Melatonin: An Old Hormone with New Tricks

Melatonin: you’ve undoubtedly seen it in the supplement aisle at the drugstore…that natural sleep remedy your aunt recommended once, sounding vaguely like a portmanteau of mellow and serotonin.  But between the occasional internet medical forum and your would-be pharmacist aunt, how much do you really know about this sandman hormone?

Melatonin is an ancient, multipurpose molecule.  It is found in many types of creatures, including plants, unicellular organisms, bacteria, algae, as well as invertebrates and vertebrates.  The area of the mammalian brain that produces melatonin is the pineal gland: a small, round structure located just behind the third ventricle.  The pineal gland secretes melatonin directly into blood circulation and cerebrospinal fluid, where it is able to act on cells throughout the body via multiple receptor pathways.  Melatonin’s primary function is to act as both a clock and a calendar to the rest of the cells in the body, regulating daily (circadian) and seasonal rhythms.  Somewhat surprisingly, melatonin is produced at night in both diurnal and nocturnal mammals, as light inhibits pineal melatonin secretion in most species.  This is the true origin of the molecule’s name: melas, meaning dark, and serotonin, the precursor from which the body synthesizes melatonin.

Wild animals use melatonin to tell the season, as the duration of nightly melatonin increases closer to winter (when day lengths decrease).  Melatonin controls the vast majority of changes in seasonal behaviors and physiological processes, including reproduction, metabolism, and immune function.  Seasonally-breeding animals use the melatonin signal to anticipate the coming winter and reorganize their physiology accordingly.  Indeed, artificial treatment with exogenous melatonin can cause seasonally breeding animals to ‘switch’ to their winter form.

Winter and summer present entirely different environmental challenges.  If animals cannot predict and adapt to these challenges, they will likely die.  In some species, such as Siberian hamsters (Phodopus sungorus), short days or melatonin implants can cause reproductive systems to all but disappear.  These hamsters cannot afford to invest energy into making testes or ovaries at -25°C!  Additionally, large changes to the immune system occur in response to seasonal melatonin secretion, allowing for enhanced survival capacity during the harsh days of winter.

Because humans show very few seasonal rhythms in breeding or other behaviors, most research on melatonin’s actions in humans has been focused on its circadian or sleep altering effects.  Indeed, due to the advent of artificial nighttime lighting in industrial society, a special research emphasis has been placed on discovering the deleterious effects of such lighting on melatonin secretion.  Because melatonin is light-dependent, concentrations are naturally higher in the winter than in the summer.  This fact bears clinical significance, as some diseases such as multiple sclerosis (MS) show seasonal patterns in severity and prevalence.

Recently, researchers (Farez and colleagues) have discovered a role for melatonin in mediating seasonal relapses in MS patients.  MS is a demyelinating disease thought to be autoimmune in origin.  Autoimmune diseases are conditions where the patient’s own immune system mistakes normal healthy tissue for an invading pathogen and begins attacking it.  Patients lose the protective ‘wrapping,’ called myelin, along nerves that ensures adequate signal transduction, similar to losing insulation along a telephone line.  Without myelinated nerves, signals can become distorted or lost completely, causing widespread loss of function.  Researchers have known for a substantial amount of time that people living farther away from the equator have a higher incidence of MS. Indeed, much research has been done on the potentially protective effects of vitamin D — synthesis of which is sun-dependent — on MS, as those living closer to the poles experience less intense sunlight and therefore synthesize less vitamin D than those living closer to the equator.  The facts, however, do not add up: if MS were dependent on vitamin D, then one would expect relapses to occur at the highest level during the winter and fall, when sun exposure drops.  However, the opposite appears to be true! Relapse rates are highest in the summer and spring, when vitamin D synthesis and sun exposure are highest.  Some other seasonally variable factor must contribute to MS relapse rates.

Farez and colleagues realized that melatonin concentrations are higher during fall and winter when compared to spring or summer and, furthermore, that melatonin could influence immune function.  Accordingly, they predicted that higher melatonin levels in winter alter the immune system so as to inhibit MS relapses.  In fact, melatonin blocks the formation of a subset of T-helper cells called Th17 cells.  These cells secrete interleukin-17 (IL-17), an inflammatory molecule that can influence disease severity.  Researchers tested whether melatonin could improve outcomes in a mouse model of MS called experimental autoimmune encephalomyelitis (EAE).  In this model, a piece of foreign myelin protein is introduced into a mouse, and the mouse’s immune system begins attacking it and other (natural) myelin, causing a disease very similar to human MS.  EAE is a ‘true’ autoimmune disease, that is, you can give a healthy mouse the disease simply by transferring T-cells from an afflicted mouse in a process called ‘adoptive cell transfer’.  The transferred T-cells will cause the healthy mouse to develop EAE, even though it was never exposed to the foreign myelin protein!

Melatonin was effective in reducing disease severity by inhibiting the development of Th17 cells and boosting the development of anti-inflammatory T-regulatory (Tr1) cells, shifting the balance of the immune response toward immune suppression.  Blocking the melatonin receptor on T-cells also blocked melatonin’s efficacy, showing that melatonin acts directly on these cells to alter their function.  This research provides evidence that melatonin mediates seasonal relapse in MS, and that using melatonin or a similar compound could be effective in the treatment of MS or other autoimmune diseases.  The authors urge caution, though, as the pathways involved are complex and likely cross-regulated.  Further research is necessary to translate this finding to the clinic.  In the meantime, perhaps you will revere your aunt’s favorite health supplement as a multifaceted molecule, which transcends its common label as a mere sleep remedy.

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Written by Jeremy Borniger.

Images by Jooyeun Lee.

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References:

Farez, M. F., Mascanfroni, I. D., Méndez-Huergo, S. P., Yeste, A., Murugaiyan, G., Garo, L. P., … & Correale, J. (2015). Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses. Cell 162: 1338-1352.

Hardeland, R., & Poeggeler, B. (2003). Non‐vertebrate melatonin. Journal of pineal research,34(4), 233-241.

Mokhtarian, F., McFarlin, D. E., & Raine, C. S. (1984). Adoptive transfer of myelin basic protein-sensitized T cells produces chronic relapsing demyelinating disease in mice. Nature 309: 356-358

Reiter, R. J. (1993). The melatonin rhythm: both a clock and a calendar. Experientia, 49(8), 654-664.

Schernhammer, E. S., & Schulmeister, K. (2004). Melatonin and cancer risk: does light at night compromise physiologic cancer protection by lowering serum melatonin levels?. British journal of cancer, 90(5), 941-943.

Weil, Z. M., Borniger, J. C., Cisse, Y. M., Salloum, B. A. A., & Nelson, R. J. (2015). Neuroendocrine control of photoperiodic changes in immune function. Frontiers in neuroendocrinology, 37, 108-118.