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Article ; Online: Melatonin as a chronobiotic/cytoprotective agent in bone. Doses involved.

Cardinali, Daniel P

2023 Volume 76, Issue 1, Page(s) e12931

Abstract: Because the chronobiotic and cytoprotective molecule melatonin diminishes with age, its involvement in postmenopausal and senescence pathology has been considered since long. One relevant melatonin target site in aging individuals is bone where melatonin ...

Abstract	Because the chronobiotic and cytoprotective molecule melatonin diminishes with age, its involvement in postmenopausal and senescence pathology has been considered since long. One relevant melatonin target site in aging individuals is bone where melatonin chronobiotic effects mediated by MT1 and MT2 receptors are demonstrable. Precursors of bone cells located in bone marrow are exposed to high quantities of melatonin and the possibility arises that melatonin acts a cytoprotective compound via an autacoid effect. Proteins that are incorporated into the bone matrix, like procollagen type I c-peptide, augment after melatonin exposure. Melatonin augments osteoprotegerin, an osteoblastic protein that inhibits the differentiation of osteoclasts. Osteoclasts are target cells for melatonin as they degrade bone partly by generating free radicals. Osteoclast activity and bone resorption are impaired via the free radical scavenger properties of melatonin. The administration of melatonin in chronobiotic doses (less than 10 mg daily) is commonly used in clinical studies on melatonin effect on bone. However, human equivalent doses allometrically derived from animal studies are in the 1-1.5 mg/kg/day range for a 75 kg human adult, a dose rarely used clinically. In view of the absence of toxicity of melatonin in phase 1 pharmacological studies with doses up to 100 mg in normal volunteers, further investigation is needed to determine whether high melatonin doses have higher therapeutic efficacy in preventing bone loss.
MeSH term(s)	Animals ; Adult ; Humans ; Melatonin/pharmacology ; Melatonin/metabolism ; Bone and Bones/metabolism ; Osteoclasts ; Bone Resorption ; Aging ; Protective Agents/pharmacology ; Circadian Rhythm
Chemical Substances	Melatonin (JL5DK93RCL) ; Protective Agents
Language	English
Publishing date	2023-12-11
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	632697-3
ISSN	1600-079X ; 0742-3098
ISSN (online)	1600-079X
ISSN	0742-3098
DOI	10.1111/jpi.12931
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Book: Hypothalamic and adipose tissue dysfunction

Spinedi, Eduardo / Cardinali, Daniel Pedro / Gagliardino, Juan J.

a risky association for obesity

(Neuroendocrinology ; vol. 104, no. 4 (2017))

2017

Author's details	guest editors Eduardo Spinedi, Daniel P. Cardinali, Juan J. Gagliardino
Series title	Neuroendocrinology ; vol. 104, no. 4 (2017)
Collection
Keywords	Endocrinology
Subject code	610
Language	English
Size	Seite 318-425, Illustrationen
Publisher	Karger
Publishing place	Basel
Publishing country	Switzerland
Document type	Book
HBZ-ID	HT019308803
ISBN	978-3-318-06022-5 ; 9783318060232 ; 3-318-06022-4 ; 3318060232
Database	Catalogue ZB MED Medicine, Health

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Article: Melatonin and healthy aging.

Cardinali, Daniel P

Vitamins and hormones

2021 Volume 115, Page(s) 67–88

Abstract: Preservation of a robust circadian rhythmicity (particulsarly of the sleep/wake cycle), a proper nutrition and adequate physical exercise are key elements for healthy aging. Aging comes along with circadian alteration, e.g. a disrupted sleep and ... ...

Abstract	Preservation of a robust circadian rhythmicity (particulsarly of the sleep/wake cycle), a proper nutrition and adequate physical exercise are key elements for healthy aging. Aging comes along with circadian alteration, e.g. a disrupted sleep and inflammation, that leads to metabolic disorders. In turn, sleep cycle disturbances cause numerous pathophysiological changes that accelerates the aging process. In the central nervous system, sleep disruption impairs several functions, among them, the clearance of waste molecules. The decrease of plasma melatonin, a molecule of unusual phylogenetic conservation present in all known aerobic organisms, plays a particular role as far as the endocrine sequels of aging. Every day, the late afternoon/nocturnal increase of melatonin synchronizes both the central circadian pacemaker located in the hypothalamic suprachiasmatic nuclei as well as myriads of peripheral cellular circadian clocks. This is called the "chronobiotic effect" of melatonin, the methoxyindole being the prototype of the endogenous family of chronobiotic agents. In addition, melatonin exerts a significant cytoprotective action by buffering free radicals and reversing inflammation via down regulation of proinflammatory cytokines, suppression of low degree inflammation and prevention of insulin resistance. Because of these properties melatonin has been advocated to be a potential therapeutic tool in COVID 19 pandemic. Melatonin administration to aged animals counteracts a significant number of senescence-related changes. In humans, melatonin is effective both as a chronobiotic and a cytoprotective agent to maintain a healthy aging. Circulating melatonin levels are consistently reduced in the metabolic syndrome, ischemic and non-ischemic cardiovascular diseases and neurodegenerative disorders like the Alzheimer's and Parkinson's diseases. The potential therapeutic value of melatonin has been suggested by a limited number of clinical trials generally employing melatonin in the 2-10mg/day range. However, from animal studies the cytoprotective effects of melatonin need higher doses to become apparent (i.e. in the 100mg/day range). Hence, controlled studies employing melatonin doses in this range are urgently needed.
MeSH term(s)	Animals ; Antioxidants/pharmacology ; Antioxidants/therapeutic use ; Circadian Rhythm/drug effects ; Healthy Aging/drug effects ; Humans ; Melatonin/pharmacology ; Melatonin/therapeutic use
Chemical Substances	Antioxidants ; Melatonin (JL5DK93RCL)
Language	English
Publishing date	2021-02-05
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	201161-x
ISSN	2162-2620 ; 0083-6729
ISSN (online)	2162-2620
ISSN	0083-6729
DOI	10.1016/bs.vh.2020.12.004
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Article: Melatonin as a Chronobiotic/Cytoprotective Agent in REM Sleep Behavior Disorder.

Cardinali, Daniel P / Garay, Arturo

Brain sciences

2023 Volume 13, Issue 5

Abstract: Dream-enactment behavior that emerges during episodes of rapid eye movement (REM) sleep without muscle atonia is a parasomnia known as REM sleep behavior disorder (RBD). RBD constitutes a prodromal marker of α-synucleinopathies and serves as one of the ... ...

Abstract	Dream-enactment behavior that emerges during episodes of rapid eye movement (REM) sleep without muscle atonia is a parasomnia known as REM sleep behavior disorder (RBD). RBD constitutes a prodromal marker of α-synucleinopathies and serves as one of the best biomarkers available to predict diseases such as Parkinson disease, multiple system atrophy and dementia with Lewy bodies. Most patients showing RBD will convert to an α-synucleinopathy about 10 years after diagnosis. The diagnostic advantage of RBD relies on the prolonged prodromal time, its predictive power and the absence of disease-related treatments that could act as confounders. Therefore, patients with RBD are candidates for neuroprotection trials that delay or prevent conversion to a pathology with abnormal α-synuclein metabolism. The administration of melatonin in doses exhibiting a chronobiotic/hypnotic effect (less than 10 mg daily) is commonly used as a first line treatment (together with clonazepam) of RBD. At a higher dose, melatonin may also be an effective cytoprotector to halt α-synucleinopathy progression. However, allometric conversion doses derived from animal studies (in the 100 mg/day range) are rarely employed clinically regardless of the demonstrated absence of toxicity of melatonin in phase 1 pharmacological studies with doses up to 100 mg in normal volunteers. This review discusses the application of melatonin in RBD: (a) as a symptomatic treatment in RBD; (b) as a possible disease-modifying treatment in α-synucleinopathies. To what degree melatonin has therapeutic efficacy in the prevention of α-synucleinopathies awaits further investigation, in particular multicenter double-blind trials.
Language	English
Publishing date	2023-05-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci13050797
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: An Assessment of Melatonin's Therapeutic Value in the Hypoxic-Ischemic Encephalopathy of the Newborn.

Cardinali, Daniel P

Frontiers in synaptic neuroscience

2019 Volume 11, Page(s) 34

Abstract: Hypoxic-ischemic encephalopathy (HIE) is one of the most frequent causes of brain injury in the newborn. From a pathophysiological standpoint, a complex process takes place at the cellular and tissue level during the development of newborn brain damage ... ...

Abstract	Hypoxic-ischemic encephalopathy (HIE) is one of the most frequent causes of brain injury in the newborn. From a pathophysiological standpoint, a complex process takes place at the cellular and tissue level during the development of newborn brain damage in the absence of oxygen. Initially, the lesion is triggered by a deficit in the supply of oxygen to cells and tissues, causing a primary energy insufficiency. Subsequently, high energy phosphate levels recover transiently (the latent phase) that is followed by a secondary phase, in which many of the pathophysiological mechanisms involved in the development of neonatal brain damage ensue (i.e., excitotoxicity, massive influx of Ca
Language	English
Publishing date	2019-12-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2592086-8
ISSN	1663-3563
ISSN	1663-3563
DOI	10.3389/fnsyn.2019.00034
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Article: Melatonin: Clinical Perspectives in Neurodegeneration.

Cardinali, Daniel P

Frontiers in endocrinology

2019 Volume 10, Page(s) 480

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 ... ...

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.
Language	English
Publishing date	2019-07-16
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2592084-4
ISSN	1664-2392
ISSN	1664-2392
DOI	10.3389/fendo.2019.00480
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Article ; Online: Possible Application of Melatonin in Long COVID.

Cardinali, Daniel P / Brown, Gregory M / Pandi-Perumal, Seithikurippu R

Biomolecules

2022 Volume 12, Issue 11

Abstract: Clinical sequelae and symptoms for a considerable number of COVID-19 patients can linger for months beyond the acute stage of SARS-CoV-2 infection, "long COVID". Among the long-term consequences of SARS-CoV-2 infection, cognitive issues (especially ... ...

Abstract	Clinical sequelae and symptoms for a considerable number of COVID-19 patients can linger for months beyond the acute stage of SARS-CoV-2 infection, "long COVID". Among the long-term consequences of SARS-CoV-2 infection, cognitive issues (especially memory loss or "brain fog"), chronic fatigue, myalgia, and muscular weakness resembling myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are of importance. Melatonin may be particularly effective at reducing the signs and symptoms of SARS-CoV-2 infection due to its functions as an antioxidant, anti-inflammatory, and immuno-modulatory agent. Melatonin is also a chronobiotic medication effective in treating delirium and restoring the circadian imbalance seen in COVID patients in the intensive care unit. Additionally, as a cytoprotector, melatonin aids in the prevention of several COVID-19 comorbidities, including diabetes, metabolic syndrome, and ischemic and non-ischemic cardiovascular diseases. This narrative review discusses the application of melatonin as a neuroprotective agent to control cognitive deterioration ("brain fog") and pain in the ME/CFS syndrome-like documented in long COVID. Further studies on the therapeutic use of melatonin in the neurological sequelae of SARS-CoV-2 infection are warranted.
MeSH term(s)	Humans ; COVID-19/drug therapy ; Melatonin/therapeutic use ; SARS-CoV-2 ; Fatigue Syndrome, Chronic/drug therapy ; Fatigue Syndrome, Chronic/diagnosis
Chemical Substances	Melatonin (JL5DK93RCL)
Language	English
Publishing date	2022-11-07
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom12111646
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Melatonin's Benefits and Risks as a Therapy for Sleep Disturbances in the Elderly: Current Insights.

Cardinali, Daniel P / Brown, Gregory M / Pandi-Perumal, Seithikurippu R

Nature and science of sleep

2022 Volume 14, Page(s) 1843–1855

Abstract: Aging is accompanied by circadian changes, including disruptive alterations in the sleep/wake cycle, as well as the beginning of low-degree inflammation ("inflammaging"), a scenario that leads to several chronic illnesses, including cancer, and metabolic, ...

Abstract	Aging is accompanied by circadian changes, including disruptive alterations in the sleep/wake cycle, as well as the beginning of low-degree inflammation ("inflammaging"), a scenario that leads to several chronic illnesses, including cancer, and metabolic, cardiovascular, and neurological dysfunctions. As a result, any effective approach to healthy aging must consider both the correction of circadian disturbance and the control of low-grade inflammation. One of the most important prerequisites for healthy aging is the preservation of robust circadian rhythmicity (particularly of the sleep/wake cycle). Sleep disturbance disrupts various activities in the central nervous system, including waste molecule elimination. Melatonin is a chemical with extraordinary phylogenetic conservation found in all known aerobic creatures whose alteration plays an important role in sleep changes with aging. Every day, the late afternoon/nocturnal surge in pineal melatonin helps to synchronize both the central circadian pacemaker found in the hypothalamic suprachiasmatic nuclei (SCN) and a plethora of peripheral cellular circadian clocks. Melatonin is an example of an endogenous chronobiotic substance that can influence the timing and amplitude of circadian rhythms. Moreover, melatonin is also an excellent anti-inflammatory agent, buffering free radicals, down-regulating proinflammatory cytokines, and reducing insulin resistance, among other things. We present both scientific and clinical evidence that melatonin is a safe drug for treating sleep disturbances in the elderly.
Language	English
Publishing date	2022-10-14
Publishing country	New Zealand
Document type	Journal Article ; Review
ZDB-ID	2587468-8
ISSN	1179-1608
ISSN	1179-1608
DOI	10.2147/NSS.S380465
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Article: Melatonin as a Chronobiotic and Cytoprotective Agent in Parkinson's Disease.

Pérez-Lloret, Santiago / Cardinali, Daniel P

Frontiers in pharmacology

2021 Volume 12, Page(s) 650597

Abstract: This article discusses the role that melatonin may have in the prevention and treatment of Parkinson's disease (PD). In parkinsonian patients circulating melatonin levels are consistently disrupted and the potential therapeutic value of melatonin on ... ...

Abstract	This article discusses the role that melatonin may have in the prevention and treatment of Parkinson's disease (PD). In parkinsonian patients circulating melatonin levels are consistently disrupted and the potential therapeutic value of melatonin on sleep disorders in PD was examined in a limited number of clinical studies using 2-5 mg/day melatonin at bedtime. The low levels of melatonin MT1 and MT2 receptor density in substantia nigra and amygdala found in PD patients supported the hypothesis that the altered sleep/wake cycle seen in PD could be due to a disrupted melatonergic system. Motor symptomatology is seen in PD patients when about 75% of the dopaminergic cells in the substantia nigra pars compacta region degenerate. Nevertheless, symptoms like rapid eye movement (REM) sleep behavior disorder (RBD), hyposmia or depression may precede the onset of motor symptoms in PD for years and are index of worse prognosis. Indeed, RBD patients may evolve to an α-synucleinopathy within 10 years of RBD onset. Daily bedtime administration of 3-12 mg of melatonin has been demonstrated effective in RDB treatment and may halt neurodegeneration to PD. In studies on animal models of PD melatonin was effective to curtail symptomatology in doses that allometrically projected to humans were in the 40-100 mg/day range, rarely employed clinically. Therefore, double-blind, placebo-controlled clinical studies are urgently needed in this respect.
Language	English
Publishing date	2021-04-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2587355-6
ISSN	1663-9812
ISSN	1663-9812
DOI	10.3389/fphar.2021.650597
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Article ; Online: An Exploratory Study of Sleep-Wake Differences of Autonomic Activity in Patients with Mild Cognitive Impairment: The Role of Melatonin as a Modulating Factor.

Abulafia, Carolina / Vidal, María F / Olivar, Natividad / Odzak, Andrea / Brusco, Ignacio / Guinjoan, Salvador M / Cardinali, Daniel P / Vigo, Daniel E

Clinical interventions in aging

2023 Volume 18, Page(s) 771–781

Abstract: ... not taking melatonin (RMSSD -7 ± 1 vs 4 ± 4, p = 0.004). In addition, we observed that melatonin ... treatment was associated with greater parasympathetic activity during sleep (VLF 15.5 ± 0.1 vs 15.1 ± 0.1, p ... 0.010) and in sleep-wake differences in MCI patients (VLF 0.5 ± 0.1 vs 0.2 ± 0.0, p = 0.004 ...

Abstract	Purpose: The objective of the present study was to assess sleep-wake differences of autonomic activity in patients with mild cognitive impairment (MCI) compared to control subjects. As a post-hoc objective, we sought to evaluate the mediating effect of melatonin on this association. Patients and methods: A total of 22 MCI patients (13 under melatonin treatment) and 12 control subjects were included in this study. Sleep-wake periods were identified by actigraphy and 24hr-heart rate variability measures were obtained to study sleep-wake autonomic activity. Results: MCI patients did not show any significant differences in sleep-wake autonomic activity when compared to control subjects. Post-hoc analyses revealed that MCI patients not taking melatonin displayed lower parasympathetic sleep-wake amplitude than controls not taking melatonin (RMSSD -7 ± 1 vs 4 ± 4, p = 0.004). In addition, we observed that melatonin treatment was associated with greater parasympathetic activity during sleep (VLF 15.5 ± 0.1 vs 15.1 ± 0.1, p = 0.010) and in sleep-wake differences in MCI patients (VLF 0.5 ± 0.1 vs 0.2 ± 0.0, p = 0.004). Conclusion: These preliminary findings hint at a possible sleep-related parasympathetic vulnerability in patients at prodromal stages of dementia as well as a potential protective effect of exogenous melatonin in this population.
MeSH term(s)	Humans ; Melatonin/pharmacology ; Melatonin/therapeutic use ; Sleep Wake Disorders/drug therapy ; Sleep/physiology ; Cognitive Dysfunction/drug therapy ; Cognitive Dysfunction/complications ; Actigraphy ; Circadian Rhythm/physiology
Chemical Substances	Melatonin (JL5DK93RCL)
Language	English
Publishing date	2023-05-12
Publishing country	New Zealand
Document type	Journal Article
ZDB-ID	2364924-0
ISSN	1178-1998 ; 1176-9092
ISSN (online)	1178-1998
ISSN	1176-9092
DOI	10.2147/CIA.S394749
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