Melatonin Receptor Research Articles

The Interaction of SRL-2 Peptide with LRP-1 Receptor and Identification of Breast Cancer Related Biomarkers: An In-silico Approach

Background: Breast cancer is a multifaceted disease characterized by genetic and epigenetic changes that lead to uncontrolled cell growth and metastasis. Early detection and treatment are crucial for managing diseases. Objectives: The objective of this study is to investigate the potential of chimeric peptides for drug delivery and to identify biomarkers associated with breast cancer. Recent studies have shown that the low-density lipoprotein receptor-related protein 1 (LRP-1) receptor has a significant impact on the development of breast cancer. In order to facilitate the identification of biomarkers, we have created a chimeric peptide that has been proven to bind successfully to the LRP-1 receptor. Methods: To identify biomarkers, we utilized advanced computational methods to conduct a meta-analysis of microarray data. Specifically, the g:Profiler and eXpression2Kinases (X2K) databases were utilized to identify gene ontologies and transcription factors. We then used the Human Protein Atlas to identify and assess crucial gene expressions. Results: Our results demonstrated that nucleolar and spindle-associated protein 1 (NUSAP1), melatonin receptor 1A (MELT), and cyclin-dependent kinase 1 (CDK1) are three hub genes that play pivotal roles in the pathogenesis of breast cancer. Conclusions: The research findings provide a deeper understanding of the molecular mechanisms involved in developing breast cancer. These findings have significant implications for developing novel therapies and diagnostics for this disease.

Photoperiod Induces DNA Methylation Changes in the Melatonin Receptor 1A Gene in Ewes

Research has shown that MTNR1A plays an essential role in the estrus cycle and seasonal reproduction changes in sheep. However, few people have focused on the DNA methylation of MTNR1A by season or photoperiod. In this study, using qPCR and Western blotting, we measured the MTNR1A expression in the hypothalamus of ovariectomized and estradiol-treated (OVX + E2) sheep under different photoperiod treatment conditions. Subsequently, the core promoter of the MTNR1A gene was identified, and its methylation level in sheep exposed to different photoperiod treatments was measured by pyrosequencing. The results showed that MTNR1A gene expression significantly differed between the short 42-day photoperiod (SP42) and the LP42 or combined SP-LP42 treatment groups (p < 0.05). In addition, we determined that the core MTNR1A promoter region was within 540 bp upstream of the transcriptional start site (TSS) and that the DNA methylation levels at CpG sites in the SP42 vs. LP42 and SP42 vs. SP-LP42 groups significantly differed. Finally, a significant negative correlation (p < 0.001) between gene expression and DNA methylation levels was revealed, suggesting that photoperiod may induce DNA methylation of the MTNR1A gene and thus change its expression. The findings provide valuable bases for the further study of seasonal reproduction in sheep.

Synthesis and Fluorescence Properties of 4-Cyano and 4-Formyl Melatonin as Putative Melatoninergic Ligands.

Fluorescent ligands are imperative to many facets of chemical biology and medicinal chemistry. Herein, we report the syntheses of two fluorescent melatonin-based derivatives as potential ligands of melatonin receptors. The two compounds, namely, 4-cyano and 4-formyl melatonin (4CN-MLT and 4CHO-MLT, respectively), which differ from melatonin by only two/three atoms that are very compact in size, were prepared using the selective C3-alkylation of indoles with N-acetyl ethanolamines involving the "borrowing hydrogen" strategy. These compounds exhibit absorption/emission spectra that are red-shifted from those of melatonin. Binding studies on two melatonin receptor subtypes showed that these derivatives have a modest affinity and selectivity ratio.

Melatonin in Th17/Treg differentiation: the contribution of the hormone's own production by T lymphocytes

The hormone melatonin is involved in regulation of functioning of almost all organs and systems of the organism. In the immune system, T lymphocytes are an important target of melatonin: they express specific melatonin receptors with different affinities – membrane MT1 and MT2 and nuclear RORa, as well as intracellular molecules that nonspecifically bind melatonin at high concentrations. Moreover, many in vitro studies reveal their own production of melatonin by T lymphocytes in response to polyclonal activation and its involvement as autocrine or paracrine factor in the induction of IL-2 and IL-2 receptor (IL-2R) synthesis by T cells, with melatonin receptors involvement in implementation of these effects. Since IL-2/IL-2R-dependent signal is a key event in T lymphocytes proliferative response induction, intrinsic melatonin seems to be directly involved at least in the clonal expansion of these cells. In this work, we investigated the contribution of T cells’ melatonin to regulation of the next stage of T lymphocyte activation, namely, the differentiation of T helper populations Th17 and Treg. It was shown that blockade of both membrane and nuclear melatonin receptors did not cause statistically significant changes in Th17 differentiation, although the trend was fixed for a decrease. Simultaneously, CD4+FoxP3+Т cells level decreased under the nonselective blockade of membrane hormone receptors, and Treg-associated cytokine TGF-b concentration in activated cultures supernatants decreased both in case of MT1/MT2 nonselective blockade and MT2 selective blockade. The data indicate that melatonin produced by T lymphocytes in culture can contribute to the control of naive CD4+T cell differentiation into Treg in vitro, and the hormone effects are mediated by membrane melatonin receptors. The presence of a large number targets with different affinities for melatonin in T lymphocytes determines the key role of the hormone concentration in its effects on these cells. And when interpreting data on melatonin-dependent regulation of Treg, it is important to take into account the hormone’s own production by lymphocytes, since T cells’ melatonin can mask the exogenous hormone effects or interfere with its action due to competitive binding to hormone receptors.

Characterization and co-localization of thyroid stimulating hormone and melatonin receptors in the pars tuberalis of mares during the breeding and non-breeding seasons

Control of seasonal reproduction in horses has yet to be fully elucidated; however, duration of melatonin secretion is a seasonal regulator of the hypothalamic-pituitary-gonadal (HPG) axis. The hypophyseal pars tuberalis (PT) appears to play a key role in the transduction of melatonin signal through melatonin responsive, PT-specific cells that produce thyroid stimulating hormone (TSH). The objectives of these experiments were to characterize and colocalize TSH-producing cells and melatonin receptors (MT1r) in the PT during breeding and non-breeding seasons. Pituitaries from nine light-horse type mares, aged 6 to 26 years, were obtained following euthanasia during the breeding and non-breeding seasons. Mares were determined to be either cycling (n = 5) or seasonally anovulatory (n = 4) based on season, gross inspection of ovarian structures, and plasma progesterone concentrations. Immediately following euthanasia, the carotid artery was perfused with sodium nitrite and 4% paraformaldehyde before decapitation and dissection of PT from the hypophysis. Immunofluorescent detection of TSH was carried out on fixed-frozen PT sections and number of immunopositive cells per 1 mm2 were counted and averaged for three replications per horse to compare TSH distribution between breeding and non-breeding season using Mann Whitney U test. TSH-immunoreactive cells were present in PT and were greater (P < 0.05) in PT during the breeding season comparedto non-breeding season; few to no immunoreactive cells were seen in PT from non-breeding season. In situ hybridization (ISH) was carried out using RNAscope HD Red Detection Kit and a custom MT1r probe (Ec-MTNR1A) to confirm MT1r localization and compare MT1r distribution between breeding and non-breeding seasons. Mean percentage of MT1r immunopositive cells, determined as a percentage of total number of cells, and expression of MT1r mRNA per cell, determined as mean number of dots (representing mRNA) per cell, were analyzed using Mann Whitney U test. Melatonin receptor mRNA was densely expressed in glandular cells of the PT and no differences were found in either percent immunopositive cells or mean number of mRNA dots per cell between breeding and non-breeding seasons. To determine if MT1r colocalize with TSH-producing cells, ISH was carried out alongside immunofluorescent detection of TSH as previously described. In cycling mares, MT1r mRNA colocalized with TSH-producing cells in the PT; however, not all TSH-producing cells colocalized with MT1r and vice versa. Lack of TSH-producing cells accounted for absence of colocalization in seasonally anovulatory mares. The PT is considered a major target for melatonin, and colocalization with TSH supports a role for TSH as a modulator of seasonal reproduction in the mare. This is further evidenced by increased TSH immunosignal during the breeding season.

Effect of melatonin in maturation medium on equine oocyte maturation, cleavage, and blastocyst production following ICSI

Melatonin has been shown to have beneficial effects in in vitro oocyte maturation and embryo production through antioxidant activity but also through melatonin receptors on oocytes and cumulus cells as well. The purpose of this study was to investigate the effects of melatonin in maturation medium on equine oocyte maturation, cleavage, and blastocyst production with maturation performed in a reduced oxygen atmosphere. Oocytes were recovered via trans-vaginal follicular aspiration and divided randomly into three groups each with 5 replicates. The oocytes were placed in maturation medium containing no added melatonin (Control), 10−9 M melatonin (Group 1), or 10−7 M melatonin (Group 2) in an atmosphere of 5% CO2, 5% O2, and 90% N2. ICSI was performed on metaphase II oocytes after 28-30 hours of maturation. Presumptive zygotes were observed on day 2 post-injection for cleavageand on days 5 through 10 for blastocyst development. Results: No significant difference (p>.01) was determined for maturation to metaphase II, 59/86 (68.6%), 63/88 (71.5%), 66/89 (74.2%) for Control Group, Group 1, and Group 2 respectively. No significant difference (p>.01) was determined for cleavage 43/59 (72.9%), 43/63 (68.2%), 44/66 (66.7%) for Control Group, Group 1, and Group 2 respectively. No significant difference (p>.01) was determined for blastocyst formation 19/59 (32.2%), 25/63 (39.6%), 26/66 (39.4%) for Control Group, Group 1, and Group 2 respectively. While there was a slight trend towards an increase in blastocyst production with the addition of melatonin to maturation medium under reduced oxygen concentration, the difference was not statistically significant and further work would be required to evaluate its effect.

Hypnotic prescriptions in Japan may be shifting from benzodiazepine receptor agonists to other types of hypnotics, melatonin receptor agonists, and orexin receptor antagonists.

Hypnotic prescriptions in Japan may be shifting from benzodiazepine receptor agonists to other types of hypnotics, melatonin receptor agonists, and orexin receptor antagonists.

Enhancement of ocular anti-glaucomic activity of agomelatine through fabrication of hyaluronic acid modified-elastosomes: formulation, statistical optimisation, in vitro characterisation, histopathological study, and in vivo assessment

Aim The aim of this manuscript was to fabricate agomelatine (AGM) loaded elastosomes to improve its corneal permeation and ocular bioavailability. AGM is a biopharmaceutical classification system (BCS) class II with low water solubility and high membrane permeability. It has a potent agonistic action on melatonin receptors, so it is used for glaucoma treatment. Methods Elastosomes were made using modified ethanol injection technique according to a 22 × 41 full factorial design. The chosen factors were: edge activators (EAs) type, surfactant percent (SAA %w/w), and cholesterol:surfactant ratio (CH:SAA ratio). The studied responses were encapsulation efficiency percent (EE%), mean diameter, polydispersity index (PDI), zeta potential (ZP), percentage of drug released after two hours (Q 2h%), and 24 hours (Q 24h%). Results The optimum formula with the desirability of 0.752 was composed of Brij98 as EA type, 15%w/w SAA%, and 1:1 CH:SAA ratio. It revealed EE% of 73.22%w/v and mean diameter, PDI, ZP, Q 2h%, and Q 24h% values of 484.25 nm, 0.31, −30.75 mV, 32.7%w/v, and 75.6%w/v, respectively. It demonstrated acceptable stability for three months and superior elasticity than its conventional liposome. The histopathological study ensured the tolerability of its ophthalmic application. Also, it was proven to be safe from the results of the pH and refractive index tests. The in vivo pharmacodynamic parameters of the optimum formula revealed dominance in a maximum % decrease in intraocular pressure (IOP), the area under the IOP response curve, and mean residence time with the value of 82.73%w/v, 820.69%h, and 13.98 h compared to that of the AGM solution (35.92%w/v, 181.30%h, and 7.52 h). Conclusions Elastosomes can be a promising option to improve AGM ocular bioavailability.

0991 Dual Therapy to Treat Circadian Rhythm Disturbance in Unique Genetic Mutation of Smith-Magenis Syndrome

Abstract Introduction Smith-Magenis syndrome (SMS) is a rare disorder associated with several genetic mutations. Patients with SMS experience circadian rhythm sleep-wake disorders, which may lead to significant behavioral concerns. A proposed etiology of sleep disturbances is diurnal melatonin secretion. Treatment approaches aim at blocking the abnormal morning secretion of melatonin and providing exogenous melatonin in the evening. Report of case(s) We present a patient with SMS having persistent sleep-wake disturbance despite dual therapy with beta-1 adrenergic antagonist in the morning and over-the-counter melatonin at night. Our patient switched to therapy with beta-1 adrenergic antagonist in the mornings and melatonin receptor agonist, tasimelteon, at night with significant improvement. In addition, our patient has mutations in JAKMIP1 and ZBTB18 genes. ZBTB18 mutation is a novel mutation in the setting of clinical features of SMS. Conclusion To the authors’ knowledge, this is the first case report of successful combination therapy to optimize treatment of sleep-wake disturbances in patients with SMS. Support (if any)

Nocturnal melatonin increases glucose uptake via insulin-independent action in the goldfish brain.

Melatonin, a neurohormone nocturnally produced by the pineal gland, is known to regulate the circadian rhythm. It has been recently reported that variants of melatonin receptors are associated with an increased risk of hyperglycemia and type 2 diabetes, suggesting that melatonin may be involved in the regulation of glucose homeostasis. Insulin is a key hormone that regulates circulating glucose levels and cellular metabolism after food intake in many tissues, including the brain. Although cells actively uptake glucose even during sleep and without food, little is known regarding the physiological effects of nocturnal melatonin on glucose homeostasis. Therefore, we presume the involvement of melatonin in the diurnal rhythm of glucose metabolism, independent of insulin action after food intake. In the present study, goldfish (Carassius auratus) was used as an animal model, since this species has no insulin-dependent glucose transporter type 4 (GLUT4). We found that in fasted individuals, plasma melatonin levels were significantly higher and insulin levels were significantly lower during the night. Furthermore, glucose uptake in the brain, liver, and muscle tissues also significantly increased at night. After intraperitoneal administration of melatonin, glucose uptake by the brain and liver showed significantly greater increases than in the control group. The administration of melatonin also significantly decreased plasma glucose levels in hyperglycemic goldfish, but failed to alter insulin mRNA expression in Brockmann body and plasma insulin levels. Using an insulin-free medium, we demonstrated that melatonin treatment increased glucose uptake in a dose-dependent manner in primary cell cultures of goldfish brain and liver cells. Moreover, the addition of a melatonin receptor antagonist decreased glucose uptake in hepatocytes, but not in brain cells. Next, treatment with N1-acetyl-5-methoxykynuramine (AMK), a melatonin metabolite in the brain, directly increased glucose uptake in cultured brain cells. Taken together, these findings suggest that melatonin is a possible circadian regulator of glucose homeostasis, whereas insulin acquires its effect on glucose metabolism following food intake.

Association between the type of hypnotic drug and in-hospital fractures in older patients with neurocognitive disorders: A case-control study using a nationwide database.

Hypnotics might increase the risk of falls and fractures in older patients with neurocognitive disorders. Orexin receptor antagonists have recently been approved, but the relationship between the new drugs and fractures remains unclarified. This study aimed to evaluate the association between the type of hypnotic and in-hospital fractures in older patients with neurocognitive disorders using a nationwide inpatient database. Using the Japanese Diagnosis Procedure Combination database, we collected information on inpatients aged ≥65 years with neurocognitive disorders between April 2014 and March 2021. We examined trends in the prescription patterns of benzodiazepine drugs, Z-drugs, orexin receptor antagonists and melatonin receptor agonists. We also carried out a 1:4 matched case-control analysis of in-hospital fractures. The odds ratio of each hypnotic drug was estimated using a generalized estimating equation with adjustment for walking ability, comorbidities, osteoporosis, dialysis, selective serotonin reuptake inhibitor use and anti-dementia drug use. The prescription of benzodiazepine hypnotics decreased and that of orexin receptor antagonists increased. This case-control analysis included 6832 patients with fractures and 23 463 controls. Ultrashort-acting benzodiazepines, short-acting benzodiazepines and Z-drugs were associated with an increased risk of bone fracture (odds ratio [95% confidence interval] 1.38 [1.08-1.77], 1.38 [1.27-1.50], 1.49 [1.37-1.61], respectively). Orexin receptor antagonists were not associated with an increased risk of bone fracture (1.07 [0.95-1.19]). In contrast to other types of hypnotics, orexin receptor antagonists were not associated with in-hospital fractures in older patients with neurocognitive disorders. Geriatr Gerontol Int 2023; 23: 500-505.

Melatonin alleviates lung injury in H1N1-infected mice by mast cell inactivation and cytokine storm suppression.

Influenza A virus (IAV) H1N1 infection is a constant threat to human health and it remains so due to the lack of an effective treatment. Since melatonin is a potent antioxidant and anti-inflammatory molecule with anti-viral action, in the present study we used melatonin to protect against H1N1 infection under in vitro and in vivo conditions. The death rate of the H1N1-infected mice was negatively associated with the nose and lung tissue local melatonin levels but not with serum melatonin concentrations. The H1N1-infected AANAT-/- melatonin-deficient mice had a significantly higher death rate than that of the WT mice and melatonin administration significantly reduced the death rate. All evidence confirmed the protective effects of melatonin against H1N1 infection. Further study identified that the mast cells were the primary targets of melatonin action, i.e., melatonin suppresses the mast cell activation caused by H1N1 infection. The molecular mechanisms involved melatonin down-regulation of gene expression for the HIF-1 pathway and inhibition of proinflammatory cytokine release from mast cells; this resulted in a reduction in the migration and activation of the macrophages and neutrophils in the lung tissue. This pathway was mediated by melatonin receptor 2 (MT2) since the MT2 specific antagonist 4P-PDOT significantly blocked the effects of melatonin on mast cell activation. Via targeting mast cells, melatonin suppressed apoptosis of alveolar epithelial cells and the lung injury caused by H1N1 infection. The findings provide a novel mechanism to protect against the H1N1-induced pulmonary injury, which may better facilitate the progress of new strategies to fight H1N1 infection or other IAV viral infections.

Effects of melatonin on phosphorylation of memory-related proteins in the hippocampus and the perirhinal cortex in male mice.

We recently demonstrated that a single post-training administration of either melatonin, an MT1/MT2 melatonin receptor agonist ramelteon, or a brain melatonin metabolite N1-acetyl-5-methoxyquinuramine (AMK) enhanced object recognition memory. The present study aims to investigate the effects of melatonin, ramelteon, and AMK on relative phosphorylation levels of memory-related proteins in order to explore candidate signaling pathways associated with the receptor-mediated and nonreceptor-mediated memory-enhancing effects of melatonin. We first confirmed that post-training administration of either melatonin, ramelteon, or AMK at 1 mg/kg promoted long-term memory formation, using the novel object recognition task. Next, the effects of the same doses of these drugs on relative phosphorylation levels of the extracellular signal-regulated kinase (ERK) and calcium/calmodulin-dependent kinases (CaMKs) in the hippocampus and the perirhinal cortex (PRC) were examined by western blot analysis. In the hippocampus, treatment with ramelteon or AMK significantly increased and decreased phosphorylation levels of ERK and cAMP-response element binding protein (CREB) and those of CaMKIIα and β, respectively. In the PRC, phosphorylation levels of ERK and those of CaMKIIβ were significantly increased by both ramelteon and AMK and by ramelteon, respectively. Neither ramelteon nor AMK altered the phosphorylation levels of CaMKIV in either hippocampus or PRC. These results suggest that melatonin may be involved in promoting the formation of long-term object recognition memory in a similar, if not identical, manner by modulating the phosphorylation levels of memory-related proteins such as ERK, CaMKIIs, and CREB in both receptor-mediated and nonreceptor-mediated signaling pathways.

Evaluation of the Anxiolytic Effect of Ramelteon in Various Rat Models of Anxiety.

Background Melatonin was found to have anxiolytic properties in several animal and human studies. The melatonin receptor agonist ramelteon might also have a similar anxiolytic action. Objectives The objective of the study was to evaluate the effect of ramelteon in various rat models of anxiety and to explore the possible mechanism of action. Methods The anxiolytic effect was compared between the control group, diazepam group (1 mg/kg and 0.5 mg/kg), and ramelteon group (0.25 mg/kg, 0.5 mg/kg, and1 mg/kg) by an elevated plus maze, light-dark box, hole board apparatus, and open field test in Sprague Dawley rats. Antagonists flumazenil, picrotoxin, and Luzindole were used to explore the possible mechanism of action of ramelteon if it showed an anxiolytic property. Results Ramelteon as a standalone drug did not show an anxiolytic effect. However, a combination of ramelteon (1 mg/kg) and diazepam (0.5 mg/kg) showed an anxiolytic effect. Conclusion Further studies can evaluate the use of a fixed-dose combination of ramelteon and already-approved anxiolytic drugs to reduce the dose of the latter.

Association of rotating night shift work, CLOCK, MTNR1A, MTNR1B genes polymorphisms and their interactions with type 2 diabetes among steelworkers: a case–control study

BackgroundThe purpose of this study is to investigate the association of rotating night shift work, CLOCK, MTNR1A, MTNR1B genes polymorphisms and their interactions with type 2 diabetes among steelworkers.MethodsA case–control study was conducted in the Tangsteel company in Tangshan, China. The sample sizes of the case group and control group were 251 and 451, respectively. The logistic regression, log-linear model and generalized multifactor dimensionality (GMDR) method were used to investigate the interaction between circadian clock gene, melatonin receptor genes and rotating night shift work on type 2 diabetes among steelworkers. Relative excess risk due to interaction (RERI) and attributable proportions (AP) were used to evaluate additive interactions.ResultsRotating night shift work, current shift status, duration of night shifts, and average frequency of night shifts were associated with an increased risk of type 2 diabetes after adjustment for confounders. Rs1387153 variants in MTNR1B was found to be associated with an increased risk of type 2 diabetes, which was not found between MTNR1A gene rs2119882 locus, CLOCK gene rs1801260 locus and the risk of type 2 diabetes. The association between rotating night shift work and risk of type 2 diabetes appeared to be modified by MTNR1B gene rs1387153 locus (RERI = 0.98, (95% CI, 0.40–1.55); AP = 0.60, (95% CI, 0.07–1.12)). The interaction between MTNR1A gene rs2119882 locus and CLOCK gene rs1801260 locus was associated with the risk of type 2 diabetes (RERI = 1.07, (95% CI, 0.23–1.91); AP = 0.77, (95% CI, 0.36–1.17)). The complex interaction of the MTNR1A-MTNR1B-CLOCK-rotating night shift work model based on the GMDR methods may increase the risk of type 2 diabetes (P = 0.011).ConclusionsRotating night shift work and rs1387153 variants in MTNR1B were associated with an increased risk of type 2 diabetes among steelworkers. The complex interaction of MTNR1A-MTNR1B-CLOCK-rotating night shift work may increase the risk of type 2 diabetes.

Genetic and neural mechanisms of sleep disorders in children with autism spectrum disorder: a review.

The incidence of sleep disorders in children with autism spectrum disorder (ASD) is very high. Sleep disorders can exacerbate the development of ASD and impose a heavy burden on families and society. The pathological mechanism of sleep disorders in autism is complex, but gene mutations and neural abnormalities may be involved. In this review, we examined literature addressing the genetic and neural mechanisms of sleep disorders in children with ASD. The databases PubMed and Scopus were searched for eligible studies published between 2013 and 2023. Prolonged awakenings of children with ASD may be caused by the following processes. Mutations in the MECP2, VGAT and SLC6A1 genes can decrease GABA inhibition on neurons in the locus coeruleus, leading to hyperactivity of noradrenergic neurons and prolonged awakenings in children with ASD. Mutations in the HRH1, HRH2, and HRH3 genes heighten the expression of histamine receptors in the posterior hypothalamus, potentially intensifying histamine's ability to promote arousal. Mutations in the KCNQ3 and PCDH10 genes cause atypical modulation of amygdala impact on orexinergic neurons, potentially causing hyperexcitability of the hypothalamic orexin system. Mutations in the AHI1, ARHGEF10, UBE3A, and SLC6A3 genes affect dopamine synthesis, catabolism, and reuptake processes, which can elevate dopamine concentrations in the midbrain. Secondly, non-rapid eye movement sleep disorder is closely related to the lack of butyric acid, iron deficiency and dysfunction of the thalamic reticular nucleus induced by PTCHD1 gene alterations. Thirdly, mutations in the HTR2A, SLC6A4, MAOA, MAOB, TPH2, VMATs, SHANK3, and CADPS2 genes induce structural and functional abnormalities of the dorsal raphe nucleus (DRN) and amygdala, which may disturb REM sleep. In addition, the decrease in melatonin levels caused by ASMT, MTNR1A, and MTNR1B gene mutations, along with functional abnormalities of basal forebrain cholinergic neurons, may lead to abnormal sleep-wake rhythm transitions. Our review revealed that the functional and structural abnormalities of sleep-wake related neural circuits induced by gene mutations are strongly correlated with sleep disorders in children with ASD. Exploring the neural mechanisms of sleep disorders and the underlying genetic pathology in children with ASD is significant for further studies of therapy.

Melatonin receptor 1A (MTNR1A) gene linkage and association to type 2 diabetes in Italian families.

Melatonin regulates the mammalian circadian rhythm and plays metabolic functions such as glucose homeostasis. Both melatonin receptors (MTNR1A and MTNR1B, encoded by the MTNR1A and MTNR1B genes, respectively) are expressed in pancreatic beta cells and mediate the glucometabolic roles of melatonin as well as insulin secretion. The MTNR1B gene is a well-known genetic risk factor in type 2 diabetes (T2D); however, little is known about the involvement of the MTNR1A gene in here T2D. We aimed to investigate whether MTNR1A is linked to and/or associated with familial T2D. We genotyped 14 single nucleotide polymorphisms within the MTNR1A gene in 212 peninsular Italian families with T2D. We performed parametric linkage and linkage disequilibrium analyses to investigate the role of MTNR1A variants in conferring T2D risk. We considered variants statistically significant if conferring linkage or linkage disequilibrium with p < 0.05. We found 3 novel variants (rs62350392, rs2119883, and rs13147179) significantly linked to and/or associated with T2D in multigenerational Italian families. This is the first study to report MTNR1A as a novel risk gene in T2D. Functional studies are needed to confirm these results.

Potent Lipophilic Melatoninergic x-fluoro-y-methoxy Substituted Phenylalkylamides: Molecular Dynamics Calculations and in vitro Modified Release in Aqueous Media from Tablet Formulations.

We report herein on the design and development of matrix tablets containing potent synthetic melatonin (MLT) receptor analogues, the x-fluoro-y-methoxy substitiuted phenylalkylamides (compounds I-IV), the preparation and melatoninergic potency of which was recently communicated. > Methods: The presence of the fluorine atom in compounds I-IV, besides not affecting their binding affinity, compared to the pineal hormone melatonin, it also slows down their metabolism, which is a major drawback of MLT. However, as fluorine increases the lipophilicity, solid pharmaceutical formulations of I-IV, involving the appropriate biopolymers for their modified release in aqueous media, were developed in the context of the present work. > Results: The release profile of analogues I-IV was found to be similar to that of MLT and also of the commercially available drug, Circadin®. Some of these systems are suitable for dealing with sleep onset problems, whilst others for dealing with combined sleep onset/sleep maintenance problems. > Conclusion: Apart from the nature and relevant content of the formulants used, this bimodal release profile of the new analogues depends, to a large extent, on the diverse structural arrangement of their side chains in space, as nicely demonstrated by the molecular dynamics calculations, conducted in the context of this study. >.

Hypnotics and injuries among older adults with Parkinson’s disease: a nested case–control design

BackgroundPatients with Parkinson’s disease often experience sleep disorders. Hypnotics increase the risk of adverse events, such as injuries due to falls. In this study, we evaluated the association between hypnotics and injuries among older adults with Parkinson’s disease.MethodsThe study used a nested case–control design. The participants were 5009 patients with Parkinson’s disease aged ≥ 75 years based on claims data between April 2016 and March 2019 without prescription hypnotics 1 year before the study started. Hypnotics prescribed as oral medications included benzodiazepines, non-benzodiazepines, orexin receptor antagonists, and melatonin receptor agonists. The incidences of outcomes, including injuries, fractures, and femoral fractures, were determined. Each case had four matched controls. Conditional logistic regression analyses were performed to calculate the odds ratios and 95% confidence intervals for the number of hypnotics taken per day for each type of hypnotic.ResultsThe proportion of participants taking at least one type of hypnotic was 18.6%, with benzodiazepines being the most common. The incidence of injuries, fractures, and femoral fractures was 66.7%, 37.8%, and 10.2%, respectively. Benzodiazepines significantly increased the risk of injuries (odds ratio: 1.12; 95% confidence interval: 1.03–1.22), and melatonin receptor agonists significantly increased the risk of femoral fractures (odds ratio: 2.84; 95% confidence interval: 1.19–6.77).ConclusionsBenzodiazepines and non-benzodiazepines, which are not recommended according to current guidelines, were the most prevalent among older adults with Parkinson’s disease. Benzodiazepines significantly increased the risk of injuries, and melatonin receptor agonists significantly increased the risk of femoral fractures.

Hypnotic Drugs

Insomnia is one of the most frequently encountered diseases in clinical practice, and about half of the patients have a long-term course. Therefore, proactive prevention against chronicity is required, using a non-pharmacological approach for insomnia (sleep hygiene). Pharmacological treatment, needs to decrease the risk of appearance of rebound insomnia, the risk of the patient falling, drug dependence, and cognitive dysfunctions caused by hypnotics. In view of this, it is recommended to use novel sleep medications such as orexin receptor antagonists and melatonin receptor agonists.