Advertisement
Research Article| Volume 27, ISSUE 2, P202-209, March 2009

Melatonin: circadian rhythm regulator, chronobiotic, antioxidant and beyond

      Abstract

      For many years, melatonin has been known to interact with circadian rhythms.
      New evidence indicates that melatonin acts as a free radical scavenger and antioxidant.
      Moreover, melatonin prevents apoptosis in different types of cells, because it induces mRNA levels of several antioxidant enzymes.
      It is evident that melatonin is involved in the cellular bioenergetic system as a mechanism that counteracts the progression of Alzheimer's disease.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinics in Dermatology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Lezoual'h F.
        • Skutella T.
        • Widmann M.
        • et al.
        Melatonin prevents oxidative stress-induced cell death in hippocampal cells.
        NeuroReport. 1996; 7: 2071-2077
        • Borlongan C.V.
        • Yamamoto M.
        • Takei N.
        • et al.
        Glial cell survival is enhanced during melatonin-induced neuroprotection against cerebral ischemia.
        FASEB J. 1998; 12: 725-731
        • Chen S.T.
        • Chuang J.I.
        The antioxidant melatonin reduces cortical neuronal death after intrastriatal injection of kainate in the rat.
        Exp Brain Res. 1999; 124: 241-247
        • Mayo J.C.
        • sainz R.M.
        • Uria H.
        • et al.
        Melatonin prevents apoptosis induced by 6-hydroxydopamine in neuronal cells: implications for Parkinson's disease.
        J Pineal Res. 1998; 24: 179-192
        • Hasegawa A.
        • Ohtsubo K.
        • Mori W.
        Pineal gland in old age; quantitative and qualitative morphological study of 168 human autopsy cases.
        Brain Res. 1987; 409: 343-349
        • Swaab D.F.
        Aminoff M.J. Francois B. Swaab D.F. The human hypothalamus basic and clinical aspects. Handbook of Clinical Neurology. vol 79. Elsevier, Amsterdam2003: 63-123
        • Arendt J.
        Melatonin and the Mammalian Pineal Gland. Chapman & Hall, London1995: 27-59
        • Dai J.
        • Swaab D.F.
        • van der Vliet J.
        • et al.
        Postmortem tracing reveals the organization of hypothalamic projections of the suprachiasmatic nucleus in the human brain.
        J Comp Neurol. 1998; 400: 87-102
        • Reiter R.J.
        The melatonin rhythm: both a clock and a calendar.
        Experientia. 1993; 49: 654-664
        • Coon S.L.
        • Del Olmo E.
        • Young III, W.S.
        • et al.
        Melatonin synthesis enzymes in Mecaca mulatta: focus on arylalkylamine N-acetyltransferase (EC 2. 3. 1. 87).
        J Clin Endocrinol Metab. 2002; 87: 4699-4706
        • Wu Y.H.
        • Feenstra M.G.
        • Zhou J.N.
        • et al.
        Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages.
        J Clin Endocrinol Metab. 2003; 88: 5898-5906
        • Dai J.
        • Van Der Vliet J.
        • Swaab D.F.
        • et al.
        Humans retinohypothalamic tract as revealed by in vitro post-mortem tracing.
        J Comp Neurol. 1998; 397: 357-370
        • Teclemariam-Mesbah R.
        • Ter Horst G.J.
        • Postema F.
        • et al.
        Anatomical demonstration of the suprachiasmatic nucleus-pineal pathway.
        J Comp Neurol. 1999; 406: 171-182
        • Skene D.J.
        • Lockely S.W.
        • James K.
        • et al.
        Correlation between urinary cortisol and 6-sulphatoxymeltonin rhythms in field studies of blind subjects.
        Clin Endocrinol. 1999; 50: 715-719
        • Karasek M.
        • Stankiewicz A.
        • Bandurska-Stankiewicz E.
        • et al.
        Melatonin concentrations in patients with large goiter before and after surgery.
        Neuroendocrinol Lett. 2000; 21: 437-439
        • Bruce J.
        • Tamarkin L.
        • Riedel C.
        • et al.
        Sequential cerebrospinal fluid and plasm sampling in humans: 24-hour melatonin measurements in normal subjects and after peripheral sympathectomy.
        J Clin Endocrinol Metab. 1991; 72: 819-823
        • Oxenkrug G.F.
        • Anderson G.F.
        • Gragovic L.
        • et al.
        Circadian rhythms of human pineal melatonin, related indoles, and beta adrenoreceptors: post-mortem evaluation.
        J Pineal Res. 1990; 9: 1-11
        • Stoschitzky K.
        • Sakotnik A.
        • Lercher P.
        • et al.
        Influence of beta-blockers on melatonin release.
        Eur J Clin Pharmacol. 1999; 55: 111-115
        • Liu C.
        • Weaver D.R.
        • Jin X.
        • et al.
        Molecular dissection of two dinstinct actions of melatonin on the suprachiasmatic circadian clock.
        Neuron. 1997; 19: 91-102
        • Fisher S.
        • Smolnik R.
        • Herms M.
        • et al.
        Melatonin acutely improves the neuroendocrine architecture of sleep in blind individuals.
        J Clin Endocrinol Metab. 2003; 88: 5315-5320
        • Spitzer R.L.
        • Terman M.
        • Williamns J.B.W.
        • et al.
        Jet lag: clinical features, validation of a new syndrome-specific scale, and lack of response to melatonin in a randomised, double-blind trial.
        Am J Psychiatry. 1999; 156: 1392-1396
        • Herxhaimer A.
        • Petrie K.J.
        Melatonin for the prevention and treatment of jet lag (Cochrane Review). Cochrane Library, Issue 3. Update Software, Oxford2001: 8
        • Westchester I.L.
        The international classification of sleep disorders: diagnostic and coding manual.
        Am Acad Sleep Med. 2005;
        • Weitzman E.D.
        • Czeister C.A.
        • Coleman R.M.
        • Spielman A.J.
        • Zimmerman J.C.
        • Dement W.
        Delayed sleep phase syndrome: a chronobiological disorder with sleep-onset insomnia.
        Arch Gen Psychiatry. 1981; 38: 137-146
        • Kerkhof G.
        • Vian Vianen B.
        Circadian phase estimation of chronic insomniacs relates to their sleep characteristics.
        Arch Physiol Biochem. 1999; 107: 383-392
        • Watanabe T.
        • Kajimura N.
        • Kato M.
        • et al.
        Sleep and circadian rhythm disturbances in patients with Delayed Sleep Phase Syndrome.
        Sleep. 2003; 26: 657-661
        • Strogatz S.h.
        • Kronauer R.E.
        Circadian wake maintenance zones and insomnia in man.
        Sleep Res. 1985; 14: 219
        • Dawson D.
        • Lack L.
        • Morris M.
        Phase resetting of the human circadian pacemaker with use of a single pulse of bright light.
        Chronobiol Int. 1999; 10: 94-102
        • Sack R.
        • Lewy A.
        • Hughes R.
        Use of melatonin for sleep and circadian rhythm disorders.
        Ann Med. 1998; 30: 115-121
        • Lewy A.
        • Ahmed S.
        • Jackson J.M.
        • Sack R.L.
        Melatonin shifts human circadian rhythms according to phase-response curve.
        Chronobiol Int. 1992; 9: 380-392
        • Revell V.L.
        • Burgess H.J.
        • Gazda C.J.
        • Smith M.R.
        • Fogg L.F.
        • Eastman C.I.
        Advancing human circadian rhythms with afternoon melatonin and morning intermittent bright light.
        J Clin Endocrinol Metab. 2006; 91: 54-59
        • Buscemi N.
        • Vandermeer B.
        • Hooton N.
        • et al.
        The efficacy and safety of exogenous melatonin for primary sleep disorders: A meta-analysis.
        J Gen Intern Med. 2005; 20: 1151-1158
        • Brzezinski A.
        • Vangel M.G.
        • Wurtman R.J.
        • et al.
        Effects of exogenous melatonin on sleep: a meta-analysis.
        Sleep Med Rev. 2005; 9: 41-50
        • Hardeland R.
        • Poeggeler B.
        Non-vertebrate melatonin.
        J Pineal Res. 2003; 34: 233-234
        • Srinivasan V.
        • Pandi-Perumal S.R.
        • Cardinali D.P.
        • Poeggler B.
        • Harderland R.
        Melatonin in Alzheimer's disease and other neurodegenerative disorders.
        Behav Brain Funct. 2006; : 2-15
        • Tan D.X.
        • Reiter R.J.
        • Manchester L.C.
        • et al.
        Chemical and physical properties and potential mechanism: melatonin as a broad spectrum antioxidant and free rdical scavenger.
        Curr Top Med Chem. 2002; 2: 181-197
        • Buyukavci M.
        • Ozdemir O.
        • Buck S.
        • Stout M.
        • Ravindranath Y.
        • Savasan S.
        Melatonin cytotoxicity in human leukaemia cells: relation with its prooxidant effect.
        Fundam Clin Pharmacol. 2006; 20: 73-79
        • Lahiri D.K.
        • Ge Y.W.
        • Sharman E.H.
        • Bondy S.C.
        Age-related changes in serum melatonin in mice: higher levels of combined melatonin and 6-hydroxymelatonin sulphate in the cerebral cortex than serum, heart, liver and kidney tissues.
        J Pineal Res. 2004; 36: 217-223
        • Sanchez-Moreno C.
        • Dorfman S.E.
        • Lichtenstein A.H.
        • Martin A.
        Dietary fat type affects vitamins C and E and biomarkers of oxidative status in peripheral and brain tissue of golden Syrian hamsters.
        J Nutr. 2004; 134: 655-660
        • Filadelfi A.M.
        • Castrucci A.M.
        Comparative aspects of the pineal melatonin system of poikilothermic vertebrates.
        J Pineal Res. 1996; 20: 175-186
        • Kotler M.
        • Rodriguez C.
        • Sainz R.M.
        • Antolin I.
        • Menendez-Pelaez A.
        Melatonin increases gene expression for antioxidant enzymes in rat brain cortex.
        J Pineal Res. 1998; 24: 83-89
        • Rodriguez C.
        • Mayo J.C.
        • Sainz R.M.
        • Antolin I.
        • Herrera F.
        • Martin V.
        • Reiter R.J.
        Regulation of antioxidant enzymes: a significant role for melatonin.
        J Pineal Res. 2004; 36: 1-9
        • Anisimov S.V.
        • Popovic N.
        Genetic aspects of melatonin biology.
        Rev Neurosci. 2004; 15: 209-230
        • Reiter R.J.
        • Acuna-Castroviejo D.
        • Tan D.X.
        • Burkhardt S.
        Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system.
        Ann N Y Acad Sci. 2001; 939: 200-215
        • Conway S.
        • Drew J.E.
        • Mowat P.
        • Barret P.
        • Delagrange P.
        • Morgan P.J.
        Chimeric melatonin mtl and melatonin-related receptors. Identification of domains and residues participating in ligand binding and receptor activation of the melatonin mtl receptor.
        J Biol Chem. 2000; 275: 20602-20609
        • Garcia-Maurino S.
        • Pozo D.
        • Calvo J.R.
        • Guerrero J.M.
        Correlation between nuclear melatonin receptor expression and enhanced cytokine production in human lymphocytic and monocytic cell lines.
        J Pineal Res. 2000; 29: 129-137
        • Carlberg C.
        • Wiesenberg I.
        The orphan receptor family RZR/ROR, melatonin and 5-lipoxygenase. An unexpected relationship.
        J Pineal Res. 1995; 18: 171-178
        • Yu B.P.
        • Chung H.V.
        Adaptive mechanism to oxidative stress during aging.
        Mech Ageing Dev. 2006; 127: 436-443
        • Skene D.J.
        • Swaab D.F.
        Melatonin rhythmicity: effect of age and Alzheimer's disease.
        Exp Gerontol. 2003; 38: 199-206
        • Duffy J.F.
        • Zeitzer J.M.
        • Rimmer D.W.
        • et al.
        Peak of circadian melatonin rhythm occurs later within the sleep of older subjects.
        Am J Physiol Endocrinol Metab. 2002; 282: E297-E303
        • Kunz D.
        • Schmitz S.
        • Mahlberg R.
        • et al.
        A new concept for melatonin deficit: on pineal calcification and melatonin excretion.
        Neuropsychopharmacology. 1999; 21: 765-772
        • Kunz D.
        • Bes F.
        • Schlattmann P.
        • et al.
        On pineal calcification and its relation to subjective sleep perception: a hypothesis-driven pilot study.
        Psychiatry Res. 1998; 82: 187-191
        • Urata Y.
        • Honma S.
        • Goto S.
        • et al.
        Melatonin induces glutamylcysteine synthase mediated by activator protein-I in human vascular endothelial cells.
        Free Radic Biol Med. 1999; 27: 838-847
        • Martin M.
        • Macias G.
        • Escames G.
        • et al.
        Melatonin-induced increased activity of the respiratory chain complexes I and IV can prevent mitochondrial damage induced by ruthenium red in vivo.
        J Pineal Res. 2000; 28: 242-248
        • Harrison T.
        • Churcher I.
        • Beher D.
        Gamma-secretase as a target for drug intervention in Alzheimer's disease.
        Curr Opin Drug Discov Devel. 2004; 7: 709-719
        • Zatta P.
        • Tognon G.
        • Carampin P.
        Melatonin prevents free radical formation due to the interaction between beta-amyloid peptides and metal ions [Al(III), Zn(II), Cu(II), Mn(II), Fe(II)].
        J Pineal Res. 2003; 35: 98-103
        • Acuna-Castroviejo D.
        • Martin M.
        • Macias M.
        • et al.
        Melatonin, mitochondria, and cellular bioenergetics.
        J Pineal Res. 2001; 30: 65-74
        • Liu R.Y.
        • Zhou J.N.
        • Van Heerikhuize J.
        • Hofman M.A.
        • Swaab D.F.
        Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer's disease, and apolipoprotein E-epsilon4/4 genotype.
        J Clin Endocrinol Metab. 1999; 84: 323-327
        • Beal M.F.
        Mitochondria, free radicals, and neurodegeneration.
        Curr Opin Neurobiol. 1996; 6: 661-666
        • Floyd R.A.
        • Hensley K.
        Oxidative stress in brain aging, Implications fot therapeutics of neurodegenerative diseases.
        Neurobiol Aging. 2002; 23: 795-807
        • Huang X.
        • Moir R.D.
        • Tanzi R.E.
        • Bush A.I.
        • Rogers J.T.
        Redox-active metals, oxidative stress, and Alzheimer's disease pathology.
        Ann N Y Acad Sci. 2004; 1012: 153-163
        • Zhu X.
        • Raina A.K.
        • Perry G.
        • Smith M.A.
        Alzheimer's disease:the two-hit hypothesis.
        Lancet Neurol. 2004; 3: 219-226
        • Cheng Y.
        • Feng Z.
        • Zhang Q.Z.
        • Zhang J.T.
        Beneficial effects of melatonin in experimental models of Alzheimer disease.
        Acta Pharmacol Sin. 2006; 2: 129-139
        • Blennow K.
        • Cowburn R.F.
        The neurochemistry of Alzheimer's disease.
        Acta Neurol Scand. 1996; 168: 77-86
        • Ancoli -Israel S.
        • Klauber M.R.
        • Jones D.W.
        • et al.
        Variations in circadian rhythms of activity, sleep, and light exposure related to dementia in nursing-home patients.
        Sleep. 1997; 20: 18-23
        • Martin J.
        • Marler M.
        • Shochat T.
        • et al.
        Circadian rhythms of agitation in institutionalized patients with Alzheimer's disease.
        Chronobiol Int. 2000; 17: 405-418
        • Ohashi Y.
        • Okamoto N.
        • Uchida K.
        • et al.
        Daily rhythm of serum melatonin levels and effect of light exposure in patients with dementia of the Alzheimer's type.
        Biol Psychiatry. 1999; 45: 1646-1652
        • Wu Y.H.
        • Swaab D.F.
        The human pineal gland and melatonin in aging and Alzheimer's disease.
        J Pineal Res. 2005; 38: 145-152
        • Zhou J.N.
        • Liu R.Y.
        • Kamphorst W.
        • et al.
        Early neuropathological Alzheimer's changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels.
        J Pineal Res. 2003; 35: 125-130
        • Pappola M.A.
        • Chyan Y.J.
        • Poeggeler B.
        • et al.
        An assessment of the antioxidant and antiamyloidogenic properties of melatonin: Implications for Alzheimer's disease.
        J Neural Transm. 2000; 107: 203-231
        • Rousseau A.
        • Petren S.
        • Plannthin J.
        • et al.
        Serum and cerebrospinal fluid concentrations of melatonin: a pilot study in healthy male volunteers.
        J Neural Transm. 1999; 106: 883-888
        • Reiter R.J.
        • Tan D.X.
        • Machester L.C.
        • et al.
        Melatonin reduces oxidant damage and promotes mitochondrial respiration: implications for aging.
        Ann N Y Acad Sci. 2002; 959: 238-250
        • Pardo C.A.
        • Martin L.J.
        • Troncoso J.C.
        • et al.
        The human pineal gland in aging and Alzheimer's disease: patterns of cytoskeletal antigen immunoreactivity.
        Acta Neuropathol. 1990; 80: 535-540
        • Liu R.Y.
        • Zhou J.N.
        • Hoogenduk W.J.
        • et al.
        Decreased vasopressing gene expression in the biological clock of Alzheimer disease patients with and without depression.
        J Neuropathol Exp Neurol. 2000; 59: 314-322
        • Van De Nes J.A.
        • Kamphorst W.
        • Ravid R.
        • et al.
        Comparison of beta-protein/A4 deposits and Alz-50-stained cytoskeletal changes in the hypothalamus and adjoining areas of Alzheimer's disease patients: amorphic plaques and cytoskeletal changes occur independently.
        Acta Neuropathol. 1998; 96: 129-138
        • Stopa E.G.
        • Volicer L.
        • Kuo-Leblanc V.
        • et al.
        Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia.
        J Neuropathol Exp Neurol. 1999; 58: 29-39
        • Campbell S.S.
        • Kripke D.F.
        • Gillin J.C.
        • et al.
        Exposure to light in healthy elderly subjects and Alzheimer's patients.
        Physiol Behav. 1998; 42: 141-144
        • Blanks J.C.
        • Torigoe Y.
        • Hinton D.R.
        • et al.
        Retinal pathology in Alzheimer's disease. I. Ganglion cell loss in foveal/parafoveal retina.
        Neurobiol Aging. 1996; 17: 377-384
        • Blanks J.C.
        • Schmidt S.Y.
        • Torigoe T.
        • et al.
        Retinal pathology in Alzheimer's disease. II. Regional neuron loss and glial changes in GCL.
        Neurobiol Aging. 1996; 17: 385-395
        • Cohen-Mansfield J.
        • Garfinkel D.
        • Lipson S.
        Melatonin for treatment of sundowning in elderly persons with dementia – a preliminary study.
        Arch Gerontol Geriatr. 2000; 31: 65-76
        • Brusco L.I.
        • Marquez M.
        • Cardinali D.P.
        Melatonin treatment stabilizes chronobiologic and cognitive symptoms in Alzheimer's disease. Neuroendocrinol.
        Letter. 2000; 21: 39-42
        • Cardinali D.P.
        • Brusco L.I.
        • Liberczuk C.
        • et al.
        REVIEW. The use of melatonin in Alzheimer's disease.
        Neuroendocrinol Lett. 2002; 23: 20-23
        • Singer C.
        • Tractenberg R.E.
        • Kaye J.
        • et al.
        A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer's disease.
        Sleep. 2003; 26: 893-901
        • Sefarty M.
        • Kennel-Webb S.
        • Warner J.
        • et al.
        Double blind rendomised placebo controlled trial of low dose melatonin for sleep disorders in dementia.
        Int J Geriatr Psychiatry. 2002; 17: 1120-1127