Effect of Melatonin on Differentiation of Human Mesenchymal Stem Cells and a Study on C-Terminal Domains of MT1 and MT2 Melatonin Receptors

Melatonin has been reported to enhance the differentiation of osteoblasts. The purpose of this study was to determine the melatonin treatment that would differentiate human mesenchymal stem cells (hAMSCs) into osteoblasts. A 21 d continuous melatonin treatment significantly increased the alkaline phosphatase (ALP) activity and the deposition of calcium in hAMSCs. These effects were inhibited by MT2 specific antagonist- 4P-PDOT. The time periods of melatonin treatment that increased the expression of osteogenic genes indicated both a sensitized and desensitized receptors with respect to cAMP signaling, signifying two distinct mechanisms of melatonin\u27s action. Unlike the parathyroid hormone which is administered in intermittent doses to increase bone mass, a continuous melatonin treatment may be effective in having an anabolic effect on bone

Melatonin Alters Age-Related Changes in Transcription Factors and Kinase Activation

Male mice were fed 40 ppm melatonin for 2 months prior to sacrifice at age 26 months, and compared with both 26 and 4 month-old untreated controls. The nuclear translocation of NF-κB increased with age in both brain and spleen and this was reversed by melatonin only in brain. Another transcription factor, AP-1 was increased with age in the spleen and not in brain and this could be blocked by melatonin treatment. The fraction of the active relative to the inactive form of several enabling kinases was compared. The proportion of activated ERK was elevated with age in brain and spleen but this change was unresponsive to melatonin. A similar age-related increase in glial fibrillary acidic protein (GFAP) was also refractory to melatonin treatment. The cerebral melatonin M1 receptor decreased with age in brain but increased in spleen. The potentially beneficial nature of melatonin for the preservation of brain function with aging was suggested by the finding that an age-related decline in cortical synaptophysin levels was prevented by dietary melatonin

To what extent does photoperiod affect cattle reproduction? Clinical perspectives of melatonin administration

The seasonality of reproduction in most mammals is dictated by photoperiod, temperature and nutrition. Melatonin, mainly synthesized in the pineal gland, is generally accepted as the active mediator of photoperiod responses including reproduction. While non-pregnant heifers and cows show continuous sexual activity and are therefore not seasonal breeders, it has been suggested that photo-periodicity may influence the appearance of puberty in heifers and the onset of parturition. Further, the light/dark ratio may influence endocrine patterns of gestation and a shorter light period correlates with the incidence of twin pregnancies. This review considers specific aspects of the effects of photoperiod and melatonin on reproduction in dairy cattle and discusses the clinical applications of melatonin

The effect of melatonin on bacterial translocation following ischemia/reperfusion injury in a rat model of superior mesenteric artery occlusion

Background: Acute mesenteric ischemia is a life-threatening vascular emergency resulting in tissue destruction due to ischemia-reperfusion injury. Melatonin, the primary hormone of the pineal gland, is a powerful scavenger of reactive oxygen species (ROS), including the hydroxyl and peroxyl radicals, as well as singlet oxygen, and nitric oxide. In this study, we aimed to investigate whether melatonin prevents harmful effects of superior mesenteric ischemia-reperfusion on intestinal tissues in rats. Methods: Rats were randomly divided into three groups, each having 10 animals. In group I, the superior mesenteric artery (SMA) was isolated but not occluded. In group II and group III, the SMA was occluded immediately distal to the aorta for 60 minutes. After that, the clamp was removed and the reperfusion period began. In group III, 30 minutes before the start of reperfusion, 10 mg/kg melatonin was administered intraperitonally. All animals were sacrified 24 hours after reperfusion. Tissue samples were collected to evaluate the I/R-induced intestinal injury and bacterial translocation (BT). Results: There was a statistically significant increase in myeloperoxidase activity, malondialdehyde levels and in the incidence of bacterial translocation in group II, along with a decrease in glutathione levels. These investigated parameters were found to be normalized in melatonin treated animals (group III). Conclusion: We conclude that melatonin prevents bacterial translocation while precluding the harmful effects of ischemia/reperfusion injury on intestinal tissues in a rat model of superior mesenteric artery occlusion. © 2015 Ozban et al.; licensee BioMed Central

Identification of Melatonin-Regulated Genes in the Ovine Pituitary Pars Tuberalis, a Target Site for Seasonal Hormone Control

The pars tuberalis (PT) of the pituitary gland expresses a high density of melatonin (MEL) receptors and is believed to regulate seasonal physiology by decoding changes in nocturnal melatonin secretion. Circadian clock genes are known to be expressed in the PT in response to the decline (Per1) and onset (Cry1) of MEL secretion, but to date little is known of other molecular changes in this key MEL target site. To identify transcriptional pathways that may be involved in the diurnal and photoperiod-transduction mechanism, we performed a whole genome transcriptome analysis using PT RNA isolated from sheep culled at three time points over the 24-h cycle under either long or short photoperiods. Our results reveal 153 transcripts where expression differs between photoperiods at the light-dark transition and 54 transcripts where expression level was more globally altered by photoperiod (all time points combined). Cry1 induction at night was associated with up-regulation of genes coding for NeuroD1 (neurogenic differentiation factor 1), Pbef / Nampt (nicotinamide phosphoribosyltransferase) , Hif1α (hypoxia-inducible factor-1α), and Kcnq5 (K channel) and down-regulation of Rorβ, a key clock gene regulator. Using in situ hybridization, we confirmed day-night differences in expression for Pbef / Nampt, NeuroD1, and Rorβ in the PT. Treatment of sheep with MEL increased PT expression for Cry1, Pbef / Nampt, NeuroD1, and Hif1α, but not Kcnq5. Our data thus reveal a cluster of Cry1-associated genes that are acutely responsive to MEL and novel transcriptional pathways involved in MEL action in the PT

Management of rapid eye movement sleep behavior disorder in patients with Parkinson's disease

Among all of the devastating effects that Parkinson’s disease (PD) has on an individual, sleep dysfunction is one that can have a profound effect on the entire family of the patient. The most potentially destructive of these sleep syndromes being that of Rapid Eye Movement Sleep Behavior Disorder (RBD). This disorder not only causes sleep impairment to the patient, but can occasionally result in life-threatening injury to the individual or their bed partner. While this condition is manageable with medication, the current treatment of choice is a long-acting benzodiazepine, clonazepam. This drug, while effective in treating RBD, comes with a significant burden of side effects. Patients with neurodegenerative disorders, like PD, are at even higher risk of suffering the negative impacts of this treatment. One potential alternative treatment that has been considered is a supplement of exogenous melatonin, a hormone that plays a role in maintaining one’s circadian rhythm. Several small case studies have shown potential efficacy of this treatment, and with very few side effects. However, this efficacy has not yet been proven by randomized clinical trial. This proposed study will perform a double-blind randomized clinical trial of melatonin vs. placebo in a population of PD patients with RBD. Subjects will be analyzed via polysomnographic sleep study, where symptoms will be scored on the RBD Severity Scale (RBDSS) at baseline and after a treatment intervention. Statistical analysis will then ascertain whether or not a significant symptom reduction is seen following melatonin treatment, compared to a group receiving placebo. If melatonin proves to be efficacious in this patient population, this would give clinicians a new treatment option to consider to effectively manage symptoms of RBD with a much lower risk of potentially harmful side effects. Finding an effective method of managing this condition, the prevalence of which continues to rise worldwide, will have a great impact on improving the safety and quality of life of these patients

Melatonin attenuates oxidative stress and modulates inflammatory response after experimental burn trauma

Introduction. Thermal injury activates an inflammatory response. Melatonin possesses anti-oxidant and anti-inflammatory properties. The objective of the present work was to study melatonin effects on the inflammatory response under conditions of oxidative stress during the early stage of thermal injury. Materials and methods. We used 24 white male rats of Wistar breed, randomly divided into three experimental groups. Group one was the control, group two was inflicted with burn trauma, and group three was inflicted with burn trauma, with melatonin application following the thermal injury. Melatonin was applied twice in doses of 10 g/kg b.m. immediately after the burn trauma and again at 12 hours. Plasma levels of tumor necrosis-factor-α (TNF-α), a pro-inflammatory mediator, and of interleukin-10 (Il-10), an anti-inflammatory mediator, were examined and their ratio was calculated. The levels of malondialdehyde (MDA), an oxidative stress marker, were also estimated. Results. Thermal trauma significantly increased plasma TNF-α levels (ð\u3c0.01) and TNF-α /IL-10 ratio but did not change IL-10 ones. Plasma MDA concentrations were significantly elevated as well (ð\u3c0.0001). Melatonin application significantly reduced TNF-α (ð\u3c0.05), increased IL-10 (ð\u3c0.05), down-regulated TNF-α/IL-10 ratio and changed MDA concentrations (ð\u3c0.01). In conclusion, our results show that local alteration induces oxidative stress and inflammatory response with TNF-α /IL-10 disbalance. Melatonin modulates this response and attenuates oxidative stress in experimental burn injury

Abnormal hippocampal melatoninergic system: a potential link between absence epilepsy and depression-like behavior in WAG/Rij rats?

Absence epilepsy and depression are comorbid disorders, but the molecular link between the two disorders is unknown. Here, we examined the role of the melatoninergic system in the pathophysiology of spike and wave discharges (SWDs) and depression-like behaviour in the Wistar Albino Glaxo from Rijswijk (WAG/Rij) rat model of absence epilepsy. In WAG/Rij rats, SWD incidence was higher during the dark period of the light-dark cycle, in agreement with previous findings. However, neither pinealectomy nor melatonin administration had any effect on SWD incidence, suggesting that the melatoninergic system was not involved in the pathophysiology of absence-like seizures. Endogenous melatonin levels were lower in the hippocampus of WAG/Rij rats as compared to non-epileptic control rats, and this was associated with higher levels of melatonin receptors in the hippocampus, but not in the thalamus. In line with the reduced melatonin levels, cell density was lower in the hippocampus ofWAG/Rij rats and was further reduced by pinealectomy. As expected, WAG/Rij rats showed an increased depression-like behaviour in the sucrose preference and forced swim tests, as compared to non-epileptic controls. Pinealectomy abolished the difference between the two strains of rats by enhancing depression-like behaviour in non-epileptic controls. Melatonin replacement displayed a significant antidepressant-like effect in bothWAG/Rij and control rats. These findings suggest that a defect of hippocampal melatoninergic system may be one of the mechanisms underlying the depression-like phenotype inWAG/Rij rats and that activation of melatonin receptors might represent a valuable strategy in the treatment of depression associated with absence epilepsy

From implantation to birth: insight into molecular melatonin functions

Melatonin is a lipophilic hormone synthesized and secreted mainly in the pineal gland, acting as a neuroendocrine transducer of photoperiodic information during the night. In addition to this activity, melatonin has shown an antioxidant function and a key role as regulator of physiological processes related to human reproduction. Melatonin is involved in the normal outcome of pregnancy, beginning with the oocyte quality, continuing with embryo implantation, and finishing with fetal development and parturition. Melatonin has been shown to act directly on several reproductive events, including folliculogenesis, oocyte maturation, and corpus luteum (CL) formation. The molecular mechanism of action has been investigated through several studies which provide solid evidence on the connections between maternal melatonin secretion and embryonic and fetal development. Melatonin administration, reducing oxidative stress and directly acting on its membrane receptors, melatonin thyroid hormone receptors (MT1 and MT2), displays effects on the earliest phases of pregnancy and during the whole gestational period. In addition, considering the reported positive effects on the outcomes of compromised pregnancies, melatonin supplementation should be considered as an important tool for supporting fetal development, opening new opportunities for the management of several reproductive and gestational pathologies

The influence of season, photoperiod, and pineal melatonin on immune function.

In addition to the well-documented seasonal cycles of mating and birth, there are also significant seasonal cycles of illness and death among many animal populations. Challenging winter conditions (i.e., low ambient temperature and decreased food availability) can directly induce death via hypothermia, starvation, or shock. Coping with these challenges can also indirectly increase morbidity and mortality by increasing glucocorticoid secretion, which can compromise immune function. Many environmental challenges are recurrent and thus predictable; animals could enhance survival, and presumably increase fitness, if they could anticipate immunologically challenging conditions in order to cope with these seasonal threats to health. The annual cycle of changing photoperiod provides an accurate indicator of time of year and thus allows immunological adjustments prior to the deterioration of conditions. Pineal melatonin codes day length information. Short day lengths enhance several aspects of immune function in laboratory studies, and melatonin appears to mediate many of the enhanced immunological effects of photoperiod. Generally, field studies report compromised immune function during the short days of autumn and winter. The conflict between laboratory and field data is addressed with a multifactor approach. The evidence for seasonal fluctuations in lymphatic tissue size and structure, as well as immune function and disease processes, is reviewed. The role of pineal melatonin and the hormones regulated by melatonin is discussed from an evolutionary and adaptive functional perspective. Finally, the clinically significance of seasonal fluctuations in immune function is presented. Taken together, it appears that seasonal fluctuations in immune parameters, mediated by melatonin, could have profound effects on the etiology and progression of diseases in humans and nonhuman animals. An adaptive functional perspective is critical to gain insights into the interaction among melatonin, immune function, and disease processes