Maternal Melatonin Deficiency Leads to Endocrine Pathologies in Children in Early Ontogenesis.

The review summarizes the results of experimental and clinical studies aimed at elucidating the causes and pathophysiological mechanisms of the development of endocrine pathology in children. The modern data on the role of epigenetic influences in the early ontogenesis of unfavorable factors that violate the patterns of the formation of regulatory mechanisms during periods of critical development of fetal organs and systems and contribute to the delayed development of pathological conditions are considered. The mechanisms of the participation of melatonin in the regulation of metabolic processes and the key role of maternal melatonin in the formation of the circadian system of regulation in the fetus and in the protection of the genetic program of its morphofunctional development during pregnancy complications are presented. Melatonin, by controlling DNA methylation and histone modification, prevents changes in gene expression that are directly related to the programming of endocrine pathology in offspring. Deficiency and absence of the circadian rhythm of maternal melatonin underlies violations of the genetic program for the development of hormonal and metabolic regulatory mechanisms of the functional systems of the child, which determines the programming and implementation of endocrine pathology in early ontogenesis, contributing to its development in later life. The significance of this factor in the pathophysiological mechanisms of endocrine disorders determines a new approach to risk assessment and timely prevention of offspring diseases even at the stage of family planning.

Autism Spectrum Disorder patients may be susceptible to COVID-19 disease due to deficiency in melatonin.

Patients with Autism Spectrum Disorder (ASD) may be particularly prone to develop COVID-19. An unusual extended course of COVID-19 disease illness has been reported in one ASD patient and a group of patients have COVID-19 disease in a neurodevelopmental facility. It has been widely reported that many of those with ASD have substantial sleep disorders with low levels of melatonin and various genetic alterations related to melatonin production have been found. Several lines of evidence point to a substantial role of melatonin in the body's innate defense system including acting as a scavenger, an antioxidant and modulating the immune system. We therefore hypothesize that melatonin deficiency may predispose those ASD patients who have low melatonin output to COVID-19 disease. Potential implications for treatment are discussed.

Melatonin ameliorates the sleep disorder induced by surgery under sevoflurane anaesthesia in aged mice.

Post-operative sleep disorders induce adverse effects on patients, especially the elderly, which may be associated with surgery and inhalational anaesthetics. Melatonin is a neuroendocrine regulator of the sleep-wake cycle. In this study, we analysed the alterations of post-operative sleep in aged melatonin-deficient (C57BL/6J) mice, and investigated if exogenous melatonin could facilitate entrainment of circadian rhythm after laparotomy under sevoflurane anaesthesia. The results showed that laparotomy under sevoflurane anaesthesia had a greater influence on post-operative sleep than sevoflurane alone. Laparotomy under anaesthesia led to circadian rhythm shifting forward, altered EEG power density and delta power of NREM sleep, and lengthened REM and NREM sleep latencies. In the light phase, the number of waking episodes tended to decline, and wake episode duration elevated. However, these indicators presented the opposite tendency during the dark phase. Melatonin showed significant efficacy for ameliorating the sleep disorder and restoring physiological sleep, and most of the beneficial effect of melatonin was antagonized by luzindole, a melatonin receptor antagonist.

The melatonin metabolite N1-acetyl-5-methoxykynuramine facilitates long-term object memory in young and aging mice.

Melatonin (MEL) has been reported to enhance cognitive processes, making it a potential treatment for cognitive decline. However, the role of MEL's metabolites, N1-acetyl-N2-formyl-5-methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in these effects are unknown. The current study directly investigated the acute effects of systemic MEL, AFMK, and AMK on novel object recognition. We also analyzed MEL, AFMK, and AMK levels in hippocampus and temporal lobe containing the perirhinal cortex following systemic MEL and AMK treatment. AMK administered post-training had a more potent effect on object memory than MEL and AFMK. AMK was also able to rescue age-associated declines in memory impairments when object memory was tested up to 4 days following training. Results from administering AMK at varying times around the training trial and the metabolism time course in brain tissue suggest that AMK's memory-enhancing effects reflect memory consolidation. Furthermore, inhibiting the MEL-to-AMK metabolic pathway disrupted object memory at 24 hours post-training, suggesting that endogenous AMK might play an important role in long-term memory formation. This is the first study to report that AMK facilitates long-term object memory performance in mice, and that MEL crosses the blood-brain barrier and is immediately converted to AMK in brain tissue. Overall, these results support AMK as a potential therapeutic agent to improve or prevent memory decline.

Diabetes and atherothrombosis: The circadian rhythm and role of melatonin in vascular protection.

Obesity-related euglycaemic insulin resistance clusters with cardiometabolic risk factors, contributing to the development of both type 2 diabetes and cardiovascular disease. An increased thrombotic tendency in diabetes stems from platelet hyperactivity, enhanced activity of prothrombotic coagulation factors and impaired fibrinolysis. Furthermore, a low-grade inflammatory response and increased oxidative stress accelerate the atherosclerotic process and, together with an enhanced thrombotic environment, result in premature and more severe cardiovascular disease. The disruption of circadian cycles in man secondary to chronic obesity and loss of circadian cues is implicated in the increased risk of developing diabetes and cardiovascular disease. Levels of melatonin, the endogenous synchronizer of circadian rhythm, are reduced in individuals with vascular disease and those with deranged glucose metabolism. The anti-inflammatory, antihypertensive, antioxidative and antithrombotic activities of melatonin make it a potential therapeutic agent to reduce the risk of vascular occlusive disease in diabetes. The mechanisms behind melatonin-associated reduction in procoagulant response are not fully known. Current evidence suggests that melatonin inhibits platelet aggregation and might affect the coagulation cascade, altering fibrin clot structure and/or resistance to fibrinolysis. Large-scale clinical trials are warranted to investigate the effects of modulating the circadian clock on insulin resistance, glycaemia and cardiovascular outcome.

Seasonal Variations of Locomotor Activity Rhythms in Melatonin-Proficient and -Deficient Mice under Seminatural Outdoor Conditions.

Locomotor activity patterns of laboratory mice are widely used to analyze circadian mechanisms, but most investigations have been performed under standardized laboratory conditions. Outdoors, animals are exposed to daily changes in photoperiod and other abiotic cues that might influence their circadian system. To investigate how the locomotor activity patterns under outdoor conditions compare to controlled laboratory conditions, we placed 2 laboratory mouse strains (melatonin-deficient C57Bl and melatonin-proficient C3H) in the garden of the Dr. Senckenbergische Anatomie in Frankfurt am Main. The mice were kept singly in cages equipped with an infrared locomotion detector, a hiding box, nesting material, and with food and water ad libitum. The locomotor activity of each mouse was recorded for 1 year, together with data on ambient temperature, light, and humidity. Chronotype, chronotype stability, total daily activity, duration of the activity period, and daily diurnality indices were determined from the actograms. C3H mice showed clear seasonal differences in the chronotype, its stability, the total daily activity, and the duration of the activity period. These pronounced seasonal differences were not observed in the C57Bl. In both strains, the onset of the main activity period was mainly determined by the evening dusk, whereas the offset was influenced by the ambient temperature. The actograms did not reveal infra-, ultradian, or lunar rhythms or a weekday/weekend pattern. Under outdoor conditions, the 2 strains retained their nocturnal locomotor identity as observed in the laboratory. Our results indicate that the chronotype displays a seasonal plasticity that may depend on the melatoninergic system. Photoperiod and ambient temperature are the most potent abiotic entraining cues. The timing of the evening dusk mainly affects the onset of the activity period; the ambient temperature during this period influences the latter's duration. Humidity, overall light intensities, and human activities do not affect the locomotor behavior.

Effect of endurance training on diurnal rhythms of superoxide dismutase activity, glutathione and lipid peroxidation in plasma of pinealectomized rats.

Melatonin deficit is characterized by disturbed circadian rhythms of many physiological and biochemical parameters including markers of oxidative stress. Moderate endurance training exerts protection against oxidative stress. In the present study, we aimed to explore the impact of endurance treadmill training on disturbed rhythmic fluctuations of some markers of oxidative stress in pinealectomized rats. Animals were divided into four groups: sham-operated sedentary rats (sham-sed), a sham group with exercise (sham-ex), pinealectomized sedentary rats (pin-sed) and pin rats with exercise (pin-ex). Animals were sacrificed by decapitation at 4-h intervals for biochemical analysis of plasma melatonin and markers of oxidative stress. The activity of superoxide dismutase (SOD) and the levels of glutathione (GSH) and lipid peroxidation demonstrated diurnal variations in the sham-sed group. The peak values of SOD were detected during the dark period that coincided with the peak plasma levels of melatonin in the sham-sed rats. The malondialdehyde (MDA) levels also showed a tendency to a progressive raise during the dark period. Pinealectomy was characterized by a remarkable melatonin deficit in plasma of sedentary rats, compromised fluctuations with decreased SOD activity and increased lipid peroxidation. While endurance training was unable to restore the melatonin deficit, it partly prevented the oxidative stress at selected time points in the pinealectomised rats. Our findings indicate the important role of endurance training against oxidative stress both in physiological conditions and melatonin deficit.

Mice Reach Higher Visual Sensitivity at Night by Using a More Efficient Behavioral Strategy.

Circadian clocks predictively adjust the physiology of organisms to the day/night cycle. The retina has its own clock, and many diurnal changes in its physiology have been reported. However, their implications for retinal functions and visually guided behavior are largely unresolved. Here, we study the impact of diurnal rhythm on the sensitivity limit of mouse vision. A simple photon detection task allowed us to link well-defined retinal output signals directly to visually guided behavior. We show that visually guided behavior at its sensitivity limit is strongly under diurnal control, reaching the highest sensitivity and stability at night. The diurnal differences in visual sensitivity did not arise in the retina, as assessed by spike recordings from the most sensitive retinal ganglion cell types: ON sustained, OFF sustained, and OFF transient alpha ganglion cells. Instead, we found that mice, as nocturnal animals, use a more efficient search strategy for visual cues at night. Intriguingly, they can switch to the more efficient night strategy even at their subjective day after first having performed the task at night. Our results exemplify that the shape of visual psychometric functions depends robustly on the diurnal state of the animal, its search strategy, and even its diurnal history of performing the task. The results highlight the impact of the day/night cycle on high-level sensory processing, demonstrating a direct diurnal impact on the behavioral strategy of the animal.

[Perimenopausal melatonin deficiency syndrome in system of personalized management of quality of life of women with climacteric syndrome.]

The aim of our study is to search diagnostic tools for early detection of prenosological melatonin deficiency in postmenopausal women and women in menopausal transition with climacteric syndrome for establishment effective personalized prevention and treatment programs. In this study 221 women were enrolled. They were divided into four groups: the 1st group - 39 women in menopausal transition with climacteric syndrome, the 2nd group - 104 menopausal women with climacteric syndrome, the 3rd group - 41 women with physiological menopause, the 4th group - 37 healthy women in reproductive-age. The study was conducted using the test for detecting melatonin deficiency, women's health questionnaire (WHQ), and morning level detection of 6-sulfatoxymelatonin in urine. A new prenosological state - perimenopausal melatonin deficiency syndrome was build on the data obtained. It is appropriate to evaluate prognosis of melatonin treatment in women with climacteric syndrome during the planning of personalized prevention and treatment programs. The assessment of prognosis is carried out with the help of the discriminant mathematical model, which is the basis of personalized management of quality of life in women with climacteric syndrome. This system is based on participatory principles.

Melatonin Deficiency Confers Tolerance to Multiple Abiotic Stresses in Rice via Decreased Brassinosteroid Levels.

Melatonin has long been recognized as a positive signaling molecule and potent antioxidant in plants, which alleviates damage caused by adverse conditions such as salt, cold, and heat stress. In this study, we found a paradoxical role for melatonin in abiotic stress responses. Suppression of the serotonin N-acetyltransferase 2 (snat2) gene encoding the penultimate enzyme in melatonin biosynthesis led to simultaneous decreases in both melatonin and brassinosteroid (BR) levels, causing a semi-dwarf with erect leaf phenotype, typical of BR deficiency. Here, we further characterized snat2 rice in terms of grain morphology and abiotic stress tolerance, to determine whether snat2 rice exhibited characteristics similar to those of BR-deficient rice. As expected, the snat2 rice exhibited tolerance to multiple stress conditions including cadmium, salt, cold, and heat, as evidenced by decreased malondialdehyde (MDA) levels and increased chlorophyll levels, in contrast with SNAT2 overexpression lines, which were less tolerant to stress than wild type plants. In addition, the length and width of grain from snat2 plants were reduced relative to the wild type, which is reminiscent of BR deficiency in rice. Other melatonin-deficient mutant rice lines with suppressed BR synthesis (i.e., comt and t5h) also showed tolerance to salt and heat stress, whereas melatonin-deficient rice seedlings without decreased BR levels (i.e., tdc) failed to exhibit increased stress tolerance, suggesting that stress tolerance was increased not by melatonin deficiency alone, but by a melatonin deficiency-mediated decrease in BR.

Melatonin deficiency at tissue level: a possible aetiological factor in nasal polyposis.

OBJECTIVE: The aim of this study was to examine whether melatonin is involved in the pathogenesis of nasal polyposis. METHOD: This study included 29 patients with nasal polyposis and undergoing functional endoscopic sinus surgery. As a control group, 26 patients who had been operated on for a deviated nasal septum and concha bullosa were enrolled. Samples were taken from the nasal polyp tissue and from the resected middle concha bullosa mucosa of the control group. Serum samples were taken from all patients. RESULTS: It was found that the tissue and serum melatonin levels in the nasal polyp group were significantly lower compared with the tissue and serum melatonin levels in the control group. CONCLUSION: In nasal polyposis, the melatonin level in the serum and tissue is lower than in individuals without polyposis. This deficiency may play a role in the pathogenesis of nasal polyposis.

The Absence of Pineal Melatonin Abolishes the Daily Rhythm of Tph1 (Tryptophan Hydroxylase 1), Asmt (Acetylserotonin O-Methyltransferase), and Aanat (Aralkylamine N-Acetyltransferase) mRNA Expressions in Rat Testes.

This study examined the effects of pinealectomy in Wistar rats and melatonin replacement therapy on the daily mRNA expression of melatonin (Tph1, Aanat, Asmt, Mt1, Mt2, and Rorα), and steroidogenic (Star, 17ßhsd3, and Lhr) related genes as well as clock genes (Rev-erbα, Bmal1, Per1, Per2, Cry1, and Cry2) in testes. The testes of control animals express the Tph1, Aanat, and Asmt and Per2 genes with 24-h rhythms in mRNA, reaching the maximal values during the dark phase. Pinealectomy abolished and melatonin treatment restored the 24-h rhythmicity. Daytime differences in mRNA expression were significant for Star, Lhr, Mt1, Mt2, Rorα, Rev-erbα, Bmal1, Cry1, and Cry2 genes in testes of control rats. Conversely, 17ßhsd3 and Per1 mRNA expression did not show a daytime difference in testes of control animals. Pinealectomy abolished the peak time of Mt1 and Mt2 mRNA expression, phase shifted the peak time of Star, Rorα, Rev-erbα, Bmal1, and Cry2 mRNA expression, downregulated the 24-h Lhr mRNA expression, and inverted the peak time of Per1, Per2, and Cry1 mRNA expression to the light phase. The melatonin replacement therapy completely restored the control levels of Lhr, Rev-erbα, and Per1 mRNA expression patterns, partially restored the daily control of Star, Mt2, Rorα, Bmal1, Cry1, and Cry2 mRNA expression but did not re-establish the daily control of Mt1 mRNA expression. This suggests that the daily mRNA expression of these genes is probably driven by pineal melatonin and melatonin treatment restores (partially or completely) the daily control of gene expression patterns.

The Role of Melatonin in Oxidative Stress, DNA Damage, Apoptosis and Angiogenesis in Fetal Eye under Preeclampsia and Melatonin Deficiency Stress.

Aim: The aim of this study was to investigate the possible mechanisms of ocular damage induced by pinealectomy (PNX) and preeclampsia (PE), and to determine the cellular and molecular effects of melatonin treatment on oxidative stress, DNA damage, molecular chaperone responses, induction of apoptosis and angiogenesis in the fetal eye of both PNX and PNX+PE animals. Material and Methods: We analysed therapeutic potential of melatonin on fetal eye damage in PNX and PNX+PE animals using Malondialdehyde (MDA), Random Amplified Polymorphic DNA (RAPD), qRT-PCR and Western blot assays. Results: Our study presents three preliminary findings: (a) in fetal eye tissues, PNX and PNX+PE significantly induce oxidative damage to both DNA and protein contents, leading to a dramatic increase in caspase-dependent apoptotic signalling in both mitochondrial and death receptor pathways; (b) the same conditions trigger hypoxia biomarkers in addition to significant overexpression of HIF1-α, HIF1-ß, MMP9 and VEGF genes in the fetal eye; (c) finally, melatonin regulates not only the expression of genes encoding antioxidant enzymes and increase in DNA damage as well as lipid peroxidation but also limits programmed cell death processes in the fetal eye of PNX and PNX+PE animals . Furthermore, melatonin can relatively modulate genes in the HIF1 family, TNF-α and VEGF, thus acting as a direct anti-angiogenic molecule. In conclusion, both PNX and PNX+PE induce ocular damage at both cellular and molecular levels in fetal eye tissue of rats. Conclusion: Our results clearly indicate the potential of melatonin as a preventative therapeutic intervention for fetal ocular damage triggered by both PNX and PNX+PE.

The effect of exogenous melatonin on reducing scoliotic curvature and improving bone quality in melatonin-deficient C57BL/6J mice.

It is well-documented that melatonin deficiency has been linked to the etiopathogenesis of adolescent idiopathic scoliosis. In this study, we intended to apply melatonin in melatonin-deficient mice to ascertain whether melatonin could reduce the incidence/severity of scoliosis, and investigate the role of melatonin on bone mineral density in scoliosis. A total of 80 mice were divided into 4 groups: 20 quadrupedal mice and 20 bipedal mice served as controls; 20 quadrupedal and 20 bipedal mice received oral melatonin (8 mg/kg BW) daily. After 5th, 10th, 15th and 20th weeks of treatment, radiographs and in vivo micro-CT were used to determine the incidence of scoliosis and bone qualities, respectively. Upon sacrifice, the levels of melatonin were measured in each group. At 20th week, the occurrence of scoliosis was 80%, 30%, 22% and 5% in bipedal, quadrupedal, bipedal + melatonin and quadrupedal + melatonin group, respectively. The trabecular bone quality of the vertebral body was significantly ameliorated in the melatonin-treated bipedal models. Likewise, the number of osteoclasts was significantly less in those treated with melatonin. Our results indicated that melatonin deficiency may be crucial for scoliotic development, and restoration of melatonin levels can prevent scoliotic development with the improvement in bone density.

Melatonin attenuates caspase-dependent apoptosis in the thoracic aorta by regulating element balance and oxidative stress in pinealectomised rats.

The aim of this study was to explain the possible mechanisms by which melatonin deficiency results in cardiovascular injury and to investigate the effects of melatonin administration on important signalling pathways and element equilibrium in the thoracic aorta (TA). For this purpose, we analysed the cellular and molecular effects of melatonin deficiency or administration on oxidative stress, DNA damage, molecular chaperone response, and apoptosis induction in TA tissues of pinealectomised rats using ELISA, RAPD, qRT-PCR, and Western blot assays. The results showed that melatonin deficiency led to an imbalance in essential element levels, unfolded or misfolded proteins, increased lipid peroxidation, and selectively induced caspase-dependent apoptosis in TA tissues without significantly affecting the Bcl-2/BAX ratio (2.28 in pinealectomised rats, 2.73 in pinealectomised rats treated with melatonin). In pinealectomised rats, the genomic template stability (80.22%) was disrupted by the significantly increased oxidative stress, and heat shock protein 70 (20.96-fold), TNF-α (1.73-fold), caspase-8 (2.03-fold), and caspase-3 (2.87-fold) were markedly overexpressed compared with the sham group. Melatonin treatment was protective against apoptosis and inhibited oxidative damage. In addition, melatonin increased the survivin level and improved the regulation of element equilibrium in TA tissues. The results of the study indicate that melatonin deficiency induces TNF-α-related extrinsic apoptosis signals and that the administration of pharmacological doses of melatonin attenuates cardiovascular toxicity by regulating the increase in the rate of apoptosis caused by melatonin deficiency in TA tissue of Sprague-Dawley rats.

The case for a chronobiological approach to neonatal care.

Time of day is a critical factor for most biological functions, but concepts from the field of chronobiology have yet to be fully translated to clinical practice. Circadian rhythms, generated internally and synchronised to the external environment, promote function and support survival in almost every living species. Fetal circadian rhythms can be observed in utero from 30weeks gestation, coupled to the maternal rhythm, but synchronise to the external environment only after birth. Important cues for synchronisation include the light/dark cycle, the timing of feeding, and exposure to melatonin in breast milk. Disruption to these cues may occur during admission to the neonatal intensive care unit. This can impair the development of circadian rhythms, and influence survival and function in the neonatal period, with a potential to impact health and well-being throughout adult life. Here we outline the rationale and evidence to support a chronobiological approach to neonatal care.

Low serum melatonin levels are associated with erectile dysfunction

ABSTRACT Objective: Melatonin is a hormone secreted from the pineal gland and has anti-oxidative and anti-inflammatory effects. Oxidative stress is considered as an important factor in the etiology of erectile dysfunction (ED), and in many experimental models, positive results have been obtained with melatonin treatment. This study aimed to measure serum melatonin levels in ED patients and to investigate the possible relationship between ED and melatonin levels. Materials and Methods: Sixty-two patients diagnosed with mild, moderate or severe ED according to the five-item International Erectile Function Index (IIEF-5) and 22 healthy individuals were included in the study. The serum melatonin levels, anthropometric data, and other biochemical and hormonal parameters of all the subjects were recorded. Detailed anamnesis was also obtained in terms of diabetes, hypertension, cardiovascular diseases, smoking status, and alcohol use. Results: The serum melatonin level was found 34.2±13.3 ng/dL in the mild ED group, 33.3±14.7 ng/dL in the moderate ED group, 34.8±17.2 ng/dL in the severe ED group, and 44.6±16.5 ng/dL in the control group. The serum melatonin levels were significantly lower in all ED groups compared to the control group (p=0.019). There was no significant difference in the serum melatonin levels between the three ED groups. Diabetes, hypertension, cardiovascular diseases, smoking and alcohol use were not significantly different between the ED groups (p>0.05). Conclusion: We consider that if our findings are supported by further studies with larger populations, the measurement of the serum melatonin level may have a future role in the diagnosis and treatment of ED.

Low serum melatonin levels are associated with erectile dysfunction.

OBJECTIVE: Melatonin is a hormone secreted from the pineal gland and has anti-oxidative and anti-inflammatory effects. Oxidative stress is considered as an important factor in the etiology of erectile dysfunction (ED), and in many experimental models, positive results have been obtained with melatonin treatment. This study aimed to measure serum melatonin levels in ED patients and to investigate the possible relationship between ED and melatonin levels. MATERIALS AND METHODS: Sixty-two patients diagnosed with mild, moderate or severe ED according to the five-item International Erectile Function Index (IIEF-5) and 22 healthy individuals were included in the study. The serum melatonin levels, anthropometric data, and other biochemical and hormonal parameters of all the subjects were recorded. Detailed anamnesis was also obtained in terms of diabetes, hypertension, cardiovascular diseases, smoking status, and alcohol use. RESULTS: The serum melatonin level was found 34.2±13.3 ng/dL in the mild ED group, 33.3±14.7 ng/dL in the moderate ED group, 34.8±17.2 ng/dL in the severe ED group, and 44.6±16.5 ng/dL in the control group. The serum melatonin levels were significantly lower in all ED groups compared to the control group (p=0.019). There was no significant difference in the serum melatonin levels between the three ED groups. Diabetes, hypertension, cardiovascular diseases, smoking and alcohol use were not significantly different between the ED groups (p>0.05). CONCLUSION: We consider that if our findings are supported by further studies with larger populations, the measurement of the serum melatonin level may have a future role in the diagnosis and treatment of ED.

Endogenous melatonin promotes rhythmic recruitment of neutrophils toward an injury in zebrafish.

Neutrophil recruitment to injured tissue appears to be an evolutionarily conserved strategy for organisms to fight against exogenous insults. Recent studies have shown rhythmic migration of neutrophils and several factors, including melatonin, have been implicated in regulating this rhythmic migration. The mechanisms underlying how endogenous melatonin regulates rhythmic neutrophils migration, however, are unclear. Here we generated a zebrafish annat2 mutant that lacks endogenous melatonin and, subsequently, a Tg(lyz:EGFP);aanat2 -/- transgenic line that allows for monitoring neutrophils migration visually in live zebrafish. We observed that migrating neutrophils are significantly reduced in aanat2 -/- mutant zebrafish under a light/dark condition, and the disrupted migrating rhythmicity of neutrophils in aanat2 -/- zebrafish is independent of the circadian clock. Further, we also found that endogenous melatonin enhances neutrophils migration likely by inducing the expression of cytokines such as interleukin-8 and interleukin-1ß. Together, our findings provide evidence that endogenous melatonin promotes rhythmic migration of neutrophils through cytokines in zebrafish.

The Role of the Melatoninergic System in Light-Entrained Behavior of Mice.

The role of endogenous melatonin for the control of the circadian system under entrained conditions and for the determination of the chronotype is still poorly understood. Mice with deletions in the melatoninergic system (melatonin deficiency or the lack of melatonin receptors, respectively) do not display any obvious defects in either their spontaneous (circadian) or entrained (diurnal) rhythmic behavior. However, there are effects that can be detected by analyzing the periodicity of the locomotor behaviors in some detail. We found that melatonin-deficient mice (C57Bl), as well as melatonin-proficient C3H mice that lack the melatonin receptors (MT) 1 and 2 (C3H MT1,2 KO), reproduce their diurnal locomotor rhythms with significantly less accuracy than mice with an intact melatoninergic system. However, their respective chronotypes remained unaltered. These results show that one function of the endogenous melatoninergic system might be to stabilize internal rhythms under conditions of a steady entrainment, while it has no effects on the chronotype.