to <em>5</em>-MTP. The physiological relevance of <em>5</em>-MTP as an endogenous regulator of inflammation and cancer metastasis remains to be investigated. On the other hand, <em>5</em>-methoxyindole metabolites of tryptophan are valuable lead compounds for development of new anti-inflammatory drugs and cancer chemoprevention.

1. The interaction of melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) with <em>5</em>-hydroxytryptamine4 (<em>5</em>-HT4) receptors and/or with melatonin receptors (ML1, ML2 sites) has been assessed in isolated strips of the guinea-pig proximal colon. In the same preparation, the pharmacological profile of a series of melatonin agonists (2-iodomelatonin, 6-chloromelatonin, <em>N</em>-<em>acetyl</em>-<em>5</em>-hydroxytryptamine (<em>N</em>-<em>acetyl</em>-<em>5</em>-HT), <em>5</em>-methoxycarbonylamino-<em>N</em>-<em>acetyl</em>tryptamine (<em>5</em>-MCA-<em>N</em>AT)) was investigated. 2. In the presence of <em>5</em>-HT1/2/3 receptor blockade with methysergide (1 microM) and ondansetron (10 microM), melatonin (0.1 nM-10 microM), <em>5</em>-HT (1 nM-1 microM) and the <em>5</em>-HT4 receptor agonist, <em>5</em>-<em>methoxytryptamine</em> (<em>5</em>-MeOT: 1 nM-1 microM) caused concentration-dependent contractile responses. <em>5</em>-HT and <em>5</em>-MeOT acted as full agonists with a potency (-log EC<em>5</em>0) of 7.8 and 8.0, respectively. The potency value for melatonin was 8.7, but its maximum effect was only <em>5</em>8% of that elicited by <em>5</em>-HT. 3. Melatonin responses were resistant to atropine (0.1 microM), tetrodotoxin (0.3 microM), and to blockade of <em>5</em>-HT4 receptors by SDZ 20<em>5</em>,<em>5</em><em>5</em>7 (0.3 microM) and GR 12<em>5</em>487 (3, 30 and 300 nM). The latter antagonist (3 nM) inhibited <em>5</em>-HT-induced contractions with an apparent pA2 value of 9.6 GR 12<em>5</em>487 antagonism was associated with 30% reduction of the <em>5</em>-HT response maximum. Contractions elicited by <em>5</em>-HT were not modified when melatonin (1 and 10 nM) was used as an antagonist. 4. Like melatonin, the four melatonin analogues concentration-dependently contracted colonic strips. The rank order of agonist potency was: 2-iodomelatonin (10.8)>> 6-chloromelatonin (9.9)>> or = <em>N</em>-<em>acetyl</em>-<em>5</em>-HT (9.8)>> or = <em>5</em>-MCA-<em>N</em>AT (9.6)>> melatonin (8.7), an order typical for ML2 sites. In comparison with the other agonists, <em>5</em>-MCA-<em>N</em>AT had the highest intrinsic activity. <em>5</em>. The melatonin ML1B receptor antagonist luzindole (0.3, 1 and 3 microM) had no effect on the concentration-response curve to melatonin. Prazosin, an alpha-adrenoceptor antagonist possessing moderate/ high affinity for melatonin ML2 sites did not affect melatonin-induced contractions at 0.1 microM. Higher prazosin concentrations (0.3 and 1 microM) caused a non-concentration-dependent depression of the maximal response to melatonin without changing its potency. Prazosin (0.1 and 1 microM) showed a similar depressant behaviour towards the contractile responses to <em>5</em>-MCA-<em>N</em>AT. 6. In the guinea-pig proximal colon, melatonin despite some structural similarity with the <em>5</em>-HT4 receptor agonist <em>5</em>-MeOT, does not interact with <em>5</em>-HT4 receptors (or with <em>5</em>-HT1/2/3 receptors). As indicated by the rank order of agonist potencies and by the inefficacy of luzindole, the most likely sites of action of melatonin are postjunctional ML2 receptors. However, this assumption could not be corroborated with the use of prazosin as this 'ML2 receptor antagonist' showed only a non-concentration-dependent depression of the maximal contractile response to both melatonin and <em>5</em>-MCA-<em>N</em>AT. Further investigation with the use of truly selective antagonists at melatonin ML2 receptors is required to clarify this issue.

OBJECTIVE

Effect of exogenously administered melatonin (<em>N</em>-<em>acetyl</em> <em>5</em>-<em>methoxytryptamine</em>) on antioxidant systems in experimental Ischemia-Reperfusion (I-R) of rat gastrointestinal system (GIS) was examined.

METHODS

A total of 40 rats were divided into 4 groups: Group 1 (Sham), Group 2 (I-R), Group 3 (I-R + 10 mg/kg melatonin) and Group 4 (I-R + 20 mg/kg melatonin). Activity levels of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were determined in small intestines.

RESULTS

There was a significant (p<0.0<em>5</em>) reduction in GSH-Px levels in Group 2 (64.16+/-7.02 U/mg protein) compared to Group 1 (80.1<em>5</em>+/-9.32 U/mg protein). We observed a meaningful increase in GSH-Px levels in melatonin applied groups (Group 3: 7<em>5</em>.94+/-9.83 U/mg protein, Group 4: 78.<em>5</em><em>5</em>+/-9.11 U/mg protein) compared to Group 2. Correspondingly, SOD activity levels were significantly reduced (p<0.001) in Group 2 (24.14+/-4.3<em>5</em> U/mg protein) compared to controls (<em>5</em>2.91+/-6.13 U/mg protein). A stronger effect (p<0.001) of melatonin was observed on SOD levels compared to GSH-Px levels in both doses (Group 3: 38.96+/-6.39 U/mg protein, Group 4: 43.07+/-7.76 U/mg protein). Levels of selenium were reduced significantly in Group 2 (1.11+/-0.31 microg/g tissue) compared to Group 1 (2.01+/-0.19 microg/g tissue). Melatonin application in Group 3 (1.13+/-0.28 microg/g tissue) and Group 4 (1.89+/-0.48 microg/g tissue) caused an increase in selenium levels. There was a strong correlation between increases in selenium and GSH-Px levels in Group 4 (r:0.6<em>5</em>1 p<0.01).

CONCLUSIONS

Melatonin seems to exert its antioxidant effect in GIS tract by stimulating SOD and GSH-Px. Selenium also seems to have an antioxidant contribution on protecting rat gastrointestinal tract I-R injury.

Forty-four different animal biles obtained from both invertebrates and vertebrates (including human bile) have been used for centuries for a host of maladies in traditional Chinese medicine (TCM) beginning with dog, ox and common carp biles approximately in the Zhou dynasty (c. 1046-2<em>5</em>6 BCE). Overall, different animal biles were prescribed principally for the treatment of liver, biliary, skin (including burns), gynecological and heart diseases, as well as diseases of the eyes, ears, nose, mouth and throat. We present an informed opinion of the clinical efficacy of the medicinal uses of the different animal biles based on their presently known principal chemical components which are mostly steroidal detergent-like molecules and the membrane lipids such as unesterified cholesterol and mixed phosphatidylcholines and sometimes sphingomyelin, as well as containing lipopigments derived from heme principally bilirubin glucuronides. All of the available information on the ethnopharmacological uses of biles in TCM were collated from the rich collection of ancient Chinese books on materia medica held in libraries in China and United States and the composition of various animal biles was based on rigorous separatory and advanced chemical identification techniques published since the mid-20(th) century collected via library (Harvard's Countway Library) and electronic searches (PubMed and Google Scholar). Our analysis of ethnomedical data and information on biliary chemistry shows that specific bile salts, as well as the common bile pigment bilirubin and its glucuronides plus the minor components of bile such as vitamins A, D, E, K, as well as melatonin (<em>N</em>-<em>acetyl</em>-<em>5</em>-<em>methoxytryptamine</em>) are salutary in improving liver function, dissolving gallstones, inhibiting bacterial and viral multiplication, promoting cardiac chronotropsim, as well as exhibiting anti-inflammatory, anti-pyretic, anti-oxidant, sedative, anti-convulsive, anti-allergic, anti-congestive, anti-diabetic and anti-spasmodic effects. Pig, wild boar and human biles diluted with alcohol were shown to form an artificial skin for burns and wounds one thousand years ago in the Tang dynasty (618-907 CE). Although various animal biles exhibit several generic effects in common, a number of biles appear to be advantageous for specific therapeutic indications. We attempt to understand these effects based on the pharmacology of individual components of bile as well as attempting to identify a variety of future research needs.