Cited by 845Circadian rhythm and melatoninmelanin and skin pigmentationImpact of Light on Environment and Health

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Melatonin—A pleiotropic, orchestrating regulator molecule

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Hardeland, Rüdiger, Cardinali, Daniel P., Srinivasan, Venkatramanujam, Spence, D. Warren, Brown, Gregory M., Pandi-Perumal, Seithikurippu R.·2011·Progress in Neurobiology

DOI 10.1016/j.pneurobio.2010.12.004

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Abstract

Melatonin, the neurohormone of the pineal gland, is also produced by various other tissues and cells. It acts via G protein-coupled receptors expressed in various areas of the central nervous system and in peripheral tissues. Parallel signaling mechanisms lead to cell-specific control and recruitment of downstream factors, including various kinases, transcription factors and ion channels. Additional actions via nuclear receptors and other binding sites are likely. By virtue of high receptor density in the circadian pacemaker, melatonin is involved in the phasing of circadian rhythms and sleep promotion. Additionally, it exerts effects on peripheral oscillators, including phase coupling of parallel cellular clocks based on alternate use of core oscillator proteins. Direct central and peripheral actions concern the up- or downregulation of various proteins, among which inducible and neuronal NO synthases seem to be of particular importance for antagonizing inflammation and excitotoxicity. The methoxyindole is also synthesized in several peripheral tissues, so that the total content of tissue melatonin exceeds by far the amounts in the circulation. Emerging fields in melatonin research concern receptor polymorphism in relation to various diseases, the control of sleep, the metabolic syndrome, weight control, diabetes type 2 and insulin resistance, and mitochondrial effects. Control of electron flux, prevention of bottlenecks in the respiratory chain and electron leakage contribute to the avoidance of damage by free radicals and seem to be important in neuroprotection, inflammatory diseases and, presumably, aging. Newly discovered influences on sirtuins and downstream factors indicate that melatonin has a role in mitochondrial biogenesis.

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Rapid and transient stimulation of intracellular reactive oxygen species by melatonin in normal and tumor leukocytes
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Melatonin and cortisol secretion in patients with primary obsessive-compulsive disorder
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Melatonin and Nitric Oxide: Two Required Antagonists for Mitochondrial Homeostasis
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Melatonin synthesized by Jurkat human leukemic T cell line is implicated in IL‐2 production
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Neuroprotection by Radical Avoidance: Search for Suitable Agents
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Acutely administered melatonin restores hepatic mitochondrial physiology in old mice
Okatani, Y., Wakatsuki, A., Reiter, R. J., & Miyahara, Y. (2003) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(02)00260-1 · Cited by 65
Evidence of immune system melatonin production by two pineal melatonin deficient mice, C57BL/6 and Swiss strains
Gómez-Corvera, A., Cerrillo, I., Molinero, P., Naranjo, M. C., Lardone, P. J., Sánchéz‐Hidalgo, M., Carrascosa-Salmoral, M. P., Medrano‐Campillo, P., Guerrero, J. M., & Rubio, A. (2009) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2009.00683.x · Cited by 65
The end of a myth: cloning and characterization of the ovine melatonin MT2 receptor
Cogé, F., Guenin, S., Féry, I., Migaud, M., Devavry, S., Slugocki, C., Legros, C., Ouvry, C., Cohen, W., Renault, N., et al. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2009.00453.x · Cited by 64
Possible Involvement of the Nuclear RZR/ROR-Alpha Receptor in the Antitumor Action of Melatonin on Murine Colon 38 Cancer
Winczyk, K., Pawlikowski, M., Guerrero, J. M., & Karasek, M. (2002) · Tumor Biology · doi:10.1159/000068569 · Cited by 64
Melatonin prevents ischemic brain injury through activation of the mTOR/p70S6 kinase signaling pathway.
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Age-dependent lipopolysaccharide-induced iNOS expression and multiorgan failure in rats: Effects of melatonin treatment
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Hepatic mitochondrial dysfunction in senescence‐accelerated mice: correction by long‐term, orally administered physiological levels of melatonin
Okatani, Y., Wakatsuki, A., Reiter, R. J., & Miyahara, Y. (2002) · Journal of Pineal Research · doi:10.1034/j.1600-079x.2002.02109.x · Cited by 64
Endogenous melatonin provides an effective circadian message to both the suprachiasmatic nuclei and the pars tuberalis of the rat
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Selective effect of methoxyindoles on the lymphocyte proliferation and melatonin binding to activated human lymphoid cells
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Pineal melatonin synthesis is decreased in type 2 diabetic Goto–Kakizaki rats
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Potential involvement of mt1 receptor and attenuated sex steroid‐induced calcium influx in the direct anti‐proliferative action of melatonin on androgen‐responsive LNCaP human prostate cancer cells
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MELATONIN DEFICIENCY AND DISRUPTED CIRCADIAN RHYTHMS IN PEDIATRIC SURVIVORS OF CRANIOPHARYNGIOMA
Lipton, J., Megerian, J. T., Kothare, S. V., Cho, Y.-J., Shanahan, T., Chart, H., Ferber, R., Adler-Golden, L., Cohen, L. E., Czeisler, C. A., et al. (2009) · Neurology · doi:10.1212/wnl.0b013e3181af78a5 · Cited by 63
Antioxidative effects of melatonin in Drosophila melanogaster: Antagonization of damage induced by the inhibition of catalase
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Dietary Supplements and Weight Control in a Middle-Age Population
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Melatonin-induced depression of locomotor activity in hamsters: Time-dependency and inhibition by the central-type benzodiazepine antagonist Ro 15-1788
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Melatonin Induces Akt Phosphorylation through Melatonin Receptor- and PI3K-Dependent Pathways in Primary Astrocytes
Kong, P., Byun, J.-S., Lim, S.-Y., Lee, J.-J., Hong, S. J., Kwon, K.-J., & Kim, S. (2008) · Korean Journal of Physiology and Pharmacology · doi:10.4196/kjpp.2008.12.2.37 · Cited by 63
Human hydroxyindole-O-methyltransferase in pineal gland, retina and Y79 retinoblastoma cells
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Decreased nocturnal plasma melatonin levels in patients with recurrent acute intermittent porphyria attacks
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Nocturnal Plasma Melatonin Profile and Melatonin Kinetics During Infusion in Status Migrainosus
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Time-dependent anticonvulsant activity of melatonin in hamsters
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Melatonin is responsible for the nocturnal increase observed in serum and thymus of thymosin α1 and thymulin concentrations: observations in rats and humans
Molinero, P., Soutto, M., Benot, S., Hmadcha, A., & Guerrero, J. M. (2000) · Journal of Neuroimmunology · doi:10.1016/s0165-5728(99)00237-4 · Cited by 62
Enhanced modification of cardiolipin during ischemia in the aged heart
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MTNR1B rs10830963 is associated with fasting plasma glucose, HbA1Cand impaired beta-cell function in Chinese Hans from Shanghai
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Investigational melatonin receptor agonists
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MT1 melatonin receptor internalization underlies melatonin‐induced morphologic changes in Chinese hamster ovary cells and these processes are dependent on Gi proteins, MEK 1/2 and microtubule modulation
Bondi, C., McKeon, R. M., Bennett, J. M., Ignatius, P. F., Brydon, L., Jockers, R., Melan, M. A., & Witt‐Enderby, P. A. (2007) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2007.00525.x · Cited by 61
Melatonin Prevents Age-Related Mitochondrial Dysfunction in Rat Brain Via Cardiolipin Protection
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Chronic administration of melatonin reduces cerebral injury biomarkers in SAMP8
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The melatonin-producing system is fully functional in retinal pigment epithelium (ARPE-19)
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Does melatonin play a disease-promoting role in rheumatoid arthritis?
Maestroni, G. J. M., Cardinali, D. P., Esquifino, A. I., & Pandi-Perumal, S. R. (2004) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2004.08.015 · Cited by 61
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Melatonin as modulator of pancreatic enzyme secretion and pancreatoprotector.
Jaworek, J. M., Nawrot‐Porąbka, K., Leja‐Szpak, A., Bonior, J., Szklarczyk, J., Kot, M., Konturek, S. J., & Pawlik, W. W. (2007) · PubMed · Cited by 61
Does melatonin help save dopaminergic cells in MPTP-treated mice?
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Melatonin sensitizes human malignant glioma cells against TRAIL-induced cell death
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Nuclear Hormone Receptors in Human Skin
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Protective effect of melatonin against liver injury in mice induced by Bacillus Calmette-Guerin plus lipopolysaccharide
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Interfibrillar cardiac mitochondrial comples III defects in the aging rat heart
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Prostaglandin E release by rat medial basal hypothalamus in vitro. Inhibition by melatonin at submicromolar concentrations
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Tissue retention and subcellular distribution of continuously infused melatonin in rats under near physiological conditions
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Melatonin Attenuates the Cerebral Ischemic Injury via the MEK/ERK/p90RSK/Bad Signaling Cascade
Koh, P. (2008) · Journal of Veterinary Medical Science · doi:10.1292/jvms.70.1219 · Cited by 58
Melatonin stimulates inositol‐1,4,5‐trisphosphate and Ca2+release from INS1 insulinoma cells
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Induction of GDNF mRNA expression by melatonin in rat C6 glioma cells
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Melatonin and the human gonadotrophin-releasing hormone pulse generator
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Melatonin - From Molecules to Therapy
Pandi-Perumal, S. R. (2007) · Cited by 57
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Oxidative Toxicity in Models of Neurodegeneration: Responses to Melatonin
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Old and new inhibitors of quinone reductase 2
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Circadian rhythm disorder in a rare disease: Smith–Magenis syndrome
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Melatonin and its relevance to jet lag
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The Effects of Melatonin Premedication on Propofol and Thiopental Induction Dose–Response Curves: A Prospective, Randomized, Double-Blind Study
Naguib, M., Samarkandi, A. H., Moniem, M. A., Mansour, E., Alshaer, A. A., Alayyaf, H. A., Fadin, A., & Al-Harby, S. (2006) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000244534.24216.3a · Cited by 55
Melatonin deficiencies in women
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Therapeutic Potential of Melatonin Ligands
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Melatonin Beyond Its Classical Functions
Hardeland, R., & Pöeggeler, B. (2008) · The Open Physiology Journal · doi:10.2174/1874360900801010001 · Cited by 55
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Melatonin synthesis and melatonin‐membrane receptor (MT1) expression during rat thymus development: role of the pineal gland
Jiménez‐Jorge, S., Jiménez‐Caliani, A. J., Guerrero, J. M., Naranjo, M. C., Lardone, P. J., Carrillo‐Vico, A., Osuna, C., & Molinero, P. (2005) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2005.00220.x · Cited by 55
Clock gene expression in the retina of melatonin‐proficient (C3H) and melatonin‐deficient (C57BL) mice
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Melatonin-induced calcium signaling in clusters of human and rat duodenal enterocytes
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Possible participation of the nitric oxide-cyclic GMP-protein kinase G-K+ channels pathway in the peripheral antinociception of melatonin
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24h VARIATION IN THE EXPRESSION OF THE mt1MELATONIN RECEPTOR SUBTYPE IN CORONARY ARTERIES DERIVED FROM PATIENTS WITH CORONARY HEART DISEASE
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Mice, melatonin and the circadian system
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Intra-hypothalamic melatonin blocks photoperiodic responsiveness in the male syrian hamster
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Domoic acid-induced neurotoxicity in the hippocampus of adult rats
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Immortalized cells from the rat suprachiasmatic nucleus express functional melatonin receptors
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Evidence for Electron Equilibrium between the Two Hemes bL in the Dimeric Cytochrome bc1 Complex
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Intracellular Prooxidant Activity of Melatonin Induces a Survival Pathway Involving NF‐κB Activation
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Melatonin as a therapeutic tool in ophthalmology: implications for glaucoma and uveitis
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Expression of melatoninergic receptors in human placental choriocarcinoma cell lines
Lanoix, D., Ouellette, R. J., & Vaillancourt, C. (2006) · Human Reproduction · doi:10.1093/humrep/del120 · Cited by 53
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Consequences of MnSOD interactions with nitric oxide: Nitric oxide dismutation and the generation of peroxynitrite and hydrogen peroxide
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The Effects of Melatonin on Colonic Transit Time in Normal Controls and IBS Patients
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Functional analysis of retinoid Z receptor beta, a brain-specific nuclear orphan receptor.
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Anticonvulsant effects of the selective melatonin receptor agonist ramelteon
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Melatonin and RZR/ROR receptor ligand CGP 52608 induce apoptosis in the murine colonic cancer
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Kynurenamines as Neural Nitric Oxide Synthase Inhibitors
Entrena, A., Camacho, M. E., Carriòn, M. D., Lopez-Cara, L. C., Velasco, G., León, J., Escames, G., Acuña-Castroviejo, D., Tapias, V., Gallo, M. Á., et al. (2005) · Journal of Medicinal Chemistry · doi:10.1021/jm050740o · Cited by 51
Melatonin provides signal 3 to unprimed CD4+ T cells but failed to stimulate LPS primed B cells
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Melatonin Sensitizes Human Myometrial Cells to Oxytocin in a Protein Kinase Cα/Extracellular-Signal Regulated Kinase-Dependent Manner
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Melatonin Receptor Signaling in Pregnant and Nonpregnant Rat Uterine Myocytes as Probed by Large Conductance Ca2+-Activated K+ Channel Activity
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Immune‐Modulating Effects of Melatonin, N‐Acetylserotonin, and N‐Acetyldopamine
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The effect of melatonin on cellular activation processes in human blood
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Increased delta aminolevulinic acid and decreased pineal melatonin production. A common event in acute porphyria studies in the rat.
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Direct, real-time monitoring of superoxide generation in isolated mitochondria
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Central gabaergic mechanisms as targets for melatonin activity in brain
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Chronopharmacology of Melatonin: Inhibition by Benzodiazepine Antagonism
Golombek, D. A., Escolar, E., Burin, L. J., Sanchez, M. G. D. B., Duque, D. F., & Cardinali, D. P. (1992) · Chronobiology International · doi:10.3109/07420529209064523 · Cited by 50
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Lipoxygenase-mediated pro-radical effect of melatonin via stimulation of arachidonic acid metabolism
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Nocturnal melatonin concentration is correlated with illness severity in patients with septic disease
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Are G Protein‐Coupled Receptor Heterodimers of Physiological Relevance?—Focus on Melatonin Receptors
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Melatonin receptors on human granulosa cell membranes
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Sleep and Rhythm Consequences of a Genetically Induced Loss of Serotonin
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See all 845

Authors: Hardeland, R., Cardinali, D. P., Srinivasan, V., Spence, D. W., Brown, G. M., & Pandi-Perumal, S. R.
Affiliations: University of Göttingen (DE)
Pontificia Universidad Católica Argentina (AR)
Karpagam Academy of Higher Education (IN)
Centre for Addiction and Mental Health (CA)
Corresponding author: Hardeland, Rüdiger
ORCID: Hardeland, Rüdiger
Cardinali, Daniel P.
Spence, D. Warren
Brown, Gregory M.
Pandi-Perumal, Seithikurippu R.
Venue: Progress in Neurobiology
Publisher: Elsevier BV
Published: 2011-03
Volume: 93
Issue: 3
Pages: 350-384
ISSN: 0301-0082 (ISSN-L)
DOI: 10.1016/j.pneurobio.2010.12.004
OpenAlex: W2157611470
Cited by: 843
References: 733
Citations by year: 2026: 20 · 2025: 38 · 2024: 34 · 2023: 57 · 2022: 71 · 2021: 64 · 2020: 72 · 2019: 67 · 2018: 74 · 2017: 59 · 2016: 61 · 2015: 53 · 2014: 49 · 2013: 58 · 2012: 45
FWCI: 17.92
Type: journal article
Language: en
Open access: green
repositorio.uca.edu.ar
Licence: cc-by-nc-sa
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Progress in Neurobiology (publishedVersion)
PubMed (publishedVersion)
LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
Americanae (AECID Library) (submittedVersion, cc-by-nc-sa)
GRO (submittedVersion)
Topics: Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › melanin and skin pigmentation
Physical Sciences › Environmental Science › Global and Planetary Change › Impact of Light on Environment and Health
Keywords: melatonin, pineal gland, G protein-coupled receptors, circadian rhythm, sleep regulation, peripheral oscillators, nitric oxide synthase, inflammation, excitotoxicity, metabolic syndrome, type 2 diabetes, insulin resistance, mitochondrial function, mitochondrial biogenesis, sirtuins, neuroprotection, aging
MeSH terms: Aging, Animals, Binding Sites, Circadian Rhythm, Energy Metabolism, Humans, Immune System, Melatonin, Mitochondria, Pineal Gland, Signal Transduction, Receptors, Melatonin

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Melatonin—A pleiotropic, orchestrating regulator molecule

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