Abstract
Aging is associated with increasing impairments in brain homeostasis and represents the main risk factor across most neurodegenerative disorders. Melatonin, a neuroendocrine hormone that regulates mammalian chronobiology and endocrine functions is well known for its antioxidant potential, exhibiting both cytoprotective and chronobiotic abilities. Age-related decline of melatonin disrupting mitochondrial homeostasis and cytosolic DNA-mediated inflammatory reactions in neurons is a major contributory factor in the emergence of neurological abnormalities. There is scattered literature on the possible use of melatonin against neurodegenerative mechanisms in the aging process and its associated diseases. We have searched PUBMED with many combinations of key words for available literature spanning two decades. Based on the vast number of experimental papers, we hereby review recent advancements concerning the potential impact of melatonin on cellular redox balance and mitochondrial dynamics in the context of neurodegeneration. Next, we discuss a broader explanation of the involvement of disrupted redox homeostasis in the pathophysiology of age-related diseases and its connection to circadian mechanisms. Our effort may result in the discovery of novel therapeutic approaches. Finally, we summarize the current knowledge on molecular and circadian regulatory mechanisms of melatonin to overcome neurodegenerative diseases (NDDs) such as Alzheimer’s, Parkinson’s, Huntington’s disease, and amyotrophic lateral sclerosis, however, these findings need to be confirmed by larger, well-designed clinical trials. This review is also expected to uncover the associated molecular alterations in the aging brain and explain how melatonin-mediated circadian restoration of neuronal homeodynamics may increase healthy lifespan in age-related NDDs.
This is a preview of subscription content, access via your institution.
References
Abeysinghe AADT, Deshapriya RDUS, Udawatte C (2020) Alzheimer’s disease; a review of the pathophysiological basis and therapeutic interventions. Life Sci 256:117996. https://doi.org/10.1016/j.lfs.2020.117996
Adi N, Mash DC, Ali Y et al (2010) Melatonin MT1 and MT2 receptor expression in Parkinson’s disease. Med Sci Monit 16:BR61–BR67
Afzaal A, Rehman K, Kamal S, Akash MSH (2022) Versatile role of sirtuins in metabolic disorders: from modulation of mitochondrial function to therapeutic interventions. J Biochem Mol Toxicol 36:e23047. https://doi.org/10.1002/jbt.23047
Akbulut K, Güney Ş, Çetin F et al (2013) Melatonin delays brain aging by decreasing the nitric oxide level. Neurophysiology 45. https://doi.org/10.1007/s11062-013-9368-3
Alghamdi BS (2018) The neuroprotective role of melatonin in neurological disorders. J Neurosci Res 96:1136–1149. https://doi.org/10.1002/jnr.24220
Alvira D, Tajes M, Verdaguer E et al (2006) Inhibition of the cdk5/p25 fragment formation may explain the antiapoptotic effects of melatonin in an experimental model of Parkinson’s disease. J Pineal Res 40:251–258. https://doi.org/10.1111/j.1600-079X.2005.00308.x
Andersen LPH, Gögenur I, Rosenberg J, Reiter RJ (2016) The safety of melatonin in humans. Clin Drug Investig 36:169–175. https://doi.org/10.1007/s40261-015-0368-5
Andrabi SA, Sayeed I, Siemen D et al (2004) Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti-apoptotic effects of melatonin. FASEB J 18:869–871. https://doi.org/10.1096/fj.03-1031fje
Arribas RL, Romero A, Egea J, de los Ríos C (2018) Modulation of serine/threonine phosphatases by melatonin: therapeutic approaches in neurodegenerative diseases: modulation of Ser/Thr phosphatases by melatonin. Br J Pharmacol 175:3220–3229. https://doi.org/10.1111/bph.14365
Asemi-Rad A, Moafi M, Aliaghaei A et al (2022) The effect of dopaminergic neuron transplantation and melatonin co-administration on oxidative stress-induced cell death in Parkinson’s disease. Metab Brain Dis. https://doi.org/10.1007/s11011-022-01021-5
Atayik MC, Çakatay U (2022a) Mitochondria-targeted senotherapeutic interventions. Biogerontology 23:401–423. https://doi.org/10.1007/s10522-022-09973-y
Atayik MC, Çakatay U (2022b) Melatonin-related signaling pathways and their regulatory effects in aging organisms. Biogerontology 23:529–539. https://doi.org/10.1007/s10522-022-09981-y
Ateş-Alagöz Z, Coban T, Suzen S (2005) A comparative study: evaluation of antioxidant activity of melatonin and some indole derivatives. Med Chem Res 14:169–179. https://doi.org/10.1007/s00044-005-0132-0
Azouzi S, Santuz H, Morandat S et al (2017) Antioxidant and membrane binding properties of serotonin protect lipids from oxidation. Biophys J 112:1863–1873. https://doi.org/10.1016/j.bpj.2017.03.037
Bald EM, Nance CS, Schultz JL (2021) Melatonin may slow disease progression in amyotrophic lateral sclerosis: findings from the Pooled Resource Open-Access ALS Clinic Trials database. Muscle Nerve 63:572–576. https://doi.org/10.1002/mus.27168
Beker MC, Caglayan B, Caglayan AB et al (2019) Interaction of melatonin and Bmal1 in the regulation of PI3K/AKT pathway components and cellular survival. Sci Rep 9:19082. https://doi.org/10.1038/s41598-019-55663-0
Benitez-King G, Ramírez-Rodríguez G, Ortíz L, Meza I (2004) The neuronal cytoskeleton as a potential therapeutical target in neurodegenerative diseases and schizophrenia. Curr Drug Targets CNS Neurol Disord 3:515–533. https://doi.org/10.2174/1568007043336761
Bona S, Fernandes SA, Moreira ACJ et al (2022) Melatonin restores zinc levels, activates the Keap1/Nrf2 pathway, and modulates endoplasmic reticular stress and HSP in rats with chronic hepatotoxicity. WJGPT 13:11–22. https://doi.org/10.4292/wjgpt.v13.i2.11
Breen DP, Vuono R, Nawarathna U et al (2014) Sleep and circadian rhythm regulation in early Parkinson disease. JAMA Neurol 71:589–595. https://doi.org/10.1001/jamaneurol.2014.65
Breen DP, Nombela C, Vuono R et al (2016) Hypothalamic volume loss is associated with reduced melatonin output in Parkinson’s disease. Mov Disord 31:1062–1066. https://doi.org/10.1002/mds.26592
Buffenstein R, Edrey YH, Yang T, Mele J (2008) The oxidative stress theory of aging: embattled or invincible? Insights from non-traditional model organisms. Age 30:99–109. https://doi.org/10.1007/s11357-008-9058-z
Burkhardt S, Reiter RJ, Tan DX et al (2001) DNA oxidatively damaged by chromium(III) and H(2)O(2) is protected by the antioxidants melatonin, N(1)-acetyl-N(2)-formyl-5-methoxykynuramine, resveratrol and uric acid. Int J Biochem Cell Biol 33:775–783. https://doi.org/10.1016/s1357-2725(01)00052-8
Caballero B, Vega-Naredo I, Sierra V et al (2008) Favorable effects of a prolonged treatment with melatonin on the level of oxidative damage and neurodegeneration in senescence-accelerated mice. J Pineal Res 45:302–311. https://doi.org/10.1111/j.1600-079X.2008.00591.x
Caballero B, Vega-Naredo I, Sierra V et al (2009) Melatonin alters cell death processes in response to age-related oxidative stress in the brain of senescence-accelerated mice. J Pineal Res 46:106–114. https://doi.org/10.1111/j.1600-079X.2008.00637.x
Cai Y, Liu S, Sothern RB et al (2010) Expression of clock genes Per1 and Bmal1 in total leukocytes in health and Parkinson’s disease: clock genes in PD. Eur J Neurol 17:550–554. https://doi.org/10.1111/j.1468-1331.2009.02848.x
Calabrese EJ, Kozumbo WJ (2021) The hormetic dose-response mechanism: Nrf2 activation. Pharmacol Res 167:105526. https://doi.org/10.1016/j.phrs.2021.105526
Cardinali DP (2019) Melatonin: clinical perspectives in neurodegeneration. Front Endocrinol 10:480. https://doi.org/10.3389/fendo.2019.00480
Cardinali DP, Vigo DE, Olivar N et al (2014) Melatonin therapy in patients with Alzheimer’s disease. Antioxidants 3:245–277. https://doi.org/10.3390/antiox3020245
Cardoso S, Moreira PI (2022) Targeting mitochondria and redox dyshomeostasis in brain ageing: an update. In: Çakatay U (ed) Redox signaling and biomarkers in ageing. Springer, Cham, pp 147–183
Casas C (2017) GRP78 at the centre of the stage in cancer and neuroprotection. Front Neurosci 11:177. https://doi.org/10.3389/fnins.2017.00177
Cecon E, Oishi A, Jockers R (2018) Melatonin receptors: molecular pharmacology and signalling in the context of system bias. Br J Pharmacol 175:3263–3280. https://doi.org/10.1111/bph.13950
Chang C-F, Huang H-J, Lee H-C et al (2012) Melatonin attenuates kainic acid-induced neurotoxicity in mouse hippocampus via inhibition of autophagy and α-synuclein aggregation. J Pineal Res 52:312–321. https://doi.org/10.1111/j.1600-079X.2011.00945.x
Chen L-J, Gao Y-Q, Li X-J et al (2005) Melatonin protects against MPTP/MPP+ -induced mitochondrial DNA oxidative damage in vivo and in vitro. J Pineal Res 39:34–42. https://doi.org/10.1111/j.1600-079X.2005.00209.x
Chen K-Y, Cheng C-J, Wang L-C (2015) Activation of sonic hedgehog leads to survival enhancement of astrocytes via the GRP78-dependent pathway in mice infected with Angiostrongylus cantonensis. Biomed Res Int 2015:674371. https://doi.org/10.1155/2015/674371
Chen Q, Sun L, Chen ZJ (2016) Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat Immunol 17:1142–1149. https://doi.org/10.1038/ni.3558
Chen K-Y, Chiu C-H, Wang L-C (2017) Anti-apoptotic effects of Sonic hedgehog signalling through oxidative stress reduction in astrocytes co-cultured with excretory-secretory products of larval Angiostrongylus cantonensis. Sci Rep 7:41574. https://doi.org/10.1038/srep41574
Chen D, Zhang T, Lee TH (2020a) Cellular mechanisms of melatonin: insight from neurodegenerative diseases. Biomolecules 10:1158. https://doi.org/10.3390/biom10081158
Chen G, Kroemer G, Kepp O (2020b) Mitophagy: an emerging role in aging and age-associated diseases. Front Cell Dev Biol 8:200. https://doi.org/10.3389/fcell.2020.00200
Cheng S, Ma C, Qu H et al (2008) Differential effects of melatonin on hippocampal neurodegeneration in different aged accelerated senescence prone mouse-8. Neuro Endocrinol Lett 29:91–99
Chenn A, Walsh CA (2002) Regulation of cerebral cortical size by control of cell cycle exit in neural precursors. Science 297:365–369. https://doi.org/10.1126/science.1074192
Chinchalongporn V, Shukla M, Govitrapong P (2018) Melatonin ameliorates Aβ42 -induced alteration of βAPP-processing secretases via the melatonin receptor through the Pin1/GSK3β/NF-κB pathway in SH-SY5Y cells. J Pineal Res 64:e12470. https://doi.org/10.1111/jpi.12470
Cobley JN, Fiorello ML, Bailey DM (2018) 13 reasons why the brain is susceptible to oxidative stress. Redox Biol 15:490–503. https://doi.org/10.1016/j.redox.2018.01.008
Dabbeni-Sala F, Di Santonull S, Franceschini D et al (2001) Melatonin protects against 6-OHDA-induced neurotoxicity in rats: a role for mitochondrial complex I activity. FASEB J 15:164–170. https://doi.org/10.1096/fj.00-0129com
Dardiotis E, Panayiotou E, Feldman ML et al (2013) Intraperitoneal melatonin is not neuroprotective in the G93ASOD1 transgenic mouse model of familial ALS and may exacerbate neurodegeneration. Neurosci Lett 548:170–175. https://doi.org/10.1016/j.neulet.2013.05.058
Davies JMS, Cillard J, Friguet B et al (2017) The Oxygen Paradox, the French Paradox, and age-related diseases. GeroScience 39:499–550. https://doi.org/10.1007/s11357-017-0002-y
Delgado-Lara DL, González-Enríquez GV, Torres-Mendoza BM et al (2020) Effect of melatonin administration on the PER1 and BMAL1 clock genes in patients with Parkinson’s disease. Biomed Pharmacother 129:110485. https://doi.org/10.1016/j.biopha.2020.110485
Ding K, Wang H, Xu J et al (2014) Melatonin stimulates antioxidant enzymes and reduces oxidative stress in experimental traumatic brain injury: the Nrf2–ARE signaling pathway as a potential mechanism. Free Radic Biol Med 73:1–11. https://doi.org/10.1016/j.freeradbiomed.2014.04.031
Dragicevic N, Copes N, O’Neal-Moffitt G et al (2011) Melatonin treatment restores mitochondrial function in Alzheimer’s mice: a mitochondrial protective role of melatonin membrane receptor signaling: melatonin restores mito. function in AD mice. J Pineal Res 51:75–86. https://doi.org/10.1111/j.1600-079X.2011.00864.x
Du A-T, Schuff N, Chao LL et al (2006) Age effects on atrophy rates of entorhinal cortex and hippocampus. Neurobiol Aging 27:733–740. https://doi.org/10.1016/j.neurobiolaging.2005.03.021
Duan H, Wearne SL, Rocher AB et al (2003) Age-related dendritic and spine changes in corticocortically projecting neurons in macaque monkeys. Cereb Cortex 13:950–961. https://doi.org/10.1093/cercor/13.9.950
Dubrovsky YV, Samsa WE, Kondratov RV (2010) Deficiency of circadian protein CLOCK reduces lifespan and increases age-related cataract development in mice. Aging 2:936–944. https://doi.org/10.18632/aging.100241
Egea J, Buendia I, Parada E et al (2015) Melatonin-sulforaphane hybrid ITH12674 induces neuroprotection in oxidative stress conditions by a “drug-prodrug” mechanism of action. Br J Pharmacol 172:1807–1821. https://doi.org/10.1111/bph.13025
Fabrizio FP, Sparaneo A, Trombetta D, Muscarella LA (2018) Epigenetic versus genetic deregulation of the KEAP1/NRF2 axis in solid tumors: focus on methylation and noncoding RNAs. Oxid Med Cell Longev 2018:2492063. https://doi.org/10.1155/2018/2492063
Fallahi E, O’Driscoll NA, Matallanas D (2016) The MST/hippo pathway and cell death: a non-canonical affair. Genes 7:E28. https://doi.org/10.3390/genes7060028
Fan R, Peng X, Xie L et al (2022) Importance of Bmal1 in Alzheimer’s disease and associated aging-related diseases: mechanisms and interventions. Aging Cell 21:e13704. https://doi.org/10.1111/acel.13704
Fang Y, Zhao C, Xiang H et al (2019) Melatonin inhibits formation of mitochondrial permeability transition pores and improves oxidative phosphorylation of frozen-thawed ram sperm. Front Endocrinol 10:896. https://doi.org/10.3389/fendo.2019.00896
Favaro R, Valotta M, Ferri ALM et al (2009) Hippocampal development and neural stem cell maintenance require Sox2-dependent regulation of Shh. Nat Neurosci 12:1248–1256. https://doi.org/10.1038/nn.2397
Ferlazzo N, Andolina G, Cannata A et al (2020) Is melatonin the cornucopia of the 21st century? Antioxidants 9:1088. https://doi.org/10.3390/antiox9111088
Frank M, Duvezin-Caubet S, Koob S et al (2012) Mitophagy is triggered by mild oxidative stress in a mitochondrial fission dependent manner. Biochim Biophys Acta 1823:2297–2310. https://doi.org/10.1016/j.bbamcr.2012.08.007
Fulco M, Sartorelli V (2008) Comparing and contrasting the roles of AMPK and SIRT1 in metabolic tissues. Cell Cycle 7:3669–3679. https://doi.org/10.4161/cc.7.23.7164
Galano A (2016) Computational-aided design of melatonin analogues with outstanding multifunctional antioxidant capacity. RSC Adv 6:22951–22963. https://doi.org/10.1039/C6RA00549G
Galano A, Reiter RJ (2018) Melatonin and its metabolites vs oxidative stress: from individual actions to collective protection. J Pineal Res 65:e12514. https://doi.org/10.1111/jpi.12514
Galano A, Tan D-X, Reiter RJ (2018) Melatonin: a versatile protector against oxidative DNA damage. Molecules 23:E530. https://doi.org/10.3390/molecules23030530
Garza-Lombó C, Pappa A, Panayiotidis MI, Franco R (2020) Redox homeostasis, oxidative stress and mitophagy. Mitochondrion 51:105–117. https://doi.org/10.1016/j.mito.2020.01.002
Godin JD, Poizat G, Hickey MA et al (2010) Mutant huntingtin-impaired degradation of beta-catenin causes neurotoxicity in Huntington’s disease. EMBO J 29:2433–2445. https://doi.org/10.1038/emboj.2010.117
Guarente L (2008) Mitochondria—a nexus for aging, calorie restriction, and sirtuins? Cell 132:171–176. https://doi.org/10.1016/j.cell.2008.01.007
Gudenschwager C, Chavez I, Cardenas C, Gonzalez-Billault C (2021) Directly reprogrammed human neurons to understand age-related energy metabolism impairment and mitochondrial dysfunction in healthy aging and neurodegeneration. Oxid Med Cell Longev 2021:5586052. https://doi.org/10.1155/2021/5586052
Gupta A, Behl T, Sehgal A et al (2021) Therapeutic potential of Nrf-2 pathway in the treatment of diabetic neuropathy and nephropathy. Mol Biol Rep 48:2761–2774. https://doi.org/10.1007/s11033-021-06257-5
Gürkök G, Coban T, Suzen S (2009) Melatonin analogue new indole hydrazide/hydrazone derivatives with antioxidant behavior: synthesis and structure-activity relationships. J Enzyme Inhib Med Chem 24:506–515. https://doi.org/10.1080/14756360802218516
Hacışevki A, Baba B (2018) An overview of melatonin as an antioxidant molecule: a biochemical approach. In: Manuela Drăgoi C, Crenguţa Nicolae A (eds) Melatonin—molecular biology, clinical and pharmaceutical approaches. IntechOpen
Hanagasi HA, Ayribas D, Baysal K, Emre M (2005) Mitochondrial complex I, II/III, and IV activities in familial and sporadic Parkinson’s disease. Int J Neurosci 115:479–493. https://doi.org/10.1080/00207450590523017
Hardeland R (2013) Melatonin and the theories of aging: a critical appraisal of melatonin’s role in antiaging mechanisms. J Pineal Res 55:325–356. https://doi.org/10.1111/jpi.12090
Hardeland R (2017a) Melatonin in healthy aging and longevity. In: Rattan S, Sharma R (eds) Hormones in ageing and longevity. Springer, Cham, pp 209–242
Hardeland R (2017b) Melatonin and the electron transport chain. Cell Mol Life Sci 74:3883–3896. https://doi.org/10.1007/s00018-017-2615-9
Hardeland R (2019) Aging, melatonin, and the pro- and anti-inflammatory networks. Int J Mol Sci 20:1223. https://doi.org/10.3390/ijms20051223
Hou Y, Dan X, Babbar M et al (2019) Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol 15:565–581. https://doi.org/10.1038/s41582-019-0244-7
Huang W-J, Zhang X, Chen W-W (2016) Role of oxidative stress in Alzheimer’s disease. Biomed Rep 4:519–522. https://doi.org/10.3892/br.2016.630
Huang M, Liang Y, Chen H et al (2018) The role of fluoxetine in activating Wnt/β-catenin signaling and repressing β-amyloid production in an Alzheimer mouse model. Front Aging Neurosci 10:164. https://doi.org/10.3389/fnagi.2018.00164
Ikeno T, Nelson RJ (2015) Acute melatonin treatment alters dendritic morphology and circadian clock gene expression in the hippocampus of Siberian hamsters. Hippocampus 25:142–148. https://doi.org/10.1002/hipo.22358
Imai Y, Kobayashi Y, Inoshita T et al (2015) The Parkinson’s disease-associated protein kinase LRRK2 modulates notch signaling through the endosomal pathway. PLoS Genet 11:e1005503. https://doi.org/10.1371/journal.pgen.1005503
Jaiswal MK (2016) Riluzole but not melatonin ameliorates acute motor neuron degeneration and moderately inhibits SOD1-mediated excitotoxicity induced disrupted mitochondrial Ca2+ signaling in amyotrophic lateral sclerosis. Front Cell Neurosci 10:295. https://doi.org/10.3389/fncel.2016.00295
Jauhari A, Baranov SV, Suofu Y et al (2020) Melatonin inhibits cytosolic mitochondrial DNA–induced neuroinflammatory signaling in accelerated aging and neurodegeneration. J Clin Investig 130:3124–3136. https://doi.org/10.1172/JCI135026
Jeong J-K, Park S-Y (2015) Melatonin regulates the autophagic flux via activation of alpha-7 nicotinic acetylcholine receptors. J Pineal Res 59:24–37. https://doi.org/10.1111/jpi.12235
Jeong J-K, Lee J-H, Moon J-H et al (2014) Melatonin-mediated β-catenin activation protects neuron cells against prion protein-induced neurotoxicity. J Pineal Res 57:427–434. https://doi.org/10.1111/jpi.12182
Jiang J, Liang S, Zhang J et al (2021) Melatonin ameliorates PM2.5-induced cardiac perivascular fibrosis through regulating mitochondrial redox homeostasis. J Pineal Res 70:e12686. https://doi.org/10.1111/jpi.12686
Jonas EA, Porter GA, Beutner G et al (2015) Cell death disguised: the mitochondrial permeability transition pore as the c-subunit of the F1FO ATP synthase. Pharmacol Res 99:382–392. https://doi.org/10.1016/j.phrs.2015.04.013
Kalliolia E, Silajdžić E, Nambron R et al (2014) Plasma melatonin is reduced in Huntington’s disease. Mov Disord 29:1511–1515. https://doi.org/10.1002/mds.26003
Kang J-Y, Xu M-M, Sun Y et al (2022) Melatonin attenuates LPS-induced pyroptosis in acute lung injury by inhibiting NLRP3-GSDMD pathway via activating Nrf2/HO-1 signaling axis. Int Immunopharmacol 109:108782. https://doi.org/10.1016/j.intimp.2022.108782
Kilic U, Kilic E, Tuzcu Z et al (2013) Melatonin suppresses cisplatin-induced nephrotoxicity via activation of Nrf-2/HO-1 pathway. Nutr Metab 10:7. https://doi.org/10.1186/1743-7075-10-7
Kondratov RV, Kondratova AA, Gorbacheva VY et al (2006) Early aging and age-related pathologies in mice deficient in BMAL1, the core componentof the circadian clock. Genes Dev 20:1868–1873. https://doi.org/10.1101/gad.1432206
Kondratov RV, Vykhovanets O, Kondratova AA, Antoch MP (2009) Antioxidant N-acetyl-L-cysteine ameliorates symptoms of premature aging associated with the deficiency of the circadian protein BMAL1. Aging 1:979–987. https://doi.org/10.18632/aging.100113
Kubben N, Misteli T (2017) Shared molecular and cellular mechanisms of premature ageing and ageing-associated diseases. Nat Rev Mol Cell Biol 18:595–609. https://doi.org/10.1038/nrm.2017.68
Kumar Verma A, Singh S, Srivastava P, Ibrahim Rizvi S (2022) Melatonin stabilizes age-dependent alterations in erythrocyte membrane induced by “Artificial Light at Night” in a chronodisrupted model of rat. Gen Comp Endocrinol 316:113960. https://doi.org/10.1016/j.ygcen.2021.113960
Lahiri DK (1999) Melatonin affects the metabolism of the beta-amyloid precursor protein in different cell types. J Pineal Res 26:137–146. https://doi.org/10.1111/j.1600-079x.1999.tb00575.x
Lananna BV, Musiek ES (2020) The wrinkling of time: aging, inflammation, oxidative stress, and the circadian clock in neurodegeneration. Neurobiol Dis 139:104832. https://doi.org/10.1016/j.nbd.2020.104832
Lee JH, Yoon YM, Song K et al (2020) Melatonin suppresses senescence-derived mitochondrial dysfunction in mesenchymal stem cells via the HSPA1L–mitophagy pathway. Aging Cell 19:e13111. https://doi.org/10.1111/acel.13111
Lee YH, Park JY, Lee H et al (2021) Targeting mitochondrial metabolism as a strategy to treat senescence. Cells 10:3003. https://doi.org/10.3390/cells10113003
Lemaitre H, Goldman AL, Sambataro F et al (2012) Normal age-related brain morphometric changes: nonuniformity across cortical thickness, surface area and gray matter volume? Neurobiol Aging 33:617. https://doi.org/10.1016/j.neurobiolaging.2010.07.013
Leston J, Harthé C, Brun J et al (2010) Melatonin is released in the third ventricle in humans. A study in movement disorders. Neurosci Lett 469:294–297. https://doi.org/10.1016/j.neulet.2009.12.008
Leyane TS, Jere SW, Houreld NN (2022) Oxidative stress in ageing and chronic degenerative pathologies: molecular mechanisms involved in counteracting oxidative stress and chronic inflammation. IJMS 23:7273. https://doi.org/10.3390/ijms23137273
Li T, Chen ZJ (2018) The cGAS–cGAMP–STING pathway connects DNA damage to inflammation, senescence, and cancer. J Exp Med 215:1287–1299. https://doi.org/10.1084/jem.20180139
Li Y, Zhang J, Wan J et al (2020) Melatonin regulates Aβ production/clearance balance and Aβ neurotoxicity: a potential therapeutic molecule for Alzheimer’s disease. Biomed Pharmacother 132:110887. https://doi.org/10.1016/j.biopha.2020.110887
Li Z, Zhang Z, Ren Y et al (2021) Aging and age-related diseases: from mechanisms to therapeutic strategies. Biogerontology 22:165–187. https://doi.org/10.1007/s10522-021-09910-5
Limón-Pacheco JH, Gonsebatt ME (2010) The glutathione system and its regulation by neurohormone melatonin in the central nervous system. Cent Nerv Syst Agents Med Chem 10:287–297. https://doi.org/10.2174/187152410793429683
Lin Q, Chen J, Gu L et al (2021) New insights into mitophagy and stem cells. Stem Cell Res Ther 12:452. https://doi.org/10.1186/s13287-021-02520-5
Lister JP, Barnes CA (2009) Neurobiological changes in the hippocampus during normative aging. Arch Neurol 66:829–833. https://doi.org/10.1001/archneurol.2009.125
Liu F, Ng TB (2000) Effect of pineal indoles on activities of the antioxidant defense enzymes superoxide dismutase, catalase, and glutathione reductase, and levels of reduced and oxidized glutathione in rat tissues. Biochem Cell Biol 78:447–453. https://doi.org/10.1139/o00-018
Luo F, Sandhu AF, Rungratanawanich W et al (2020) Melatonin and autophagy in aging-related neurodegenerative diseases. Int J Mol Sci 21:7174. https://doi.org/10.3390/ijms21197174
Madabhushi R, Pan L, Tsai L-H (2014) DNA damage and its links to neurodegeneration. Neuron 83:266–282. https://doi.org/10.1016/j.neuron.2014.06.034
Maharaj DS, Maharaj H, Antunes EM et al (2005) 6-Hydroxymelatonin protects against quinolinic-acid-induced oxidative neurotoxicity in the rat hippocampus. J Pharm Pharmacol 57:877–881. https://doi.org/10.1211/0022357056424
Majidinia M, Sadeghpour A, Mehrzadi S et al (2017) Melatonin: a pleiotropic molecule that modulates DNA damage response and repair pathways. J Pineal Res 63:e12416. https://doi.org/10.1111/jpi.12416
Majidinia M, Reiter RJ, Shakouri SK, Yousefi B (2018) The role of melatonin, a multitasking molecule, in retarding the processes of ageing. Ageing Res Rev 47:198–213. https://doi.org/10.1016/j.arr.2018.07.010
Mammucari C, Rizzuto R (2010) Signaling pathways in mitochondrial dysfunction and aging. Mech Ageing Dev 131:536–543. https://doi.org/10.1016/j.mad.2010.07.003
Manchester LC, Coto-Montes A, Boga JA et al (2015) Melatonin: an ancient molecule that makes oxygen metabolically tolerable. J Pineal Res 59:403–419. https://doi.org/10.1111/jpi.12267
Mannino G, Pernici C, Serio G et al (2021) Melatonin and phytomelatonin: chemistry, biosynthesis, metabolism, distribution and bioactivity in plants and animals—an overview. Int J Mol Sci 22:9996. https://doi.org/10.3390/ijms22189996
Marathe S, Jaquet M, Annoni J-M, Alberi L (2017) Jagged1 is altered in Alzheimer’s disease and regulates spatial memory processing. Front Cell Neurosci 11:220. https://doi.org/10.3389/fncel.2017.00220
Markus RP, Sousa KS, da Silveira C-M et al (2021) Possible role of pineal and extra-pineal melatonin in surveillance, immunity, and first-line defense. Int J Mol Sci 22:12143. https://doi.org/10.3390/ijms222212143
Martín Giménez VM, de Las Heras N, Lahera V et al (2022) Melatonin as an anti-aging therapy for age-related cardiovascular and neurodegenerative diseases. Front Aging Neurosci 14:888292. https://doi.org/10.3389/fnagi.2022.888292
Matsubara E, Bryant-Thomas T, Pacheco Quinto J et al (2003) Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer’s disease. J Neurochem 85:1101–1108. https://doi.org/10.1046/j.1471-4159.2003.01654.x
Mattam U, Jagota A (2014) Differential role of melatonin in restoration of age-induced alterations in daily rhythms of expression of various clock genes in suprachiasmatic nucleus of male Wistar rats. Biogerontology 15:257–268. https://doi.org/10.1007/s10522-014-9495-2
Mattam U, Jagota A (2015) Daily rhythms of serotonin metabolism and the expression of clock genes in suprachiasmatic nucleus of rotenone-induced Parkinson’s disease male Wistar rat model and effect of melatonin administration. Biogerontology 16:109–123. https://doi.org/10.1007/s10522-014-9541-0
Mattis J, Sehgal A (2016) Circadian rhythms, sleep, and disorders of aging. Trends Endocrinol Metab 27:192–203. https://doi.org/10.1016/j.tem.2016.02.003
Mayo JC, Sainz RM, González Menéndez P et al (2017) Melatonin and sirtuins: a “not-so unexpected” relationship. J Pineal Res 62:e12391. https://doi.org/10.1111/jpi.12391
McHugh D, Gil J (2018) Senescence and aging: causes, consequences, and therapeutic avenues. J Cell Biol 217:65–77. https://doi.org/10.1083/jcb.201708092
Mehrzadi S, Pourhanifeh MH, Mirzaei A et al (2021) An updated review of mechanistic potentials of melatonin against cancer: pivotal roles in angiogenesis, apoptosis, autophagy, endoplasmic reticulum stress and oxidative stress. Cancer Cell Int 21:188. https://doi.org/10.1186/s12935-021-01892-1
Mendiola-Precoma J, Berumen LC, Padilla K, Garcia-Alcocer G (2016) Therapies for prevention and treatment of Alzheimer’s disease. Biomed Res Int 2016:2589276. https://doi.org/10.1155/2016/2589276
Mochel F, Haller RG (2011) Energy deficit in Huntington disease: why it matters. J Clin Invest 121:493–499. https://doi.org/10.1172/JCI45691
Monayo SM, Liu X (2022) The prospective application of melatonin in treating epigenetic dysfunctional diseases. Front Pharmacol 13:867500. https://doi.org/10.3389/fphar.2022.867500
Montilla P, Cruz A, Padillo FJ et al (2001) Melatonin versus vitamin E as protective treatment against oxidative stress after extra-hepatic bile duct ligation in rats. J Pineal Res 31(2):138–144. https://doi.org/10.1034/j.1600-079x.2001.310207.x
Morioka N, Okatani Y, Wakatsuki A (1999) Melatonin protects against age-related DNA damage in the brains of female senescence-accelerated mice. J Pineal Res 27:202–209. https://doi.org/10.1111/j.1600-079x.1999.tb00616.x
Mu S, Lin E, Liu B et al (2014) Melatonin reduces projection neuronal injury induced by 3-nitropropionic acid in the rat striatum. Neurodegener Dis 14:139–150. https://doi.org/10.1159/000365891
Musiek ES, Xiong DD, Holtzman DM (2015) Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease. Exp Mol Med 47:e148–e148. https://doi.org/10.1038/emm.2014.121
Nakamura TJ, Nakamura W, Tokuda IT et al (2015) Age-related changes in the circadian system unmasked by constant conditions. eNeuro 2(4):15. https://doi.org/10.1523/ENEURO.0064-15.2015
Nam E, Lee SM, Koh SE et al (2005) Melatonin protects against neuronal damage induced by 3-nitropropionic acid in rat striatum. Brain Res 1046:90–96. https://doi.org/10.1016/j.brainres.2005.03.053
Nassar E, Mulligan C, Taylor L et al (2007) Effects of a single dose of N-Acetyl-5-methoxytryptamine (Melatonin) and resistance exercise on the growth hormone/IGF-1 axis in young males and females. J Int Soc Sports Nutr 4:14. https://doi.org/10.1186/1550-2783-4-14
Ng TB, Liu F, Zhao L (2000) Antioxidative and free radical scavenging activities of pineal indoles. J Neural Transm 107:1243–1251. https://doi.org/10.1007/s007020070014
Ng KY, Leong MK, Liang H, Paxinos G (2017) Melatonin receptors: distribution in mammalian brain and their respective putative functions. Brain Struct Funct 222:2921–2939. https://doi.org/10.1007/s00429-017-1439-6
Niles LP, Armstrong KJ, Rincón Castro LM et al (2004) Neural stem cells express melatonin receptors and neurotrophic factors: colocalization of the MT1 receptor with neuronal and glial markers. BMC Neurosci 5:41. https://doi.org/10.1186/1471-2202-5-41
Oishi A, Cecon E, Jockers R (2018) Melatonin receptor signaling: impact of receptor oligomerization on receptor function. In: International Review of Cell and Molecular Biology. Elsevier, pp 59–77
Okatani Y, Wakatsuki A, Reiter RJ, Miyahara Y (2002) Melatonin reduces oxidative damage of neural lipids and proteins in senescence-accelerated mouse. Neurobiol Aging 23:639–644. https://doi.org/10.1016/s0197-4580(02)00005-2
Olcese JM, Cao C, Mori T et al (2009) Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease. J Pineal Res 47:82–96. https://doi.org/10.1111/j.1600-079X.2009.00692.x
Oliva CA, Montecinos-Oliva C, Inestrosa NC (2018) Wnt signaling in the central nervous system: new insights in health and disease. Prog Mol Biol Transl Sci 153:81–130. https://doi.org/10.1016/bs.pmbts.2017.11.018
Ono K, Mochizuki H, Ikeda T et al (2012) Effect of melatonin on α-synuclein self-assembly and cytotoxicity. Neurobiol Aging 33:2172–2185. https://doi.org/10.1016/j.neurobiolaging.2011.10.015
Pajares M, Rojo IA, Manda G et al (2020) Inflammation in Parkinson’s disease: mechanisms and therapeutic implications. Cells 9:E1687. https://doi.org/10.3390/cells9071687
Peng C-X, Hu J, Liu D et al (2013) Disease-modified glycogen synthase kinase-3β intervention by melatonin arrests the pathology and memory deficits in an Alzheimer’s animal model. Neurobiol Aging 34:1555–1563. https://doi.org/10.1016/j.neurobiolaging.2012.12.010
Petrosillo G, Moro N, Ruggiero FM, Paradies G (2009) Melatonin inhibits cardiolipin peroxidation in mitochondria and prevents the mitochondrial permeability transition and cytochrome c release. Free Radic Biol Med 47:969–974. https://doi.org/10.1016/j.freeradbiomed.2009.06.032
Poewe W, Seppi K, Tanner CM et al (2017) Parkinson disease. Nat Rev Dis Primers 3:17013. https://doi.org/10.1038/nrdp.2017.13
Polimeni G, Esposito E, Bevelacqua V et al (2014) Role of melatonin supplementation in neurodegenerative disorders. Front Biosci 19:429–446. https://doi.org/10.2741/4217
Pollari E, Goldsteins G, Bart G et al (2014) The role of oxidative stress in degeneration of the neuromuscular junction in amyotrophic lateral sclerosis. Front Cell Neurosci 8:131. https://doi.org/10.3389/fncel.2014.00131
Ramirez Reyes JMJ, Cuesta R, Pause A (2021) Folliculin: a regulator of transcription through AMPK and mTOR signaling pathways. Front Cell Dev Biol 9:667311. https://doi.org/10.3389/fcell.2021.667311
Ramis MR, Esteban S, Miralles A et al (2015) Caloric restriction, resveratrol and melatonin: role of SIRT1 and implications for aging and related-diseases. Mech Ageing Dev 146–148:28–41. https://doi.org/10.1016/j.mad.2015.03.008
Rao G, Verma R, Mukherjee A et al (2016) Melatonin alleviates hyperthyroidism induced oxidative stress and neuronal cell death in hippocampus of aged female golden hamster, Mesocricetus auratus. Exp Gerontol 82:125–130. https://doi.org/10.1016/j.exger.2016.06.014
Rattan SIS (2022) Physiological hormesis and hormetins in biogerontology. Curr Opin Toxicol 29:19–24. https://doi.org/10.1016/j.cotox.2022.01.001
Reina M, Castañeda-Arriaga R, Perez-Gonzalez A et al (2018) A computer-assisted systematic search for melatonin derivatives with high potential as antioxidants. Melatonin Res 1:27–58. https://doi.org/10.32794/mr11250003
Reiter RJ, Manchester LC, Tan D-X (2010) Neurotoxins: free radical mechanisms and melatonin protection. Curr Neuropharmacol 8:194–210. https://doi.org/10.2174/157015910792246236
Reiter RJ, Tan D-X, Galano A (2014) Melatonin reduces lipid peroxidation and membrane viscosity. Front Physiol 5:377. https://doi.org/10.3389/fphys.2014.00377
Reiter RJ, Mayo JC, Tan D-X et al (2016) Melatonin as an antioxidant: under promises but over delivers. J Pineal Res 61:253–278. https://doi.org/10.1111/jpi.12360
Reiter RJ, Rosales-Corral S, Tan DX et al (2017) Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas. Cell Mol Life Sci 74:3863–3881. https://doi.org/10.1007/s00018-017-2609-7
Reiter RJ, Tan DX, Rosales-Corral S et al (2018) Mitochondria: central organelles for melatonin’s antioxidant and anti-aging actions. Molecules 23:E509. https://doi.org/10.3390/molecules23020509
Reiter RJ, Ma Q, Sharma R (2020) Melatonin in mitochondria: mitigating clear and present dangers. Physiology 35:86–95. https://doi.org/10.1152/physiol.00034.2019
Reiter RJ, Sharma R, Ma Q (2021) Switching diseased cells from cytosolic aerobic glycolysis to mitochondrial oxidative phosphorylation: a metabolic rhythm regulated by melatonin? J Pineal Res 70:e12677. https://doi.org/10.1111/jpi.12677
Rudnitskaya EA, Muraleva NA, Maksimova KY et al (2015) Melatonin attenuates memory impairment, amyloid-β accumulation, and neurodegeneration in a rat model of sporadic Alzheimer’s disease. J Alzheimers Dis 47:103–116. https://doi.org/10.3233/JAD-150161
Ruiz A, Matute C, Alberdi E (2010) Intracellular Ca2+ release through ryanodine receptors contributes to AMPA receptor-mediated mitochondrial dysfunction and ER stress in oligodendrocytes. Cell Death Dis 1:e54. https://doi.org/10.1038/cddis.2010.31
Saftig P, Lichtenthaler SF (2015) The alpha secretase ADAM10: a metalloprotease with multiple functions in the brain. Prog Neurobiol 135:1–20. https://doi.org/10.1016/j.pneurobio.2015.10.003
Salminen A, Kaarniranta K (2010) Insulin/IGF-1 paradox of aging: regulation via AKT/IKK/NF-kappaB signaling. Cell Signal 22:573–577. https://doi.org/10.1016/j.cellsig.2009.10.006
Sarlak G, Htoo HH, Hernandez J-F et al (2016) Sox2 functionally interacts with βAPP, the βAPP intracellular domain and ADAM10 at a transcriptional level in human cells. Neuroscience 312:153–164. https://doi.org/10.1016/j.neuroscience.2015.11.022
Sarti P, Magnifico M, Altieri F et al (2013) New evidence for cross talk between melatonin and mitochondria mediated by a circadian-compatible interaction with nitric oxide. IJMS 14:11259–11276. https://doi.org/10.3390/ijms140611259
Saso L, Gürer-Orhan H, Stepanić V (2020) Modulators of oxidative stress: chemical and pharmacological aspects. Antioxidants 9:657. https://doi.org/10.3390/antiox9080657
Seabra ML, Bignotto M, Pinto LR, Tufik S (2000) Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res 29:193–200. https://doi.org/10.1034/j.1600-0633.2002.290401.x
Shao S, Wang G-L, Raymond C et al (2017) Activation of Sonic hedgehog signal by Purmorphamine, in a mouse model of Parkinson’s disease, protects dopaminergic neurons and attenuates inflammatory response by mediating PI3K/AKt signaling pathway. Mol Med Rep 16:1269–1277. https://doi.org/10.3892/mmr.2017.6751
Shirinzadeh H, Eren B, Gurer-Orhan H et al (2010) Novel indole-based analogs of melatonin: synthesis and in vitro antioxidant activity studies. Molecules 15:2187–2202. https://doi.org/10.3390/molecules15042187
Shukla M, Govitrapong P, Boontem P et al (2017) Mechanisms of melatonin in alleviating Alzheimer’s disease. Curr Neuropharmacol 15:1010–1031. https://doi.org/10.2174/1570159X15666170313123454
Singh S, Mishra A, Bharti S et al (2018) Glycogen synthase kinase-3β regulates equilibrium between neurogenesis and gliogenesis in rat model of Parkinson’s disease: a crosstalk with wnt and notch signaling. Mol Neurobiol 55:6500–6517. https://doi.org/10.1007/s12035-017-0860-4
Song J (2019) Pineal gland dysfunction in Alzheimer’s disease: relationship with the immune-pineal axis, sleep disturbance, and neurogenesis. Mol Neurodegener 14:28. https://doi.org/10.1186/s13024-019-0330-8
Sotthibundhu A, Phansuwan-Pujito P, Govitrapong P (2010) Melatonin increases proliferation of cultured neural stem cells obtained from adult mouse subventricular zone. J Pineal Res 49:291–300. https://doi.org/10.1111/j.1600-079X.2010.00794.x
Srinivasan V, Spence DW, Pandi-Perumal SR et al (2011) Melatonin in mitochondrial dysfunction and related disorders. Int J Alzheimer’s Dis 2011:1–16. https://doi.org/10.4061/2011/326320
Sumsuzzman DMd, Choi J, Jin Y, Hong Y (2021) Neurocognitive effects of melatonin treatment in healthy adults and individuals with Alzheimer’s disease and insomnia: a systematic review and meta-analysis of randomized controlled trials. Neurosci Biobehav Rev 127:459–473. https://doi.org/10.1016/j.neubiorev.2021.04.034
Sun L, Wu J, Du F et al (2013) Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339:786–791. https://doi.org/10.1126/science.1232458
Sun X, Ran D, Zhao X et al (2016) Melatonin attenuates hLRRK2-induced sleep disturbances and synaptic dysfunction in a Drosophila model of Parkinson’s disease. Mol Med Rep 13:3936–3944. https://doi.org/10.3892/mmr.2016.4991
Suofu Y, Li W, Jean-Alphonse FG et al (2017) Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release. Proc Natl Acad Sci USA 114:E7997–E8006. https://doi.org/10.1073/pnas.1705768114
Suzen S (2013) Melatonin and synthetic analogs as antioxidants. Curr Drug Deliv 10:71–75. https://doi.org/10.2174/1567201811310010013
Suzen S, Bozkaya P, Coban T, Nebioğu D (2006) Investigation of the in vitro antioxidant behaviour of some 2-phenylindole derivatives: discussion on possible antioxidant mechanisms and comparison with melatonin. J Enzyme Inhib Med Chem 21:405–411. https://doi.org/10.1080/14756360500381210
Suzen S, Cihaner SS, Coban T (2012) Synthesis and comparison of antioxidant properties of indole-based melatonin analogue indole amino acid derivatives. Chem Biol Drug Des 79:76–83. https://doi.org/10.1111/j.1747-0285.2011.01216.x
Süzen S, Atayik MC, Sirinzade H et al (2022) Melatonin and redox homeostasis. Melatonin Res 5:304–324. https://doi.org/10.32794/mr112500134
Tabrizi SJ, Ghosh R, Leavitt BR (2019) Huntingtin lowering strategies for disease modification in Huntington’s disease. Neuron 101:801–819. https://doi.org/10.1016/j.neuron.2019.01.039
Tabrizi SJ, Flower MD, Ross CA, Wild EJ (2020) Huntington disease: new insights into molecular pathogenesis and therapeutic opportunities. Nat Rev Neurol 16:529–546. https://doi.org/10.1038/s41582-020-0389-4
Tan DX, Manchester LC, Reiter RJ et al (1998) Melatonin protects hippocampal neurons in vivo against kainic acid-induced damage in mice. J Neurosci Res 54:382–389. https://doi.org/10.1002/(SICI)1097-4547(19981101)54:3%3c382::AID-JNR9%3e3.0.CO;2-Y
Tan BL, Norhaizan ME, Liew W-P-P, Sulaiman Rahman H (2018) Antioxidant and oxidative stress: a mutual interplay in age-related diseases. Front Pharmacol 9:1162. https://doi.org/10.3389/fphar.2018.01162
Tan HY, Ng KY, Koh RY, Chye SM (2020) Pharmacological effects of melatonin as neuroprotectant in rodent model: a review on the current biological evidence. Cell Mol Neurobiol 40:25–51. https://doi.org/10.1007/s10571-019-00724-1
Tjahjono E, Kirienko DR, Kirienko NV (2022) The emergent role of mitochondrial surveillance in cellular health. Aging Cell 21:e13710. https://doi.org/10.1111/acel.13710
Tocharus C, Puriboriboon Y, Junmanee T et al (2014) Melatonin enhances adult rat hippocampal progenitor cell proliferation via ERK signaling pathway through melatonin receptor. Neuroscience 275:314–321. https://doi.org/10.1016/j.neuroscience.2014.06.026
Túnez I, Montilla P, Del Carmen MM et al (2004) Protective effect of melatonin on 3-nitropropionic acid-induced oxidative stress in synaptosomes in an animal model of Huntington’s disease. J Pineal Res 37:252–256. https://doi.org/10.1111/j.1600-079X.2004.00163.x
van de Veerdonk FL, Netea MG, Dinarello CA, Joosten LAB (2011) Inflammasome activation and IL-1β and IL-18 processing during infection. Trends Immunol 32:110–116. https://doi.org/10.1016/j.it.2011.01.003
Van Den Bosch L, Van Damme P, Bogaert E, Robberecht W (2006) The role of excitotoxicity in the pathogenesis of amyotrophic lateral sclerosis. Biochem Biophys Acta 1762:1068–1082. https://doi.org/10.1016/j.bbadis.2006.05.002
Venegas C, García JA, Escames G et al (2012) Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. J Pineal Res 52:217–227. https://doi.org/10.1111/j.1600-079X.2011.00931.x
Verma AK, Singh S, Rizvi SI (2019) Redox homeostasis in a rodent model of circadian disruption: effect of melatonin supplementation. Gen Comp Endocrinol. https://doi.org/10.1016/j.ygcen.2019.04.016
Verma AK, Garg G, Singh S, Rizvi SI (2020a) Melatonin protects against membrane alterations affected by ‘Artificial Light at Night’ in a circadian-disrupted model of rat. Biol Rhythm Res. https://doi.org/10.1080/09291016.2020.1741265
Verma AK, Singh S, Rizvi SI (2020b) Age-dependent altered redox homeostasis in the chronodisrupted rat model and moderation by melatonin administration. Chronobiol Int. https://doi.org/10.1080/07420528.2020.1792483
Verma AK, Singh S, Garg G, Rizvi SI (2021a) Melatonin exerts neuroprotection in a chronodisrupted rat model through reduction in oxidative stress and modulation of autophagy. Chronobiol Int. https://doi.org/10.1080/07420528.2021.1966025
Verma AK, Singh S, Rizvi SI (2021b) Age-dependent effect of continuous ‘artificial light at night’ on circadian rhythm in male rats: neuroprotective role of melatonin. Biogerontology. https://doi.org/10.1007/s10522-021-09933-y
Videnovic A, Noble C, Reid KJ et al (2014) Circadian melatonin rhythm and excessive daytime sleepiness in Parkinson disease. JAMA Neurol 71:463–469. https://doi.org/10.1001/jamaneurol.2013.6239
Vincent B (2018) Protective roles of melatonin against the amyloid-dependent development of Alzheimer’s disease: a critical review. Pharmacol Res 134:223–237. https://doi.org/10.1016/j.phrs.2018.06.011
Vorobyeva AG, Saunders AJ (2018) Amyloid-β interrupts canonical Sonic hedgehog signaling by distorting primary cilia structure. Cilia 7:5. https://doi.org/10.1186/s13630-018-0059-y
Vriend J, Reiter RJ (2015) The Keap1-Nrf2-antioxidant response element pathway: a review of its regulation by melatonin and the proteasome. Mol Cell Endocrinol 401:213–220. https://doi.org/10.1016/j.mce.2014.12.013
Wang X (2009) The antiapoptotic activity of melatonin in neurodegenerative diseases. CNS Neurosci Ther 15:345–357. https://doi.org/10.1111/j.1755-5949.2009.00105.x
Wang J, Wang Z (2006) Role of melatonin in Alzheimer-like neurodegeneration. Acta Pharmacol Sin 27:41–49. https://doi.org/10.1111/j.1745-7254.2006.00260.x
Wang X, Sirianni A, Pei Z et al (2011) The melatonin MT1 receptor axis modulates mutant Huntingtin-mediated toxicity. J Neurosci 31:14496–14507. https://doi.org/10.1523/JNEUROSCI.3059-11.2011
Wang J, Wang X, He Y et al (2019) Antioxidant and pro-oxidant activities of melatonin in the presence of copper and polyphenols in vitro and in vivo. Cells 8:E903. https://doi.org/10.3390/cells8080903
Wasdell MB, Jan JE, Bomben MM et al (2008) A randomized, placebo-controlled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal Res 44:57–64. https://doi.org/10.1111/j.1600-079X.2007.00528.x
Weishaupt JH, Bartels C, Pölking E et al (2006) Reduced oxidative damage in ALS by high-dose enteral melatonin treatment. J Pineal Res 41:313–323. https://doi.org/10.1111/j.1600-079X.2006.00377.x
Welz P-S, Benitah SA (2020) Molecular connections between circadian clocks and aging. J Mol Biol 432:3661–3679. https://doi.org/10.1016/j.jmb.2019.12.036
West AP, Shadel GS (2017) Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat Rev Immunol 17:363–375. https://doi.org/10.1038/nri.2017.21
Wishart TM, Parson SH, Gillingwater TH (2006) Synaptic vulnerability in neurodegenerative disease. J Neuropathol Exp Neurol 65:733–739. https://doi.org/10.1097/01.jnen.0000228202.35163.c4
Xu C, He Z, Li J (2022) Melatonin as a potential neuroprotectant: mechanisms in subarachnoid hemorrhage-induced early brain injury. Front Aging Neurosci 14:899678. https://doi.org/10.3389/fnagi.2022.899678
Xue F, Shi C, Chen Q et al (2017) Melatonin mediates protective effects against kainic acid-induced neuronal death through safeguarding ER stress and mitochondrial disturbance. Front Mol Neurosci 10:49. https://doi.org/10.3389/fnmol.2017.00049
Zhai Z, Xie D, Qin T et al (2022) Effect and mechanism of exogenous melatonin on cognitive deficits in animal models of Alzheimer’s disease: a systematic review and meta-analysis. Neuroscience 505:91–110. https://doi.org/10.1016/j.neuroscience.2022.09.012
Zhang H-M, Zhang Y (2014) Melatonin: a well-documented antioxidant with conditional pro-oxidant actions. J Pineal Res 57:131–146. https://doi.org/10.1111/jpi.12162
Zhang Y, Cook A, Kim J et al (2013) Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits MT1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 55:26–35. https://doi.org/10.1016/j.nbd.2013.03.008
Zhang L, Li F, Su X et al (2019) Melatonin prevents lung injury by regulating apelin 13 to improve mitochondrial dysfunction. Exp Mol Med 51:1–12. https://doi.org/10.1038/s12276-019-0273-8
Zisapel N (2018) New perspectives on the role of melatonin in human sleep, circadian rhythms and their regulation: melatonin in human sleep and circadian rhythms. Br J Pharmacol 175:3190–3199. https://doi.org/10.1111/bph.14116
Acknowledgements
AKV gratefully acknowledges the Council of Scientific and Industrial Research (CSIR), Government of India for providing financial support in the form of a Senior Research Fellowship (09/001(0426)/2018-EMR-I). The Department of Biotechnology, Government of India, provided financial support for this work through a project of “Research Resources, Service Facilities, and Platforms”. The FIST Grant of DST, New Delhi, and SAP DRS I from the UGC, India, both provide funding for the Department of Biochemistry.
Author information
Authors and Affiliations
Contributions
AKV prepared the first draft of the manuscript. The figures were prepared by AKV and SS. SIR assisted with subsequent drafts of the manuscript. All authors have read and approved the final version of the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no competing interests.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Verma, A.K., Singh, S. & Rizvi, S.I. Therapeutic potential of melatonin and its derivatives in aging and neurodegenerative diseases. Biogerontology 24, 183–206 (2023). https://doi.org/10.1007/s10522-022-10006-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10522-022-10006-x