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Daniel P. Cardinali - One of the best experts on this subject based on the ideXlab platform.

  • melatonin as a Chronobiotic and cytoprotective agent in parkinson s disease
    Frontiers in Pharmacology, 2021
    Co-Authors: Santiago Perezlloret, Daniel P. Cardinali
    Abstract:

    This review article discusses the special role that melatonin, an unusual phylogenetically conserved molecule present in all aerobic organisms, may have in prevention and treatment of Parkinson´s disease (PD). In human parkinsonism circulating melatonin levels are consistently disrupted and the potential therapeutic value of melatonin on sleep disorder in PD was suggested by a limited number of clinical trials, usually employing melatonin in the 2-5 mg/day range. Patients with PD showed decreased melatonin MT1 and MT2 receptor density in amygdala and substantia nigra, supporting the view that a disrupted melatonergic system could be involved in the altered sleep/wake cycle seen in PD. Approximately 3/4 of the dopaminergic cells in the substantia nigra pars compacta need to be lost to uncover motor symptomatology in PD. However, non-motor symptoms like hyposmia, depression or REM sleep behavior disorder (RBD) (characterized by the occurrence of vivid, intense and violent movements during REM sleep) precede the onset of PD for years and are index of worse prognosis Indeed, most of patients showing RBD (particularly men >50 years of age) will convert to an α-synucleinopathy within the 10 years of RBD. Daily administration of 3-12 mg of melatonin at bedtime is effective in the treatment of RBD and may halt neurodegeneration to PD. In animal model studies of PD melatonin was effective to curtail symptomatology. Allometric conversion of animal doses to projected cytoprotective melatonin doses for humans indicates a range in the 40-100 mg/day rarely employed clinically. Therefore, double-blind, placebo-controlled studies are urgently needed in this respect.

  • melatonin as a Chronobiotic cytoprotector its role in healthy aging
    Biological Rhythm Research, 2019
    Co-Authors: Daniel P. Cardinali
    Abstract:

    ABSTRACTPreservation of sleep, a proper nutrition and adequate physical exercise are key elements for healthy aging. Aging causes sleep alterations, and in turn, sleep disturbances lead to numerous...

  • The polycystic ovary syndrome and the metabolic syndrome : a possible Chronobiotic-cytoprotective adjuvant therapy
    International journal of endocrinology, 2018
    Co-Authors: Eduardo Spinedi, Daniel P. Cardinali
    Abstract:

    Polycystic ovary syndrome is a highly frequent reproductive-endocrine disorder affecting up to 8–10% of women worldwide at reproductive age. Although its etiology is not fully understood, evidence suggests that insulin resistance, with or without compensatory hyperinsulinemia, and hyperandrogenism are very common features of the polycystic ovary syndrome phenotype. Dysfunctional white adipose tissue has been identified as a major contributing factor for insulin resistance in polycystic ovary syndrome. Environmental (e.g., chronodisruption) and genetic/epigenetic factors may also play relevant roles in syndrome development. Overweight and/or obesity are very common in women with polycystic ovary syndrome, thus suggesting that some polycystic ovary syndrome and metabolic syndrome female phenotypes share common characteristics. Sleep disturbances have been reported to double in women with PCOS and obstructive sleep apnea is a common feature in polycystic ovary syndrome patients. Maturation of the luteinizing hormone-releasing hormone secretion pattern in girls in puberty is closely related to changes in the sleep-wake cycle and could have relevance in the pathogenesis of polycystic ovary syndrome. This review article focuses on two main issues in the polycystic ovary syndrome-metabolic syndrome phenotype development: (a) the impact of androgen excess on white adipose tissue function and (b) the possible efficacy of adjuvant melatonin therapy to improve the chronobiologic profile in polycystic ovary syndrome-metabolic syndrome individuals. Genetic variants in melatonin receptor have been linked to increased risk of developing polycystic ovary syndrome, to impairments in insulin secretion, and to increased fasting glucose levels. Melatonin therapy may protect against several metabolic syndrome comorbidities in polycystic ovary syndrome and could be applied from the initial phases of patients’ treatment.

  • alteration of biological rhythms in diseases of the central dopaminergic system focus on parkinson s disease
    2016
    Co-Authors: Santiago Perezlloret, Dario Acunacastroviejo, Victor Demariapesce, Daniel P. Cardinali
    Abstract:

    Parkinson’s Disease (PD) is characterized by profound alterations of the circadian timing system, as evidenced by studies in animals and patients. Alterations in activity, temperature and heart rate rhythms have been observed in several animal models of PD. Deposition of alpha-synuclein in the hypothalamic suprachiasmatic nuclei (SCN) (i.e, the site of central oscillator) has been detected in transgenic mice and altered rhythms in clock genes have been reported in both the striatum and the SCN. Furthermore, enucleation of the lateral hypothalamus, leading to “functional blindness” aggravated parkinsonian symptoms in one PD animal model. Disturbances in biological rhythms have also been observed in PD patients. Of note, polymorphisms of the ARNTL and PER1 clock genes were more frequent in PD patients compared to controls. Together with the extensive cross-talk between the basal ganglia and SCN, these pieces of evidence suggest that disturbances in the circadian timing system might be part of the core features of PD and not just a “collateral damage”. According to this view, a disturbed clockwork might actively contribute to neurodegeneration and a chronotherapeutic approach to PD might be considered. Melatonin, as a prototype Chronobiotic agent, has been shown to have some efficacy for sleep disorder treatment in PD and exhibit neuroprotection in animal models of PD. Bright light has also been effective for depression and insomnia in PD patients. Novel chronobiological therapies might have a great impact on the clinical management of PD.

  • melatonin as a Chronobiotic that opens the gates of sleep the 1990s
    2016
    Co-Authors: Daniel P. Cardinali
    Abstract:

    Chronopharmacology takes into account variations in drug effects depending on the time of administration as well as the effects of drugs on circadian mechanisms. Among the latter, melatonin is the prototypical Chronobiotic drug; it is able to affect the main components (period, amplitude, phase) of circadian rhythmicity, which are disrupted in acute and chronic diseases. The introduction of melatonin as an over-the-counter medication in Argentina (1995) allowed the author to examine clinical applications of the drug. As a direct outcome of the basic studies on the gamma-aminobutyric acid (GABA) mediation of melatonin’s effect, it was shown that melatonin given to individuals on benzodiazepine treatment was able to reduce or suppress its use. Recent pharmacoepidemiologic studies give support to such a use. Melatonin was also effective in fibromyalgia, a disabling disease that affects 2–5 % of the population, mostly young and middle-aged women, as well as in related clinical syndromes, including migraine and irritable bowel syndrome, with a similar pathophysiologic process of central pain processing. Another significant area of importance is the use of melatonin to treat sleep disorders in childhood. Often hypnotic medications cause paradoxical effects on children, and this is a major reason for the popularity of melatonin as a treatment for sleep disorders in childhood, as recognized by several consensus statements. A last Chronobiotic effect of melatonin discussed is its application in jet lag; it is a recognized agent that can be used to resynchronize circadian rhythms to new time zones.

Cardinali, Daniel Pedro - One of the best experts on this subject based on the ideXlab platform.

  • The polycystic ovary syndrome and the metabolic syndrome: a possible Chronobiotic-cytoprotective adjuvant therapy
    2020
    Co-Authors: Spinedi, Eduardo Julio, Cardinali, Daniel Pedro
    Abstract:

    Polycystic ovary syndrome is a highly frequent reproductive-endocrine disorder affecting up to 8?10% of women worldwide atreproductive age. Although its etiology is not fully understood, evidence suggests that insulin resistance, with or withoutcompensatory hyperinsulinemia, and hyperandrogenism are very common features of the polycystic ovary syndrome phenotype.Dysfunctional white adipose tissue has been identified as a major contributing factor for insulin resistance in polycystic ovarysyndrome. Environmental (e.g., chronodisruption) and genetic/epigenetic factors may also play relevant roles in syndromedevelopment. Overweight and/or obesity are very common in women with polycystic ovary syndrome, thus suggesting thatsome polycystic ovary syndrome and metabolic syndrome female phenotypes share common characteristics. Sleep disturbanceshave been reported to double in women with PCOS and obstructive sleep apnea is a common feature in polycystic ovarysyndrome patients. Maturation of the luteinizing hormone-releasing hormone secretion pattern in girls in puberty is closelyrelated to changes in the sleep-wake cycle and could have relevance in the pathogenesis of polycystic ovary syndrome. Thisreview article focuses on two main issues in the polycystic ovary syndrome-metabolic syndrome phenotype development: (a) theimpact of androgen excess on white adipose tissue function and (b) the possible efficacy of adjuvant melatonin therapy toimprove the chronobiologic profile in polycystic ovary syndrome-metabolic syndrome individuals. Genetic variants in melatoninreceptor have been linked to increased risk of developing polycystic ovary syndrome, to impairments in insulin secretion, and toincreased fasting glucose levels. Melatonin therapy may protect against several metabolic syndrome comorbidities in polycysticovary syndrome and could be applied from the initial phases of patients? treatment.Centro de Endocrinología Experimental y Aplicad

  • Melatonin as a Chronobiotic/cytoprotector : its role in healthy aging
    'Informa UK Limited', 2019
    Co-Authors: Cardinali, Daniel Pedro
    Abstract:

    Abstract: Preservation of sleep, a proper nutrition and adequate physical exercise are key elements for healthy aging. Aging causes sleep alterations, and in turn, sleep disturbances lead to numerous pathophysiological changes that accelerates the aging process. In the central nervous system, sleep loss impairs the clearance of waste molecules like amyloid-β or tau peptides. Melatonin, a molecule of unusual phylogenetic conservation present in all known aerobic organisms, is effective both as a Chronobiotic and a cytoprotective agent to maintain a healthy aging. The late afternoon increase of melatonin “opens the sleep doors” every night and its therapeutic use to preserve slow wave sleep has been demonstrated. Melatonin reverses inflammaging via prevention of insulin resistance, suppression of inflammation and down regulation of proinflammatory cytokines. Melatonin increases the expression of α- and γ-secretase and decreases β-secretase expression. It also inhibits tau phosphorylation. Clinical data support the efficacy of melatonin to treat Alzheimer’s disease, particularly at the early stages of disease. From animal studies the cytoprotective effects of melatonin need high doses to become apparent (i.e. in the 40–100 mg/day range). The potentiality of melatonin as a nutraceutical is discussed

  • Melatonin : clinical perspectives in neurodegeneration
    'Frontiers Media SA', 2019
    Co-Authors: Cardinali, Daniel Pedro
    Abstract:

    Abstract: Prevention of neurodegenerative diseases is presently a major goal for our Society and melatonin, an unusual phylogenetically conserved molecule present in all aerobic organisms, merits consideration in this respect. Melatonin combines both Chronobiotic and cytoprotective properties. As a Chronobiotic, melatonin can modify phase and amplitude of biological rhythms. As a cytoprotective molecule, melatonin reverses the low degree inflammatory damage seen in neurodegenerative disorders and aging. Low levels of melatonin in blood characterizes advancing age. In experimental models of Alzheimer's disease (AD) and Parkinson's disease (PD) the neurodegeneration observed is prevented by melatonin. Melatonin also increased removal of toxic proteins by the brain glymphatic system. A limited number of clinical trials endorse melatonin's potentiality in AD and PD, particularly at an early stage of disease. Calculations derived from animal studies indicate cytoprotective melatonin doses in the 40-100 mg/day range. Hence, controlled studies employing melatonin doses in this range are urgently needed. The off-label use of melatonin is discussed

  • Are melatonin doses employed clinically adequate for melatonin-induced cytoprotection?
    'ST Bio-life', 2019
    Co-Authors: Cardinali, Daniel Pedro
    Abstract:

    Abstract: This review article discusses the special role that melatonin, a molecule with Chronobiotic/cytoprotective properties, may have in prevention and treatment of the metabolic syndrome (MS), ischemic and non-ischemic cardiovascular diseases and Alzheimer ́s disease (AD). Prevention of these diseases is a major goal for governmental and non-governmental organizations, and melatonin, an unusual phylogenetically conserved molecule present in all aerobic organisms, merits consideration in this respect. In humans, circulating melatonin levels are consistently reduced in MS, ischemic and non-ischemic cardiovascular diseases and AD, the potential therapeutic value of melatonin being suggested by a limited number of clinical trials generally employing melatonin in the 2-5 mg/day range. In animal model studies of MS, ischemic and non-ischemic cardiovascular diseases and AD melatonin was very effective to curtail symptomatology. However, calculations derived from animal studies indicate projected cytoprotective melatonin doses for humans in the 40-100 mg/day range, doses that are rarely employed clinically. Hence, controlled studies employing melatonin doses in this range are urgently needed. Since the pharmaceutical industry is refractive to support them because of the lack of protective patents for a natural compound, only the involvement of governmental and non-profit organizations can achieve that goal. Within this prospect, the off-label use of melatonin is discussed

  • Melatonin, mitochondria, and the metabolic syndrome
    'Springer Science and Business Media LLC', 2017
    Co-Authors: Cardinali, Daniel Pedro, Vigo, Daniel Eduardo
    Abstract:

    Abstract: A number of risk factors for cardiovascular disease including hyperinsulinemia, glucose intolerance, dyslipidemia, obesity, and elevated blood pressure are collectively known as metabolic syndrome (MS). Since mitochondrial activity is modulated by the availability of energy in cells, the disruption of key regulators of metabolism in MS not only affects the activity of mitochondria but also their dynamics and turnover. Therefore, a link of MS with mitochondrial dysfunction has been suspected since long. As a Chronobiotic/cytoprotective agent, melatonin has a special place in prevention and treatment of MS. Melatonin levels are reduced in diseases associated with insulin resistance like MS. Melatonin improves sleep efficiency and has antioxidant and anti-inflammatory properties, partly for its role as a metabolic regulator and mitochondrial protector. We discuss in the present review the several cytoprotective melatonin actions that attenuate inflammatory responses in MS. The clinical data that support the potential therapeutical value of melatonin in human MS are reviewed

Russel J Reiter - One of the best experts on this subject based on the ideXlab platform.

  • inter relationships of the Chronobiotic melatonin with leptin and adiponectin implications for obesity
    Journal of Pineal Research, 2015
    Co-Authors: Karolina Szewczykgolec, Alina Woźniak, Russel J Reiter
    Abstract:

    Obesity and its medical complications represent a significant problem throughout the world. In recent decades, mechanisms underlying the progression of obesity have been intensively examined. The involvement of both the behavioral aspects, such as calorie-rich diet, low physical activity and sleep deprivation, and the intrinsic factors, including adipose tissue deregulation, chronic inflammation, oxidative stress, and chronodisruption, has been identified. The circadian disturbances of the adipose tissue endocrine function have been correlated with obesity. Leptin and adiponectin are adipokines strongly associated with glucose and lipid metabolism and with energy balance. Their synthesis and secretion display circadian rhythms that are disturbed in the obese state. Hyperleptinemia resulting in leptin resistance, and hypo-adiponectinemia have been linked to the pathophysiology of the obesity-related disorders. A deficiency of melatonin, one of the consequences of sleep deprivation, has also been demonstrated to correlate with obesity. Melatonin is a pineal secretory product involved in numerous actions, such as regulation of internal biological clocks and energy metabolism, and it functions as an antioxidant and as an anti-inflammatory agent. There exists a substantial amount of evidence supporting the beneficial effects of melatonin supplementation on obesity and its complications. In the current review, the results of studies related to the interactions between melatonin, and both leptin and adiponectin are discussed. Despite the existence of some inconsistencies, melatonin has been found to normalize the expression and secretion patterns of both adipokines. These results support the concept of melatonin as a potential therapeutic agent for obesity and related disorders.

  • melatonin energy metabolism and obesity a review
    Journal of Pineal Research, 2014
    Co-Authors: Jose Cipollaneto, Fernanda Gaspar Do Amaral, S C Afeche, D X Tan, Russel J Reiter
    Abstract:

    Melatonin is an old and ubiquitous molecule in nature showing multiple mechanisms of action and functions in practically every living organism. In mammals, pineal melatonin functions as a hormone and a Chronobiotic, playing a major role in the regulation of the circadian temporal internal order. The anti-obesogen and the weight-reducing effects of melatonin depend on several mechanisms and actions. Experimental evidence demonstrates that melatonin is necessary for the proper synthesis, secretion, and action of insulin. Melatonin acts by regulating GLUT4 expression and/or triggering, via its G-protein-coupled membrane receptors, the phosphorylation of the insulin receptor and its intracellular substrates mobilizing the insulin-signaling pathway. Melatonin is a powerful Chronobiotic being responsible, in part, by the daily distribution of metabolic processes so that the activity/feeding phase of the day is associated with high insulin sensitivity, and the rest/fasting is synchronized to the insulin-resistant metabolic phase of the day. Furthermore, melatonin is responsible for the establishment of an adequate energy balance mainly by regulating energy flow to and from the stores and directly regulating the energy expenditure through the activation of brown adipose tissue and participating in the browning process of white adipose tissue. The reduction in melatonin production, as during aging, shift-work or illuminated environments during the night, induces insulin resistance, glucose intolerance, sleep disturbance, and metabolic circadian disorganization characterizing a state of chronodisruption leading to obesity. The available evidence supports the suggestion that melatonin replacement therapy might contribute to restore a more healthy state of the organism.

  • circadian system functionality hippocampal oxidative stress and spatial memory in the appswe ps1de9 transgenic model of alzheimer disease effects of melatonin or ramelteon
    Chronobiology International, 2012
    Co-Authors: Beatriz Bano Otalora, Russel J Reiter, Natalija Topic Popovic, Juan Gambini, Miroljub Popovic, Jose Vina, Vicent Bonetcosta, Pedro J Camello, Maria Angeles Rol, J A Madrid
    Abstract:

    Alzheimer disease (AD) is a neurodegenerative disorder that primarily causes β-amyloid accumulation in the brain, resulting in cognitive and behavioral deficits. AD patients, however, also suffer from severe circadian rhythm disruptions, and the underlying causes are still not fully known. Patients with AD show reduced systemic melatonin levels. This may contribute to their symptoms, since melatonin is an effective Chronobiotic and antioxidant with neuroprotective properties. Here, the authors critically assessed the effects of long-term melatonin treatment on circadian system function, hippocampal oxidative stress, and spatial memory performance in the APPswe/PS1 double transgenic (Tg) mouse model of AD. To test if melatonin MT1/MT2 receptor activation, alone, was involved, the authors chronically treated some mice with the selective MT1/MT2 receptor agonist ramelteon. The results indicate that many of the circadian and behavioral parameters measured, including oxidative stress markers, were not signific...

  • melatonin and circadian biology in human cardiovascular disease
    Journal of Pineal Research, 2010
    Co-Authors: Alberto Dominguezrodriguez, Pedro Abreugonzalez, Juan J Sanchezsanchez, Juan Carlos Kaski, Russel J Reiter
    Abstract:

    Diurnal rhythms influence cardiovascular physiology, i.e. heart rate and blood pressure, and they appear to also modulate the incidence of serious adverse cardiac events. Diurnal variations occur also at the molecular level including changes in gene expression in the heart and blood vessels. Moreover, the risk/benefit ratio of some therapeutic strategies and the concentration of circulating cardiovascular system biomarkers may also vary across the 24-hr light/dark cycle. Synchrony between external and internal diurnal rhythms and harmony among molecular rhythms within the cell are essential for normal organ biology. Diurnal variations in the responsiveness of the cardiovascular system to environmental stimuli are mediated by a complex interplay between extracellular (i.e. neurohumoral factors) and intracellular (i.e. specific genes that are differentially light/dark regulated) mechanisms. Neurohormones, which are particularly relevant to the cardiovascular system, such as melatonin, exhibit a diurnal variation and may play a role in the synchronization of molecular circadian clocks in the peripheral tissue and the suprachiasmatic nucleus. Moreover, mounting evidence reveals that the blood melatonin rhythm has a crucial role in several cardiovascular functions, including daily variations in blood pressure. Melatonin has antioxidant, anti-inflammatory, Chronobiotic and, possibly, epigenetic regulatory functions. This article reviews current knowledge related to the biological role of melatonin and its circadian rhythm in cardiovascular disease.

  • the potential of melatonin in reducing morbidity mortality after craniocerebral trauma
    Journal of Pineal Research, 2007
    Co-Authors: M D Maldonado, D X Tan, Francisco Murillocabezas, M P Terron, Luis J Flores, Lucien C Manchester, Russel J Reiter
    Abstract:

    Craniocerebral trauma (CCT) is the most frequent cause of morbidity-mortality as a result of an accident. The probable origins and etiologies are multifactorial and include free radical formation and oxidative stress, the suppression of nonspecific resistance, lymphocytopenia (disorder in the adhesion and activation of cells), opportunistic infections, regional macro and microcirculatory alterations, disruptive sleep-wake cycles and toxicity caused by therapeutic agents. These pathogenic factors contribute to the unfavorable development of clinical symptoms as the disease progresses. Melatonin (N-acetyl-5-methoxytryptamine) is an indoleamine endogenously produced in the pineal gland and in other organs and it is protective agent against damage following CCT. Some of the actions of melatonin that support its pharmacological use after CCT include its role as a scavenger of both oxygen and nitrogen-based reactants, stimulation of the activities of a variety of antioxidative enzymes (e.g. superoxide dismutase, glutathione peroxidase, glutathione reductase and catalase), inhibition of pro-inflammatory cytokines and activation-adhesion molecules which consequently reduces lymphocytopenia and infections by opportunistic organisms. The Chronobiotic capacity of melatonin may also reset the natural circadian rhythm of sleep and wakefulness. Melatonin reduces the toxicity of the drugs used in the treatment of CCT and increases their efficacy. Finally, melatonin crosses the blood-brain barrier and reduces contusion volume and stabilizes cellular membranes preventing vasospasm and apoptosis of endothelial cells that occurs as a result of CCT.

Frederik Bes - One of the best experts on this subject based on the ideXlab platform.

  • treatment of isolated rem sleep behavior disorder using melatonin as a Chronobiotic
    Journal of Pineal Research, 2021
    Co-Authors: Dieter Kunz, Sophia Stotz, Frederik Bes
    Abstract:

    Melatonin is recommended as a first-line treatment in isolated REM sleep behavior disorder (iRBD), although no large patient group has been reported. To assess effects, time course and confounding factors in the treatment of patients with iRBD using melatonin, 209 consecutive patients were included in this single-center, observational cohort study. A total of 171 patients had taken melatonin according to our Chronobiotic protocol (2 mg, ≥6 months, always-at-the-same-clock time, 10-11pm, corrected for chronotype), 13 had applied melatonin for about 1-3 months, and 25 underwent mixed treatments. In total, 1529 clinical evaluations were performed, including Clinical Global Impression (CGI) and a newly developed RBD symptom severity scale (Ikelos-RS), analyzed using linear mixed models. Validation of Ikelos-RS showed excellent inter-rater reliability (ρ = 0.9, P < .001), test-retest reliability (ρ = 0.9, P < .001) and convergent validity (ρ = 0.9, P < .001). With melatonin, RBD symptom severity gradually improved over the first 4 weeks of treatment (Ikelos-RS: 6.1 vs. 2.5; CGI Severity: 5.7 vs. 3.2) and remained stably improved (mean follow-up 4.2 ± 3.1years; range: 0.6-21.7years). Initial response was slowed to up to 3 months with melatonin-suppressing (betablockers) or REM sleep spoiling co-medication (antidepressants) and failed with inadequately timed melatonin intake. When melatonin was discontinued after 6 months, symptoms remained stably improved (mean follow-up after discontinuation of 4.9 ± 2.5years; range: 0.6-9.2). When administered only 1-3 months, RBD symptoms gradually returned. Without any melatonin, RBD symptoms persisted and did not wear off over time. Clock-timed, low-dose, long-term melatonin treatment in patients with iRBD appears to be associated with the improvement of symptoms. The outlasting improvement over years questions a pure symptomatic effect. Clock-time dependency challenges existing prescription guidelines for melatonin.

  • conversion to parkinsonism and dementia in rem sleep behavior disorder using the Chronobiotic melatonin
    medRxiv, 2020
    Co-Authors: Dieter Kunz, Sophia Stotz, Frederik Bes
    Abstract:

    ABSTRACT Background Isolated REM sleep behavior disorder (iRBD), a reliable prodromal stage marker of α-synucleinopathies like Parkinson’s disease or Lewy body dementia, offers an early window for disease-modifying intervention. Current treatments of iRBD, including the two level B therapies with clonazepam and melatonin, are considered symptomatic. However, numbers of reported patients treated with melatonin are low and whether melatonin has disease-modifying potential is unclear. Methods This single-center, prospective cohort study included 206 consecutive patients diagnosed with iRBD until January 2020. Thirty-nine patients had applied mixed treatments on the advice of the referring physician, 167 had administered melatonin according to our Chronobiotic protocol (low dose, ≥ 6 months, always-at-the-same-clock-time, between 10 and 11 pm - corrected for chronotype), which differs from existing melatonin prescriptions. Clinical examination to determine phenoconversion was performed from October 2018 to August 2020. To evaluate generalizability, we compared factors such as neuropsychological and neuromotor performance, olfactory ability, neurovegetative behavior, and dopamine transporter density in our patients with those reported for other cohorts. Primary outcome was phenoconversion to clinical synucleinopathy, assessed using Kaplan-Meier analysis. Secondary outcomes were changes in cognitive and motor performance, and in RBD-symptom severity, analyzed using mixed models. Results RBD characteristics were comparable to those in other published cohorts, including frequency of phenoconversion in our patients with mixed treatments (10/39; follow-up 3.1±2.1 years). In contrast, long-term melatonin-treated patients rarely converted (4/167; follow-up 4.2±3.1 years; hazard-ratio 0.07, 95% CI, 0.02-0.22, p Conclusion Clock-timed melatonin treatment in patients with iRBD appears to be associated with a marked reduction in the development of parkinsonism and dementia as well as with an improvement in neuromotor, cognitive, and specific RBD symptoms. Findings suggest that melatonin treatment may have disease-modifying effects in synucleinopathies. The fact that melatonin is available anywhere at low cost provides the perspective of immediate clinical application in patients at risk for clinical synucleinopathy. On the other hand, clock-time dependency challenges existing prescription guidelines for melatonin. Melatonin should be acknowledged as the darkness signal to circadian clock-work rather than a hypnotic.

Isabelle Arnulf - One of the best experts on this subject based on the ideXlab platform.

  • Loss of REM sleep features across nighttime in REM sleep behavior disorder
    Sleep Medicine, 2016
    Co-Authors: Dario Arnaldi, Marie Vidailhet, Alice Latimier, Smaranda Leu-semenescu, Isabelle Arnulf
    Abstract:

    Objectives Melatonin is a Chronobiotic treatment which also alleviates rapid eye movement (REM) sleep behavior disorder (RBD). Because the mechanisms of this benefit are unclear, we evaluated the clock-dependent REM sleep characteristics in patients with RBD, whether idiopathic (iRBD) or associated with Parkinson's Disease (PD), and we compared findings with PD patients without RBD and with healthy subjects. Methods An overnight videopolysomnography was performed in ten iRBD patients, ten PD patients with RBD (PD + RBD+), ten PD patients without RBD (PD + RBD−), and ten controls. The rapid eye movement frequency per minute (REMs index), the tonic and phasic electromyographic (EMG) activity of the levator menti muscle, and the duration of each REM sleep episode were evaluated. A generalized linear model was applied in each group, with the REM sleep cycle (four ordinal levels) as the dependent variable, as a function of REMs index, REM sleep duration, and tonic and phasic EMG activity. Results From the first to the fourth sleep cycle, REM sleep duration progressively increased in controls only, REMs index increased in subjects without RBD but not in patients with RBD, whether idiopathic or associated with PD, whereas tonic and phasic EMG activity did not change. Conclusions Patients with PD or iRBD lost the physiologic nocturnal increase in REM sleep duration, and patients with RBD (either with or without PD) lost the increase of REMs frequency across the night, suggesting an alteration in the circadian system in RBD. This supports the hypothesis of a direct effect of melatonin on RBD symptoms by its Chronobiotic activity.