A Randomized, Double-Blind, Crossover Study to Investigate the Pharmacokinetics of Extended-Release Melatonin Compared to Immediate-Release Melatonin in Healthy Adults.

Exogenous melatonin can be helpful for treatment of some sleep disorders. However, immediate-release formulations are rapidly absorbed and cleared from the body making it difficult to provide coverage for an entire sleep period. Extended-release melatonin formulations can better mimic the naturally occurring melatonin profile and increase efficacy, but few studies have reported on their pharmacokinetics. To assess the pharmacokinetics of extended-release melatonin, we conducted a randomized, double-blind, crossover study of extended-release melatonin (4 mg) compared to immediate-release melatonin (4 mg) in 18 healthy adults, ages 18-65 years. Participants received immediate-release or extended-release melatonin in clinic after an 8 h fast, and blood samples were taken over a 10-h period. After a 7-day washout period, the same procedures were repeated with the melatonin form not previously received. Extended-release melatonin had a longer time to peak concentration (1.56 vs 0.6 h) and elimination half-life (1.63 vs 0.95 h) compared with immediate-release melatonin. Maximum concentration was lower for extended-release melatonin compared with immediate-release melatonin (7581 pg/mL vs 13120 pg/mL). Extended-release melatonin raised melatonin levels in as little as 15 min and sustained elevated melatonin levels (>300 pg/mL) for 6 h before falling below 50 pg/mL by 9 h. No clinically relevant adverse events were observed, and safety parameters remained within normal ranges for both formulations. The pharmacokinetic profile of this extended-release melatonin formulation suggests that it could be used for future efficacy studies of melatonin and sleep outcomes. This trial is registered at ClinicalTrials.gov, NCT04067791.

Application and Efficacy of Melatonin Elastic Liposomes in Photoaging Mice.

Transdermal drug delivery system is a preferable choice to overcome the low bioavailability of oral medication. Elastic liposomes have shown great effectiveness for percutaneous transport of melatonin (MLT). In this study, the elastic liposomes loaded with MLT were prepared using thin-film dispersion method and optimized through the central composite design (CCD) approach. The physicochemical properties and skin permeation against UV-induced skin photoaging efficacy of the developed MLT-ELs were assessed. The average size of the MLT-ELs was about 49 nm with a spherical shape and high encapsulation efficiency (73.91%) and drug loading (9.92%). The results of FTIR, DSC, and XRD revealed that the chemical structure of MLT was not changed after prepared elastic liposomes, and the drug was successfully encapsulated in the elastic liposome membrane material. In vitro skin permeation evaluation showed that the cumulative penetration of elastic liposomes was 1.5 times higher than that of conventional liposomes, highlighting that the elastic liposomes more easily penetrated into the body. The photoaging experiment results indicated that topical MLT-EL treatment ameliorated the skin elasticity, enhanced the skin hydration level, and preserved the integrity of dermal collagen and elastic fibers. It could be concluded that the elastic liposomes might serve as a promising platform for the transdermal delivery of melatonin.

Melatonin/Cyclodextrin Inclusion Complexes: A Review.

Melatonin (MLT) is involved in many functions of the human body, mainly in sleeping-related disorders. It also has anti-oxidant potential and has been proven very effective in the treatment of seasonal affective disorders (SAD), which afflict some people during short winter days. Melatonin has been implicated in a range of other conditions, including Parkinson's disease, Alzheimer's and other neurological conditions, and in certain cancers. Its poor solubility in water leads to an insufficient absorption that led scientists to investigate MLT inclusion in cyclodextrins (CDs), as inclusion of drugs in CDs is a way of increasing the solubility of many lipophilic moieties with poor water solubility. The aim of this review is to gather all the key findings on MLT/CD complexes. The literature appraisal concluded that MLT inclusion leads to a 1:1 complex with the majority of CDs and increases the solubility of the hormone. The interactions of MLT with CDs can be studied by a variety of techniques, such as NMR, FT-IR, XRD and DCS. More importantly, the in vivo experiments showed an increase in the uptake of MLT when included in a CD.

Melatonin Treatment Improves Renal Fibrosis via miR-4516/SIAH3/PINK1 Axis.

Dysregulation in mitophagy, in addition to contributing to imbalance in the mitochondrial dynamic, has been implicated in the development of renal fibrosis and progression of chronic kidney disease (CKD). However, the current understanding of the precise mechanisms behind the pathogenic loss of mitophagy remains unclear for developing cures for CKD. We found that miR-4516 is downregulated and its target SIAH3, an E3 ubiquitin protein ligase that reduces PINK1 accumulation to damaged mitochondria, is upregulated in the renal cortex of CKD mice. Here, we demonstrated that melatonin injection induces miR-4516 expression and suppresses SIAH3, and promotes PINK1/Parkin-mediated mitophagy. Furthermore, we demonstrated that melatonin injection attenuates the pathological features of CKD by improving mitochondrial homeostasis. Our data supports that mitochondrial autophagy regulation by activating miR-4516/SIAH3/PINK1 mitophagy signaling axis can be a viable new strategy for treating CKD.

Evaluation of Polymeric Matrix Loaded with Melatonin for Wound Dressing.

The development of scaffolds mimicking the extracellular matrix containing bioactive substances has great potential in tissue engineering and wound healing applications. This study investigates melatonin-a methoxyindole present in almost all biological systems. Melatonin is a bioregulator in terms of its potential clinical importance for future therapies of cutaneous diseases. Mammalian skin is not only a prominent melatonin target, but also produces and rapidly metabolizes the multifunctional methoxyindole to biologically active metabolites. In our methodology, chitosan/collagen (CTS/Coll)-contained biomaterials are blended with melatonin at different doses to fabricate biomimetic hybrid scaffolds. We use rat tail tendon- and Salmo salar fish skin-derived collagens to assess biophysical and cellular properties by (i) Fourier transform infrared spectroscopy-attenuated total reflectance (FTIR-ATR), (ii) thermogravimetric analysis (TG), (iii) scanning electron microscope (SEM), and (iv) proliferation ratio of cutaneous cells in vitro. Our results indicate that melatonin itself does not negatively affect biophysical properties of melatonin-immobilized hybrid scaffolds, but it induces a pronounced elevation of cell viability within human epidermal keratinocytes (NHEK), dermal fibroblasts (NHDF), and reference melanoma cells. These results demonstrate that this indoleamine accelerates re-epithelialization. This delivery is a promising technique for additional explorations in future dermatotherapy and protective skin medicine.

In vitro gastrointestinal digestion and simulated colonic fermentation of pistachio nuts determine the bioaccessibility and biosynthesis of chronobiotics.

Chronodisruption leads to obesity and other metabolic disorders that can be alleviated by food-derived potential chronobiotics, such as phytomelatonin (PMT), phenolic compounds (PCs) and dietary fiber rich pistachios. Pistachios with (PN + SC) or without (PN) the seed coat were investigated for their in vitro chronobiotic potential since they are one of the main reported PMT sources. Consequently we evaluated the bioaccessibility, permeability, and biosynthesis of pistachio chronobiotics, particularly PMT, during gastrointestinal and colonic fermentation. The maximum in vitro bioaccessibility and apparent permeability (efflux-prone) of PCs, flavonoids and PMT were sample-specific [∼1.3% (both), 27 and 3.4% (PN + SC)], but additional amounts (flavonoids > PCs > PMT) were released under simulated colonic conditions. Short-chain fatty acids (SCFAs; 38 mM; >50% butyrate, PN + SC > PN) and some metabolites (e.g., indole, benzaldehyde, phenolic acids, and aliphatic/aromatic hydrocarbons) were detected depending on the sample. The predominant pistachio butyrate production during in vitro colonic fermentation can improve chronodisruption and benefit obese individuals. Pistachio's digestion increases the bioaccessibility and intestinal permeability of potential chronobiotics (PMT and PCs) and the biosynthesis of colonic metabolites (SCFAs, among others) also with chronobiotic potential.

Melatonin: From Pharmacokinetics to Clinical Use in Autism Spectrum Disorder.

The role of melatonin has been extensively investigated in pathophysiological conditions, including autism spectrum disorder (ASD). Reduced melatonin secretion has been reported in ASD and led to many clinical trials using immediate-release and prolonged-release oral formulations of melatonin. However, melatonin's effects in ASD and the choice of formulation type require further study. Therapeutic benefits of melatonin on sleep disorders in ASD were observed, notably on sleep latency and sleep quality. Importantly, melatonin may also have a role in improving autistic behavioral impairments. The objective of this article is to review factors influencing treatment response and possible side effects following melatonin administration. It appears that the effects of exposure to exogenous melatonin are dependent on age, sex, route and time of administration, formulation type, dose, and association with several substances (such as tobacco or contraceptive pills). In addition, no major melatonin-related adverse effect was described in typical development and ASD. In conclusion, melatonin represents currently a well-validated and tolerated treatment for sleep disorders in children and adolescents with ASD. A more thorough consideration of factors influencing melatonin pharmacokinetics could illuminate the best use of melatonin in this population. Future studies are required in ASD to explore further dose-effect relationships of melatonin on sleep problems and autistic behavioral impairments.

Melatonin in Wine and Beer: Beneficial Effects.

Melatonin is a hormone secreted in the pineal gland with several functions, especially regulation of circadian sleep cycle and the biological processes related to it. This review evaluates the bioavailability of melatonin and resulting metabolites, the presence of melatonin in wine and beer and factors that influence it, and finally the different benefits related to treatment with melatonin. When administered orally, melatonin is mainly absorbed in the rectum and the ileum; it has a half-life of about 0.45-1 h and is extensively inactivated in the liver by phase 2 enzymes. Melatonin (MEL) concentration varies from picograms to ng/mL in fermented beverages such as wine and beer, depending on the fermentation process. These low quantities, within a dietary intake, are enough to reach significant plasma concentrations of melatonin, and are thus able to exert beneficial effects. Melatonin has demonstrated antioxidant, anticarcinogenic, immunomodulatory and neuroprotective actions. These benefits are related to its free radical scavenging properties as well and the direct interaction with melatonin receptors, which are involved in complex intracellular signaling pathways, including inhibition of angiogenesis and cell proliferation, among others. In the present review, the current evidence on the effects of melatonin on different pathophysiological conditions is also discussed.

Pharmacokinetics and Safety of Intravenous, Intravesical, Rectal, Transdermal, and Vaginal Melatonin in Healthy Female Volunteers: A Cross-Over Study.

INTRODUCTION: We aimed to investigate the pharmacokinetic properties and safety of melatonin administered by alternative routes of administration. METHODS: This study employed a cross-over design in healthy female volunteers. Twenty-five milligrams of melatonin was administered intravenously, intravesically, rectally, transdermally, and vaginally. Blood samples were collected at specified time points up to 24 h following intravenous, intravesical, rectal, and vaginal administration, and up to 48 h following transdermal administration. Plasma melatonin concentrations were determined by radioimmunoassay. Sedation was evaluated by a simple reaction-time test, and sleepiness was assessed by the Karolinska Sleepiness Scale. Adverse events were registered for each route of administration. RESULTS: Ten participants were included. We documented a mean (SD) time to maximal concentration of 51 (29) min for intravesical, 24 (20) min for rectal, 21 (8) h for transdermal, and 147 (56) min for vaginal administration. The mean (SD) elimination half-life was 47 (6) min for intravenous, 58 (7) min for intravesical, 60 (18) min for rectal, 14.6 (11.1) h for transdermal, and 129 (17) min for vaginal administration. The mean (SD) bioavailability was 3.6 (1.9)% for intravesical, 36.0 (28.6)% for rectal, 10.0 (5.7)% for transdermal, and 97.8 (31.7)% for vaginal administration. No significant changes in reaction times were observed following administration of melatonin by any of the administration routes. Increased tiredness was documented following transdermal administration only. No serious adverse effects were documented. CONCLUSION: Rectally and vaginally administered melatonin may serve as relevant alternatives to standard oral melatonin therapy. Transdermal delivery of melatonin displayed an extended absorption and can be applied if prolonged effects are intended. Intravesical administration displayed, as expected, a very limited bioavailability. Melatonin administered by these routes of administration was safe.

Melatonina, coronavirus, enfermedad cardiovascular y emergencia geriátrica: ¡usemos todo lo que tenemos! / Melatonin, coronavirus, cardiovascular disease, and the geriatric emergency: let's use everything we have!

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Melatonina, coronavirus, enfermedad cardiovascular y emergencia geriátrica: ¡usemos todo lo que tenemos! Respuesta / Melatonin, coronavirus, cardiovascular disease, and the geriatric emergency: let's use everything we have! Response

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In vitro and in vivo evaluation of organic solvent-free injectable melatonin nanoformulations.

Melatonin is a neurohormone with potenial therapeutic effects in many diseases including neonatal hypoxic-ischemic (HI) brain injury. Due to limited solubility in water there is currently no clinically available melatonin formulation for parenteral use. Clinical use of melatonin has thus relied on oral administration, which in many cases is hampered by low and variable bioavailability. In animal treatment studies of neonatal HI, this issue have been circumvented by using parenteral administration of melatonin dissolved in ethanol (EtOH) or dimethyl sulfoxide (DMSO), solvents that are potentially neurotoxic, especially to the newborn brain. Thus, there is an urgent need for a non-toxic injectable melatonin formulation. The aim of this study was to develop such a formulation comprised of melatonin and biocompatible lipid-based nanoparticles with improved melatonin bioavailability. We herein report the development and characterization of an injectable system composed of melatonin and liposomes (LP) or oil-in-water nanoemulsions (NE). Nanoparticle characterization confirmed physicochemical stability over a week and an improvement with respect to melatonin solubilization in water (2.6 mg/mL in our injectable system). Determination of the in vitro release kinetics showed a prolonged release when melatonin is solubilized in nanoparticles (T1/2: 81 min vs 50 min vs 26 min for melatonin-LP, melatonin-NE, and melatonin-EtOH respectively). The pharmacokinetic (PK) parameters were confirmed in vivo in adult rats as similar melatonin levels detected in blood and indicated higher bioavailability in brain after intravenous administration of melatonin nanoformulations (10 mg/kg) in comparison to the free-melatonin administration. In conclusion, we have developed an organic solvent-free injectable formulation for melatonin by utilizing FDA-approved components, as a safe alternative for facilitating the potential of melatonin against variety of pathological conditions.

High-Dose Melatonin and Ethanol Excipient Combined with Therapeutic Hypothermia in a Newborn Piglet Asphyxia Model.

With the current practice of therapeutic hypothermia for neonatal encephalopathy, disability rates and the severity spectrum of cerebral palsy are reduced. Nevertheless, safe and effective adjunct therapies are needed to optimize outcomes. This study's objective was to assess if 18 mg/kg melatonin given rapidly over 2 h at 1 h after hypoxia-ischemia with cooling from 1-13 h was safe, achieved therapeutic levels within 3 h and augmented hypothermic neuroprotection. Following hypoxia-ischemia, 20 newborn piglets were randomized to: (i) Cooling 1-13 h (HT; n = 6); (ii) HT+ 2.5% ethanol vehicle (HT+V; n = 7); (iii) HT + Melatonin (HT+M; n = 7). Intensive care was maintained for 48 h; aEEG was acquired throughout, brain MRS acquired at 24 and 48 h and cell death (TUNEL) evaluated at 48 h. There were no differences for insult severity. Core temperature was higher in HT group for first hour after HI. Comparing HT+M to HT, aEEG scores recovered more quickly by 19 h (p < 0.05); comparing HT+V to HT, aEEG recovered from 31 h (p < 0.05). Brain phosphocreatine/inorganic phosphate and NTP/exchangeable phosphate were higher at 48 h in HT+M versus HT (p = 0.036, p = 0.049 respectively). Including both 24 h and 48 h measurements, the rise in Lactate/N-acetyl aspartate was reduced in white (p = 0.030) and grey matter (p = 0.038) after HI. Reduced overall TUNEL positive cells were observed in HT+M (47.1 cells/mm2) compared to HT (123.8 cells/mm2) (p = 0.0003) and HT+V (97.5 cells/mm2) compared to HT (p = 0.012). Localized protection was seen in white matter for HT+M versus HT (p = 0.036) and internal capsule for HT+M compared to HT (p = 0.001) and HT+V versus HT (p = 0.006). Therapeutic melatonin levels (15-30mg/l) were achieved at 2 h and were neuroprotective following HI, but ethanol vehicle was partially protective.

Melatonin long-lasting beneficial effects on pulmonary vascular reactivity and redox balance in chronic hypoxic ovine neonates.

Pulmonary arterial hypertension of the neonate (PAHN) is a pathophysiological condition characterized by maladaptive pulmonary vascular remodeling and abnormal contractile reactivity. This is a multifactorial syndrome with chronic hypoxia and oxidative stress as main etiological drivers, and with limited effectiveness in therapeutic approaches. Melatonin is a neurohormone with antioxidant and vasodilator properties at the pulmonary level. Therefore, this study aims to test whether a postnatal treatment with melatonin during the neonatal period improves in a long-lasting manner the clinical condition of PAHN. Ten newborn lambs gestated and born at 3600 m were used in this study, five received vehicle and five received melatonin in daily doses of 1 mg kg-1 for the first 3 weeks of life. After 1 week of treatment completion, lung tissue and small pulmonary arteries (SPA) were collected for wire myography, molecular biology, and morphostructural analyses. Melatonin decreased pulmonary arterial pressure the first 4 days of treatment. At 1 month old, melatonin decreased the contractile response to the vasoconstrictors K+ , TX2 , and ET-1. Further, melatonin increased the endothelium-dependent and muscle-dependent vasodilation of SPA. Finally, the treatment decreased pulmonary oxidative stress by inducing antioxidant enzymes and diminishing pro-oxidant sources. In conclusion, melatonin improved vascular reactivity and oxidative stress at the pulmonary level in PAHN lambs gestated and born in chronic hypoxia.

A Randomized, Crossover, Pharmacokinetics Evaluation of a Novel Continuous Release and Absorption Melatonin Formulation.

OBJECTIVE: To evaluate the pharmacokinetic and safety profile of a novel continuous release and absorption melatonin (CRA-melatonin) compared with an immediate-release melatonin (IR-melatonin) product. METHODS: The REM Absorption Kinetics Trial (REMAKT), an open-label, single-center, randomized, single-dose, 2-way crossover trial, compared the pharmacokinetic and safety profile of CRA-melatonin (5 mg) with IR-melatonin (5 mg) in healthy adult volunteers. The study was conducted from March 18, 2016, to April 20, 2016. RESULTS: Ten subjects completed REMAKT. Plasma melatonin levels exceeded the targeted maintenance threshold level of 1,000 pg/mL for a median of 6.7 hours for CRA-melatonin compared with 3.7 hours for IR-melatonin. The median Cmax was 4,690 pg/mL for CRA-melatonin and 23,352 pg/mL for IR-melatonin. In REMAKT, there were no treatment-emergent adverse events reported in the CRA-melatonin arm. Five treatment-emergent adverse events occurred with IR-melatonin. CONCLUSIONS: The novel, well-tolerated CRA-melatonin was shown to achieve quick release and then continuous release and absorption of melatonin for up to 7 hours, making it a significant advancement in the pharmacokinetic release profile of exogenous melatonin delivery and, therefore, an important potential consideration as a baseline therapy for sleep.

Increased Nose-to-Brain Delivery of Melatonin Mediated by Polycaprolactone Nanoparticles for the Treatment of Glioblastoma.

PURPOSE: Intranasal administration has been extensively applied to deliver drugs to the brain. In spite of its unfavorable biopharmaceutic properties, melatonin (MLT) has demonstrated anticancer effects against glioblastoma. This study describes the nose-to-brain delivery of MLT-loaded polycaprolactone nanoparticles (MLT-NP) for the treatment of glioblastoma. METHODS: MLT-NP were prepared by nanoprecipitation. Following intranasal administration in rats, brain targeting of the formulation was demonstrated by fluorescence tomography. Brain and plasma pharmacokinetic profiles were analyzed. Cytotoxicity against U87MG glioblastoma cells and MRC-5 non-tumor cells was evaluated. RESULTS: MLT-NP increased the drug apparent water solubility ~35 fold. The formulation demonstrated strong activity against U87MG cells, resulting in IC50 ~2500 fold lower than that of the free drug. No cytotoxic effect was observed against non-tumor cells. Fluorescence tomography images evidenced the direct translocation of nanoparticles from nasal cavity to the brain. Intranasal administration of MLT-NP resulted in higher AUCbrain and drug targeting index compared to the free drug by either intranasal or oral route. CONCLUSIONS: Nanoencapsulation of MLT was crucial for the selective antitumoral activity against U87MG. In vivo evaluation confirmed nose-to-brain delivery of MLT mediated by nanoparticles, highlighting the formulation as a suitable approach to improve glioblastoma therapy.

Melatonin in Medicinal and Food Plants: Occurrence, Bioavailability, and Health Potential for Humans.

Melatonin is a widespread molecule among living organisms involved in multiple biological, hormonal, and physiological processes at cellular, tissue, and organic levels. It is well-known for its ability to cross the blood-brain barrier, and renowned antioxidant effects, acting as a free radical scavenger, up-regulating antioxidant enzymes, reducing mitochondrial electron leakage, and interfering with proinflammatory signaling pathways. Detected in various medicinal and food plants, its concentration is widely variable. Plant generative organs (e.g., flowers, fruits), and especially seeds, have been proposed as having the highest melatonin concentrations, markedly higher than those found in vertebrate tissues. In addition, seeds are also rich in other substances (lipids, sugars, and proteins), constituting the energetic reserve for a potentially growing seedling and beneficial for the human diet. Thus, given that dietary melatonin is absorbed in the gastrointestinal tract and transported into the bloodstream, the ingestion of medicinal and plant foods by mammals as a source of melatonin may be conceived as a key step in serum melatonin modulation and, consequently, health promotion.

Pharmacological, Mechanistic, and Pharmacokinetic Assessment of Novel Melatonin-Tamoxifen Drug Conjugates as Breast Cancer Drugs.

Tamoxifen is used to prevent and treat estrogen receptor-positive (ER+) breast cancer (BC); however, its chronic use can increase uterine cancer risk and induce tamoxifen resistance. Novel melatonin-tamoxifen drug conjugates may be promising to treat BC and may help offset the adverse effects of tamoxifen usage alone due to the presence of melatonin. We synthesized and screened five drug conjugates (C2, C4, C5, C9, and C15 linked) for their effects on BC cell (MCF-7, tamoxifen-resistant MCF-7, mouse mammary carcinoma, MDA-MB-231, and BT-549) viability, migration, and binding affinity to melatonin receptor 1 (MT1R) and estrogen receptor 1 (ESR1). C4 and C5 demonstrated the most favorable pharmacological characteristics with respect to binding profiles (affinity for ESR1 and MT1R) and their potency/efficacy to inhibit BC cell viability and migration in four phenotypically diverse invasive ductal BC cell lines. C4 and C5 were further assessed for their actions against tamoxifen-resistant MCF-7 cells and a patient-derived xenograft triple-negative BC cell line (TU-BcX-4IC) and for their mechanisms of action using selective mitogen-activated protein kinase kinase MEK1/2, MEK5, and phosphoinositide 3-kinase (PI3K) inhibitors. C4 and C5 inhibited tamoxifen-resistant MCF-7 cells with equal potency (IC50 = 4-8 µM) and efficacy (∼90% inhibition of viability and migration) but demonstrated increased potency (IC50 = 80-211 µM) and efficacy (∼140% inhibition) to inhibit migration versus cell viability (IC50 = 181-304 mM; efficacy ∼80% inhibition) in TU-BcX-4IC cells. Unique pharmacokinetic profiles were observed, with C4 having greater bioavailability than C5. Further assessment of C4 and C5 demonstrates that they create novel pharmacophores within each BC cell that is context specific and involves MEK1/2/pERK1/2, MEK5/pERK5, PI3K, and nuclear factor κB. These melatonin-tamoxifen drug conjugates show promise as novel anticancer drugs and further preclinical and clinical evaluation is warranted.

Melatonin and Multiple Sclerosis: From Plausible Neuropharmacological Mechanisms of Action to Experimental and Clinical Evidence.

Multiple sclerosis (MS) is a devastating chronic autoimmune demyelinating disease of the central nervous system (CNS), thought to affect more than 2.5 million people worldwide. Regulation of the sleep-wake cycle might influence disease activity and the frequency of relapses in patients. As melatonin (or sleep hormone) involves the regulation of circadian rhythms, much attention has been paid to the management of MS symptoms with melatonin. This review describes the pharmacological mechanisms underlying the neuroprotective effects of melatonin and recent clinical evidence from MS patients. Apparent risks and benefits of melatonin therapies are also discussed. Various in vivo and clinical data presented in this up-to-date review suggest that melatonin may possibly possess a protective role against the behavioral deficits and neuropathological characteristics of MS. Multiple mechanisms of the neuroprotective effects of melatonin such as mitochondrial protection and antioxidant, anti-inflammatory, and anti-apoptotic properties, as well as its anti-demyelinating function are also discussed. A large body of evidence shows that melatonin potently regulates the immune system, demyelination, free radical generation, and inflammatory responses in neural tissue, which are mediated by multiple signal transduction cascades. In the present article, we focus on different pathways that are targeted by melatonin to prevent the development and progression of MS.

Melatonin as a master regulator of cell death and inflammation: molecular mechanisms and clinical implications for newborn care.

Melatonin, more commonly known as the sleep hormone, is mainly secreted by the pineal gland in dark conditions and regulates the circadian rhythm of the organism. Its intrinsic properties, including high cell permeability, the ability to easily cross both the blood-brain and placenta barriers, and its role as an endogenous reservoir of free radical scavengers (with indirect extra activities), confer it beneficial uses as an adjuvant in the biomedical field. Melatonin can exert its effects by acting through specific cellular receptors on the plasma membrane, similar to other hormones, or through receptor-independent mechanisms that involve complex molecular cross talk with other players. There is increasing evidence regarding the extraordinary beneficial effects of melatonin, also via exogenous administration. Here, we summarize molecular pathways in which melatonin is considered a master regulator, with attention to cell death and inflammation mechanisms from basic, translational and clinical points of view in the context of newborn care.