Protective effect of melatonin against oxygen-induced retinopathy: a study based on the HMGB1/NF-κB/NLRP3 axis / 中国当代儿科杂志

OBJECTIVES@#To study the protective effect of melatonin (Mel) against oxygen-induced retinopathy (OIR) in neonatal mice and the role of the HMGB1/NF-κB/NLRP3 axis.@*METHODS@#Neonatal C57BL/6J mice, aged 7 days, were randomly divided into a control group, a model group (OIR group), and a Mel treatment group (OIR+Mel group), with 9 mice in each group. The hyperoxia induction method was used to establish a model of OIR. Hematoxylin and eosin staining and retinal flat-mount preparation were used to observe retinal structure and neovascularization. Immunofluorescent staining was used to measure the expression of proteins and inflammatory factors associated with the HMGB1/NF-κB/NLRP3 axis and lymphocyte antigen 6G. Colorimetry was used to measure the activity of myeloperoxidase.@*RESULTS@#The OIR group had destruction of retinal structure with a large perfusion-free area and neovascularization, while the OIR+Mel group had improvement in destruction of retinal structure with reductions in neovascularization and perfusion-free area. Compared with the control group, the OIR group had significant increases in the expression of proteins and inflammatory factors associated with the HMGB1/NF-κB/NLRP3 axis, the expression of lymphocyte antigen 6G, and the activity of myeloperoxidase (P<0.05). Compared with the OIR group, the OIR+Mel group had significant reductions in the above indices (P<0.05). Compared with the control group, the OIR group had significant reductions in the expression of melatonin receptors in the retina (P<0.05). Compared with the OIR group, the OIR+Mel group had significant increases in the expression of melatonin receptors (P<0.05).@*CONCLUSIONS@#Mel can alleviate OIR-induced retinal damage in neonatal mice by inhibiting the HMGB1/NF-κB/NLRP3 axis and may exert an effect through the melatonin receptor pathway.

Changes of the Melatonergic System in Bipolar Disorder: A Literature Review / 우울ㆍ조울병

Recently, melatonergic agents have been gaining much interest in the treatment of mood disorders. The elucidation of the underlying biological mechanisms related to the melatonergic system in mood disorders is warranted to ensure the proper use of melatonergic agents. Changes of the melatonergic system have been investigated in several studies of patients with bipolar disorder (BP) and depression. Accumulating evidence has indicated that patients with BP might exhibit abnormal melatonin secretion patterns, increased light-induced melatonin suppression, altered pineal gland volume, genetically abnormal melatonin synthesis enzyme, and modified melatonin receptors. In this review, the findings of studies performed to explore the association between the melatonergic system and BP are discussed. Moreover, the interpretations and limitations of these findings are described.

The Relief Effects of Ramelteon on Refractory Chronic Migraine: A Case Report

The selective melatonin receptor agonism effect of ramelteon is useful for insomnia. Here we wanted to present a refractory chronic migraine case, who had significant improvements in migraine after using ramelteon. The possible mechanism for the ramelteon in the migraine relief might be related to melatonin effects.

The role of melatonin in diabetes: therapeutic implications

Melatonin referred as the hormone of darkness is mainly secreted by pineal gland, its levels being elevated during night and low during the day. The effects of melatonin on insulin secretion are mediated through the melatonin receptors (MT1 and MT2). It decreases insulin secretion by inhibiting cAMP and cGMP pathways but activates the phospholipaseC/IP3 pathway, which mobilizes Ca2+from organelles and, consequently increases insulin secretion. Both in vivo and in vitro, insulin secretion by the pancreatic islets in a circadian manner, is due to the melatonin action on the melatonin receptors inducing a phase shift in the cells. Melatonin may be involved in the genesis of diabetes as a reduction in melatonin levels and a functional interrelationship between melatonin and insulin was observed in diabetic patients. Evidences from experimental studies proved that melatonin induces production of insulin growth factor and promotes insulin receptor tyrosine phosphorylation. The disturbance of internal circadian system induces glucose intolerance and insulin resistance, which could be restored by melatonin supplementation. Therefore, the presence of melatonin receptors on human pancreatic islets may have an impact on pharmacotherapy of type 2 diabetes.

Effects of Kaixin Powder on melatonin receptor expression and (125)I-Mel binding affinity in a rat model of depression / 中国结合医学杂志

<p><b>OBJECTIVE</b>To explore the effects of Kaixin Powder (, KXP) on melatonin receptor (MR) expression and (125)I-Mel binding affinity in a depression rat model.</p><p><b>METHODS</b>Seventy-two male Wistar rats were divided into six groups: a blank control group, model group, ramelteon group, KXP high-dosage group (HKXP), medium-dosage group (MKXP) and low-dosage group (LKXP). To establish the depression model, all groups except the blank control group were singly housed and exposed to chronic unpredictable mild stress. Weight gain, sucrose consumption and the open-field test were used to evaluate induction of depression. KXP at 260, 130 and 65 mg/(kg•d) was also respectively administered to the rats in the HKXP, MKXP and LKXP groups for 21 days. Ramelteon [0.83 mg/(kg•d)] was given to the positive drug control group. An equivalent volume of physiological saline was given to the blank and model groups. The liquid chip method was used to measure the concentration of plasma melatonin (MT). Mel1a (MT1) and Mel1b (MT2) expression levels were determined by Western blotting. In addition, a radioactive ligand-binding assay was used to analyze the specific binding properties and dynamic characteristics between MR and (125)I-Mel.</p><p><b>RESULTS</b>The results of weight gain, sucrose consumption and the open-field test showed that our model successfully produced depressive symptoms and depressive-like behavior. The concentration of plasma MT in the model group decreased significantly at night but increased in the MKXP group (P<0.05). The HKXP group showed significantly increased expression of MT1 (P<0.05); however, the expression of MT2 in all groups exhibited no significant differences (P>0.05). The maximum binding capacity (B(max)) for specific binding between MR and 125I-Mel in the MKXP group was significantly higher than that in the model group (P<0.05), but no significant differences were found in the equilibrium dissociation constant (K(d)) of each group (P>0.05).</p><p><b>CONCLUSIONS</b>KXP may have a similar effect as ramelteon. KXP improved depressive-like behavior by increasing the concentration of plasma MT and MT1 expression, thereby increasing three B(max) of MR to achieve the desired antidepressant effect.</p>

Melatonin in Psychiatric Disorders / 수면정신생리

The secretion of melatonin exhibits a circadian rhythm entrained with the sleep-wake cycle. An alteration of this secretory rhythm has been found in various psychiatric disorders. This review summarizes the regulation of melatonin and its relationship to the circadian rhythm, major depressive disorder, bipolar disorder, seasonal affective disorder, Alzheimer's disease and autism. The review also looks at the effect of melatonin and melatonin agonist on sleep and symptoms of depression, bipolar disorder and seasonal affective disorder. In Alzheimer's disease, the circadian rhythm alterations are associated with the change of melatonin levels and melatonin receptors. It has been reported that melatonin and melatonin synthetic enzyme levels decrease in autism spectrum disorder.

Melatonin: An internal signal for daily and seasonal timing.

Melatonin is secreted only during night, irrespective of the habitat of an organism and the site of its synthesis and secretion, and hence known as “darkness hormone”. Elevated melatonin levels reflect the nighttime. In vertebrates, the main site of melatonin production is the pineal gland. Species in which melatonin is also secreted from sources other than the pineal, as in some birds, relative contributions of different melatonin producing tissues to the blood melatonin level can vary from species to species. Melatonin acts through its receptors, which are members of the G protein-coupled (GPCR) superfamily. Three melatonin receptors subtypes MT1 (mel1a), MT2 (mel1b), and MT3 (mel1c) have been identified in different brain areas and other body organs of vertebrates. Melatonin synthesis and secretion are circadianly rhythmic. Changes and differences in specific features of melatonin signal can vary among species, and under a variety of natural environmental conditions. Two major physiological roles of melatonin are established in vertebrates. First, melatonin is involved in the circadian system regulated behavioural and physiological functions. Second, it is critical for the photoperiodic system. Besides, melatonin has been implicated in various ways both directly and indirectly to human health, including jet lag, sleep, immune system and cancer.

Agomelatine: The Novel Antidepressant / 대한정신약물학회지

Major depression is a common mental illness, associated with high morbidity and mortality. Antidepressants have been the first-line therapies due to their confirmed efficacy, however, considering high rate of poor treatment response to these therapies, distressing side effects, and delayed onset of their efficacy, there has been much effort to find alternative treatments for major depression. Recently, evidence regarding disturbed circadian rhythms involved in the pathophysiology of major depression has emerged, the interest on this area has been increasing. Agomelatine is an emerging antidepressant, with a unique profile of selective antagonist at serotonin 2C (5-HT2C) receptors and melatonin receptor agonist. Previous studies have shown its superior efficacy over placebo in treating major depression. Previous trials have shown comparable antidepressant efficacy of agomelatine compared to other standard antidepressants including venlafaxine, sertraline, and fluoxetine. Regarding safety profile of agomelatine, it seems to be not associated with sexual dysfunction and it has less potential for serotonin syndrome or discontinuation syndrome than standard antidepressants including selective serotonin reuptake inhibitors. Considering favorable results on the efficacy and safety of agomelatine in treating depression, it could be a good, safe treatment alternative in the treatment of depression.

Melatonin in Chagas´ disease: Possible therapeutic value / La melatonina en la enfermedad de Chagas: Su posible valor terapéutico

Chagas' disease is a severe health problem in Latin America, causing approximately 50 000 deaths a year, with approximately 18 million infected people. About 25-30% of the patients infected with Trypanosoma cruzi develop the chronic form of the disease. The protective response against T. cruzi depends on both innate and acquired immunity involving macrophages, natural killer cells, T and B lymphocytes, and the production of proinflammatory Th-1 cytokines. In addition, an increased nitric oxide (NO) production in macrophages leading to effective microbicidal action is needed to control parasitemia. Melatonin is detectable in T. cruzi and may play a role in promoting infection whereas, when administered in high doses during the acute phase of T. cruzi infection, it can decrease parasitemia while reducing NO production. During chronic disease progression, the sustained oxidative stress concomitant to myocardial damage could be reduced by administering melatonin. It is hypothesized that the coordinated administration of a melatonin agonist like the MT1/MT2 agonist ramelteon, that lacks antioxidant activity and may not affect NO production during the acute phase, and of melatonin in doses high enough to decrease oxidative damage, to preserve mitochondrial and to prevent cardiomyopathy during the chronic phase, could be a novel add-on treatment of Chagas´ disease.

La enfermedad de Chagas es un problema grave de salud en América Latina, causando cerca de 50 000 muertes al año y unos 18 millones de infectados. Alrededor del 25-30% de los pacientes infectados con Trypanosoma cruzi desarrollan la forma crónica de la enfermedad. La respuesta de defensa ante el T. cruzi depende de la inmunidad innata y adquirida con la participación de macrófagos, células “natural killer”, linfocitos T y B, y la producción de citoquinas proinflamatorias de tipo Th-1. Además, el aumento en la producción de óxido nítrico (NO) en los macrófagos lleva a una acción microbicida eficaz necesaria para controlar la parasitemia. La melatonina es detectable en T. cruzi y podría desempeñar un papel en la promoción de la infección como lo hace en el paludismo, mientras que, cuando se administra en dosis farmacológicas altas durante la fase aguda de la infección por T. cruzi, disminuye la parasitemia, aun en presencia de una reducción de la producción de NO. Durante la progresión de la enfermedad de Chagas a la cronicidad, el estrés oxidativo aumentado con el concomitante daño miocárdico podría reducirse por la administración de melatonina, de reconocida acción antioxidante. Se propone como un nuevo enfoque complementario en el tratamiento de la enfermedad de Chagas la administración durante la fase aguda de un agonista MT1/MT2 de la melatonina como el ramelteon, que carece de actividad antioxidante y podría no afectar a la producción de NO, y de melatonina durante la fase crónica de en dosis suficientemente altas como para disminuir el daño oxidativo y prevenir la miocardiopatía.

Ramelteon: a melatonin receptor agonist for the treatment of insomnia.

Ramelteon is a novel MT1 and MT2 melatonin receptor selective agonist recently approved for the treatment of insomnia characterized by difficulty in sleep onset. It is a nonscheduled drug since it lacks the potential for abuse and does not interact with neurotransmitter receptors most associated with these phenomena. Although the effects of ramelteon use > 5 weeks are unknown, the available data confirms its safety and efficacy for short-term use. Clinical use and future research should uncover more information about ramelteon's properties.

Melatonin Induces Akt Phosphorylation through Melatonin Receptor- and PI3K-Dependent Pathways in Primary Astrocytes

Melatonin has been reported to protect neurons from a variety of neurotoxicity. However, the underlying mechanism by which melatonin exerts its neuroprotective property has not yet been clearly understood. We previously demonstrated that melatonin protected kainic acid-induced neuronal cell death in mouse hippocampus, accompanied by sustained activation of Akt, a critical mediator of neuronal survival. To further elucidate the neuroprotective action of melatonin, we examined in the present study the causal mechanism how Akt signaling pathway is regulated by melatonin in a rat primary astrocyte culture model. Melatonin resulted in increased astrocytic Akt phosphorylation, which was significantly decreased with wortmannin, a specific inhibitor of PI3K, suggesting that activation of Akt by melatonin is mediated through the PI3K-Akt signaling pathway. Furthermore, increased Akt activation was also significantly decreased with luzindole, a non-selective melatonin receptor antagonist. As downstream signaling pathway of Akt activation, increased levels of CREB phoshorylation and GDNF expression were observed, which were also attenuated with wortmannin and luzindole. These results strongly suggest that melatonin exerts its neuroprotective property in astrocytes through the activation of plasma membrane receptors and then PI3K-Akt signaling pathway.

Comparison of melatonin receptor mRNA expression in bilateral paravertebral muscles in adolescent idiopathic scoliosis / 中华外科杂志

<p><b>OBJECTIVE</b>To study the change of melatonin receptor mRNA expression in paravertebral muscles in adolescent idiopathic scoliosis (AIS), and analyze its relationship with the etiology of AIS.</p><p><b>METHODS</b>Twenty cases with average age of (15.1 +/- 2.2) years and average Cobb angle of 56 degrees +/- 16 degrees , including 10 cases with Cobb angle > 50 degrees and 10 cases with Cobb angle <or= 50 degrees , were in AIS group. The apical vertebrae were from T(6 - 11). Twelve cases with average age of (11.6 +/- 3.2) years and average Cobb angle of 59 degrees +/- 33 degrees were in congenital scoliosis (CS) group. The apical vertebrae were from T(7 - 12). Ten cases without scoliosis were in control group. The mRNA expression of melatonin receptor subtype MT1 and MT2 were detected by RT-PCR method.</p><p><b>RESULTS</b>The MT2 mRNA expression of paravertebral muscles on concave side was higher than that on convex side in AIS and CS groups (P < 0.05), but the MT1 mRNA expression showed no significant difference (P > 0.05). In AIS group, the ratio of MT2 mRNA expression on concave side compared with convex side in cases with Cobb angle > 50 degrees and cases with Cobb angle <or= 50 degrees showed no significant difference (P > 0.05). The MT1 and MT2 mRNA expression showed no significant difference in control group (P > 0.05).</p><p><b>CONCLUSIONS</b>The melatonin receptor expression in bilateral paravertebral muscles in AIS is asymmetric, which may be a secondary change and has no important role in the pathogenesis of AIS.</p>

Evaluation of the role of melatonin in formalin-induced pain response in mice.

BACKGROUND: Melatonin, the major secretory product of pineal gland has been suggested to play a regulatory role in the circadian rhythm of body activities including the pain sensitivity. Three subtypes of melatonin receptors, i.e. ML1, ML2 and ML3 have been identified. AIM: To investigate the antinociceptive activity of melatonin and to unravel the underlying receptor mechanisms involved in this action. MATERIAL AND METHODS: Effect of melatonin (25-100 mg/kg, ip) and its interaction with putative melatonin receptor antagonists and opioidergic and serotoninergic agents have been studied in formalin test, a model of tonic continuous pain. Formalin (0.1 ml of 1% solution) was injected under the plantar surface of right hind paw of mice and the time an animal spent in licking the injected paw was measured. STATISTICAL ANALYSIS: The data were analysed by one-way ANOVA followed by Tukey's test for multiple comparisons. RESULTS: Injection of formalin produced two phases of intense licking, an early phase (0-5 min) and a late phase (20-25 min). Melatonin dose-dependently decreased the licking response in both the phases, effect being more marked in the late phase. Luzindole, a ML1 receptor antagonist did not block but rather enhanced the antinociceptive activity of melatonin. However, prazosin, a ML2 receptor antagonist in the low dose (0.5 mg/kg) significantly attenuated but in higher dose (1 mg/kg) enhanced the analgesic effect of melatonin. Naloxone, an opioid receptor antagonist did not reverse but morphine, an opioid agonist enhanced the antinociceptive activity of melatonin. Both mianserin and ondansetron the 5HT2 and 5HT3 receptor antagonists, respectively increased the analgesic effect of melatonin. CONCLUSION: The present results suggest the involvement of ML2 receptors in mediating the antinociceptive activity of melatonin in formalin-induced pain response. Further an interplay between melatonin, alpha-1 adrenergic and 5HT2 and 5HT3 serotoninergic receptors may also be participating in this action.

The role of melatonin receptor and GABAA receptor in the sleeping time prolonged by melatonin in mice / 中国应用生理学杂志

<p><b>AIM</b>To observe the role of melatonin receptor and GABAA receptor in sleeping time prolonged by melatonin in mice.</p><p><b>METHODS</b>The absence of the righting reflex was considered as the sleep onset and the duration of the loss of the righting reflex was recorded as the sleeping time. The effects of receptor agonist and antagonist on hypnotic activity of melatonin were studied in the paper.</p><p><b>RESULTS</b>Prazosin hydrochloride, the blocker of melatonin 3 receptor, didn't affect the sleeping time prolonged by melatonin in mice. GABA, the endogenous agonist of GABA receptor, significantly potentiated the hypnotic activity of melatonin. When picrotoxin, the ligand of picrotoxin site on GABAA receptor, used together with melatonin, it significantly antagonized the sleeping time prolonged by melatonin, however, bicuculline, the specific antagonist of GABA binding site in GABAA receptor, didn't affect the hypnotic activity of melatonin in mice.</p><p><b>CONCLUSION</b>Melatonin does not exhibit its potentiation sleeping time in mice through melatonin 3 receptor. Hypnotic activity of melatonin may be mediated through picrotoxin site on GABAA receptor.</p>

Melatonin, biological rhythm disorders and phototherapy.

Biological rhythms are endogenous in nature and are generated by self sustained oscillators present in the living organisms themselves. Of these, circadian rhythms are the most thoroughly studied and are driven by the suprachiasmatic (SCN) of hypothalamus. The recent discovery of high affinity melatonin receptors ML1, ML2 in SCN suggests that melatonin is involved in the control of circadian rhythm generation. The fact that biological rhythm disorders like delayed sleep phase syndrome (DSPS), Jet lag, shift-work disorders, seasonal effective disorder (SAD) respond well either to phototherapy or melatonin adds further support to the concept that melatonin is involved in the pathogenesis of these conditions. Indeed altered melatonin rhythms have bee documented in MDP, shift work disorder, endogenous depression etc. In addition to functioning as a rhythm regulator, melatonin is also involved in the control of sleep, regulation of body temperature, reproduction, and as a free radical scavanger and antioxidant protecting the cells and tissues of our body against oxidative damage. Low levels of melatonin in cancer patients and patients with coronary heart disease indicate that melatonin may be involved in these disorders also.

Melatonin: a master hormone and a candidate for universal panacea.

The molecule of melatonin seems to have been evolutionarily conserved. Its presence has been demonstrated in almost all groups of organisms, from plants, protozoa to people. During evolution, melatonin is claimed to have mediated dark adaptation. The universal presence of melatonin may be because it is lipophilic in nature which enables it to cross all biological (lipid membrane) barriers and to diffuse into every compartment of the cell, and because it serves as an antioxidant and is used as a free radical scavenger. In vertebrates, the pineal gland is the single largest source of melatonin production although, especially in non-mammalian vertebrates, other organs (e.g. retina, harderian gland etc.) may contribute significantly to the blood melatonin levels. In invertebrates, on the other hand, the pineal gland is absent and, therefore, melatonin secretion is clearly derived from another source(s). Regardless of the site of synthesis and the nature of organisms (diurnal, nocturnal or crepuscular), melatonin is secreted in the night and melatonin biosynthetic pathway remains essentially the same. Tryptophan, an amino acid derived from dietary sources, undergoes a series of enzymatic reactions to produce melatonin. The rhythm in melatonin secretion is generated endogenously by the circadian pacemaker(s) in the suprachiasmatic nuclei (SCN), and regulated by environmental light:dark cycle. Melatonin through its action on the SCN synchronizes disrupted or free-running circadian rhythms, and regulates a variety of daily and seasonal changes in the physiology and behaviour of animals. Emerging scientific evidence for the role of melatonin as therapeutic agent in the treatment of circadian rhythm-associated sleep disorders in persons having normal social working hours and shift workers, in jet lag, in immunological functions etc. have considerably increased interest in this hormone molecule. The role of melatonin in organisms physiology has now been widely recognized, and the wealth of information accumulated in the past two decades indicate it to be the best hormone candidate to be investigated for a universal panacea.