Melatonin phase advances circadian rhythm

We studied the effect of acute (1 day) and subacute (7 days) treatment with melatonin (0.5 mg) on the endogenous rhythms of melatonin secretion in 12 healthy male volunteers, using a placebo-controlled, double-blind, cross-over design. Melatonin given at 1700 h for 7 days significantly advanced the onset of endogenous melatonin secretion, while a single dose was without effect. These data are consistent with the hypothesis that melatonin plays a role in the organisation of circadian rhythms in humans and suggests that appropriately timed melatonin administration may provide a means of altering the timing of circadian cycles.     

Biological rhythm disturbances in mood disorders

From earliest times, psychiatrists have described biological rhythm disturbances as characteristic of mood disorders. The present flourishing of circadian biology has revealed the molecular basis of 24-h rhythmicity driven by 'clock' genes, as well as the importance of zeitgebers (synchronisers). Winter depression was first modelled on regulation of animal behaviour by seasonal changes in daylength, and led to application of light as the first successful chronobiological treatment in psychiatry. Light therapy has great promise for many other disorders (e.g. sleep-wake cycle disturbances in Alzheimer's dementia, bulimia, premenstrual disorder, depression during pregnancy) and, importantly, as an adjuvant to antidepressant medication in major non-seasonal depression. The pineal hormone melatonin is also a zeitgeber for the human circadian system, in addition to possessing direct sleep-promoting effects. Chronobiology has provided efficacious non-pharmaceutical treatments for mood disorders (such as sleep deprivation or light therapy) as well as novel approaches to new drugs (e.g. agomelatine).     

Rosacea, light, and phototherapy

The long-established notion that rosacea is worsened by light is of particular concern in the phototherapy of diseases such as psoriasis, eczema, or vitiligo, which often can be coexistent with rosacea. A literature search was conducted and much evidence was found to challenge this belief that light adversely affects rosacea. In fact, more patients actually improved with sunlight in a more recent published survey. Several other studies have also shown that rosacea patients were similar to control subjects in sun exposure, solar skin damage, and sun sensitivity. Additionally, all clinical trials to date have failed to find a difference between rosacea patients and control subjects when challenged with ultraviolet light. Thus, phototherapy with rosacea may be safer than is commonly believed.     

Affective disorders and biological rhythms

Disruptions of circadian rhythms are described in affective disorders, including unipolar and bipolar disorder, but also seasonal affective disorder. Sleep-wake and hormone circadian rhythms are among the most quoted examples. Depression could be conceptualized as a desynchronization between the endogenous circadian pacemaker and the exogenous stimuli, such as sunlight and social rhythms. Accordingly, Clock genes have been studied and the literature suggests that variants in these genes confer a higher risk of relapse, more sleep disturbances associated with depression, as well as incomplete treatment response. Most of therapeutic interventions in depression have an impact on biological rhythms. Some of them exclusively act via a biological pathway, such as sleep deprivation or light therapy. Some psychosocial interventions are specifically focusing on social rhythms, particularly in bipolar disorder, in which the promotion of stabilization is emphasized. Finally, all antidepressant medications could improve biological rhythms, but some new agents are now totally focusing this novel approach for the treatment of depression.     

Development of new chronopharmacotherapies based on biological rhythm

The mammalian circadian pacemaker resides in the paired suprachiasmatic nuclei (SCN). Clock genes are the genes that control the circadian rhythms of physiology and behavior. The effectiveness and toxicity of many drugs vary depending on dosing time associated with 24-h rhythms of biochemical, physiological, and behavioral processes under the control of the circadian clock. However, many drugs are still administered without regard to the time of day. Identification of a rhythmic marker for selecting dosing time will lead to improved progress and diffusion of chronopharmacotherapy. The monitoring of rhythmic markers may be useful in choosing the most appropriate time of day for administration of drugs and may increase their therapeutic effects and/or reduce their side effects. On the other hand, several drugs can cause alterations in 24-h rhythms, leading to illness and altered homeostatic regulation. Here, we show the disruptive effect of interferon on the rhythm of locomotor activity, body temperature, and clock gene mRNA expression in the periphery and SCN. The alteration of the clock function, a new concept of adverse effects, can be overcome by devising a dosing schedule that minimizes adverse drug effects on clock function. Furthermore, to produce new rhythmicity by manipulating the conditions of living organs using rhythmic administration of altered feeding schedules or several drugs appears to lead to the new concept of chronopharmacotherapy. One approach to increasing the efficiency of pharmacotherapy is administering drugs at times during which they are best effective and/or tolerated.     

Melatonin sensitivity to dim white light in affective disorders.

Both dim and bright light has been shown to suppress the nocturnal secretion of the pineal hormone melatonin. Early reports suggests that an abnormal response to light occurs in patients with bipolar affective disorder, where as patients with major depressive disorder respond similarly to controls. It has been suggested that this abnormal sensitivity of the melatonin response to light could be a trait marker of bipolar affective disorder. However reports lack consistency. Hence, we investigated the melatonin suppression by dim light (200 lux) in patients with bipolar affective disorder, seasonal affective disorder and major depressive disorder. Results suggest that a supersensitive melatonin suppression to light in bipolar affective disorder (p < .005), and seasonal affective disorder (p < .05), whereas patients with major depressive disorder display similar suppression to controls. The supersensitivity may be a mechanism where by phase-delayed rhythms, are resynchronised to a new circadian position. Conversely, an abnormality may exist in the pathway from the retina to the suprachiamatic nucleus.     

Melatonin receptors: potential targets for central nervous system disorders

The pineal hormone melatonin has become the subject of considerable speculation in both the scientific and lay press. Media coverage, coupled with scientific interest fuelled by the recent molecular cloning of a family of melatonin receptors, has led to a renaissance in melatonin research. While numerous physiological effects have been attributed to melatonin, the lack of selective agonists and antagonists for individual melatonin receptor subtypes has hampered progress towards the elucidation of the roles of these receptors. This review focuses on the molecular and pharmacological characterisation of melatonin receptors, the possible clinical utility of melatonin receptor ligands, and the progress towards the identification of selective ligands for these receptors.     

Melatonin attenuates metabolic disorders due to streptozotocin-induced diabetes in rats

Enhanced oxidative stress and impairments in nitric oxide synthesis and bioavailability are of considerable importance in the pathogenesis of diabetic vascular diseases. The aim of the present work was to evaluate the metabolic effects of pharmacological doses of the melatonin, a known antioxidant, on streptozotocin-induced diabetic damage in rats. We investigated the indolamine's influence on the cellular redox-balance, nitric oxide (NO) level, and the activities of antioxidative defence enzymes, as well as the activities of enzymes involved in phase II detoxication and NADPH-generating pentose phosphate pathway. Blood glucose, glycated hemoglobin, bilirubin, as well as plasma alanine aminotransferase activities increased and body weight was reduced in rats with streptozotocin-induced (60 mg/kg, i.p.) diabetes (25 days). The NO level was markedly increased in diabetic plasma (by 50%) and aortic tissue (by 30%). The hyperglycemia resulted in reduced activities of glutathione peroxidase (by 25%), catalase (by 20%), glucose-6-phosphate dehydrogenase (by 55%) and transketolase (by 40%) in liver tissue of diabetic animals. Melatonin treatment (10 mg/kg, 18 days) did not influence the level of hyperglycemia or glycated hemoglobin and it had little effect on the activities of antioxidative enzymes. However, melatonin markedly reversed the activities of glucose-6-phosphate dehydrogenase and transketolase in liver tissue of diabetic rats. The most pronounced effect of the melatonin administration was the prevention of an increase in nitric oxide levels in blood plasma and aortic tissue during diabetes. In in vitro experiments, nitrosomelatonin formation in the presence of nitrosodonors was observed. This implies that melatonin might operate as an NO scavenger and carrier. Thus, melatonin treatment may have some beneficial effects in controlling diabetic vascular complications.     

Functional polymorphisms in clock genes and circadian rhythm sleep disorders]

Polymorphisms in clock genes induce circadian rhythm sleep disorders. Mutations in Per2 gene (S662G) or Casein Kinasel delta (CK16) gene (T44A) cause Familial advanced sleep phase syndrome. Missense polymorphisms in Per3 (V647G) and CK1e (S408N) genes increase or decrease the risk of developing delayed sleep phase syndrome. All of these polymorphisms seem to affect the phosphorylation of the clock proteins. Some of the polymorphisms in CK1, which shows reduced enzyme activity in vitro, induced increased phosphorylation of PER proteins in in vivo assays. Careful attention should be paid to analyze the complex system composed of feedback loops, such as the biological clock.     

Section Review Oncologic,Endocrine & Metabolic: Melatonin related to health promotion and biological function

Melatonin is the main hormone secreted by the pineal gland. Bright light inhibits melatonin synthesis, so the amount of hormone present in the blood increases dramatically at night. Due to its sedative effects, melatonin has been linked to quality of sleep and may be used as a sleeping agent. In addition, there seems to be some correlation between melatonin levels and seasonal affective disorder (SAD). In high doses, melatonin is able to suppress ovulation, making it a promising birth control agent. Melatonin had been accepted as a regulator for many systems, including the immune system. For this reason, melatonin is being looked at as a supplement in the treatment of acquired immunodeficiency syndrome (AIDS) and cancer. Melatonin may be helpful to the body because of its antioxidant qualities and may reduce the risk of heart disease.     

Melatonin receptor agonists: SAR and applications to the treatment of sleep-wake disorders

Melatonin (N-acetyl-5-methoxytryptamine) is synthesized and released by the pineal gland following a circadian rhythm characterized by high levels during the night. It shows several pharmacological effects on diverse cellular and animal models, mainly related to either its antioxidant activity or to its ability to activate specific receptors (MTr). Melatonin is widely used as a self-administered food additive, but its therapeutic potential needs more investigation and is hampered by its poor pharmacokinetics. This review will focus on the medicinal chemistry of agonist ligands of the two human GPCRs MT(1) and MT(2) melatonin receptors. The recent introduction of ramelteon, a non-selective MT(1)/MT(2) agonist for the treatment of insomnia, and the advancement to clinical trials of other MTr agonists have renewed interest for different classes of compounds endowed with this activity. Several chemical classes of MTr agonists are described in the literature, generally characterized by an indole, or an indole bioisostere, carrying an amide side chain and a methoxy group, or substituents with similar stereoelectronic features. Abundant information is available for non-selective MT(1)/MT(2) ligands, and several molecular models, both ligand- and receptor-based, have been proposed to rationalize their structure activity relationships. Fewer classes of selective agonists have been reported in the literature, and they could help clarifying the physiological role of the two receptor subtypes. A brief discussion on the therapeutic potential of this class of compounds is based on the clinical data available for the agonists ramelteon, agomelatine, beta-methyl-6-chloromelatonin (TIK-301) and VEC-162.     

Melatonin, immune function and cancer

Melatonin is a natural substance ubiquitous in distribution and present in almost all species ranging from unicellular organisms to humans. In mammals, melatonin is synthesized not only in the pineal gland but also in many other parts of the body, including the eyes, bone marrow, gastrointestinal tract, skin and lymphocytes. Melatonin influences almost every cell and can be traced in membrane, cytoplasmic, mitochondrial and nuclear compartments of the cell. The decline in the production of melatonin with age has been suggested as one of the major contributors to immunosenescence and development of neoplastic diseases. Melatonin is a natural antioxidant with immunoenhancing properties. T-helper cells play an important role for protection against malignancy and melatonin has been shown to enhance T-helper cell response by releasing interleukin-2, interleukin-10 and interferon-γ. Melatonin is effective in suppressing neoplastic growth in a variety of tumors like melanoma, breast and prostate cancer, and ovarian and colorectal cancer. As an adjuvant therapy, melatonin can be beneficial in treating patients suffering from breast cancer, hepatocellular carcinoma or melanoma. In this paper, a brief review of recent patents on melatonin and cancer has also been presented.