Oral Administration Of Melatonin Research Articles

Melatonin and gut microbiome

In recent years, studies of the human microbiome have led to the development of the gut-brain axis theory, which proposes a relationship between the gut bacterial community and its metabolites and chemical compounds, as well as physiological and pathological processes in the brain. Melatonin is considered one of the potential links in this relationship.The review provides brief information about the synthesis, metabolism and effects of melatonin in the body. General patterns of the effect of melatonin on the intestinal microbiota under various conditions, such as oral and intraperitoneal melatonin administration, sleep deprivation, as well as the results of studying the microbial community with measurement of hormone levels are considered.Results are presented for families and individual genera of microorganisms and are obtained from studies in animal models or in the research of diseases. The article also notes some additional parameters which are supposed to be relevant to the interaction of melatonin with gut microbiome. Special attention is paid to butyrate as one of the most studied possible parts in this interaction. Studying the relationship between melatonin and microbiome is of interest for basic science and practical medicine.Literature search was carried out using electronic information resources PubMed and eLibrary.

Melatonin ameliorates hepatic fibrosis via the melatonin receptor 2-mediated upregulation of BMAL1 and anti-oxidative enzymes

Hepatic fibrosis, when left untreated, causes serious health problems that progress to cirrhosis and, in some cases, liver cancer. Activation of hepatic stellate cells may be a key characteristic in the development of hepatic fibrosis. Melatonin, a pineal hormone, exerts anti-fibrotic effects; however, the exact mechanisms remain unclear. In this study, the beneficial effects of melatonin against hepatic fibrosis and the underlying mechanisms were investigated using the human hepatic stellate cell line, LX-2, and in vivo murine animal models. The results showed that melatonin suppressed the expression of transforming growth factor (TGF)-β1-induced fibrosis markers and production of reactive oxygen species in LX-2 cells. Either 4-phenyl-2-propionamidotetralin, a melatonin receptor 2 selective antagonist, or melatonin receptor 2 small interfering RNA abolished the suppressive effects of melatonin, suggesting the involvement of melatonin receptor 2 in melatonin-induced anti-fibrotic and anti-oxidative actions. Melatonin increased the expression of the brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1), a positive circadian clock gene. BMAL1 knockdown reduced the anti-fibrotic and anti-oxidative effects of melatonin, demonstrating the protective effects of melatonin against TGF-β1-induced hepatic stellate cell activation by exhibiting melatonin receptor 2-BMAL1-anti-oxidative effects. In high-fat diet-induced and carbon tetrachloride-induced hepatic fibrosis models, oral melatonin administration decreased the expression of hepatic fibrosis markers and increased the expression of messenger RNA and levels of proteins of BMAL1 and melatonin receptor 2. Thus, melatonin exerted protective effects against hepatic fibrosis through melatonin receptor 2 activation, followed by an upregulation of the BMAL1-anti-oxidative enzyme pathways.

IMPACT OF MELATONIN ON SOME INDICATORS OF CARBOHYDRATE METABOLISM IN LIVER OF RATS WITH DEXAMETHASONE-INDUCED DIABETES

One frequently employed experimental model, particularly in pre-clinical studies examining the hypoglycemic effects of potential antidiabetic medications, is the metasteroid diabetes model induced by the prolonged administration of glucocorticoids to animals. This experimental study aimed to elucidate the effects of exogenous melatonin (10 mg/kg) on glycogen content and the activity of key enzymes—pyruvate kinase (PK) [EC 2.7.1.40], lactate dehydrogenase (LDH) [EC 1.1.1.27], glucose-6-phosphate dehydrogenase (G-6-PDH) [EC 1.1.1.49], and glucose-6-phosphatase (G-6-P-ase) [EC 3.1.3.9]—in the livers of rats with dexamethasone-induced diabetes. Materials and Methods. The experiments were performed on 44 male 18-month-old white non-linear rats, divided into three groups: 1) control (intact rats), 2) rats with dexamethasone-induced diabetes, 3) rats that amid the progression of dexamethasone-induced diabetes, underwent daily oral administration of melatonin (Sigma, USA) in a dose of 10 mg/kg. Dexamethasone diabetes was modeled by subcutaneous injection of dexamethasone (injection solution 4 mg/ml, KRKA, Slovenia) at a dose of 0.125 mg/kg body weight daily for 13 days (O.V. Stefanov, 2001). Decapitation of animals was carried out in accordance with the norms of the "European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes" (Strasbourg, 1986). Glucose content in blood from the tail vein of rats, taken on the 14th day of fasting before decapitation of the animals, was determined using a portable glucometer (One Touch Ultra Easy, Life Scan, USA). The content of glycogen and the activity of the studied enzymes of carbohydrate metabolism in the liver were determined according to the generally accepted, previously described methods. A 5% homogenate was prepared from the cold-isolated rat liver in a chilled 50 mM Tris-HCI buffer (pH=7.4) to study the activities of pyruvate kinase, lactate dehydrogenase, glucose-6-phosphate dehydrogenase and glucose-6-phosphatase in the cytosolic fraction. The reliability of the difference between the obtained indicators was assessed using the parametric Student's t-test (for normal distribution) and the non-parametric Mann-Whitney U-test (for non-normal distribution). Differences were considered probable at p≤0.05. Results and discussion. According to our results, in the liver of diabetic rats that did not receive any means of correction of carbohydrate metabolism disorders, the glycogen content was 33% lower than in intact animals. The activities of enzymes such as pyruvate kinase and glucose-6-phosphate dehydrogenase were also reduced in the liver of rats with impaired glucose tolerance by 31.6 and 21.5%, respectively, compared to intact animals, indicating inhibition of glucose oxidation pathways, both at the level glycolysis (decrease of pyruvate kinase), as well as at the level of the oxidative stage of the pentose-phosphate pathway of glucose-6-phosphate oxidation. At the same time, the activity of lactate dehydrogenase and especially glucose-6-phosphatase in the liver of rats with diabetes by 19.5 and 56%, respectively, exceeded the indicators of animals of the control group, which demonstrates the increased activity, intensity of glycogenolysis and gluconeogenesis under conditions of insulin resistance, because glucose-6-phosphatase is the terminal enzyme of these processes. Regarding the investigated parameters of carbohydrate metabolism, both the glucose content in the blood of rats, as well as the glycogen content and the activity of all studied enzymes in the liver of rats that were injected with melatonin against the background of the development of diabetes, did not reliably differ from the parameters of intact animals, which confirms the assumption of the probable hypoglycemic effect of melatonin against the background of the development of diabetes. Conclusions: The daily two-week use of melatonin (10 mg/kg), against the background of the development of dexamethasone diabetes in rats, contributes to the normalization of certain indicators of carbohydrate metabolism in the liver of animals.

Short-Wavelength Light-Blocking Filters and Oral Melatonin Administration in Patients With Retinitis Pigmentosa: Protocol for a Randomized Controlled Trial.

The medical community is beginning to recognize that retinitis pigmentosa (RP), due to its disabling progression, eventually leads to a reduction in the patient´s quality of life, a direct economic impact, and an increase in the burden on the health care system. There is no curative treatment for the origin of the disease, and most of the current interventions fail in reducing the associated negative psychological states, such as anxiety and depression, which lead to increased variability of vision and pose a continuous threat to the patient's independence. The aim of this study is to assess the effect of oral melatonin (OM) administration alone and combined with short-wavelength light (SWL)-blocking filters on patients with RP and test their effectiveness in improving the level of stress and sleep problems in many of these patients. We have developed a low-cost therapy protocol for patients with RP with sleep disorders and negative psychological stress. Patients will be randomized to receive a combined intervention with SWL-blocking filters and OM, SWL-blocking filters alone, or OM alone. There will also be a nonintervention arm as a control group. This study will be conducted across 2 retinal units in patients with RP with sleep disorders and high perceived stress and anxiety score reports. Patients will be assessed in the preintervention period, weekly during the 4 weeks of intervention, and then at 6 months postintervention. The primary outcomes are the differences in changes from baseline to postintervention in hormone release (α-amylase, cortisol, and melatonin) and sleep quality, as measured with the visual analog scale. Secondary outcome measures include clinical macular changes, as measured with optical coherence tomography and optical coherence tomography angiography; retinal function, as measured using the visual field and best-corrected visual acuity; sleep data collected from personal wearables; and several patient-reported variables, such as self-recorded sleep diaries, quality of life, perceived stress, and functional status. This project is still a study protocol and has not yet started. Bibliographic research for information for its justification began in 2020, and this working group is currently seeking start-up funding. As soon as we have the necessary means, we will proceed with the registration and organization prior to the preliminary phase. In this feasibility randomized clinical controlled trial, we will compare the effects of SWL blocking alone, administration of OM alone, and a combined intervention with both in patients with RP. We present this study so that it may be replicated and incorporated into future studies at other institutions, as well as applied to additional inherited retinal dystrophies. The goal of presenting this protocol is to aid recent efforts in reducing the impact of sleeping disorders and other psychological disorders on the quality of life in patients with RP and recovering their self-autonomy. In addition, the results of this study will represent a significant step toward developing a novel low-cost therapy for patients with RP and validating a novel therapeutic target. PRR1-10.2196/49196.

Melatonin improves synapse development by PI3K/Akt signaling in a mouse model of autism spectrum disorder.

Abstract JOURNAL/nrgr/04.03/01300535-202407000-00043/figure1/v/2023-11-20T171125Z/r/image-tiff Autism spectrum disorders are a group of neurodevelopmental disorders involving more than 1100 genes, including Ctnnd2 as a candidate gene. Ctnnd2 knockout mice, serving as an animal model of autism, have been demonstrated to exhibit decreased density of dendritic spines. The role of melatonin, as a neurohormone capable of effectively alleviating social interaction deficits and regulating the development of dendritic spines, in Ctnnd2 deletion-induced nerve injury remains unclear. In the present study, we discovered that the deletion of exon 2 of the Ctnnd2 gene was linked to social interaction deficits, spine loss, impaired inhibitory neurons, and suppressed phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signal pathway in the prefrontal cortex. Our findings demonstrated that the long-term oral administration of melatonin for 28 days effectively alleviated the aforementioned abnormalities in Ctnnd2 gene-knockout mice. Furthermore, the administration of melatonin in the prefrontal cortex was found to improve synaptic function and activate the PI3K/Akt signal pathway in this region. The pharmacological blockade of the PI3K/Akt signal pathway with a PI3K/Akt inhibitor, wortmannin, and melatonin receptor antagonists, luzindole and 4-phenyl-2-propionamidotetralin, prevented the melatonin-induced enhancement of GABAergic synaptic function. These findings suggest that melatonin treatment can ameliorate GABAergic synaptic function by activating the PI3K/Akt signal pathway, which may contribute to the improvement of dendritic spine abnormalities in autism spectrum disorders.

Modern Approaches to Treatment of Alopecia X in Dogs: Review of Research

Introduction. Noninflammatory alopecia is a disorder of canine appearance, which brings aesthetic discomfort to dog owners. Among foreign studies there are only few publications on implementing the drugs of the humane medicine for treatment of this disorder. The publications in the national literature present the descriptions of the individual clinical cases. The reviews of research containing the analysis and summary of the canine noninflammatory alopecia treatment methods are unavailable in the scientific literature. Therefore, this work aims at providing a comparative analysis of the canine noninflammatory alopecia treatment methods (based on the literature sources analysis).Materials and Methods. Searching by subject area was conducted in the eLIBRARY.RU, PubMed, Crossref and Google Scholar databases for materials published from 2000 to 2023 by the following keywords: dog AND alopecia, dog*AND alopecia X, dog*AND “name of the drug”. The selected materials were structured, 111 publications were analysed, 69 of which were included in the present review.Results. The studies on the use of humane medicine methods and drugs for treatment of alopecia X in dogs were analysed. The information was systemized into thematic blocks depending on the physiological causes of alopecia X and the drugs used. The main methods and approaches to be investigated were the use of melatonin, mitotane, trilostane, minoxidil, hormonal drugs, microneedling and microtrauma techniques.Discussion and Conclusion. Currently, the unified protocol for treatment of alopecia X in dogs is not developed in the veterinary medicine. Upon analysis of the treatment methods described in the literature, microneedling, oral administration of melatonin and trilostane, along with the use of subcutaneous implants of deslorelin acetate have been identified as the optimal ones, combining high efficiency with minor side effects. The use of mitotane, minoxidil and osaterone acetate causes the serious side effects, that prevents them from being the future-oriented methods.

Melatonin prevents EAAC1 deletion-induced retinal ganglion cell degeneration by inhibiting apoptosis and senescence.

Normal tension glaucoma (NTG) is referred to as a progressive degenerative disorder of the retinal ganglion cells (RGCs), resulting in nonreversible visual defects, despite intraocular pressure levels within the statistically normal range. Current therapeutic strategies for NTG yield limited benefits. Excitatory amino acid carrier 1 (EAAC1) knockout (EAAC1-/- ) in mice has been shown to induce RGC degeneration without elevating intraocular pressure, mimicking pathological characteristics of NTG. In this study, we explored whether daily oral administration of melatonin could block RGCs loss and prevent retinal morphology and function defects associated with EAAC1 deletion. We also explored the molecular mechanisms underlying EAAC1 deletion-induced RGC degeneration and the neuroprotective effects of melatonin. Our RNA sequencing and in vivo data indicated EAAC1 deletion caused elevated oxidative stress, activation of apoptosis and cellular senescence pathways, and neuroinflammation in RGCs. However, melatonin administration efficiently prevented these detrimental effects. Furthermore, we investigated the potential role of apoptosis- and senescence-related redox-sensitive factors in EAAC1 deletion-induced RGCs degeneration and the neuroprotective effects of melatonin administration. We observed remarkable upregulation of p53, whereas NRF2 and Sirt1 expression were significantly decreased in EAAC1-/- mice, which were prevented by melatonin treatment, suggesting that melatonin exerted its neuroprotective effects possibly through modulating NRF2/p53/Sirt1 redox-sensitive signaling pathways. Overall, our study provided a solid foundation for the application of melatonin in the management of NTG.

Melatonin Restores Autophagic Flux by Activating the Sirt3/TFEB Signaling Pathway to Attenuate Doxorubicin-Induced Cardiomyopathy.

Doxorubicin (DOX) chemotherapy in cancer patients increases the risk of the occurrence of cardiac dysfunction and even results in congestive heart failure. Despite the great progress of pathology in DOX-induced cardiomyopathy, the underlying molecular mechanisms remain elusive. Here, we investigate the protective effects and the underlying mechanisms of melatonin in DOX-induced cardiomyopathy. Our results clearly show that oral administration of melatonin prevented the deterioration of cardiac function caused by DOX treatment, which was evaluated by left ventricular ejection fraction and fractional shortening as well as cardiac fibrosis. The ejection fraction and fractional shortening in the DOX group were 49.48% and 25.5%, respectively, while melatonin treatment increased the ejection fraction and fractional shortening to 60.33 and 31.39 in wild-type mice. Cardiac fibrosis in the DOX group was 3.97%, while melatonin reduced cardiac fibrosis to 1.95% in wild-type mice. Sirt3 is a mitochondrial deacetylase and shows protective effects in diverse cardiovascular diseases. Therefore, to test whether Sirt3 is a key factor in protection, Sirt3 knockout mice were used, and it was found that the protective effects of melatonin in DOX-induced cardiomyopathy were partly abolished. Further analysis revealed that Sirt3 and its downstream molecule TFEB were downregulated in response to DOX treatment, while melatonin administration was able to significantly enhance the expressions of Sirt3 and TFEB. Our in vitro study demonstrated that melatonin enhanced lysosomal function by increasing the Sirt3-mediated increase at the TFEB level, and the accumulation of autolysosomes induced by DOX treatment was attenuated. Thus, autophagic flux disrupted by DOX treatment was restored by melatonin supplementation. In summary, our results demonstrate that melatonin protects the heart against DOX injury by the restoration of autophagic flux via the activation of the Sirt3/TFEB signaling pathway.

EFFECT OF MELATONIN ON FIBRINIOLYSIS IN THE BRAIN OF RATS WITH DEXAMETHASONE DIABETES

The purpose of our study was to determine the effect of melatonin on the characteristics of fibrinolysis in the brain of rats with dexamethasone diabetes. Materials and Methods. The experimental study was carried out on thirty male eighteen- month-old non-linear white rats. The experimental rats were divided into three groups: 1) intact animals (control group); 2) rats with untreated dexamethasone diabetes; 3) rats, what were administered by melatonin in a dose of 10 mg per kg of body weight intragastrically daily through a metal probe during the 13 days of experiment in addition to dexamethasone injection. Results. In the cerebral cortex of rats with diabetic neurodegeneration on the 14th day of the experiment, an increase in total fibrinolysis due to enzymatic fibrinolysis was found. Thus, TFA increased by 10%, and EFA by 15% compare to the indicators of animals of the control group. In the hippocampus, NFA indicators did not change, and EFA increased by 25% compared to the indicators of control group. Daily oral administration of melatonin (10 mg/kg) to rats with diabetes-induced neurodegeneration did not significantly affect the EFA index in the cerebral cortex, but contributed to a 15% decrease in this indicator in the hippocampus, compared to the indicators of diabetic rats that did not receive any correction agents. The indicators of TFA and NFA both in the cerebral cortex and in the hippocampus were not significantly different from the indicators of rats with diabetes. Conclusions. A decrease in the intensity of the fibrinolysis process was noted in the cerebral cortex and hippocampus of rats that, in addition to dexamethasone injections, were orally administered melatonin daily for 13 days.

Controlled release of bilayer tablet comprising vitamin B6 rapid-release layer and melatonin sustained-release layer

Here, the formulation of a novel bilayer tablet comprising a vitamin B6 rapid-release layer and a melatonin sustained-release layer is described. The effects of viscosity and concentration of the sustained-release matrix material, amount of diluent, and melatonin particle size on the release characteristics of melatonin were examined. In addition, the drug-release behavior of the prepared bilayer tablets was examined in different dissolution media. Further, drug-release kinetics and melatonin behavior in the sustained-release layer were evaluated based on dissolution profiles and changes in tablet weight during dissolution. Furthermore, the stability of the bilayer tablet was established. The in vitro release test revealed that vitamin B6 was completely released within 10–15 ​min, with melatonin demonstrating ∼90% cumulative release within 8 ​h. Based on kinetic model fitting results, melatonin release was well fitted to the Ritger-Peppas model; the release mechanism was non-Fick diffusion with both diffusion and erosion. The drug-release study confirmed that the melatonin sustained-release layer predominantly underwent polymer swelling rather than polymer erosion. The stability test results showed that the bilayer tablets had good stability under high temperature, high humidity, and light conditions. The bilayer tablets offer an alternative for the controlled-release oral administration of melatonin, although their in vivo effects need to be investigated in human studies.

The effects of melatonin on the concentrations of inflammatory cytokines and proteins, serotonin, cortisol and melatonin in ovariohysterectomised female dogs

Ovariohysterectomy (OHE) induces inflammation and stress in female dogs. The anti-inflammatory effects of melatonin have been reported in several studies. The goal of this study was to assess the effects of melatonin on the concentrations of melatonin, cortisol, serotonin, α-1-acid glycoprotein (AGP), serum amyloid A (SAA), c-reactive protein (CRP), interleukin-10 (IL-10), interleukin-8 (IL-8), interleukin-1β (IL-1β) and tumour necrosis factor-α (TNF-α) before and after OHE. The total number of animals was 25 and aligned in 5 groups. Fifteen dogs were divided into three groups (n = 5): melatonin, melatonin+anaesthesia and melatonin+OHE and received melatonin (0.3mg/kg, p.o.) on days -1, 0, 1, 2 and 3. Ten dogs were assigned to the control and OHE groups (n = 5) without melatonin treatment. OHE and anaesthesia were performed on day 0. Blood samples were obtained via jugular vein on days -1, 1, 3 and 5. Melatonin and serotonin concentrations significantly increased in the melatonin, melatonin+OHE and melatonin+anaesthesia groups compared with the control group, while cortisol concentration decreased in the melatonin+OHE group compared with the OHE group. The concentrations of acute-phase proteins (APPs) and inflammatory cytokines significantly increased after OHE. The CRP, SAA and IL-10 concentrations decreased significantly in the melatonin+OHE group compared with the OHE group. The concentrations of cortisol, APPs and proinflammatory cytokines increased significantly in the melatonin+anaesthesia group compared with the melatonin group. The oral administration of melatonin before and after OHE help controlling the high levels of inflammatory APPs, cytokines and cortisol induced by OHE in female dogs.

Melatonin attenuates cholestatic liver injury via inhibition of the inflammatory response.

Melatonin, an indole neurohormone secreted mainly by the pineal gland, has been found to be involved in a variety of liver diseases. However, the underlying mechanism by which melatonin ameliorates cholestatic liver injury is not fully understood. In this study, we investigated the mechanism by which melatonin attenuates cholestatic liver injury via inhibition of the inflammatory response. We measured the levels of serum melatonin in patients with obstructive cholestasis (n = 9), patients with primary biliary cholangitis (PBC) (n = 11), and control patients (n = 7). We performed experiments with C57BL/6J mice treated with 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and melatonin to verify the role of melatonin in the mouse model of cholestasis. Primary mouse hepatocytes were used for in vitro studies to study the mechanisms of action of melatonin in cholestasis. The levels of serum melatonin were markedly increased and negatively correlated with serum markers of liver injury in cholestatic patients. As expected, oral administration of melatonin significantly attenuated cholestasis-induced liver inflammation and fibrosis in 0.1% DDC diet-fed mice. Further mechanistic studies in cholestatic mice and primary hepatocytes revealed that melatonin reduced the conjugate BA-stimulated expression of cytokines (e.g. Ccl2, Tnfα, and Il6) through the ERK/Egr1 signalling pathway in these models. The levels of serum melatonin are significantly elevated in cholestatic patients. Melatonin treatment ameliorates cholestatic liver injury by suppressing the inflammatory response in vivo and in vitro. Therefore, melatonin is a promising novel therapeutic strategy for cholestasis.

TO OBSERVE EFFECTS OF MELATONIN PREMEDICATION ON HAEMODYNAMIC RESPONSES TO LARYNGOSCOPY AND INTUBATION

Laryngoscopy using rigid metal blade produces noxious stimuli that causes stimulation of sensory receptors which in turn causes release of endogenous catecholamines, which in turn provokes hemodynamic changes called stress response. Due to its inhibitory action on CNS which causes sedation and anxiolysis as well as suppression of catecholamine release, we hypothesized that oral melatonin tablet 10 mg, administered orally about 120 minutes before the procedure should provide hemodynamic stability and blunt this response. The primary objective of the study was to observe magnitude and duration of changes in vital parameters before, during and after laryngoscopy and intubation, in a group of patients who were premedicated with 10 mg mouth dispersible tablet melatonin 120 min anesthesia. Continuous numeric data on pulse rate, blood pressure, SPO2 were analyzed as mean and standard deviation. Signicance of observation was derived by applying student's t-test. Non parametric data on complication of study drug was reported as number of patients exhibiting the complication and also as percentage. One group of 35 patients received 10 mg of oral melatonin as mouth dispersible tablet 120 minutes before conduct of anesthesia and other group did not received the study drug and acted as control group for comparison. Pre induction hemodynamic parameters after 120 minutes of oral melatonin administration were recorded and after induction of anesthesia and intubation hemodynamic parameters were recorded. In group of patients who received melatonin the magnitude of rise of heart rate, systolic, diastolic and mean arterial pressure was less returning to pre induction value within 3 minutes. .In control group patients we observed a statistically signicant rise in magnitude of heart rate and blood pressure that remained elevated till 10 minutes after laryngoscopy and intubation. The rate pressure product, an indicator of myocardial oxygen demand and consumption was signicantly higher in control group and lasted for longer time. While in melatonin treated patients insignicant rise of RPP occurred. The clinical observations made in the present study allow us to conclude that oral melatonin administered 120 minutes before induction of anesthesia effectively controlled the stress response to laryngoscopy and endotracheal intubation and shown cardio-protective effect.

ABCG2 transporter plays a key role in the biodistribution of melatonin and its main metabolites.

The ATP-binding cassette G2 (ABCG2) is an efflux transporter expressed in the apical membrane of cells from a large number of tissues, directly affecting bioavailability, tissue accumulation, and secretion into milk of both xenobiotics and endogenous compounds. The aim of this work was to characterize the role of ABCG2 in the systemic distribution and secretion into milk of melatonin and its main metabolites, 6-hydroxymelatonin, and 6-sulfatoxymelatonin. For this purpose, we first showed that these three molecules are transported by this transporter using in vitro transepithelial assays with MDCK-II polarized cells transduced with different species variants of ABCG2. Second, we tested the in vivo effect of murine Abcg2 in the systemic distribution of melatonin and its metabolites using wild-type and Abcg2-/- mice. Our results show that after oral administration of melatonin, the plasma concentration of melatonin metabolites in Abcg2-/- mice was between 1.5 and 6-fold higher compared to the wild-type mice. We also evaluated in these animals differences in tissue accumulation of melatonin metabolites. The most relevant differences between both types of mice were found for small intestine and kidney (>sixfold increase for 6-sulfatoxymelatonin in Abcg2-/- mice). Finally, melatonin secretion into milk was also affected by the murine Abcg2 transporter, with a twofold higher milk concentration in wild-type compared with Abcg2-/- lactating female mice. In addition, melatonin metabolites showed a higher milk-to-plasma ratio in wild-type mice. Overall, our results show that the ABCG2 transporter plays a critical role in the biodistribution of melatonin and its main metabolites, thereby potentially affecting their biological and therapeutic activity.

Effects of long-term oral administration of melatonin on tear production, intraocular pressure, and tear and serum melatonin concentrations in healthy dogs.

To evaluate the effects of long-term (30-day) oral administration of melatonin on tear production, intraocular pressure (IOP), and concentration of melatonin in the tears and serum of healthy dogs. 20 healthy sexually intact adult male dogs. 10 dogs were given melatonin (0.3 mg/kg, PO, q 24 h, administered in food at 9 am), and 10 dogs were given a placebo. Tear and serum melatonin concentrations, IOP, and tear production (determined with a Schirmer tear test) were recorded before (baseline) and 30 minutes, 3 hours, and 5 hours after administration of melatonin or the placebo on day 1 and 30 minutes after administration of melatonin or the placebo on days 8, 15, and 30. Data collection time had significant effects on tear production, IOP, and tear melatonin concentration but not on serum melatonin concentration. Treatment (melatonin vs placebo) had a significant effect on tear melatonin concentration, but not on tear production, IOP, or serum melatonin concentration; however, tear melatonin concentration was significantly different between groups only 30 minutes after administration on day 1 and not at other times. In healthy dogs, long-term administration of melatonin at a dosage of 0.3 mg/kg, PO, every 24 hours did not have any clinically important effects on tear production, IOP, or serum or tear melatonin concentrations.

Effects of melatonin on intestinal function and bacterial compositions in sucking piglets.

Melatonin has been reported to affect intestinal function by targeting microbiome, morphological structure, barrier integrity and nutrient absorptive system. While the effect of melatonin on intestinal development in newborn infants is obscure, thus, this study firstly attempted to investigate the hypothesis that melatonin treatment improves intestinal development in sucking piglets. 14healthy newborn piglets received 10ml melatonin solution (1mg/ml) or drinking water (n=7) for 21days. The results showed that oral administration of melatonin increased liver relative weight (p<0.05) but failed to affect growth performance in sucking piglets (p>0.05). Immunostaining jejunal samples from melatonin group showed high expressions of nnos and claudin1, indicating that melatonin improved intestinal neural development and barrier integrity. Also, melatonin promoted intestinal absorptive function evidenced by the increased serum proline concentration in melatonin-treated piglets compared with the control (p<0.05). Gut microbiota compositions were tested by 16S rDNA sequencing and the results showed that melatonin increased the relative abundance of Actinobacteria compared with the control (p<0.05) at the phylum level. However, Selenomonadales was markedly reduced compared with the control at the order level (p<0.05). Gut and faecal volatile fatty acids were tested to evaluate the microbiota metabolism, but no difference was noticed in volatile fatty acid concentrations (p>0.05). Melatonin improved intestinal development by affecting neural development, barrier integrity, nutrient absorption and microbiota in sucking piglets.

Melatonin, circadian rhythms and glaucoma: current perspective.

Melatonin, circadian rhythms and glaucoma: current perspective.

Oral administration of melatonin increases plasma calcium and magnesium and improves bone metabolism in aged male mice

We previously reported that the oral administration of melatonin from 4 to 20 months to male mice improved femoral bone strength and bone density during the aging. Additionally, melatonin receptor, MT2, was immunologically detected in both osteoblasts and osteoclasts of the mouse femoral bone. Thus, melatonin can act on both osteoblasts and osteoclasts to maintain bone strength during the aging process. Here, we analyzed plasma calcium (Ca2+), magnesium (Mg2+), and inorganic phosphorus ([PO4]3-) in 20-month-old male mice with or without administration melatonin (15-20 mg/kg/day) in drinking water. We found that plasma Ca2+ and Mg2+ levels in melatonin-treated mice increased significantly as compared with control mice. In [PO4]3-, melatonin administration tended to increase its plasma level, but did not reach statistical significance. The potential association between these divalent ions and metabolism markers of femoral bone was also examined. In the femoral diaphysis, the plasma Ca2+ and Mg2+ concentrations were positively correlated with periosteal and endosteal circumference which were significantly associated with the Strength Strain Index. Therefore, melatonin treatment enlarged femoral diaphysis and enhanced bone strength by increasing mineral depositions. In addition, the plasma melatonin levels were significantly positive correlation with total bone density and critical thickness in the femoral diaphysis. Since we had not observed the primary trabecular bone and osteoclasts in 20-month-old mice previously, it is suggested that plasma Ca2+ and Mg2+ are not elevated due to bone resorption. The increased plasma Ca2+ and Mg2+ by melatonin may originate from the intestinal absorption of these ions since melatonin binds to the vitamin D3 receptor, its activation is known to promote the intestinal absorption of Ca2+.

Melatonin improves the quality of maternally aged oocytes by maintaining intercellular communication and antioxidant metabolite supply

In mammalian ovaries, oocytes are physically coupled to somatic granulosa cells, and this coupling is crucial for the growth and development of competent oocytes as it mediates the transfer of metabolic support molecules. However, aging-mediated dysregulation in communication between the oocytes and granulosa cells affects the oocyte quality. In the present study, we examined the defected germline-soma communication and reduced mRNA levels encoding key structural components of transzonal projections (TZPs) in maternally aged oocytes. Oral administration of melatonin to aged mice substantially increased TZPs and maintained the cumulus cells-oocyte communication, which played a central role in the production of adequate oocyte ATP levels and reducing the accumulation of reactive oxygen species (ROS), apoptosis, DNA damage, endoplasmic reticulum (ER) stress and spindle/chromosomal defects. This beneficial effect of melatonin was inhibited by carbenoxolone (CBX), a gap junctional uncoupler, which disrupts bidirectional communications between oocyte and somatic cells. Simultaneously, melatonin significantly increased the mRNA and protein levels corresponding to genes associated with TZPs and prevented TZP retraction in in vitro-cultured cumulus-oocyte complex (COCs). Furthermore, we infused melatonin and CBX into the COCs in vitro culture system and monitored the levels of nicotinamide adenine dinucleotide phosphate (NADPH) and glutathione (GSH) in cumulus cells and oocytes. Notably, COCs treated with melatonin demonstrated improved NADPH and GSH levels. Of note, CBX was capable of reducing NADPH and GSH levels, aggravated the ROS accumulation and ER stress. Collectively, our data demonstrate the role of melatonin in preventing age-associated germline-soma communication defects, aiding the relay of antioxidant metabolic molecules for the maintenance of oocyte quality from cumulus cells, which have important potential for improving deficient phenotypes of maternally aged oocytes and the treatment of woman infertility.

Melatonin Reduces Oxidative Stress in the Right Ventricle of Newborn Sheep Gestated under Chronic Hypoxia.

Pulmonary arterial hypertension of newborns (PAHN) constitutes a critical condition involving both severe cardiac remodeling and right ventricle dysfunction. One main cause of this condition is perinatal hypoxia and oxidative stress. Thus, it is a public health concern for populations living above 2500 m and in cases of intrauterine chronic hypoxia in lowlands. Still, pulmonary and cardiac impairments in PAHN lack effective treatments. Previously we have shown the beneficial effects of neonatal melatonin treatment on pulmonary circulation. However, the cardiac effects of this treatment are unknown. In this study, we assessed whether melatonin improves cardiac function and modulates right ventricle (RV) oxidative stress. Ten lambs were gestated, born, and raised at 3600 m. Lambs were divided in two groups. One received daily vehicle as control, and another received daily melatonin (1 mg·kg−1·d−1) for 21 days. Daily cardiovascular measurements were recorded and, at 29 days old, cardiac tissue was collected. Melatonin decreased pulmonary arterial pressure at the end of the experimental period. In addition, melatonin enhanced manganese superoxide dismutase and catalase (CAT) expression, while increasing CAT activity in RV. This was associated with a decrease in superoxide anion generation at the mitochondria and NADPH oxidases in RV. Finally, these effects were associated with a marked decrease of oxidative stress markers in RV. These findings support the cardioprotective effects of an oral administration of melatonin in newborns that suffer from developmental chronic hypoxia.