Melatonin Receptor Agonist Research Articles

Association between nocturnal falls and hypnotic drug use in older patients at acute care hospitals.

Although hypnotic drug use is a known risk factor for falls, few reports have analyzed fall risk associated with individual hypnotic drugs after adjusting for confounding factors. While it is recommended that benzodiazepine receptor agonists not be prescribed for older adults, it is unknown whether melatonin receptor agonists and orexin receptor antagonists are safe in this population. Here, we aimed to assess the influence of various hypnotic drugs on fall risk in older patients admitted to acute care hospitals. We investigated the relationship between nocturnal falls and sleeping pill use in 8,044 hospitalized patients aged > 65years. We used a propensity score matching method to homogenize characteristics of patients with and without nocturnal falls (n = 145 patients per group) using 24 extracted factors (excluding hypnotic drugs) as covariates. Our analysis of fall risk for each hypnotic drug revealed that benzodiazepine receptor agonists were the only drugs significantly associated with falls, suggesting that use of the drugs is a risk factor for falls in older adults (p = 0.003). In addition, a multivariate analysis of 24 selected factors, excluding hypnotic drugs, revealed that patients with advanced recurrent malignancies were at greatest risk of experiencing falls (OR: 2.62; 95% CI: 1.23-5.60; p = 0.013). Benzodiazepine receptor agonists should be avoided in older hospitalized patients since they increase fall risk, with melatonin receptor agonists and orexin receptor antagonists used instead. Particularly, fall risk associated with hypnotic drugs should be considered in patients with advanced recurrent malignancies.

The Effect of Blindness on Biological Rhythms and the Consequences of Circadian Rhythm Disorder.

Various physiological systems and behaviors such as the sleep-wake cycle, vigilance, body temperature, and the secretion of certain hormones are governed by a 24-hour cycle called the circadian system. While there are many external stimuli involved the regulation of circadian rhythm, the most powerful environmental stimulus is the daily light-dark cycle. Blind individuals with no light perception develop circadian desynchrony. This leads to non-24-hour sleep-wake rhythm disorder, which is associated with sleep-wake disorders, as well as mood disorders and loss of appetite and gastrointestinal disturbances due to disrupted circadian hormone regulation. As the diagnosis is often delayed because of under-recognition in clinical practice, patients must cope with varying degrees of social and academic dysfunction. Most blind individuals report that non-24-hour sleep-wake rhythm disorder affects them more than blindness. In the treatment of totally blind patients suffering from non-24-hour sleep-wake rhythm disorder, the first-line management is behavioral approaches. Drug therapy includes melatonin and the melatonin agonist tasimelteon. Diagnosing blind individuals' sleep disorders is also relevant to treatment because they can be improved with the use of melatonin and its analogues or by phototherapy if they have residual vision. Therefore, assessing sleep problems and planning treatment accordingly for individuals presenting with blindness is an important issue for ophthalmologists to keep in mind.

Appropriate Use and Abuse of Sedative-Hypnotic Drugs

The incidence of insomnia has been increasing in recent years. In addition, due to the impact of the COVID-19 pandemic, more and more people are experiencing a variety of insomniac problems, including having difficulty in sleep initation, waking up too early, and short sleep duration. Chronic insomnia may seriously affect patients' life and work, increase their risks of developing physical and mental illnesses, and cause crushing social and economic burdens. Sedative-hypnotics, including benzodiazepine agonists, melatonin receptor agonists, orexin receptor antagonists, and antidepressants with hypnotic effects, are widely used to treat most patients suffering from insomnia. However, there is the phenomenon of the non-medical use and abuse of sedative-hypnotic drugs, especially benzodiazepine receptor agonists. The abuse of sedative-hypnotic drugs may lead to mental and physical dependence, cognitive impairment, depression and anxiety, as well as an increased risks of falls and death. Therefore, drug regulatory authorities in China and other countries have issued relevant policies to reinforce regulation. Herein, we reviewed the prevalent use and safety of sedative-hypnotic drugs and proposed suggestions concerning their appropriate use. Both the efficacy and safety of sedative-hypnotic drugs should be carefully considered so that patients suffering from insomnia receive thorough and prompt treatment and the problem of potential abuse of sedative-hypnotic drugs is assessed in an objective and scientific manner. We also hope to provide references for the standardized clinical use of insomnia drugs.

Physicians' attitudes toward hypnotics for insomnia: A questionnaire-based study.

Benzodiazepines and non-benzodiazepines are still widely prescribed despite safety concerns and the introduction of novel hypnotics (orexin receptor antagonists [ORA] and melatonin receptor agonists [MRA]), which may be influenced by physicians' attitudes toward hypnotics. A questionnaire survey was administered to 962 physicians between October 2021 and February 2022, investigating frequently prescribed hypnotics and the reasons for their selection. ORA were the most frequently prescribed at 84.3%, followed by non-benzodiazepines (75.4%), MRA (57.1%), and benzodiazepines (54.3%). Compared to non-frequent prescribers of hypnotics, a logistic regression analysis showed that frequent ORA prescribers were more concerned with efficacy (odds ratio [OR]: 1.60, 95% confidence interval [CI]: 1.01-2.54, p = 0.044) and safety (OR: 4.52, 95% CI: 2.99-6.84, p < 0.001), frequent MRA prescribers were more concerned with safety (OR: 2.48, 95% CI: 1.77-3.46, p < 0.001), frequent non-benzodiazepine prescribers were more concerned with efficacy (OR: 4.19, 95% CI: 2.91-6.04, p < 0.001), and frequent benzodiazepine prescribers were more concerned with efficacy (OR: 4.19, 95% CI: 2.91-6.04, p < 0.001) but less concerned with safety (OR: 0.25, 95% CI: 0.16-0.39, p < 0.001). This study suggested that physicians believed ORA to be an effective and safe hypnotic and were compelled to prescribe benzodiazepine and non-benzodiazepine frequently, choosing efficacy over safety.

Melatonin and Health: Insights of Melatonin Action, Biological Functions, and Associated Disorders.

Melatonin is ubiquitous molecule with wide distribution in nature and is produced by many living organisms. In human beings, pineal gland is the major site for melatonin production and to lesser extent by retina, lymphocytes, bone marrow, gastrointestinal tract, and thymus. Melatonin as a neurohormone is released into circulation wherein it penetrates all tissues of the body. Melatonin synthesis and secretion is supressed by light and enhanced by dark. Melatonin mostly exerts its effect through different pathways with melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2) being the predominant type of receptor that are mainly expressed by many mammalian organs. Melatonin helps to regulate sleep patterns and circadian rhythms. In addition, melatonin acts as an antioxidant and scavenges excessive free radicals generated in the body by anti-excitatory and anti-inflammatory properties. A multiple array of other functions are displayed by melatonin that include oncostatic, hypnotic, immune regulation, reproduction, puberty timing, mood disorders, and transplantation. Deficiencies in the production or synthesis of melatonin have been found to be associated with onset of many disorders like breast cancer and neurodegenerative disorders. Melatonin could be used as potential analgesic drug in diseases associated with pain and it has quite promising role there. In the past century, a growing interest has been developed regarding the wide use of melatonin in treating various diseases like inflammatory, gastrointestinal, cancer, mood disorders, and others. Several melatonin agonists have been synthesized and are widely used in disease treatment. In this review, an effort has been made to describe the biochemistry of melatonin along with its therapeutic potential in various diseases of humans.

Structural Basis for Agonistic Activity and Selectivity toward Melatonin Receptors hMT1 and hMT2.

Glaucoma, a major ocular neuropathy originating from a progressive degeneration of retinal ganglion cells, is often associated with increased intraocular pressure (IOP). Daily IOP fluctuations are physiologically influenced by the antioxidant and signaling activities of melatonin. This endogenous modulator has limited employment in treating altered IOP disorders due to its low stability and bioavailability. The search for low-toxic compounds as potential melatonin agonists with higher stability and bioavailability than melatonin itself could start only from knowing the molecular basis of melatonergic activity. Thus, using a computational approach, we studied the melatonin binding toward its natural macromolecular targets, namely melatonin receptors 1 (MT1) and 2 (MT2), both involved in IOP signaling regulation. Besides, agomelatine, a melatonin-derivative agonist and, at the same time, an atypical antidepressant, was also included in the study due to its powerful IOP-lowering effects. For both ligands, we evaluated both stability and ligand positioning inside the orthosteric site of MTs, mapping the main molecular interactions responsible for receptor activation. Affinity values in terms of free binding energy (ΔGbind) were calculated for the selected poses of the chosen compounds after stabilization through a dynamic molecular docking protocol. The results were compared with experimental in vivo effects, showing a higher potency and more durable effect for agomelatine with respect to melatonin, which could be ascribed both to its higher affinity for hMT2 and to its additional activity as an antagonist for the serotonin receptor 5-HT2c, in agreement with the in silico results.

Agomelatine improves streptozotocin-induced diabetic nephropathy through melatonin receptors/SIRT1 signaling pathway.

Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD). Agomelatine, a melatonin receptor agonist, has a potent anti-inflammatory activity. The current study aimed to determine the ameliorative anti-inflammatory effect of agomelatine against DN. We used 10% fructose with streptozotocin (STZ) to induce DN in male Wistar rats. Diabetic rats were treated with agomelatine in presence or absence of melatonin receptor antagonist (luzindole) or Sirtuin1 (SIRT1) inhibitor (EX527). SIRT1 expression was measured by qRT-PCR and immunohistochemical analysis. The expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), 5'adenosine monophosphate-activated protein kinase (AMPK), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion protein-1 (VCAM-1), and monocyte chemoattractant protein-1 (MCP-1) were measured using ELISA. Histological assessment was performed using hematoxylin and eosin-stained renal sections. Fructose and STZ treatment induced diabetes, insulin resistance, and renal damage accompanied by reduced SIRT1 expression, increased NFκB activation, and decreased AMPK phosphorylation in the kidney. Agomelatine treatment improved kidney histology and function and upregulated SIRT1 expression (2-fold). Inhibition of melatonin receptors and SIRT1 activity increased NFκB phosphorylation (2.13 and 1.98-folds, respectively), reduced AMPK activation (0.51 and 0.53-folds, respectively), increased inflammatory markers ICAM-1 (2.16 and 2.23-folds, respectively), VCAM-1 (2.19 and 2.26-folds, respectively), and MCP-1(2.84 and 3.12-folds, respectively), and inhibited the ameliorative effect of agomelatine on kidney structure and function. Our findings reveal the ameliorative anti-inflammatory activity of agomelatine against STZ-induced DN and this effect is SIRT1- and melatonin receptor-dependent. Therefore, agomelatine may be beneficial to prevent the development of ESRD from diabetes mellitus.

The antidepressant agomelatine attenuates morphine-induced reinstatement but not self-administration or precipitated withdrawal

BackgroundExogenous melatonin appears to have anti-addictive properties and was recently shown to improve mental health and metabolic measures in patients receiving chronic opioid maintenance therapy. Agomelatine is a marketed antidepressant which acts as a melatonin agonist. We evaluated its effects using a rat model of morphine-reinforced behavior. MethodsAfter pretreatment with noncontingent morphine, male Wistar rats were trained to self-administer intravenous morphine (1.0 mg/kg-injection) under a progressive-ratio schedule. Rats were pretreated with vehicle or agomelatine during extinction, reinstatement, and reacquisition of morphine-reinforced behavior. ResultsDaily treatment with 10 mg/kg-day of agomelatine decreased the number of ratios completed and prolonged latency during morphine-induced reinstatement. There were no significant effects on cue-induced reinstatement, morphine self-administration, or naloxone-precipitated withdrawal. Treatment with 32 mg/kg-day of agomelatine caused postural changes. That dose prolonged withdrawal-induced loss of body weight and caused delayed reductions in food reinforcement. SummaryIn addition to postural effects, high-dose agomelatine worsened the course of spontaneous withdrawal and produced nonspecific effects on food-reinforced behavior. When administered at a selective dose, agomelatine did not modify morphine self-administration or precipitated withdrawal, but decreased morphine-induced reinstatement. Our findings show potential detrimental effects of high-dose agomelatine, with reductions in opioid-seeking behavior after a lower, more selective dose.

Suvorexant, a Novel Dual Orexin Receptor Antagonist, for the Management of Insomnia.

The present investigation is a comprehensive review regarding the use of Suvorexant for insomnia treatment. It covers the background, pathophysiology, and significance of addressing insomnia, the pharmaceutical details of Suvorexant, and its safety, efficacy, and implications in treating insomnia. We further discuss Suvorexant's role in targeting insomnia with other comorbidities. Insomnia refers to poor quality and/or quantity of sleep. While there are many existing treatments such as benzodiazepines, melatonin agonists, TCAs, and atypical antipsychotics used to target various receptors involved in normal induction and maintenance of sleep, Suvorexant is an antagonist that specifically targets orexin receptors. Recent clinical studies suggest that Suvorexant is both clinically safe and effective. Quantity and quality of sleep are measured in various ways, yet the consensus points towards Suvorexant's effectiveness in improving sleep time, onset, latency, and quality compared to placebo. In addition to helping improve isolated insomnia, Suvorexant helps improve sleep in patients that have other comorbidities such as obstructive sleep apnea, Alzheimer's disease, dementia, acute stroke, and delirium. While Suvorexant is safe, there are still adverse effects associated with the drug that needs to be considered. The most common adverse effects include dizziness, somnolence, headaches, and cognitive impairment. Insomnia is a major public health concern that affects many people worldwide and has been linked to many adverse health outcomes. While there are existing treatments that target different receptors and pathways of normal sleep induction and maintenance, Suvorexant is a novel drug that targets dual orexin receptors. Its safety and efficacy, mechanism of action, pharmacokinetic parameters, and relative lack of rebound and withdrawal effects render suvorexant a reliable choice for the treatment of insomnia.

Effects of Japanese policies and novel hypnotics on long-term prescriptions of hypnotics.

The current study aimed to examine the effect of Japanese policies for appropriate hypnotics use and novel hypnotics (e.g. melatonin receptor agonist and orexin receptor antagonist [ORA]) on long-term prescriptions of hypnotics. This retrospective study was conducted using a large-scale health insurance claims database. Among subscribers prescribed hypnotics at least once between April 2005 and March 2021, those prescribed hypnotics for the first time after being included in the database in three periods (period 1: April 2012-March 2013; period 2: April 2016-March 2017; and period 3: April 2018-March 2019) were eligible. These were set considering the timing of the 2014 and 2018 medical fee revisions (2014 for polypharmacy of three or more hypnotics, 2018 for long-term prescription of benzodiazepine receptor agonists for >12months). The duration of consecutive prescriptions of hypnotics over 12months was evaluated. Factors associated with short-term prescriptions of hypnotics were also investigated. In total, 186 535 participants were newly prescribed hypnotics. The mean duration of prescriptions was 2.9 months, and 9.3% of participants were prescribed hypnotics for 12months. Prescription periods were not associated with short-term prescriptions of hypnotics. ORA use was associated with short-term prescriptions of hypnotics (adjusted hazard ratio, 1.077 [95% confidence interval, 1.035-1.120]; P < 0.001), but melatonin receptor agonist use was not. Japanese policies had no statistically significant effect on long-term prescriptions of hypnotics. Although this study suggests initiating ORA for insomniacs as a candidate strategy to prevent long-term prescriptions of hypnotics, further research is necessary to draw conclusions.

Actigraphy-based sleep and activity measurements in intensive care unit patients randomized to ramelteon or placebo for delirium prevention

Patients in the ICU often sleep poorly for various reasons, which may predispose to delirium. We previously conducted a clinical trial in which we tested the efficacy of ramelteon, a melatonin-receptor agonist used to treat insomnia, versus placebo, in preventing ICU delirium in patients who underwent elective pulmonary thromboendarterectomy (PTE) surgery. Here we examine sleep, activity, and circadian patterns, measured with actigraphy, to understand changes in these metrics with our intervention and in those with and without delirium. Participants wore wrist actigraphy devices while recovering post-operatively in the ICU. For sleep analysis, we extracted total sleep time and sleep fragmentation metrics over the 22:00 to 06:00 period nightly, and daytime nap duration from the daytime period (0:600 to 22:00) for each participant. For activity analyses, we extracted the following metrics: total daytime activity count (AC), maximum daytime AC, total nighttime AC, and maximum nighttime AC. Next, we performed a nonparametric circadian analysis on ACs over each 24-h day and extracted the following: interdaily stability (IS), intra-daily variability (IV), relative amplitude (RA), and low and high periods of activity (L5 and M10) as well as their start times. These metrics were compared between patients who received ramelteon versus placebo, and between patients who became delirious versus those who did not develop delirium. We additionally made comparisons between groups for daytime and nighttime light levels. No differences in sleep, activity, circadian metrics or light levels were found between drug groups. Delirious patients, when compared to those who were never delirious, had a lower IS (0.35 ± 0.16 vs. 0.47 ± 0.23; P = 0.006). Otherewise, no differences in IV, L5, M10, or RA were found between groups. L5 and M10 activity values increased significantly over the post-extubation for the whole cohort. No differences were found for daytime or nighttime light levels between groups. Overall, ramelteon did not impact sleep or circadian metrics in this cohort. Consistent with clinical experience, delirious patients had less inter-daily stability in their rest-activity rhythms. These data suggest that actigraphy might have value for individual assessment of sleep in the ICU, and for determining and detecting the impact of interventions directed at improving sleep and circadian activity rhythms in the ICU.Trial registration: REGISTERED at CLINICALTRIALS.GOV: NCT02691013. Registered on February 24, 2016 by principal investigator, Dr. Robert L. Owens.

Melatonin or Ramelteon for Delirium Prevention in the Intensive Care Unit: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Melatonin modulates the circadian rhythm and has been studied as a preventive measure against the development of delirium in hospitalized patients. Such an effect may be more evident in patients admitted to the ICU, but findings from the literature are conflicting. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs). We assessed whether melatonin or ramelteon (melatonin agonist) reduce delirium incidence as compared to a placebo in ICU patients. Secondary outcomes were ICU length of stay, duration of mechanical ventilation (MV) and mortality. Estimates are presented as risk ratio (RR) or mean differences (MD) with 95% confidence interval (CI). Nine RCTs were included, six of them reporting delirium incidence. Neither melatonin nor ramelteon reduced delirium incidence (RR 0.76 (0.54, 1.07), p = 0.12; I2 = 64%), although a sensitivity analysis conducted adding other four studies showed a reduction in the risk of delirium (RR = 0.67 (95%CI 0.48, 0.92), p = 0.01; I2 = 67). Among the secondary outcomes, we found a trend towards a reduction in the duration of MV (MD -2.80 (-6.06, 0.47), p = 0.09; I2 = 94%) but no differences in ICU-LOS (MD -0.26 (95%CI -0.89, 0.37), p = 0.42; I2 = 75%) and mortality (RR = 0.85 (95%CI 0.63, 1.15), p = 0.30; I2 = 0%). Melatonin and ramelteon do not seem to reduce delirium incidence in ICU patients but evidence is weak. More studies are needed to confirm this finding.

Protective effects of melatonin receptor agonists on endotoxin-induced uveitis in rats.

Melatonin has an important role in regulating a variety of physiological functions of the body. We investigated the protective effects of Agomelatine (AGO) and Ramelteon (RAME) on Endotoxin-Induced Uveitis (EIU) in rats. 70 rats were randomly divided into fourteen groups. Healthy group normal saline, (IP), Uveitis group (200 μg/kg lipopolysaccharide (LPS), SC), DEX group (200 μg/kg LPS plus 1 mg/kg dexamethasone, IP), AGO20 group received 200 μg/kg LPS plus 20 mg/kg AGO, AGO40 group received 200 μg/kg LPS plus 40 mg/kg AGO, RAME2 group received 200 μg/kg LPS plus 2 mg/kg RAME, and group RAME4 received 200 μg/kg LPS plus 4 mg/kg RAME. Each group had two subgroups: the 3rd and 24th hr. The eye tissues were collected and investigated biomicroscopically (clinical manifestations and scoring, molecularly(qRT-PCR analyses of tumor necrosis factor-α (TNF-α), vascular endothelial growth factor (VEGF), and caspase 3 and caspase 9 mRNA expression), biochemically (Superoxide dismutase activity (SOD), Glutathione (GSH), and malondialdehyde levels (MDA)) and histopathologically (staining with Harris Hematoxylin and Eosin Y). Melatonin receptor agonist treatment reduced the clinical score count of ocular inflammation in the uveitic rats. TNF-α, VEGF, caspase 9, and caspase 3 levels markedly decreased in the uveitic rats. Melatonin receptor agonists significantly ameliorated fixed changes in GSH, SOD, and MDA levels. Melatonin receptor agonists also ameliorated histopathological injury in eye tissues associated with uveitis. Melatonin receptor agonists ameliorated the inflammatory response in EIU. These findings suggest that melatonin receptor agonists may represent a potential novel therapeutic drug for uveitis treatment.

Preventing and treating delirium in clinical settings for older adults.

Delirium is a serious consequence of many acute or worsening chronic medical conditions, a side effect of medications, and a precipitant of worsening functional and cognitive status in older adults. It is a syndrome characterized by fluctuations in cognition and impaired attention that develops over a short period of time in response to an underlying medical condition, a substance (prescribed, over the counter, or recreational), or substance withdrawal and can be multi-factorial. We present a narrative review of the literature on nonpharmacologic and pharmacologic approaches to prevention and treatment of delirium with a focus on older adults as a vulnerable population. Older adult patients are most at risk due to decreasing physiologic reserves, with delirium rates of up to 80% in critical care settings. Presentation of delirium can be hyperactive, hypoactive, or mixed, making identification and study challenging as patients with hypoactive delirium are less likely to come to attention in an inpatient or long-term care setting. Studies of delirium focus on prevention and treatment with nonpharmacological or medication interventions, with the preponderance of evidence favoring multi-component nonpharmacological approaches to prevention as the most effective. Though use of antipsychotic medication in delirium is common, existing evidence does not support routine use, showing no clear benefit in clinically significant outcome measures and with evidence of harm in some studies. We therefore suggest that antipsychotics be used to treat agitation, psychosis, and distress associated with delirium at the lowest effective doses and shortest possible duration and not be considered a treatment of delirium itself. Future studies may clarify the use of other agents, such as melatonin and melatonin receptor agonists, alpha-2 receptor agonists, and anti-epileptics.

Prophylactic Use of Ramelteon for Delirium in Hospitalized Patients: A Systematic Review and Meta-Analyses.

Small prospective studies, case reports, as well as some randomized placebo-controlled trials and previous meta-analyses have shown that ramelteon, a melatonin agonist, may reduce the risk of developing delirium. The goal of this systemic review and meta-analyses was to assess the current evidence supporting the use of ramelteon in delirium prevention by including data from larger (>100 subjects) and more recent trials since the most recent meta-analyses were published in 2019. There were no exclusions for trial size, age, ramelteon dose, length of treatment, or hospital setting. Medline, Embase, PsycINFO, EBM Reviews, Scopus, and Web of Science databases were queried using the search terms delirium (with subterms including prevention and control), ramelteon, Rozerem, or melatonin receptor agonists, for English-language publications until March 16, 2021. Randomized placebo-controlled trials of hospitalized subjects receiving ramelteon for delirium prevention were included. The primary outcome of interest was delirium incidence. Odds ratios of the risk of developing incident delirium and 95% confidence intervals were calculated using a random effects model. A total of 177 articles were identified by the literature search. Five studies (n=443, 53.7% male) met criteria for inclusion in the final meta-analyses. The meta-analyses of the randomized placebo-controlled trials revealed that ramelteon did not result in a reduction in the risk of incident delirium (n=443; odds ratio=0.49; 95% confidence interval=0.13-1.85). A moderate degree of heterogeneity was noted among the studies (I2=53%). Current evidence suggests that ramelteon is ineffective as a prophylactic drug in reducing the incidence of delirium in hospitalized patients.

Modulatory effect of n-3 polyunsaturated fatty acids on depressive-like behaviors in rats with chronic sleep deprivation: potential involvement of melatonin receptor pathway and brain lipidome.

Clinical evidence suggests that a bidirectional relationship is present between sleep loss and psychiatric disorders. Both melatonin receptor agonist ramelteon (RMT) and n-3 polyunsaturated fatty acids (n-3 PUFAs) exhibit antidepressant effects, while their underlying molecular mechanisms might be different. Thus, the present study aims to investigate the add-on effects and possible mechanisms of how RMT and different n-3 PUFAs modulate the melatonin receptor pathway as well as brain lipidome to ameliorate the neuropsychiatric behaviors displayed in rats under chronic sleep deprivation. Thirty-one 6-week-old male Wistar rats were divided into five groups: control (C), sleep deprivation (S), sleep deprivation treated with RMT (SR), sleep deprivation treated with RMT and eicosapentaenoic acid (C20:5n-3, EPA) (SRE), and sleep deprivation treated with RMT and docosahexaenoic acid (C22:6n-3, DHA) (SRD) groups. The results reveal that RMT plus EPA alleviated depressive-like behavior when the rats were subjected to the forced swimming test, whereas RMT plus DHA alleviated anxiety-like behavior when the rats were subjected to the elevated plus maze test. The results of a western blot analysis further revealed that compared with the rats in the S group, those in the SRE and SRD groups exhibited a significantly increased expression of MT2 in the prefrontal cortex, with greater benefits observed in the SRE group. In addition, decreased BDNF and TrkB expression levels were upregulated only in the SRE group. Lipidomic analysis further revealed possible involvement of aberrant lipid metabolism and neuropsychiatric behaviors. RMT plus EPA demonstrated promise as having the effects of reversing the levels of the potential biomarkers of depressive-like behaviors. RMT plus EPA or DHA could ameliorate depressive- and anxiety-like behaviors in sleep-deprived rats through the alteration of the lipidome and MT2 receptor pathway in the brain, whereas EPA and DHA exerted a differential effect.

Melatonin upregulates BMAL1 to attenuate chronic sleep deprivation-related cognitive impairment by alleviating oxidative stress.

To investigate the mechanism underlying the regulatory effect of melatonin on chronic sleep deprivation-related cognitive impairment. Chronic sleep deprivation (CSD) model was established using the MMPM method. After the model was established, melatonin receptor agonist and inhibitor were given, respectively. Water maze was conducted to record the escape latency and the duration of crossing the platform of space exploration. The concentration of TNF-α, IL-6, MDA, and SOD was measured by ELISA. Immunofluorescence was used to determine the expression level of CD86 and CD206, while the mRNA expression of Bax, Bcl-2, P65, IκB, and BMAL1 was detected by qPCR. Western blotting assay was utilized to determine the protein expression of Bax, Bcl-2, P65, p-P65, IκB, p-I κB, and BMAL1. Compared with the control, the escape latency was greatly increased on the second and third day, accompanied by the increased expression of TNF-α, IL-6, MDA, and SOD in serum. Furthermore, dramatically upregulated Bax, Bcl-2, P65, IκB, and CD86 were observed in the model group, accompanied by the declined expression level of BMAL1 and CD206. Compared with the model group, the escape latency was declined, the concentration of TNF-α, IL-6, MDA, and SOD was decreased, the expression level of Bax, Bcl-2, P65, IκB, and CD86 was declined, and the level of BMAL1 and CD206 was promoted by the treatment of the melatonin agonist, while the opposite results were observed under the treatment of the melatonin inhibitor. Melatonin upregulates BMAL1 to attenuate chronic sleep deprivation-related cognitive impairment by alleviating oxidative stress.

1230: INTENSIVE CARE UNIT USE OF MELATONIN RECEPTOR AGONISTS IMPROVES OUTCOMES IN SEPSIS PATIENTS

Introduction: Delirium aggravates the morbidity and mortality of sepsis patients. Melatonin, the endogenous circadian rhythm regulating hormone, can decrease delirium. Also, melatonin possesses anti-oxidation and anti-inflammation capacity. Of note, the effects of melatonin can be activated by melatonin receptor agonists (such as tasimelteon and ramelteon). Thus, we hypothesized that using melatonin receptor agonists may improve the outcomes of sepsis patients in intensive care unit (ICU). To elucidate further on this issue, we conducted this retrospective study analyzing data retrieved from the Medical Information Mart for Intensive Care (MIMIC) IV database. Methods: Data from the MIMIC IV database were retrieved and analyzed. Only sepsis patients admitted to ICU were included. Patients who stayed in ICU less than 3 days were excluded. Between-group differences in the in-hospital mortality and overall mortality rates were analyzed using the Chi square test. The impacts of ICU use of melatonin receptor agonists on in-hospital mortality and overall mortality in sepsis patients were analyzed using logistic regression analysis. Results: A total of 3943 sepsis patients were included. Among them, 3.78% received melatonin receptor agonists (the Melatonin group, n=149), and ramelteon was the only melatonin receptor agonist these patients received. In addition, 96.22% of the included sepsis patients did not use melatonin receptor agonists (the non-Melatonin group, n=3794) during the entire course of hospitalization. In-hospital mortality rate (20.8% versus 31.0%, p=0.008) and the overall mortality rate (27.5% versus 39.3%%, p=0.004) in the Melatonin group were significantly lower than in the non-Melatonin group. Logistic regression analysis revealed that Melatonin group were associated with significantly lower risks of in-hospital mortality (odd’s ratio [OR]: 0.59, 95% confidence intervals [CI]: 0.39~0.88, p=0.009) and overall mortality (OR: 0.59, 95% CI: 0.41~0.84, p=0.004) comparing to non-Melatonin group. After adjusting for age and gender, the trend remained the same (in-hospital mortality: OR: 0.56, 95% CI: 0.37~0.84, p=0.005; overall mortality: OR: 0.56, 95% CI: 0.38~0.80, p=0.002). Conclusions: ICU use of melatonin receptor agonist ramelteon associated with outcome improvements in sepsis patients.

Ramelteon and mechanism of its restorative effect in an experimental lung disease model

Methotrexate (MTX) is an anticancer agent widely used in clinical practice for various oncological, rheumatological, autoimmune, and inflammatory diseases. However, the side effects of MTX limit its usage for treatment. In addition, diffuse alveolar damage, interstitial pneumonia, fibrosis, and pleural reactions may be encountered in MTX-induced pulmonary toxicity. Ramelteon (RML), a melatonin receptor agonist, has antioxidant, anti-inflammatory, and protective effects are shown by several studies. This study aimed to show the antioxidant, anti-inflammatory, and antiapoptotic effects of RML and its effect on the airway surface liquid volume homeostasis via aquaporins (AQP) in MTX-induced lung injury. Thirty-two female Wistar Albino rats were grouped into four groups as control, MTX (20 mg/kg, intraperitoneally, a single dose), MTX + RML, and RML (10 mg/kg, via oral gavage, for seven days) groups. Once the experiment ended, the rats’ lung tissues were taken for biochemical, genetic, histopathological, and immunohistochemical examinations. MTX significantly increased oxidative stress index and total oxidative status, and decreased total antioxidant status levels by 202.0%, 141.4%, 20.2%, respectively, relative to the control (p ˂ 0.001 for all). AQP-1/5, which is an indicator of lung damage, was also found to decrease significantly (p ˂ 0.001). In addition, a significant increase was observed in interleukin-1β, interferon-beta, and caspase-8 expressions and histopathological changes as a result of immunohistochemical and histochemical examinations (p ˂ 0.001). RML treatment ameliorated all these changes and significantly regressed lung damage. Our results suggest that RML might be used as a lung-protective agent in various models of lung and tissue injury.

Agomelatine ameliorates cadmium-induced toxicity through the modification of HMGB-1/TLR-4/NFκB pathway

Cadmium (Cd) has potential hazards on human beings. Consequently, this study was performed to explore the protective effects of agomelatine (AGO), a melatonin receptor agonist, against Cd-induced toxicity in rats. AGO (40 mg/kg/day) was administered orally concomitant with intra peritoneal injection of Cd (0.4 mg/kg/day) for 14 days. Then, blood, biochemical parameters and histological examination of affected organs including, heart and testis, were evaluated. Interestingly, AGO significantly counteracted Cd-induced elevation of serum cardiac enzymes. Similarly, AGO significantly improved the deterioration of serum testosterone level with Cd administration. The oxidative balance was corrected by AGO, as evidenced by decrease malondialdehyde (MDA), and superoxide dismutase activity in cardiac and testicular tissues. Additionally, AGO increased silent information regulator 1 protein (SIRT-1) and decreased High mobility group box 1 (HMGB1), Toll like receptor-4 (TLR-4), and Myd88 levels that subsequently reduced expression of nuclear factor-κB (NF-κB). Moreover, level of apoptotic marker; caspase-3 was inhibited by AGO. In accordance with the biochemical and molecular results, AGO restored structure of cardiac myofibers and seminiferous tubules. Collectively, AGO mitigated cardiac and testicular toxicity of Cd via modulation of SIRT-1/HMGB1 and its downstream pathway.