[1] 15w Protective roles of melatonin in central nervous system diseases by regulation of neural stem cells

[1] 29w Neuralstemcells(NSCs)areimmatureprecursorsofthecentralnervoussystem(CNS), with self-renewal and multipotential differentiation abilities. Their proliferation and differentiationaredynamicallyregulatedbyhormonalandlocalfactors.Alterationin neurogenesisisassociatedwithmanyneurologicaldisorders.Increasingevidencesuggests that modulation of NSCs can be a promising therapeutic approach for neural injuryandneurodegenerativedisorders.Melatonin,apinealgland-derivedhormone, regulatestheneuroimmuno-endocrineaxisandisfunctionallyimportanttothecircadianrhythm,tumoursuppressionandimmunity.IntheCNS,melatoninexertsneuroprotectiveeffectsinmanydiseases,suchasParkinson'sdisease,Alzheimer'sdisease andischaemicbraininjury.Emergingevidencesuggeststhatitmightalsomediatesuch protectiveactionbyinfluencingproliferationanddifferentiationofNSCs.Inthisarticle,wereviewthecurrentliteratureconcernedwitheffectsofmelatoninonNSCsin differentphysiologicalandpathologicalconditions.

[1] 48w Neural stem cells (NSCs) are immature precursor cells that possess self-renewalandmultipotentialdifferentiationabilitiesinbothdeveloping and adult brains. [1][2][3][4] Inthecentralnervoussystem(CNS),neurons,astrocytesandoligodendrocytesalloriginatefromNSCs. 5 Given their potential to replace injured and demised neurons in diseased brains,transplantationofNCSshasbeenpromulgatedasanovelther-apeuticapproachformanyCNSdisorders,suchasneuralinjuryand neurodegenerative diseases. In this connection, efforts have been made to identify extrinsic factors capable of regulating the survival, proliferationanddifferentiationofNSCs.

[2] 100w Melatonin (N-acetyl-5-methoxytryptamine) is not only secreted by the pineal gland but also other organs, such as retina, gut,ovaryandtestis.Thismoleculeisbothalocalregulatoranda hormone,which is secreted in a circadian manner. Melatonin exerts its biological effects through binding to its G protein-coupled MT1andMT2receptors. 6 Ithasvariousregulatorybiologicalfunctions in the neuroimmuno-endocrine system and influences sleepwake cycle, circadian rhythms, tumour inhibition and immune function. 7 Melatonin also plays a neuroprotective role in many CNS disorders, such as Parkinson's disease, Alzheimer's disease, and ischaemic brain injury. 8,9 Emerging evidence suggested that melatonin could influence the proliferation and differentiation of NSCs.Acomprehensiveunderstandingoftheeffectsofmelatonin on NSCs may provide valuable insight on developing new therapeutic approaches.

[3] 35w In this article, we review current literatures on the regulatory effectsofmelatoninonNSCsanddiscussitstherapeuticpotentialasa neuroprotectiveagentindifferentpathophysiologicalcontext. Nevertheless,itisnoteworthythattheproliferativeanddifferentiative abilitiesofNSCsvaryindifferentphysiologicalandpathologicalconditionsandaredynamicallyinfluencedbythehumoralandadhesive factors. Such abilities also decreasewith age. 14 In this regard, many factors that increase NSC proliferation have been demonstrated to promoteneurogenesisinischaemicandneurodegenerativediseases.

[4] 10w ment of new therapy against diseases related to neuronal death.

[1] 16w Nevertheless, the downstream molecular mechanism linking these regulatory factors to phenotypic changes in NSCs remains unclear.

[2] 12w The proliferation and differentiation of NSCs are dynamically regulatedbythehumoralandadhesivefactorsfromtheextracellularenvironment. 14 Anincreasingnumberofstudiessuggestedthatmelatonin isacrucialregulatorofprecursorcellcommitmentanddifferentiation.

[3] 1w Inthissection,wewillsummarizetheexistingevidenceontheasso-ciationbetweenmelatoninandNSCs.

[4] 3w Melatoninplaysasignificantroleincellfatespecificationduringneural commitment. 17

[5] 14w Melatoninpromotedthesurvivalofnewneuronsderivedfromneural precursor cells in adult hippocampus both in vitro and in vivo. 23 Melatoninreceptorswereinvolvedintheseeffectsasitwasblocked

[6] 92w In induced pluripotent stem cells, it was found that melatonin promoted the number of neurospheres and cell viability during neural differentiation. These promoting effects were accompanied by up-regulationofNestinandMAP2aswellasAktphosphorylation,which wereattenuatedbyluzindoleorLY294002(PI3Kinhibitor),suggesting that melatonin significantly increased neural differentiation of induced pluripotent stem cells via MT receptor-mediated activating phosphoinositide 3-kinase/Akt signalling pathway. 25 Interestingly, another study found that melatonin increased reprogramming effi-ciencyofNSC-derivedpluripotentstemcellsgeneratedfromprimary cultured bovine NSCs. This effect was mediated by downregulation of apoptosis-related genes p53 and p21. These cells are similar to typical embryonic stem cells,which expressed pluripotency markers (Oct4andNanog),formedteratomasinvivo,andpossessedthecapacitytodifferentiateintoallthreeembryonicgermlayers. 26 Thesefindingsaddedanadditionallayerofcomplexityintheroleofmelatonin inregulatingdifferentiationandmaintainingpluripotencyofinduced pluripotent stem cells.

[7] 40w Thepromotingeffectsofmelatoninontheproliferationandneuronal differentiationofNSCsmakeitapotentialadjuvantwithNSCreplacementforthetreatmentofneuraldiseases,suchascerebralinfarction andneurodegenerativediseases. 27 Moreover,lowphysiologicalconcentrations ofmelatonininducedglialcell-linederivedneurotrophicfactormRNA expressioninNSCs,whichpromotedthesurvivalofdopaminergicneurons. 16 Sharma and colleagues 28 showed that apomorphine-induced behavioural changes were significantly reduced in striatum-lesioned animals treated by NSC transplantation, melatonin or the combined regimen. Importantly, these treatments protected tyrosine hydroxylaseimmunoreactivityinthestriatumandsubstantianigraoflesioned animalscomparedwithuntreatedcontrols.Takentogether,melatonin incombinationwithNSCtransplantationmightbeusedasatherapeu-ticapproachinParkinson'sdisease.

[8] 41w Melatoninplusexercisesignificantlyimprovedthehindlimbfunction andpromotedtheproliferationofendogenousNSCsafterspinalcord injury. Furthermore, the combined therapy reduced the size of the spinal lesion through increasing the density of dendritic spines and axons. These findings showed that melatonin in combination with exercisesignificantlypromotedendogenousNSCproliferationinspinal cord injury. 29 Inanotherstudy,melatoninstimulatedMT1,which subsequentlyincreasedthesurvivalofbovineamnioticepithelialcells andpromotedtheirdifferentiationintoneuralcells.Importantly,these cellscolonizedintoinjuredspinalcord,suggestingtheirparticipation intissuerepair. 30

[9] 1w Diabeticpregnancyisassociatedwithneuraltubedefectsinoffspring.

[10] 31w In diabetic pregnant mice, intraperitoneal injection of melatonin at the dose of 10 mg/kg per day from embryonic day (E) 0.5 to E11.5 decreased neural tube defects, especially exencephaly, in embryos.

[11] 9w Mechanistically, melatonin stimulated NSC proliferation and decreasedapoptosisunderhyperglycaemiccondition.Themitoticeffect ofmelatoninwasmediatedthroughtheERKpathway. 31

[12] 76w Melatonin protects NSCs against lipopolysaccharide (LPS)-induced inflammation. 32 ThisispartiallymediatedbyactivationofSOX2and Methamphetamine, a highly addictive psycho-stimulatory drug, mayleadtoseveralneurodegenerativediseasesincludingParkinson's disease. 35 This drug has recently been reported to impair the proliferation of neural progenitor cells in the hippocampus. Experimental exposure to exogenous methamphetamine decreased neurosphere cellproliferation,increasingtheexpressionofthetumoursuppressor p53 and the cell cycle inhibitor p21 CIP1 .These were ameliorated by melatonin. These findings suggested that melatonin might prevent learning and memory impairments associated with methamphetamine exposure,possiblythroughrectifyingNSCproliferativedefects,which in turn restore neurogenesis. Hopefully,thiswillleadtodiscoveryofpotentialtherapeutictargets.