Copyright© AE&M all rights reserved. 472 2). thepinealgland(Figure reach nerves theconary fibers forming ganglia,nerve cervical of thesuperior sympathetic neuron postganglionary ofthe aprojection Following,through the spinalcord. ofthefirstthoracic segmentsof sympathetic neurons to the preganglionic andindirectly directly projecting originating in the hypothalamic paraventricular nuclei, ofaneuralsystem pineal glandisunderthecontrol andothercelltypes(1). astrocytes cellscalledpinealocytes,inadditionto producing ventriclecontaining,inmammals, melatonin- third ofthe theroof glandoriginatingfrom neuroendocrine epithalamic Thepinealglandisanunpaired a hormone. in the blood, acting as released pineal gland and directly bythe in severaltissues,melatoniniscentrallyproduced mammals inparticular, inadditionoflocalproduction 1). In vertebrates, (Figure characteristics of diffusion oftheorganism foritsamphiphilic any compartment all living organisms.in It is an indolamine present beingfound inalmost ubiquitous moleculeinnature, is a Melatonin, N-acetyl-5-methoxytryptamine, MELATONIN Melatonin; pineal;hypermelatoninemia;hypomelatoninemia Keywords synthesis and/orfunctiondisruptions. with specific mechanisms and ways of action, besides presenting the clinical syndromes related to its widely spreadintheorganism. The presentreviewaimstofocusonmelatonin asapinealhormone presents specificmechanisms and agent,being ways ofactiondevoted toitsroleasatime-giving organism’s physiology tothedailyandseasonaldemands.Besidesbeingamphiphilic,melatonin its dark. This uniquetraitturnsmelatoninintoaninternalsynchronizer thatadequatelytimesthe the light-darkcycleviaretinohypothalamic tract,placingmelatonin synthesis atnight,provided in mammals.Itspinealsynthesisistimedbythesuprachiasmatic nucleus,thatissynchronized to besides beingahormonethatiscentrallyproducedinthepinealglandofvertebrates, particularly Melatonin isaubiquitousmoleculeinnature,beinglocallysynthesized in severalcellsandtissues, ABSTRACT Fernanda Gaspardo Amaral a pinealhormone reviewA brief aboutmelatonin, review Melatonin synthesisbythepinealocytesin 1 , José Cipolla-Neto Arch EndocrinolMetab. 2018;62(4):472-9 2 breakdown in retinal photoreceptive ganglion cells that photoreceptive in retinal breakdown stimulus (mainlyintheblue range) activatesmelanopsin itisdark.Light tothenight,provided tightly restricted tothelight/darkcycle,being in synchrony produced nuclei, thattimesmelatonin synthesissothatitisdaily system, mainlythehypothalamic suprachiasmatic 3). melatonin(3)(Figure amount ofproduced time,durationand and endocrinesystemsthatregulate ofneural underthecontrol enzymesaboveare The three (HIOMT). called hydroxy-indole-O-methyltransferase O-methyltransferase(ASMT)former by acetylserotonin tomelatonin (NAS)thatisconverted N-acetylserotonin N-acetyltransferase(AANAT) to arylalkylamine whichisacetylated,by toserotonin, is converted that, in turn, in 5-hydroxytryptophan transformed is hydroxylase, that, undertheactionoftryptophan pathways totriggermelatoninsynthesis(2). and activatescAMP-PKA-CREBPLC-Ca inthemembraneofpinealocytes receptors noradrenergic alpha beta and interacts withtheclassical terminals The major control is exerted by the circadian timing bythecircadian isexerted The majorcontrol Melatonin synthesisinitiateswithtryptophan bythesympathetic released Norepinephrine Arch Metab. Endocrinol 2018;62/4 Paulo (USP),SãoPaulo, SP, Brasil Biomédicas, Universidade deSão Biofísica, Instituto deCiências 2 (Unifesp), SãoPaulo, SP, Brasil Universidade Federal deSãoPaulo 1 05508-000 –SãoPaulo, SP,05508-000 Brazil Av. LineuPrestes, 1524 Bldg 1,UniversityofSãoPaulo Institute of BiomedicalSciences, Biophysics, NeurobiologyLab, Department ofPhysiology and José Cipolla-Neto Correspondence to: DOI: 10.20945/2359-3997000000066 on Ago/31/2018Accepted Receivedon Ago/31/2018 [email protected] Departamento deFisiologia, Departamento Departamento deFisiologiae Departamento ++ -PKC

Arch Metab. Endocrinol 2018;62/4 oftheblue range),blocksmelatonin (predominance signal, mainlywiththecharacteristics ofday-light tothenightandalight is restricted production 4). (7)(Figure nuclearreceptors Zreceptors) retinoid orphan receptors/ interact with ROR/RZR (retinoid melatoninmight membrane receptors, acting through system.Inadditionto as wellinthecentralnervous foundinalmostallperipheraltissues, are MT2 receptors MT1and andIP3formation. diacylglycerol increasing and/or cAMP and cGMP production decreasing phospholipase A2 andphospholipase C, generally messengers such as adenylyl cyclase, with downstream thatinteract receptors Go andGq/11protein-coupled Gi/ heterotrimeric are membrane melatoninreceptors humans) andMT2(MTNR1Binhumans).These oftwotypes,MT1(MTNR1A,in in mammals,are Membranemelatonin receptors, cellular receptors. specific melatoninactsthrough any otherhormone, intracellular antioxidant enzymatic system. Second, as species,butalsobymobilizingthe reactive nitrogen chelating oxygenand antioxidants, notonlybydirectly natural action. Melatonin is one ofthe mostpowerful of melatoninandothermolecules,asitsantioxidant interaction andinvolvethedirect by cellularreceptors not mediated mechanismsthatare are (6). First,there mechanisms of action developed several pleiotropic N-acetyl-5- methoxykynuramine(AMK)(5). to methoxykynuramine (AFMK)thatisdeformylated melatonin isdegradedtoN-acetyl-N2-formyl-5- system 3).Inthecentralnervous (Figure production to evaluatethepinealfunctionandmelatonin method isalessintrusive measurement its urinary theplasmalevelsofmelatonin,so reflects perfectly 6-sulfatoxymelatonin production excretion. urinary 6-sulfatoxymelatonin intheliver, forthesubsequent (mainlyCYP1A2) andconjugatedto P450 isoforms bycytochrome metabolized to6-hydroxymelatonin the blood, melatonin is usually bound to albumin, In during thenight,aswellintobloodstream. system fluidofthecentralnervous the cerebrospinal into ventricle wallallowsmelatonintobereleased and itsattachment,dorsalposterior, tothethird vascularized synthetized. Thepinealglandisprofusely asitis insidethepinealocytes,beingreleased stored hypothalamus, inhibitingmelatoninsynthesis(4). pathway, viatheretinohypothalamic project, tothe As mentioned before, melatonin hormonal pineal melatonin hormonal As mentioned before, Melatonin, asanancientchemicalmessenger, melatoninisnot Due toitsamphiphilicnature, summer time. nights of occurs following the short and the reverse longplasmamelatonindurationepisodes determine night asitvariesalongtheyear. Longwinternights episodefollowsthedurationof secretion nocturnal and asaconsequence,thedurationofmelatonin night.Inaddition, oftheenvironmental representative intotheinternal profile themelatoninnocturnal turned ofnaturalselectionthat istheproduct system control well-organized neural Thiscomplexandvery secretion. paraventricular nucleus. SCG: ganglion. superiorcervical retinohypothalamic tract. SCN: suprachiasmatic nucleus. PVH: Figure 2. Figure 1. Melatoninmolecule(232,2molecularweight). Neuralcontrolofpinealmelatonin synthesis. RHT: Melatonin hormonalways ofaction 473

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 474 and 5).Depending on themoleculareffectors (Figure called Theseare molecular effectors. andimmediate consequenceofitsinteractionwith direct seenasa are classical wayinthesensethat itseffects of action(8). mechanisms ofaction,developedseveralespecialways To dothat,melatonin,usingtheclassical hormonal theseasonsof the year.hours ofthedayandallthrough way, theorganism physiologyduringthe24 tocontrol photoperiod, melatonin has, in some environmental ofthe As aconsequenceofbeingrepresentative of the daily and seasonal photoperiod. representative melatonintotheinternal its duration,converts tothe night andto to day/nightcycle,restricted membrane receptors. and non-mediatedpathwaystheinvolvementofnuclear, cytosolicand Figure 4. enzymes arewritteninitalicandthederivedmoleculesunderlined. Figure 3. Melatonin hormonalways ofaction As any other hormone, melatonin acts through the melatoninactsthrough As anyotherhormone, rhythmsynchronized Melatonin synthesiscircadian Melatoninmechanismsofaction. Classicalreceptormediated Melatoninsynthesispathwayandhepaticmetabolization. The immediate effects

extend toseveralhours.OneexampleisthecAMP/ whenitismaximal andmay melatonin production, immediately after the cessation of of the morning, proximal orconsecutive 5).Thefirstone,called oftwotypes(Figure they are called night.Theseare previous intheimmediate itwaspresent melatonin, provided during theday, intheabsenceofplasma being triggered but,instead,itisonlyseen andreleased being produced one thatisnotseenduringthenightwhenmelatonin wayofaction,melatonin developedanother hormonal intracellular melatoninsignalingpathway. dependent onthetarget tissueandthecorrespondent are theeffects it wouldbeexpectedforanyhormone, ofpotassiumandcalciumchannels;etc.As regulation DAG, IP3, PKC activity; CREB and cGMP; increased ofcAMP-PKA- antioxidantaction;reduction effects: thepossible the involvedmechanismsofaction,suchare called clock-controlled genes, that are responsible for responsible genes, that are called clock-controlled cycle, thetranscriptionand translationofothergenes, the24-hour throughout can alsocontrol, proteins 24 hours (21). These has a duration of approximately orinhibitit,sothatthecycle theprocess reinforce mighteither proteins several genes and the resulting that includesacycleoftranscriptionandtranslation ofacomplexmolecularmachinery part clock genesare genes(CCG)(14-20).The and theclock-controlled and/or translation of the well-known clock genes (CG) thetranscription on theactionofmelatonincontrolling called are effects The secondtypeofmelatoninprospective andinthiscase,especiallythemorning. anymore, seen duringtheday, whenmelatoninisnot present best thatare effects only duringthenight,determines is tosaythatmelatonin,inspiteofbeingproduced (10-13).That consecutivemelatonineffect prospective the magnitudeanddurationofpotentiating beta cells,Leydig on the system(suprachiasmatic nucleus, pancreatic anyG through toanyagoniststhatactivatesadenylyl cyclase response andpotentiated signal,anincreased of theinhibitory this signalingpathwayshows,followingthecessation itsG melatonin through adenylylcyclaseinhibition inducedby and prolonged sustained is tosaythatinconsequenceofthenocturnal seen inseveralperipheralandcentralsystems(9).That PKA/CREB pathwaysuperorhypersensitizationthatis However, inadditiontothisclassicalandexpected distal orprolongedeffects s -protein coupled receptors. Depending coupledreceptors. -protein , isseenrightatthebeginning pars tuberalis i -protein coupled receptors, coupledreceptors, -protein Arch Metab. Endocrinol 2018;62/4 . These are dependent . Theseare prospective effects , etc.)suchis and Arch Metab. Endocrinol 2018;62/4 5).Thedurationofmelatonindiurnal (26-28) (Figure totheseasonalrhythms.Itisits is related organs, etc. betacells,reproductive muscle, pancreatic genes locatedinperipheraltissueslike,adiposetissue, including thesuprachiasmaticnucleusandclock timingsystem, its actionatseverallevelsofthecircadian of melatonin depends on effect 25) The chronobiotic like phase-delayed sleep onset disorder, jet lag, etc. (22- rhythmicityincases is usedinclinicstoadjustcircadian rhythmsand ofhumancircadian synchronizers powerful 5).Melatoninisoneofthemost of melatonin(Figure rhythms. Thisshapestheso-called ofcircadian synchronizer melatonin intotheinternal tothedarkphaseofdayturns relation its perfect ofmelatoninsignaland dailyrepetition The precise melatonin. valuesofcirculating anddiurnal nocturnal of themelatoninsignalandoncontrastbetween characteristic One ofthemdependsonthecircadian melatonindevelopedotherswaysofaction. effects, night. duringthe andreleased even beingonlyproduced and tissuefunctionalloverthe24-hoursofday, cell the cyclingofCGandCCG,isabletocontrol controlling effects, prolonged itsprospective through almost allcellfunctions.Thatistosaythatmelatonin, Proximal ouconsecutive andDistalorprolongedeffects. correspondent effects. The third-lineboxesshowexamplesofthe correspondenteffects. NotethattheProspectiveeffectsarefurther classifiedin Figure 5. Another important synchronizing effect ofmelatonin effect synchronizing Another important Mediated bytheseimmediateandprospective Melatoninwaysofaction. The upper boxesrepresentthedifferentwaysofaction. The second-line boxesexplainhowmelatonincausesthe chronobiotic effect seasonal effect

(29-33). etc. bodyweightcontrol, growth, and thermogenesis, energy metabolism,immuneresponse reproduction, seasonaleventslike system, melatoninisabletocontrol other mediators.Inconsequenceofthisfunctional several tanycytes, andtothedistalhypophysisthrough the hypothalamus,mediatedbyspecialglialcellscalled pars tuberalis of melatoninismediatedbyitsactiononthepituitary change alongtheyear. effect Theseasonalsynchronizing to anticipateandadapttheevolvingenvironmental seasonal rhythms,beingfundamentalfortheorganism of synchronizer melatoninintothemostpowerful turns duration of the day andnightalongthe year,relative thatisdependentonthetypical melatonin production) durationof ordecreasing inincreasing nights resulting ordecreasing increasing change ofitsduration(towards and,mostimportantly,profile ofthedaily thedirection are seeninthefetus,particularly,are thechronobiotic organism of melatoninthatcanbeseeninthematernal melatonin (35-37).Consideringthis,severaloftheeffects of beingitsonlysource thefetuscirculation, reaches theplacentaand crosses melatoninfreely Maternal (34). asthegestationprogress increases production In mammals,inhumansparticular,pinealmelatonin transgenerational effect Finally, anothermelatoninwayofactioncalled . From there, the signal is transduced to there, . From should be mentioned (Figure 5). shouldbementioned(Figure Melatonin hormonalways ofaction 475

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 476 dysfunctionis usually aconsequenceof receptor melatonin receptor-mediated response dysfunction isduetowhat can becalled (51-54) hyperhidrosis andspontaneous hypothermia Mendenhall syndrome Rabson- polycysticovariansyndrome, nervosa, hypogonadism, anorexia like hypogonadotrophic of pineal melatonin, usually associated to other diseases factor (e.glightatnight)(44-50). systemic disease(e.g.hyperglycemia) orenvironmental event,suchasa developed asaconsequenceofprimary and the pinealglandand/oritsinnervation, as canbeclassified population.Thissyndrome sex-paired to what is expected for the age- and when compared peakvalueortotalproduction melatonin nocturnal ( classified ashypo ( of view, dysfunctioncanbe melatoninhormonal 2018 (8). of this subject can be seen in Cipolla-Neto and Amaral, andneuroplasticity,protection etc.Adetaileddiscussion immune system; neural development, neural system; cardiovascular fetal developmentandprogramming; gestationand reproduction, and blood lipidprofile functions, asenergy metabolism,glycemiccontrol, of organism; sleepandwakefulnesscycle;endocrine andseasonaltiming functions. Amongthem,circadian several,ifnotall,thephysiological andneural regulate intheCNS,isableto anddirectly the bloodstream to as describedabove,inaddition of beingdelivered mechanisms ofactionanditsuniquewaysaction, Melatonin, duetoitsphylogenetichistory, itspleiotropic AND THERAPEUTICS MELATONIN PHYSIOLOGY, CLINICAL SYNDROMES fetus (43). ofthe fortheadequateneurodevelopment is necessary melatonin be dealtwith(41,42).Inaddition,maternal to environment systemtothefuture neuroendocrine its themothertofetus,preparing from transferred the fetusorganism. Similarly, theseasonaltimingis timingandprimingof forthecircadian responsible melatoninis (38-40).Maternal and seasonaleffects Melatonin hormonalways ofaction hypermelatoninemia primary A third syndrome associatedtopinealmelatonin syndrome A third is Hypermelatoninemia Hypomelatoninemia isdefinedbydecreased theclinicalpoint from As anyotherhormone, , dependenton ) production bythepinealgland. ) production . hypomelatoninemia

defined as hyperproduction defined ashyperproduction factors that directly affect affect factors thatdirectly . This melatonin- inappropriate ) or hyper secondary , (57,58). illumination duringtheevening/night, among others sleep-wake disorder, andasaconsequenceofindoors to the Smith-Magenis disease, the phase-delayed is usually associated other symptoms. This syndrome disturbances,among metabolic andcardiovascular timingdomain,causingsleep/wake, to thecircadian syndrome. thatiscalled profile causing a phase-displacement of its plasma production melatonin the timedisplacementofnocturnal associatedto possible todefineanothersyndrome andwaysofaction,itis characteristics ofproduction dysfunctions and due to melatonin specific (55,56). MT2 receptors eitherMT1or nucleotide polymorphisms)andaffect genetic variations (e.g.single melatonin receptors melatonin does not phase displace the circadian melatonin does notphasedisplacethe circadian bedtime andextendingto 2to4hoursafterwards, theusual 1hour before the evening,beginningaround during clock;ifadministered phase-delay thecircadian melatonin would the end of the night/early morning, in if administered the sleep-wake phase-delay disorder); of rhythms (asisthecasefortreatment the circadian beginning of the evening, melatonin phase-advances inthelateafternoon/ rhythms. Ifadministered delay orevennophase-displacementofthecircadian inphase-advance,phase- clock resulting the circadian moment ofadministration,melatoninisabletoacton That is to say that depending on the curve. response bythewell-knownmelatoninphase- will bedetermined that effect evening/night willdependonthedesired Themomentofadministration duringthe production. during the evening/night, mimicking the physiological metabolism (59). in alowbioavailabilityduetothefirstpassliver melatonin,resulting minutes after orally administered 45 thepeakatapproximately concentration reaches studiesshowthatplasma patient, pharmacokinetic and sex.Usually, inayoung/middle-agedhuman dependingonage Each oftheseaspectsmightvary P450 complex, mainly CYP1A2). of cytochrome hepatic metabolizationrates(dependentontheactivity etc.)andontheindividualabsorption or cream, intravenous, nasalspray, analsuppository, skinpatches way of administration (oral, fast and/or slow-release, Melatonin pharmacokinetics will dependon the Melatonin pharmacokinetics Finally, inadditiontotheseclassicalhormonal Melatonin administrationshouldalwaysbedone The result is a misalignment of the organism The result melatonin circadian displacement Arch Metab. Endocrinol 2018;62/4 Arch Metab. Endocrinol 2018;62/4 is is toexpect, as farhypoorhyperproduction clinical endocrinology when dealing with melatonin done. Themostcommon mistakethatwefindin shouldbeadditionally dysfunction someobservations human physiologyandpathophysiology. tothemammalianand decisivelyimportant hormone considering melatonin as a time to change thispicture, melatonin isneversystematicallytaught.So,itabout medical schoolsallovertheworld,pinealglandand/or Inaddition,inseveral reported. its complexityisbarely is mostlydedicatedtopinealtumors.Melatonininall for alongtime,fullchaptertothepinealglandthat devoted, justafterit.Jameson&DeGroot scanty part organs sectionandis,nowadays,located inaseparate included foralongtimeinthecircumventricular Endocrinology, forexample,thepinealglandwas textbookof or Endocrinologybooks.InWilliams’ targeted in action the classical is Physiology scarcely & Metabolism).Inspiteofthis,melatoninhormonal ofEndocrinology inthearea (6th outof143journals showing the 2017 impact factor of 11.613 Research) ofPineal (Journal addition toadedicatedjournal peryear,or pinealandabout1,200newarticles in about33,000papersmelatonin are that there inPubMed/NCBI shows Nowadays, anyquicksearch CONCLUSIONS nightmares. somnolenceornocturnal as diurnal of adverse effects of the symptoms and the occurrence individually adjustedbytheevaluationofevolution should alwayskeepinmindthatthedosagemustbe with 1.0to5.0mgoralmelatonin.However, one usuallytreated are sleepdisorders Melatonin-responsive timing,asinjetlagforexample. circadian for proper young people.Inaddition,0.5to1.0mgisusuallyused peakin physiological concentrationatthenocturnal 100 to500pg/mL,thatis15timestheexpected from usually generatesaplasmaconcentrationvarying goal, oralmelatoninintherangeof0.1to0.5mg therapyisthe Ifreplacement effect. on thedesired administrationduringtheday.avoid itschronic discussed melatoninwaysofaction,oneshouldalways pinealectomized orelderpatients). asinthe time ofchoiceifmelatoninisbeingreplaced, clock pace (this is the the circadian rhythms, regulating Concerning the clinical aspects of melatonin Concerning andwilldepend The dosageisalwaysaconcern It shouldbesaidthat,consideringtheabove repercussions, etc. (60). It should be considered, still, etc.(60).Itshouldbeconsidered, repercussions, GITevents,reproduction/sexual loss ofperformance, system(hypertension), etc.),cardiovascular overweight, critical alterations in metabolism(insulinresistance, several inthemedium/long term, it willdetermine, bythepatientandphysician.However,perceived daywillnotbeeven 30 minutessleepepisodeevery alteration inthesleeporganization as littleshorter status inthe and willbereflected still there inotherglandsbutis is notsotintedasexpressed induces an unhealthy state whose clinical pictures andseasonaltime.Itsabsence behavior inthecircadian thatorganizes physiologyand domain actinghormone the casewithpinealandmelatoninasitisatime- Itisnot andimmediatehealthrepercussions. effects immediate to occurwiththeclassicalglandssyndromes: exactly the samethat we wouldbeexpected concerned, 6. 5. 4. 3. 2. 1. 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