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Light, Dark, and Melatonin: Emerging Evidence for the Importance Of Eye (2007) 21, 901–908 & 2007 Nature Publishing Group All rights reserved 0950-222X/07 $30.00 www.nature.com/eye 1 2 1 Light, dark, and R Brennan , JE Jan and CJ Lyons REVIEW melatonin: emerging evidence for the importance of melatonin in ocular physiology Abstract very rarely are we reminded of its phylogenetic origin as the third eye, when a mutation in its Melatonin is a hormone, which is mainly modified photoreceptors results in ‘trilateral produced by the pineal gland, a vestigial retinoblastoma’. Its product, the hormone eye. Rather than the rods and cones, it is a melatonin has been the subject of intense newly discovered subgroup of photosensitive 1Department of research and turns out to be a simple molecule retinal ganglion cells, which is responsible Ophthalmology, British of fundamental importance to many quite for mediating the light–dark cycles, thus Columbia Children’s disparate physiological systems in the human regulating melatonin’s secretion. One of Hospital, Vancouver, British body, including the eye. This review of Columbia, Canada the correlates of the circadian rhythm of melatonin describes: the nonvisual ocular melatonin release is the habitual sleep pattern. 2 photoreceptive pathway that regulates Principal investigator, Patients with circadian rhythm sleep Melatonin Research Group, melatonin production, melatonin’s influence on disorders, including some blind patients with Mental Health Research circadian rhythms, in particular its effect no light-induced suppression of melatonin, Unit, British Columbia on sleep cycles, the current knowledge benefit from melatonin treatment. Melatonin Children’s Hospital, of melatonin’s actions within the eye, Vancouver, British is synthesized in the retina, lens, ciliary body and finally its side effect profile. Columbia, Canada as well as other parts of the body. In this review, we discuss the physiological roles of Correspondence: melatonin in the eye, as well as the potential CJ Lyons, Melatonin therapeutic avenues currently under study. Department of Eye (2007) 21, 901–908; doi:10.1038/sj.eye.6702597; Melatonin, first identified in the late 1950s was Ophthalmology, Room A 136, published online 22 September 2006 given its name to reflect its melanin granule- British Columbia 1 aggregating effect. This very ancient molecule Children’s Hospital, Keywords: melatonin; circadian rhythms; retinal exists in organisms as simple and primitive as 4480 Oak Street, ganglion cells; sleep prokaryotes and as complex as humans.2 It acts Vancouver, British as a free radical scavenger and an antioxidant, Columbia, Canada V6H 3V4 possibly its initial function 2–3.5 billion years Tel: þ 001 604 875 2345; ago. Since then its actions have diversified in Introduction Fax: þ 001 604 875 3561. increasingly complex organisms and range from E-mail: [email protected] Deep beneath the cerebral cortices, a vestigial circadian adjustments,3 to a function in seasonal eye measures and keeps time. In a sense, the reproduction.4 It acts on the suprachiasmatic Received: 23 March 2006 pineal gland is ophthalmology territory. Few nucleus to modify the timing of sleep, causing Accepted in revised form: 5 8 August 2006 clinical situations draw the pineal gland to the relative hypothermia, and in the retina, rod Published online: 6 ophthalmologist’s attention: calcified in later life disc shedding. 22 September 2006 and thus radio-opaque, it was historically an Although melatonin is present in food such important radiological marker of midline shift as fruit, vegetables, and wheat,7 melatonin A presentation based on on plain X-ray. Pineal enlargement by tumour ingested with a normal diet does not this review was made at the meeting ‘Pediatric may obstruct the cerebral aqueduct causing significantly contribute to circulating levels. Ophthalmology, Adult papilloedema or damage the nearby tectal Instead, it is mostly produced by the pineal Strabismus’, Vancouver, structures causing Parinaud’s syndrome. Only gland, and the retina,8 lens,9 iris, ciliary body,10 September 2005 Melatonin and ophthalmology: a review R Brennan et al 902 lacrimal gland,11 skin,12 and gut13 also produce small only become light responsive at the 10th postnatal day, amounts. It is synthesized through conversion of whereas intrinsically photosensitive retinal ganglion cells tryptophan to serotonin, then to N-acetylserotonin, expressing melanopsin are light sensitive from birth.26 and finally to melatonin (or N-acetyl-5- These photosensitive retinal ganglion cells are directly methoxytryptamine).14 Two enzymes, arylalkylamine connected to (1) the suprachiasmatic nucleus for N-acetyltransferase (NAT) and hydoxyindole-O- circadian photoentrainment, (2) the lateral geniculate methyltransferase catalyse the rate-limiting steps. body possibly contributing to conscious visual Serum melatonin concentration varies with age: perception,23 and (3) the olivary pretectal nucleus normal neonates secrete very little but levels rise shortly to drive the pupillary light reflex. thereafter and become circadian at about 2–3 months of It is thought that at least one other photopigment must age,15 coinciding with a more rhythmical sleep–wake be involved in light–dark circadian rhythm entrainment pattern. Daytime concentrations remain low throughout because mice without melanopsin have an attenuated but life but night time concentrations peak in humans recordable bright light phase shift in circadian rhythms. between 1 and 3 years of age,16 gradually reducing Also vitamin A depletion (detrimental to melanopsin, through puberty owing to dilution in the increased body rods, and cone functioning) does not degrade pupillary volume.17 The diurnal variation persists in adulthood light responses and circadian entrainment to light–dark with peak serum levels occurring between 2 AM and 4 AM. cycle, and not all ganglion cells that project to the Eventually, in old age, this prominent night-time peak suprachiasmatic nucleus contain melanopsin. becomes markedly attenuated.18 Currently, cryptochromes that function in blue light are considered likely candidates.27 Cryptochromes undergo a conformational change on exposure to light28 Light control of pineal melatonin secretion and are involved in light responsive induction of c-fos It has been suspected for some time that different (a marker for circadian phototransduction) in the photoreceptors subserve sight and melatonin production. suprachiasmatic nucleus.27 Thus, some blind people without pupil light reflexes Photic input to the suprachiasmatic nucleus is not have light-induced suppression of melatonin secretion; the sole modulator of circadian rhythms and melatonin their eyes serve more than a cosmetic function as they do secretion. The suprachiasmatic nucleus contains not report insomnia.19 Conversely, blind patients without heterogeneous cells and is part of a large neurological light-induced suppression of melatonin do have sleep network receiving and sending synaptic and disorders. neurochemical messages. Craniopharyngiomas can cause A ‘non-rod’, ‘non-cone’ photoreceptor was suspected damage to the suprachiasmatic nucleus. Affected when transgenic mice lacking both rods and cones were patients in addition to having neuroendocrinopathies, nevertheless found to have light-responsive clocks.20 can have alterations of their sleep–wake cycles and Furthermore, monochromatic blue light of 446–477 nm cognitive abilities.29 wavelength was found to be the strongest input for The genetic basis of time keeping has recently been melatonin regulation in healthy subjects, suggesting that elucidated: it is based on a feedback loop system in a photo pigment distinct from that of rods and cones was which a gene produces a protein which inhibits the responsible for melatonin regulation.21 activation of that gene. The mouse circadian clock The mystery photoreceptor involved in melatonin depends on a complex set of interacting positive and regulation was identified a couple of years ago: it is the negative genetic transcriptional feedback loops involving retinal ganglion cell.22 A total of 0.2% of retinal ganglion transcriptional factors named Clock and BMAL1/ cells contain melanopsin and respond directly to light Mop3,30 three period genes and two cryptochrome even when isolated pharmacologically or physically from genes.31 It is likely that numerous other as yet other retinal neurons.23 In addition to being intrinsically unidentified genes are involved in rhythm generation. photosensitive, they are activated by rods and cones and Although some other mammalian tissues have been have an unusual colour-opponent receptive field where demonstrated to independently generate circadian an S cone-mediated Off response is antagonistic to an rhythms, it appears that the suprachiasmatic nucleus (L þ M) cone-mediated On response.23 The dendritic is the principal regulator of circadian behaviours.30 networks of these photosensitive retinal ganglion cells cover large areas of retina with peak densities in the Neuroanatomy parafoveal retina.23 They react slowly but tonically to luminance changes24 and stimulation of the nasal In mammals, the components of circadian melatonin hemiretina causes maximal melatonin suppression in rhythm production are distributed in three different humans.25 In the mouse, rod and cone photoreceptors areas, all in the diencephalon: the photoreceptors are Eye Melatonin and ophthalmology: a review R Brennan et al 903 in the retina, the endogenous oscillator (the ‘internal in rats the gut’s melatonin levels may by determined clock’
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