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Melatonin: Nature’s most versatile biological signal?
Open accessAbstract
Melatonin is a ubiquitous molecule and widely distributed in nature, with functional activity occurring in unicellular organisms, plants, fungi and animals. In most vertebrates, including humans, melatonin is synthesized primarily in the pineal gland and is regulated by the environmental light/dark cycle via the suprachiasmatic nucleus. Pinealocytes function as 'neuroendocrine transducers' to secrete melatonin during the dark phase of the light/dark cycle and, consequently, melatonin is often called the 'hormone of darkness'. Melatonin is principally secreted at night and is centrally involved in sleep regulation, as well as in a number of other cyclical bodily activities. Melatonin is exclusively involved in signaling the 'time of day' and 'time of year' (hence considered to help both clock and calendar functions) to all tissues and is thus considered to be the body's chronological pacemaker or 'Zeitgeber'. Synthesis of melatonin also occurs in other areas of the body, including the retina, the gastrointestinal tract, skin, bone marrow and in lymphocytes, from which it may influence other physiological functions through paracrine signaling. Melatonin has also been extracted from the seeds and leaves of a number of plants and its concentration in some of this material is several orders of magnitude higher than its night-time plasma value in humans. Melatonin participates in diverse physiological functions. In addition to its timekeeping functions, melatonin is an effective antioxidant which scavenges free radicals and up-regulates several antioxidant enzymes. It also has a strong antiapoptotic signaling function, an effect which it exerts even during ischemia. Melatonin's cytoprotective properties have practical implications in the treatment of neurodegenerative diseases. Melatonin also has immune-enhancing and oncostatic properties. Its 'chronobiotic' properties have been shown to have value in treating various circadian rhythm sleep disorders, such as jet lag or shift-work sleep disorder. Melatonin acting as an 'internal sleep facilitator' promotes sleep, and melatonin's sleep-facilitating properties have been found to be useful for treating insomnia symptoms in elderly and depressive patients. A recently introduced melatonin analog, agomelatine, is also efficient for the treatment of major depressive disorder and bipolar affective disorder. Melatonin's role as a 'photoperiodic molecule' in seasonal reproduction has been established in photoperiodic species, although its regulatory influence in humans remains under investigation. Taken together, this evidence implicates melatonin in a broad range of effects with a significant regulatory influence over many of the body's physiological functions.
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“Children typically produce more melatonin than adults, which may infer that their need for dietary supplementation may require further scrutiny and be limited to specific disease states [4,11].”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [4]
In the citing paper
“Production gradually declines as people age, starting in the late twenties to the fifties, with production leveling at approximately 30 pg/mL [4,11] (see Figure 1).”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [4]
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“Aside from aging, production of melatonin can be influenced by illness [12], diet [4], environmental factors like bright light at night [13], medication use [14], and lifestyle [15].”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [4]
In the citing paper
“Melatonin is colloquially referred to as the “hormone of darkness” since it is produced in response to darkness, as perceived by the eye’s retina [4].”
From Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements (2022) · cites this paper as [4]
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- 10.1210/jc.86.1.129 · DOI · Paper page
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Melatonin as an antioxidant: under promises but over delivers
Reiter, R. J., Mayo, J. C., Tan, D. X., Sainz, R. M., Alatorre-Jiménez, M. A., & Qin, L. (2016) · Journal of Pineal Research · doi:10.1111/jpi.12360 · Cited by 1,777
Melatonin as a natural ally against oxidative stress: a physicochemical examination
Galano, A., Tan, D. X., & Reiter, R. J. (2011) · Journal of Pineal Research · doi:10.1111/j.1600-079x.2011.00916.x · Cited by 1,167
Melatonin—A pleiotropic, orchestrating regulator molecule
Hardeland, R., Cardinali, D. P., Srinivasan, V., Spence, D. W., Brown, G. M., & Pandi-Perumal, S. R. (2011) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.12.004 · Cited by 843
Self-citationMelatonin: Pharmacology, Functions and Therapeutic Benefits
Tordjman, S., Sylvie Chokron, A., Delorme, R., Charrier, A., Bellissant, É., Jaafari, N., & Fougerou, C. (2017) · Current Neuropharmacology · doi:10.2174/1570159x14666161228122115 · Cited by 879
Physiological effects of melatonin: Role of melatonin receptors and signal transduction pathways
Pandi-Perumal, S. R., Trakht, I. N., SRINIVASAN, V., SPENCE, D., Maestroni, G. J. M., Zisapel, N., & Cardinali, D. P. (2008) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2008.04.001 · Cited by 799
Self-citation
Metadata
- Authors
- Pandi‐Perumal, S. R., Srinivasan, V., Maestroni, G. J. M., Cardinali, D. P., Poeggeler, B., & Hardeland, R.
- Affiliations
- Universiti Sains Malaysia (MY)
- Istituto Cantonale di Patologia (CH)
- Universidad de Buenos Aires (AR)
- University of Göttingen (DE)
- Venue
- The FEBS Journal
- Publisher
- Wiley
- Published
- 2006-06-15
- Volume
- 273
- Issue
- 13
- Pages
- 2813-2838
- ISSN
- 1742-464X (ISSN-L)
- 1742-4658
- OpenAlex
- W2049985521
- Cited by
- 875
- References
- 293
- Citations by year
- 2026: 15 · 2025: 29 · 2024: 33 · 2023: 33 · 2022: 42 · 2021: 56 · 2020: 47 · 2019: 49 · 2018: 42 · 2017: 45 · 2016: 34 · 2015: 38 · 2014: 53 · 2013: 53 · 2012: 51
- FWCI
- 5.54
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- FEBS Journal (publishedVersion)
- PubMed (publishedVersion)
- 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, suprachiasmatic nucleus, circadian rhythm, sleep regulation, antioxidant activity, anti-apoptotic signaling, neuroprotection, neurodegenerative diseases, immunomodulation, circadian rhythm sleep disorders, jet lag, shift work disorder, insomnia, agomelatine, photoperiodism, seasonal reproduction, melatonin analogues
- MeSH terms
- Animals, Antioxidants, Chronobiology Phenomena, Depression, Humans, Melatonin, Models, Chemical, Plant Proteins, Sleep, Signal Transduction, Free Radical Scavengers, Apoptosis, Receptors, Melatonin
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