Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PL013

Prize Lectures

From toads and sheep to chronotherapy: A melatonin story

J. Arendt1

1. University of Surrey, Guildford, United Kingdom.

In 1958 the dermatologist Aaron Lerner reported the isolation of N-acetyl-5-methoxytryptamine, the most potent amphibian skin lightening factor, from bovine pineal glands. He called it 'melatonin' from its ability to cause contraction of pigment in amphibian melanophores. This effect provided the first bioassay, but detailed studies awaited the more practical methodology of RIA and later GCMS. In 1965 as I finished my PhD (on tryptophan and its indolic analogues) there were 65 publications with the keyword melatonin in Pubmed. At the time of writing there are 23,549. At one time this small molecule acquired a popular reputation as a universal panacea and elixir of life. So where does the truth lie? Melatonin is secreted with a marked circadian rhythm, high at night in virtually all species in a 'normal' environment. Light of sufficient intensity and suitable spectral composition (short blue-green wavelengths are the most powerful) will suppress its secretion and is the most important factor maintaining synchrony with the 24h day-night cycle - as it is for the circadian system in general. The duration of secretion depends on the length of the night and this reliable indicator of daylength is used by photoperiodic species such as sheep and hamsters, to time seasonal functions such as reproduction and coat growth. This timing can be controlled using melatonin treatment to maximise benefits to producers. Even humans can show duration changes in melatonin in suitable circumstances but a clear link to human reproduction has yet to be demonstrated. The melatonin rhythm, timing and sometimes the amplitude, has proved to be the best index of human circadian function to date. Both plasma and saliva melatonin and urinary 6-sulphatoxymelatonin have been extensively used to follow states of circadian desynchrony in, for example, jet lag and shift work. It serves as a marker rhythm in much basic research on sleep and also metabolomics. Diagnosis of circadian rhythm sleep disorders such as delayed/advanced sleep phase and non-24h sleep wake disorder of the blind may need confirmation by melatonin measurement. Abnormally timed sleep in extreme environments such as Antarctica can partly be explained as circadian desynchrony evidenced by the timing of the melatonin rhythm. Melatonin is often referred to as the 'sleep hormone', whereas in fact it is a darkness hormone. It is, for example, high at night in nocturnal species. In humans surgical removal of the pineal may not be associated with sleep changes, however sleep propensity closely follows the night time rise and low dose exogenous melatonin can induce sleep during 'biological day' i.e. when the endogenous rhythm is low. More importantly exogenous melatonin can shift the timing of the circadian system by advance or delay when correctly timed, and correct timing is ideally calculated from the endogenous melatonin rhythm itself. Thus it has both chronobiotic and hypnotic properties -an ideal combination for the treatment of circadian rhythm sleep disorders. Meta-analyses have concluded that when correctly timed it is an effective therapy and to this end several analogues have been developed and are currently commercialised. Very many other properties have been attributed to this charismatic molecule and studies of its receptors and their variants are of exceptional interest. From its ability to set the timing of the circadian system and probably to reinforce 'coupling' it is not surprising to find effects on multiple systems. Our studies have considered it as a clock, a calendar, a circadian marker rhythm and a chronobiotic.

Where applicable, experiments conform with Society ethical requirements