{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:29:18Z","timestamp":1790641758845,"version":"4.1.0"},"reference-count":212,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2020,6,13]],"date-time":"2020-06-13T00:00:00Z","timestamp":1592006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Melatonin (MLT) is a powerful chronobiotic hormone that controls a multitude of circadian rhythms at several levels and, in recent times, has garnered considerable attention both from academia and industry. In several studies, MLT has been discussed as a potent neuroprotectant, anti-apoptotic, anti-inflammatory, and antioxidative agent with no serious undesired side effects. These characteristics raise hopes that it could be used in humans for central nervous system (CNS)-related disorders. MLT is mainly secreted in the mammalian pineal gland during the dark phase, and it is associated with circadian rhythms. However, the production of MLT is not only restricted to the pineal gland; it also occurs in the retina, Harderian glands, gut, ovary, testes, bone marrow, and lens. Although most studies are limited to investigating the role of MLT in the CNS and related disorders, we explored a considerable amount of the existing literature. The objectives of this comprehensive review were to evaluate the impact of MLT on the CNS from the published literature, specifically to address the biological functions and potential mechanism of action of MLT in the CNS. We document the effectiveness of MLT in various animal models of brain injury and its curative effects in humans. Furthermore, this review discusses the synthesis, biology, function, and role of MLT in brain damage, and as a neuroprotective, antioxidative, anti-inflammatory, and anticancer agent through a collection of experimental evidence. Finally, it focuses on the effect of MLT on several neurological diseases, particularly CNS-related injuries.<\/jats:p>","DOI":"10.3390\/cancers12061567","type":"journal-article","created":{"date-parts":[[2020,6,15]],"date-time":"2020-06-15T12:16:57Z","timestamp":1592223417000},"page":"1567","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Role and Therapeutic Potential of Melatonin in the Central Nervous System and Cancers"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9924-8433","authenticated-orcid":false,"given":"Sangiliyandi","family":"Gurunathan","sequence":"first","affiliation":[{"name":"Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4402-7064","authenticated-orcid":false,"given":"Min-Hee","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1232-5307","authenticated-orcid":false,"given":"Jin-Hoi","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Stem Cell and Regenerative Biotechnology, Konkuk University, Seoul 05029, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,6,13]]},"reference":[{"key":"ref_1","first-page":"174","article-title":"Neuroprotective drugs in traumatic CNS injury","volume":"2","author":"Samantaray","year":"2010","journal-title":"Open Drug Discov. J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1111\/j.1600-079X.2009.00703.x","article-title":"Therapeutic potential of melatonin in traumatic central nervous system injury","volume":"47","author":"Samantaray","year":"2009","journal-title":"J. Pineal Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/nrneurol.2013.67","article-title":"The emerging roles of microRNAs in CNS injuries","volume":"9","author":"Bhalala","year":"2013","journal-title":"Nat. Rev. Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.tibtech.2011.07.002","article-title":"Creating permissive microenvironments for stem cell transplantation into the central nervous system","volume":"30","author":"Kim","year":"2012","journal-title":"Trends Biotechnol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.brainres.2009.09.109","article-title":"Effects of epigallocatechin gallate on tissue protection and functional recovery after contusive spinal cord injury in rats","volume":"1306","author":"Khalatbary","year":"2010","journal-title":"Brain Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.bbadis.2011.10.017","article-title":"Antioxidant therapies in traumatic brain and spinal cord injury","volume":"1822","author":"Bains","year":"2011","journal-title":"Biochim. Biophys. Acta Bioenerg."},{"key":"ref_7","unstructured":"Global Burden of Disease Cancer Collaboration, Fitzmaurice, C., Allen, C., Barber, R.M., Barregard, L., Bhutta, Z.A., Brenner, H., Dicker, D.J., Chimed-Orchir, O., and Dandona, R. (2017). Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015. JAMA Oncol., 3, 524\u2013548."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1038\/bjc.2013.87","article-title":"Use of low-dose aspirin and non-aspirin nonsteroidal anti-inflammatory drugs and risk of glioma: A case\u2013control study","volume":"108","author":"Gaist","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"896","DOI":"10.1093\/neuonc\/nou087","article-title":"The epidemiology of glioma in adults: A \u201cstate of the science\u201d review","volume":"16","author":"Ostrom","year":"2014","journal-title":"Neuro Oncol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1034\/j.1600-079X.2000.280401.x","article-title":"Evidence for melatonin synthesis in mouse and human bone marrow cells","volume":"28","author":"Conti","year":"2000","journal-title":"J. Pineal Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1016\/j.pneurobio.2010.12.004","article-title":"Melatonin\u2014A pleiotropic, orchestrating regulator molecule","volume":"93","author":"Hardeland","year":"2011","journal-title":"Prog. Neurobiol."},{"key":"ref_12","first-page":"194","article-title":"Melatonin in Aging and Disease\u2014Multiple Consequences of Reduced Secretion, Options and Limits of Treatment","volume":"3","author":"Hardeland","year":"2011","journal-title":"Aging Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2997","DOI":"10.1007\/s00018-014-1579-2","article-title":"Extrapineal melatonin: Sources, regulation, and potential functions","volume":"71","author":"Escames","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3883","DOI":"10.1007\/s00018-017-2615-9","article-title":"Melatonin and the electron transport chain","volume":"74","author":"Hardeland","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1111\/jpi.12224","article-title":"Anatomical and cellular localization of melatonin MT1and MT2receptors in the adult rat brain","volume":"58","author":"Lacoste","year":"2015","journal-title":"J. Pineal Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2921","DOI":"10.1007\/s00429-017-1439-6","article-title":"Melatonin receptors: Distribution in mammalian brain and their respective putative functions","volume":"222","author":"Ng","year":"2017","journal-title":"Brain Struct. Funct."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.jchemneu.2017.01.005","article-title":"Day\/night expression of MT 1 and MT 2 receptors in hypothalamic nuclei of the primate Sapajus apella","volume":"81","author":"Pinato","year":"2017","journal-title":"J. Chem. Neuroanat."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.pneurobio.2015.02.001","article-title":"Melatonin and brain inflammaging","volume":"127","author":"Hardeland","year":"2015","journal-title":"Prog. Neurobiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"883","DOI":"10.3727\/096368915X689749","article-title":"Melatonin as an antioxidant for stroke neuroprotection","volume":"25","author":"Watson","year":"2016","journal-title":"Cell Transplant."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Acu\u00f1a-Castroviejo, D., Escames, G., Le\u00d3n, J., Carazo, A., and Khaldy, H. (2003). Mitochondrial regulation by melatonin and its metabolites. Developments in Tryptophan and Serotonin Metabolism, Springer.","DOI":"10.1007\/978-1-4615-0135-0_63"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"947","DOI":"10.2741\/2116","article-title":"Melatonin role in the mitochondrial function","volume":"12","year":"2007","journal-title":"Front. Biosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1002\/biof.23","article-title":"Melatonin: Signaling mechanisms of a pleiotropic agent","volume":"35","author":"Hardeland","year":"2009","journal-title":"BioFactors"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1111\/jpi.12090","article-title":"Melatonin and the theories of aging: A critical appraisal of melatonin\u2019s role in antiaging mechanisms","volume":"55","author":"Hardeland","year":"2013","journal-title":"J. Pineal Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e12377","DOI":"10.1111\/jpi.12377","article-title":"Melatonin and the pathologies of weakened or dysregulated circadian oscillators","volume":"62","author":"Hardeland","year":"2016","journal-title":"J. Pineal Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3863","DOI":"10.1007\/s00018-017-2609-7","article-title":"Melatonin as a mitochondria-targeted antioxidant: One of evolution\u2019s best ideas","volume":"74","author":"Reiter","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Reiter, R., Tan, D.-X., Rosales-Corral, S., Galano, A., Zhou, X.J., and Xu, B. (2018). Mitochondria: Central Organelles for Melatonin\u2032s Antioxidant and Anti-Aging Actions. Molecules, 23.","DOI":"10.3390\/molecules23020509"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3965","DOI":"10.1007\/s00018-017-2610-1","article-title":"Melatonin, clock genes and mitochondria in sepsis","volume":"74","author":"Rahim","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_28","first-page":"167","article-title":"Alzheimer\u2019s disease: Pathological mechanisms and the beneficial role of melatonin","volume":"52","author":"Boga","year":"2011","journal-title":"J. Pineal Res."},{"key":"ref_29","first-page":"52","article-title":"Medical implications of melatonin: Receptor-mediated and receptor-independent actions","volume":"52","author":"Reiter","year":"2007","journal-title":"Adv. Med. Sci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S1734-1140(09)70081-7","article-title":"Physiology and pharmacology of melatonin in relation to biological rhythms","volume":"61","author":"Zawilska","year":"2009","journal-title":"Pharmacol. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1111\/jpi.12267","article-title":"Melatonin: An ancient molecule that makes oxygen metabolically tolerable","volume":"59","author":"Manchester","year":"2015","journal-title":"J. Pineal Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"249","DOI":"10.3389\/fendo.2019.00249","article-title":"Melatonin Synthesis and Function: Evolutionary History in Animals and Plants","volume":"10","author":"Zhao","year":"2019","journal-title":"Front. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/S1521-690X(03)00016-2","article-title":"Melatonin: Clinical relevance","volume":"17","author":"Reiter","year":"2003","journal-title":"Best Pr. Res. Clin. Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1385\/ENDO:27:2:101","article-title":"Functional MT1 and MT2 Melatonin Receptors in Mammals","volume":"27","author":"Dubocovich","year":"2005","journal-title":"Endocrine"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.smrv.2004.08.001","article-title":"The basic physiology and pathophysiology of melatonin","volume":"9","author":"Claustrat","year":"2005","journal-title":"Sleep Med. Rev."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"C153","DOI":"10.1016\/0303-7207(91)90087-9","article-title":"Melatonin: The chemical expression of darkness","volume":"79","author":"Reiter","year":"1991","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3505","DOI":"10.1046\/j.1460-9568.2000.00226.x","article-title":"Neuronal, astroglial and microglial cytokine expression after an excitotoxic lesion in the immature rat brain","volume":"12","author":"Acarin","year":"2000","journal-title":"Eur. J. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"165","DOI":"10.3389\/fnagi.2017.00165","article-title":"Melatonin Supplementation, a Strategy to Prevent Neurological Diseases through Maintaining Integrity of Blood Brain Barrier in Old People","volume":"9","author":"Liu","year":"2017","journal-title":"Front. Aging Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Muxel, S.M., Lapa, M., Monteiro, A.W.A., Cecon, E., Tamura, E.K., Winter, L.M.F., and Markus, R.P. (2012). NF-\u03baB Drives the Synthesis of Melatonin in RAW 264.7 Macrophages by Inducing the Transcription of the Arylalkylamine-N-Acetyltransferase (AA-NAT) Gene. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0052010"},{"key":"ref_40","first-page":"236","article-title":"Serotoninergic and melatoninergic systems are expressed in mouse embryonic fibroblasts NIH3T3 cells","volume":"34","author":"Liu","year":"2013","journal-title":"Neuro Endocrinol. Lett."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"162","DOI":"10.2174\/157015910792246182","article-title":"Significance of High Levels of Endogenous Melatonin in Mammalian Cerebrospinal Fluid and in the Central Nervous System","volume":"8","author":"Tan","year":"2010","journal-title":"Curr. Neuropharmacol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/jpi.12044","article-title":"Melatonin and its potential biological functions in the fruits of sweet cherry","volume":"55","author":"Zhao","year":"2013","journal-title":"J. Pineal Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"228","DOI":"10.2174\/157015910792246155","article-title":"Antiinflammatory Activity of Melatonin in Central Nervous System","volume":"8","author":"Esposito","year":"2010","journal-title":"Curr. Neuropharmacol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1039\/c1ra00474c","article-title":"Glutathione: Mechanism and kinetics of its non-enzymatic defense action against free radicals","volume":"1","author":"Galano","year":"2011","journal-title":"RSC Adv."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Brown, G.M., Cardinali, D.P., Adrien, J., Agargun, M.Y., Ahmadi, N., Ahmed, I., Arnedt, J.T., Barbera, J., Beaulieu-Bonneau, S., and Beitinger, M.E. (2011). Melatonin and mental illness. Sleep Ment. Illn., 119\u2013129.","DOI":"10.1017\/CBO9781139042734.013"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.mehy.2011.09.039","article-title":"Minimizing the cancer-promotional activity of cox-2 as a central strategy in cancer prevention","volume":"78","author":"Mccarty","year":"2012","journal-title":"Med. Hypotheses"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2931","DOI":"10.1038\/onc.2011.469","article-title":"Melatonin triggers p53Ser phosphorylation and prevents DNA damage accumulation","volume":"31","author":"Santoro","year":"2011","journal-title":"Oncogene"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.ijd.2013.05.008","article-title":"Potential role of melatonin in prevention and treatment of oral carcinoma","volume":"5","author":"Mehta","year":"2014","journal-title":"Indian J. Dent."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Jardim, B.V., Ferreira, L.C., Borin, T.F., Moschetta, M.G., Gelaleti, G.B., Lopes, J.R., Maschio, L.B., Leonel, C., Gon\u00e7alves, N.N., and Martins, G.R. (2013). Evaluation of the anti-angiogenic action of melatonin in breast cancer. BMC Proc., 7.","DOI":"10.1186\/1753-6561-7-S2-P11"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1111\/j.1600-079X.2011.00962.x","article-title":"Melatonin and its analogs in insomnia and depression","volume":"52","author":"Cardinali","year":"2012","journal-title":"J. Pineal Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1146\/annurev-pharmtox-010814-124742","article-title":"MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective","volume":"56","author":"Liu","year":"2015","journal-title":"Annu. Rev. Pharmacol. Toxicol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1124\/pr.110.002832","article-title":"International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors","volume":"62","author":"Dubocovich","year":"2010","journal-title":"Pharmacol. Rev."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Bondy, S.C., and Campbell, A. (2018). Mechanisms Underlying Tumor Suppressive Properties of Melatonin. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19082205"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"E7997","DOI":"10.1073\/pnas.1705768114","article-title":"Dual role of mitochondria in producing melatonin and driving GPCR signaling to block cytochrome c release","volume":"114","author":"Suofu","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1007\/s00280-017-3441-3","article-title":"Participation of MT3 melatonin receptors in the synergistic effect of melatonin on cytotoxic and apoptotic actions evoked by chemotherapeutics","volume":"80","author":"Pariente","year":"2017","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2014\/586270","article-title":"Role of Melatonin in Traumatic Brain Injury and Spinal Cord Injury","volume":"2014","author":"Naseem","year":"2014","journal-title":"Sci. World J."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1093\/jb\/mvq121","article-title":"Fibroblast growth factors: From molecular evolution to roles in development, metabolism and disease","volume":"149","author":"Itoh","year":"2010","journal-title":"J. Biochem."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00441-010-1024-2","article-title":"Hormone-like (endocrine) Fgfs: Their evolutionary history and roles in development, metabolism, and disease","volume":"342","author":"Itoh","year":"2010","journal-title":"Cell Tissue Res."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1111\/j.1755-5949.2009.00105.x","article-title":"The antiapoptotic activity of melatonin in neurodegenerative diseases","volume":"15","author":"Wang","year":"2009","journal-title":"CNS Neurosci. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/0883-2897(91)90132-5","article-title":"PET and plasma pharmacokinetic studies after bolus intravenous administration of [11C]melatonin in humans","volume":"18","author":"Bars","year":"1991","journal-title":"Int. J. Radiat. Appl. Instrum. Part B Nucl. Med. Boil."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1732","DOI":"10.1212\/WNL.0b013e3181e0438b","article-title":"Sleep disturbance and melatonin levels following traumatic brain injury","volume":"74","author":"Shekleton","year":"2010","journal-title":"Neurology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18388\/abp.2007_3264","article-title":"Melatonin and its metabolites: New findings regarding their production and their radical scavenging actions","volume":"54","author":"Reiter","year":"2007","journal-title":"Acta Biochim. Pol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0014-2999(01)01175-X","article-title":"Pharmacological action of melatonin in shock, inflammation and ischemia\/reperfusion injury","volume":"426","author":"Cuzzocrea","year":"2001","journal-title":"Eur. J. Pharmacol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1016\/j.nut.2005.02.005","article-title":"Melatonin in walnuts: Influence on levels of melatonin and total antioxidant capacity of blood","volume":"21","author":"Reiter","year":"2005","journal-title":"Nutrition"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1096\/fasebj.9.7.7737461","article-title":"Oxidative processes and antioxidative defense mechanisms in the aging brain 1","volume":"9","author":"Reiter","year":"1995","journal-title":"FASEB J."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1111\/j.1600-079X.2004.00173.x","article-title":"Melatonin attenuates gray and white matter damage in a mouse model of transient focal cerebral ischemia","volume":"38","author":"Lee","year":"2005","journal-title":"J. Pineal Res."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/j.1600-079X.2005.00283.x","article-title":"Sustained activation of Akt by melatonin contributes to the protection against kainic acid-induced neuronal death in hippocampus","volume":"40","author":"Lee","year":"2006","journal-title":"J. Pineal Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1089\/biores.2015.0032","article-title":"Melatonin Counteracts at a Transcriptional Level the Inflammatory and Apoptotic Response Secondary to Ischemic Brain Injury Induced by Middle Cerebral Artery Blockade in Aging Rats","volume":"4","author":"Paredes","year":"2015","journal-title":"BioResearch Open Access"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2346","DOI":"10.1002\/jcb.24582","article-title":"Protective effect of melatonin on bone marrow mesenchymal stem cells against hydrogen peroxide-induced apoptosis in vitro","volume":"114","author":"Wang","year":"2013","journal-title":"J. Cell. Biochem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/jpi.12193","article-title":"Melatonin prevents cell death and mitochondrial dysfunction via a SIRT1-dependent mechanism during ischemic-stroke in mice","volume":"58","author":"Yang","year":"2014","journal-title":"J. Pineal Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"119","DOI":"10.3109\/14767058.2012.663232","article-title":"The use of melatonin in hypoxic-ischemic brain damage: An experimental study","volume":"25","author":"Balduini","year":"2012","journal-title":"J. Matern. Neonatal Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1111\/j.1600-079X.2005.00307.x","article-title":"Melatonin attenuates the postischemic increase in blood-brain barrier permeability and decreases hemorrhagic transformation of tissue-plasminogen activator therapy following ischemic stroke in mice","volume":"40","author":"Chen","year":"2006","journal-title":"J. Pineal Res."},{"key":"ref_73","first-page":"31","article-title":"Anti-Inflammatory Effect of the Epigallocatechin Gallate Following Spinal Cord Trauma in Rat","volume":"15","author":"Khalatbary","year":"2011","journal-title":"Iran. Biomed. J."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/1742-2094-10-112","article-title":"Different TLR4 expression and microglia\/macrophage activation induced by hemorrhage in the rat spinal cord after compressive injury","volume":"10","author":"Zhang","year":"2013","journal-title":"J. Neuroinflammation"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.4103\/1673-5374.238603","article-title":"Melatonin for the treatment of spinal cord injury","volume":"13","author":"Guan","year":"2018","journal-title":"Neural Regen. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.jneuroim.2011.06.007","article-title":"Modulation of traumatic brain injury using progesterone and the role of glial cells on its neuroprotective actions","volume":"237","author":"Feeser","year":"2011","journal-title":"J. Neuroimmunol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"5","DOI":"10.3389\/fnagi.2013.00026","article-title":"Brain injury, neuroinflammation and Alzheimer\u2019s disease","volume":"5","author":"Breunig","year":"2013","journal-title":"Front. Aging Neurosci."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.arcmed.2013.04.002","article-title":"Effect of Melatonin on Intracranial Pressure and Brain Edema Following Traumatic Brain Injury: Role of Oxidative Stresses","volume":"44","author":"Dehghan","year":"2013","journal-title":"Arch. Med. Res."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1111\/j.1749-6632.2009.05352.x","article-title":"Posttreatment with uridine and melatonin following traumatic brain injury reduces edema in various brain regions in rats","volume":"1199","author":"Kabadi","year":"2010","journal-title":"Ann. NY Acad. Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1002\/jnr.10140","article-title":"NF-kappaB and IkappaBalpha expression following traumatic brain injury to the immature rat brain","volume":"67","author":"Sanz","year":"2002","journal-title":"J. Neurosci. Res."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1096\/fj.03-0323fje","article-title":"Melatonin-induced neuroprotection after closed head injury is associated with increased brain antioxidants and attenuated late-phase activation of NF-\u03baB and AP-1","volume":"18","author":"Beni","year":"2004","journal-title":"FASEB J."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3530","DOI":"10.1002\/jnr.22510","article-title":"Increase in blood-brain barrier permeability, oxidative stress, and activated microglia in a rat model of blast-induced traumatic brain injury","volume":"88","author":"Readnower","year":"2010","journal-title":"J. Neurosci. Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1038\/nrneurol.2010.74","article-title":"Blood\u2013brain barrier breakdown as a therapeutic target in traumatic brain injury","volume":"6","author":"Shlosberg","year":"2010","journal-title":"Nat. Rev. Neurol."},{"key":"ref_84","first-page":"43","article-title":"The protective effect of melatonin and amlodipine against cerebral ischemia\/reperfusion-induced oxidative brain injury in rats","volume":"22","author":"Toklu","year":"2009","journal-title":"Marmara Med. J."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/sj.sc.3101483","article-title":"Post-traumatic inflammation following spinal cord injury","volume":"41","author":"Hausmann","year":"2003","journal-title":"Spinal Cord"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2010\/238321","article-title":"Disruption of Nrf2 enhances the upregulation of nuclear factor-kappaB activity, tumor necrosis factor-, and matrix metalloproteinase-9 after spinal cord injury in mice","volume":"2010","author":"Mao","year":"2010","journal-title":"Mediat. Inflamm."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1007\/s00210-009-0414-z","article-title":"Treatment with green tea extract attenuates secondary inflammatory response in an experimental model of spinal cord trauma","volume":"380","author":"Paterniti","year":"2009","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"ref_88","first-page":"115","article-title":"Melatonin and its influence on immune system","volume":"58","author":"Szczepanik","year":"2007","journal-title":"J. Physiol. Pharmacol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1590\/1414-431X20132322","article-title":"Effect of melatonin on the functional recovery from experimental traumatic compression of the spinal cord","volume":"46","author":"Defino","year":"2013","journal-title":"Braz. J. Med. Biol. Res."},{"key":"ref_90","first-page":"1631","article-title":"Protection of erythropoietin on experimental spinal cord injury by reducing the expression of thrombospondin-1 and transforming growth factor-\u03b2","volume":"122","author":"Fang","year":"2009","journal-title":"Chin. Med. J."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1111\/j.1600-079X.2004.00194.x","article-title":"Attenuation in the evolution of experimental spinal cord trauma by treatment with melatonin","volume":"38","author":"Genovese","year":"2005","journal-title":"J. Pineal Res."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1111\/j.1600-079X.2010.00751.x","article-title":"Synergistic effect of melatonin on exercise-induced neuronal reconstruction and functional recovery in a spinal cord injury animal model","volume":"48","author":"Park","year":"2010","journal-title":"J. Pineal. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1111\/j.1600-079X.2008.00633.x","article-title":"Melatonin reduces stress-activated\/mitogen-activated protein kinases in spinal cord injury","volume":"46","author":"Esposito","year":"2009","journal-title":"J. Pineal. Res."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1111\/j.1600-079X.2007.00454.x","article-title":"Effects of combination of melatonin and dexamethasone on secondary injury in an experimental mice model of spinal cord trauma","volume":"43","author":"Genovese","year":"2007","journal-title":"J. Pineal. Res."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1272\/jnms.70.334","article-title":"Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia","volume":"70","author":"Asayama","year":"2003","journal-title":"J. Nippon. Med. Sch."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.eplepsyres.2009.09.020","article-title":"Mitochondria, oxidative stress, and temporal lobe epilepsy","volume":"88","author":"Waldbaum","year":"2009","journal-title":"Epilepsy Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1038\/emm.2005.42","article-title":"\u03b2-Carotene inhibits inflammatory gene expression in lipopolysaccharide-stimulated macrophages by suppressing redox-based NF-\u03baB activation","volume":"37","author":"Bai","year":"2005","journal-title":"Exp. Mol. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1016\/j.bcp.2006.04.011","article-title":"NF-\u03baB activation by reactive oxygen species: Fifteen years later","volume":"72","author":"Gloire","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"749","DOI":"10.1016\/j.freeradbiomed.2009.12.022","article-title":"Reactive oxygen species, cellular redox systems, and apoptosis","volume":"48","author":"Circu","year":"2010","journal-title":"Free. Radic. Boil. Med."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.jocn.2006.03.023","article-title":"Comparative neuroprotective effect of sodium channel blockers after experimental spinal cord injury","volume":"14","author":"Ates","year":"2007","journal-title":"J. Clin. Neurosci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.braindev.2009.02.013","article-title":"The effects of pilocarpine-induced status epilepticus on oxidative stress\/damage in developing animals","volume":"32","author":"Tsai","year":"2010","journal-title":"Brain Dev."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1124\/jpet.111.190132","article-title":"Fumarates promote cytoprotection of central nervous system cells against oxidative stress via the nuclear factor (erythroid-derived 2)-like 2 pathway","volume":"341","author":"Scannevin","year":"2012","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_103","first-page":"147","article-title":"Melatonin involvement in oxidative processes","volume":"29","author":"Olinescu","year":"1991","journal-title":"Endocrinologie"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1111\/j.1600-079X.1993.tb00498.x","article-title":"Melatonin, hydroxyl radical-mediated oxidative damage, and aging: A hypothesis","volume":"14","author":"Poeggeler","year":"1993","journal-title":"J. Pineal Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"181","DOI":"10.2174\/1568026023394443","article-title":"Chemical and physical properties and potential mechanisms: Melatonin as a broad spectrum antioxidant and free radical scavenger","volume":"2","author":"Tan","year":"2002","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"PL271","DOI":"10.1016\/0024-3205(94)00666-0","article-title":"Melatonin: A peroxyl radical scavenger more effective than vitamin E","volume":"55","author":"Pieri","year":"1994","journal-title":"Life Sci."},{"key":"ref_107","first-page":"668","article-title":"Melatonin oxidative stress and neurodegenerative diseases","volume":"40","author":"Srinivasan","year":"2002","journal-title":"Indian J. Exp. Boil."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1111\/j.1600-079X.2007.00456.x","article-title":"Melatonin attenuates arsenite-induced apoptosis in rat brain: Involvement of mitochondrial and endoplasmic reticulum pathways and aggregation of \u03b1-synuclein","volume":"43","author":"Lin","year":"2007","journal-title":"J. Pineal Res."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1111\/j.1600-079X.2008.00629.x","article-title":"Melatonin inhibits arsenite-induced peripheral neurotoxicity","volume":"46","author":"Lin","year":"2009","journal-title":"J. Pineal Res."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"848","DOI":"10.1177\/0748233713512891","article-title":"Protective effects of melatonin against arsenic-induced apoptosis and oxidative stress in rat testes","volume":"32","author":"Uygur","year":"2013","journal-title":"Toxicol. Ind. Heal."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1473","DOI":"10.3748\/wjg.v16.i12.1473","article-title":"Melatonin and Doxorubicin synergistically induce cell apoptosis in human hepatoma cell lines","volume":"16","author":"Fan","year":"2010","journal-title":"World J. Gastroenterol."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1333","DOI":"10.1016\/j.ecoenv.2010.05.004","article-title":"Evaluation of in vitro anti-genotoxic potential of melatonin against arsenic and fluoride in human blood cultures","volume":"73","author":"Pant","year":"2010","journal-title":"Ecotoxicol. Environ. Saf."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1111\/j.1600-079X.2009.00715.x","article-title":"The role of melatonin on gastric mucosal cell proliferation and telomerase activity in ageing","volume":"47","author":"Akbulut","year":"2009","journal-title":"J. Pineal Res."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/j.1600-079X.2009.00687.x","article-title":"Induction of matrix metalloproteinase-9 and -3 in nonsteroidal anti-inflammatory drug-induced acute gastric ulcers in mice: Regulation by melatonin","volume":"47","author":"Ganguly","year":"2009","journal-title":"J. Pineal Res."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1111\/j.1600-079X.2008.00656.x","article-title":"An evaluation of the neuroprotective effects of melatonin in an in vitro experimental model of age-induced neuronal apoptosis","volume":"46","year":"2009","journal-title":"J. Pineal Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1034\/j.1600-079X.2000.280407.x","article-title":"Melatonin-induced increased activity of the respiratory chain complexes I and IV can prevent mitochondrial damage induced by ruthenium red in vivo","volume":"28","author":"Martin","year":"2000","journal-title":"J. Pineal Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1007\/BF02253360","article-title":"Actions of melatonin in the reduction of oxidative stress. A review","volume":"7","author":"Reiter","year":"2000","journal-title":"J. Biomed. Sci."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1034\/j.1600-079X.2001.300201.x","article-title":"Melatonin, mitochondria, and cellular bioenergetics","volume":"30","author":"Escames","year":"2001","journal-title":"J. Pineal Res."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1034\/j.1600-079x.2000.280108.x","article-title":"Beneficial effects of melatonin in a rat model of splanchnic artery occlusion and reperfusion","volume":"28","author":"Cuzzocrea","year":"2000","journal-title":"J. Pineal Res."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1016\/j.lfs.2003.07.038","article-title":"Melatonin treatment protects against sepsis-induced functional and biochemical changes in rat ileum and urinary bladder","volume":"74","author":"Sener","year":"2004","journal-title":"Life Sci."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1111\/j.1600-079X.2004.00138.x","article-title":"Pretreatment with melatonin exerts anti-inflammatory effects against ischemia\/reperfusion injury in a rat middle cerebral artery occlusion stroke model","volume":"37","author":"Pei","year":"2004","journal-title":"J. Pineal Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/s11010-006-9353-x","article-title":"Anti-inflammatory effect of melatonin on A\u03b2 vaccination in mice","volume":"298","author":"Jesudason","year":"2006","journal-title":"Mol. Cell. Biochem."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1111\/jpi.12191","article-title":"Melatonin blunts the mitochondrial\/NLRP3 connection and protects against radiation-induced oral mucositis","volume":"58","author":"Ortiz","year":"2014","journal-title":"J. Pineal Res."},{"key":"ref_124","doi-asserted-by":"crossref","unstructured":"Fernandez-Gil, B.I., Moneim, A.E.A., Ortiz, F., Shen, Y.-Q., Soto-Mercado, V., Mendivil-Perez, M., Guerra-Librero, A., Acu\u00f1a-Castroviejo, D., Molina-Navarro, M.M., and Garcia-Verdugo, J.M. (2017). Melatonin protects rats from radiotherapy-induced small intestine toxicity. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174474"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1111\/jpi.12300","article-title":"Melatonin attenuated early brain injury induced by subarachnoid hemorrhage via regulating NLRP3 inflammasome and apoptosis signaling","volume":"60","author":"Dong","year":"2016","journal-title":"J. Pineal Res."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1111\/j.1600-079X.2007.00489.x","article-title":"Reactions of the NO redox forms NO+, \u2022NO and HNO (protonated NO\u2013) with the melatonin metabolite N1-acetyl-5-methoxykynuramine","volume":"43","author":"Hardeland","year":"2007","journal-title":"J. Pineal Res."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/(SICI)1097-0045(19980401)35:1<27::AID-PROS4>3.0.CO;2-E","article-title":"Melatonin receptors in benign prostate epithelial cells: Evidence for the involvement of cholera and pertussis toxins-sensitive G proteins in their signal transduction pathways","volume":"35","author":"Gilad","year":"1998","journal-title":"Prostate"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"2417","DOI":"10.1038\/s41598-017-02679-z","article-title":"Melatonin-mediated mitophagy protects against early brain injury after subarachnoid hemorrhage through inhibition of NLRP3 inflammasome activation","volume":"7","author":"Cao","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1007\/s12640-012-9350-7","article-title":"The anti-inflammatory effect of melatonin on methamphetamine-induced pro-inflammatory mediators in human neuroblastoma dopamine SH-SY5Y cell lines","volume":"23","author":"Permpoonputtana","year":"2013","journal-title":"Neurotox. Res."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s11064-016-1850-z","article-title":"Proof-of Concept that an Acute Trophic Factors Intervention After Spinal Cord Injury Provides an Adequate Niche for Neuroprotection, Recruitment of Nestin-Expressing Progenitors and Regeneration","volume":"41","author":"Krityakiarana","year":"2016","journal-title":"Neurochem. Res."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"5973","DOI":"10.1007\/s12035-016-0131-9","article-title":"PPAR-\u03b1 modulates the anti-inflammatory effect of melatonin in the secondary events of spinal cord injury","volume":"54","author":"Paterniti","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.rpor.2014.11.003","article-title":"Oral administration of melatonin modulates the expression of tumor necrosis factor-alpha (TNF-alpha) gene in irradiated rat cervical spinal cord","volume":"20","author":"Haddadi","year":"2015","journal-title":"Rep. Pract. Oncol. Radiother."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1159\/000227533","article-title":"Increased survival time in brain glioblastomas by a radioneuroendocrine strategy with radiotherapy plus melatonin compared to radiotherapy alone","volume":"53","author":"Lissoni","year":"1996","journal-title":"Oncology"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1159\/000069427","article-title":"Biotherapy with the pineal immunomodulating hormone melatonin versus melatonin plus aloe vera in untreatable advanced solid neoplasms","volume":"16","author":"Lissoni","year":"1998","journal-title":"Nat. Immun."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1212\/WNL.46.1.261","article-title":"Melatonin replacement corrects sleep disturbances in a child with pineal tumor","volume":"46","author":"Etzioni","year":"1996","journal-title":"Neurology"},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1523\/JNEUROSCI.17-05-01683.1997","article-title":"Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide","volume":"17","author":"Pappolla","year":"1997","journal-title":"J. Neurosci."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1177\/088307380101600215","article-title":"Melatonin replacement therapy in a child with a pineal tumor","volume":"16","author":"Jan","year":"2001","journal-title":"J. Child Neurol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"B311","DOI":"10.1093\/gerona\/56.7.B311","article-title":"Melatonin increases both life span and tumor incidence in female CBA mice","volume":"56","author":"Anisimov","year":"2001","journal-title":"J. Gerontol. Ser. A Biol. Sci. Med. Sci."},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1034\/j.1600-079X.2001.310303.x","article-title":"Effects of melatonin on doxorubicin cytotoxicity in sensitive and pleiotropically resistant tumor cells","volume":"31","author":"Granzotto","year":"2001","journal-title":"J. Pineal Res."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1111\/j.1600-079X.2005.00305.x","article-title":"Inhibitory effects of melatonin on the growth of pituitary prolactin-secreting tumor in rats","volume":"40","author":"Yang","year":"2006","journal-title":"J. Pineal Res."},{"key":"ref_141","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1158\/0008-5472.CAN-05-2354","article-title":"Intracellular Signaling Pathways Involved in the Cell Growth Inhibition of Glioma Cells by Melatonin","volume":"66","author":"Martin","year":"2006","journal-title":"Cancer Res."},{"key":"ref_142","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1111\/j.1600-079X.2006.00342.x","article-title":"Melatonin induces apoptosis in human neuroblastoma cancer cells","volume":"41","author":"Herrera","year":"2006","journal-title":"J. Pineal Res."},{"key":"ref_143","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.patbio.2006.12.025","article-title":"Biochemotherapy with standard chemotherapies plus the pineal hormone melatonin in the treatment of advanced solid neoplasms","volume":"55","author":"Lissoni","year":"2007","journal-title":"Pathol. Boil."},{"key":"ref_144","first-page":"1377","article-title":"Neuroimmunomodulation in medical oncology: Application of psychoneuroimmunology with subcutaneous low-dose IL-2 and the pineal hormone melatonin in patients with untreatable metastatic solid tumors","volume":"28","author":"Lissoni","year":"2008","journal-title":"Anticancer. Res."},{"key":"ref_145","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1111\/j.1600-079X.2009.00727.x","article-title":"Synergistic antitumor effect of melatonin with several chemotherapeutic drugs on human Ewing sarcoma cancer cells: Potentiation of the extrinsic apoptotic pathway","volume":"48","author":"Rodriguez","year":"2010","journal-title":"J. Pineal Res."},{"key":"ref_146","doi-asserted-by":"crossref","first-page":"2005","DOI":"10.1038\/bjc.2013.188","article-title":"Melatonin-induced methylation of the ABCG2\/BCRP promoter as a novel mechanism to overcome multidrug resistance in brain tumour stem cells","volume":"108","author":"Martin","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_147","doi-asserted-by":"crossref","first-page":"11174","DOI":"10.1158\/0008-5472.CAN-05-1945","article-title":"Melatonin-depleted blood from premenopausal women exposed to light at night stimulates growth of human breast cancer xenografts in nude rats","volume":"65","author":"Blask","year":"2005","journal-title":"Cancer Res."},{"key":"ref_148","doi-asserted-by":"crossref","unstructured":"Blask, D.E., Dauchy, R.T., Dauchy, E.M., Mao, L., Hill, S.M., Greene, M.W., Belancio, V.P., Sauer, L.A., and Davidson, L. (2014). Light exposure at night disrupts host\/cancer circadian regulatory dynamics: Impact on the Warburg effect, lipid signaling and tumor growth prevention. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0102776"},{"key":"ref_149","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1111\/jpi.12170","article-title":"Involvement of autophagy in melatonin-induced cytotoxicity in glioma-initiating cells","volume":"57","author":"Martin","year":"2014","journal-title":"J. Pineal Res."},{"key":"ref_150","doi-asserted-by":"crossref","first-page":"1448","DOI":"10.1007\/s11064-015-1613-2","article-title":"Melatonin Protects Methamphetamine-Induced Neuroinflammation Through NF-\u03baB and Nrf2 Pathways in Glioma Cell Line","volume":"40","author":"Jumnongprakhon","year":"2015","journal-title":"Neurochem. Res."},{"key":"ref_151","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1111\/jpi.12310","article-title":"Melatonin prevents abnormal mitochondrial dynamics resulting from the neurotoxicity of cadmium by blocking calcium-dependent translocation of Drp1 to the mitochondria","volume":"60","author":"Xu","year":"2016","journal-title":"J. Pineal Res."},{"key":"ref_152","doi-asserted-by":"crossref","first-page":"93580","DOI":"10.18632\/oncotarget.20525","article-title":"Melatonin attenuates hypoxia-induced epithelial-mesenchymal transition and cell aggressive via Smad7\/CCL20 in glioma","volume":"8","author":"Chen","year":"2017","journal-title":"Oncotarget"},{"key":"ref_153","doi-asserted-by":"crossref","first-page":"2433","DOI":"10.3892\/or.2017.5446","article-title":"Melatonin inhibits angiogenesis in SH-SY5Y human neuroblastoma cells by downregulation of VEGF","volume":"37","author":"Cos","year":"2017","journal-title":"Oncol. Rep."},{"key":"ref_154","doi-asserted-by":"crossref","first-page":"e12496","DOI":"10.1111\/jpi.12496","article-title":"Melatonin disturbs SUMO ylation-mediated crosstalk between c-Myc and nestin via MT 1 activation and promotes the sensitivity of paclitaxel in brain cancer stem cells","volume":"65","author":"Lee","year":"2018","journal-title":"J. Pineal Res."},{"key":"ref_155","doi-asserted-by":"crossref","first-page":"e12556","DOI":"10.1111\/jpi.12556","article-title":"Inhibition of TFEB oligomerization by co-treatment of melatonin with vorinostat promotes the therapeutic sensitivity in glioblastoma and glioma stem cells","volume":"66","author":"Sung","year":"2019","journal-title":"J. Pineal Res."},{"key":"ref_156","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1111\/fcp.12490","article-title":"Anticonvulsant effect of melatonin through ATP-sensitive channels in mice","volume":"34","author":"Mohammadi","year":"2019","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_157","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1016\/j.bbrc.2018.02.010","article-title":"The melatonin-MT1 receptor axis modulates tumor growth in PTEN-mutated gliomas","volume":"496","author":"Ma","year":"2018","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_158","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/BF02782192","article-title":"Long-term survival with metastatic cancer to the brain","volume":"17","author":"Hall","year":"2000","journal-title":"Med. Oncol."},{"key":"ref_159","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s11060-004-8093-6","article-title":"Brain metastases: Epidemiology and pathophysiology","volume":"75","author":"Gavrilovic","year":"2005","journal-title":"J. Neuro Oncol."},{"key":"ref_160","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1093\/neuonc\/nos152","article-title":"Toward determining the lifetime occurrence of metastatic brain tumors estimated from 2007 United States cancer incidence data","volume":"14","author":"Davis","year":"2012","journal-title":"Neuro Oncol."},{"key":"ref_161","first-page":"4655","article-title":"Recent trends in epidemiology of brain metastases: An overview","volume":"32","author":"Tabouret","year":"2012","journal-title":"Anticancer. Res."},{"key":"ref_162","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1093\/neuonc\/now127","article-title":"Updates in the management of brain metastases","volume":"18","author":"Arvold","year":"2016","journal-title":"Neuro Oncol."},{"key":"ref_163","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1038\/s41571-018-0003-5","article-title":"Current state of immunotherapy for glioblastoma","volume":"15","author":"Lim","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_164","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1016\/S1470-2045(14)70314-6","article-title":"Single-agent bevacizumab or lomustine versus a combination of bevacizumab plus lomustine in patients with recurrent glioblastoma (BELOB trial): A randomised controlled phase 2 trial","volume":"15","author":"Taal","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_165","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1093\/neuonc\/nov272","article-title":"Colony stimulating factor 1 receptor inhibition delays recurrence of glioblastoma after radiation by altering myeloid cell recruitment and polarization","volume":"18","author":"Stafford","year":"2016","journal-title":"Neuro Oncol."},{"key":"ref_166","doi-asserted-by":"crossref","first-page":"73","DOI":"10.2217\/17435889.3.1.73","article-title":"Upconverting nanoparticles as nanotransducers for photodynamic therapy in cancer cells","volume":"3","author":"Chatterjee","year":"2008","journal-title":"Nanomedince"},{"key":"ref_167","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/ni.1923","article-title":"Complement: A key system for immune surveillance and homeostasis","volume":"11","author":"Ricklin","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_168","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/nrclinonc.2012.204","article-title":"Diagnostic and therapeutic avenues for glioblastoma: No longer a dead end?","volume":"10","author":"Tanaka","year":"2013","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_169","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1038\/nrclinonc.2018.27","article-title":"Immunotherapy: Cancer immunotherapy and the value of cure","volume":"15","year":"2018","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_170","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1038\/s41388-017-0024-z","article-title":"Immunotherapies for malignant glioma","volume":"37","author":"Boussiotis","year":"2018","journal-title":"Oncogene"},{"key":"ref_171","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4103\/glioma.glioma_2_19","article-title":"Glioma special issue introduction","volume":"2","author":"Jackson","year":"2019","journal-title":"Glioma"},{"key":"ref_172","doi-asserted-by":"crossref","first-page":"10333","DOI":"10.1166\/jnn.2011.5010","article-title":"Thermal analysis in the rat glioma model during directly multipoint injection hyperthermia incorporating magnetic nanoparticles","volume":"11","author":"Liu","year":"2011","journal-title":"J. Nanosci. Nanotechnol."},{"key":"ref_173","doi-asserted-by":"crossref","first-page":"3223","DOI":"10.7150\/thno.40298","article-title":"Combined-therapeutic strategies synergistically potentiate glioblastoma multiforme treatment via nanotechnology","volume":"10","author":"Yang","year":"2020","journal-title":"Theranostics"},{"key":"ref_174","doi-asserted-by":"crossref","first-page":"4401","DOI":"10.1158\/1078-0432.CCR-09-0155","article-title":"Release of HMGB1 in Response to Proapoptotic Glioma Killing Strategies: Efficacy and Neurotoxicity","volume":"15","author":"Candolfi","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_175","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.lfs.2017.08.027","article-title":"RNA interference for glioblastoma therapy: Innovation ladder from the bench to clinical trials","volume":"188","year":"2017","journal-title":"Life Sci."},{"key":"ref_176","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1186\/s12943-019-1074-3","article-title":"The role of exosomal PD-L1 in tumor progression and immunotherapy","volume":"18","author":"Xie","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_177","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1126\/scisignal.2002796","article-title":"Selective Effects of PD-1 on Akt and Ras Pathways Regulate Molecular Components of the Cell Cycle and Inhibit T Cell Proliferation","volume":"5","author":"Patsoukis","year":"2012","journal-title":"Sci. Signal."},{"key":"ref_178","doi-asserted-by":"crossref","first-page":"723","DOI":"10.7150\/ijbs.19642","article-title":"Exosomes from Melatonin Treated Hepatocellularcarcinoma Cells Alter the Immunosupression Status through STAT3 Pathway in Macrophages","volume":"13","author":"Cheng","year":"2017","journal-title":"Int. J. Boil. Sci."},{"key":"ref_179","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1056\/NEJMoa1709684","article-title":"Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma","volume":"377","author":"Wolchok","year":"2017","journal-title":"New Engl. J. Med."},{"key":"ref_180","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1016\/S1470-2045(18)30139-6","article-title":"Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: A multicentre randomised phase 2 study","volume":"19","author":"Long","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_181","doi-asserted-by":"crossref","unstructured":"Moretti, E., Favero, G., Rodella, L.F., and Rezzani, R. (2020). Melatonin\u2019s Antineoplastic Potential Against Glioblastoma. Cells, 9.","DOI":"10.3390\/cells9030599"},{"key":"ref_182","doi-asserted-by":"crossref","first-page":"245","DOI":"10.7150\/ijbs.16818","article-title":"Melatonin Inhibits Glioblastoma Stem-like cells through Suppression of EZH2-NOTCH1 Signaling Axis","volume":"13","author":"Zheng","year":"2017","journal-title":"Int. J. Boil. Sci."},{"key":"ref_183","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1007\/s13577-017-0169-7","article-title":"Ramelteon, a selective MT1\/MT2 receptor agonist, suppresses the proliferation and invasiveness of endometrial cancer cells","volume":"30","author":"Osanai","year":"2017","journal-title":"Hum. Cell"},{"key":"ref_184","doi-asserted-by":"crossref","first-page":"21952","DOI":"10.18632\/oncotarget.8009","article-title":"Melatonin inhibits TPA-induced oral cancer cell migration by suppressing matrix metalloproteinase-9 activation through the histone acetylation","volume":"7","author":"Yeh","year":"2016","journal-title":"Oncotarget"},{"key":"ref_185","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1111\/jpi.12365","article-title":"Melatonin suppresses TPA-induced metastasis by downregulating matrix metalloproteinase-9 expression through JNK\/SP-1 signaling in nasopharyngeal carcinoma","volume":"61","author":"Ho","year":"2016","journal-title":"J. Pineal Res."},{"key":"ref_186","doi-asserted-by":"crossref","first-page":"69384","DOI":"10.18632\/oncotarget.12082","article-title":"Functional genetic variant in the Kozak sequence of WW domain-containing oxidoreductase (WWOX) gene is associated with oral cancer risk","volume":"7","author":"Cheng","year":"2016","journal-title":"Oncotarget"},{"key":"ref_187","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1038\/ng.277","article-title":"A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk","volume":"41","author":"Bonnefond","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_188","doi-asserted-by":"crossref","first-page":"39896","DOI":"10.18632\/oncotarget.16379","article-title":"Melatonin for the prevention and treatment of cancer","volume":"8","author":"Li","year":"2017","journal-title":"Oncotarget"},{"key":"ref_189","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1210\/er.2018-00084","article-title":"Melatonin as a Hormone: New Physiological and Clinical Insights","volume":"39","author":"Amaral","year":"2018","journal-title":"Endocr. Rev."},{"key":"ref_190","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1111\/jpi.12137","article-title":"Melatonin, energy metabolism, and obesity: A review","volume":"56","author":"Amaral","year":"2014","journal-title":"J. Pineal Res."},{"key":"ref_191","doi-asserted-by":"crossref","first-page":"203","DOI":"10.2174\/157015908785777201","article-title":"Cellular and Biochemical Actions of Melatonin which Protect Against Free Radicals: Role in Neurodegenerative Disorders","volume":"6","author":"Ortiz","year":"2008","journal-title":"Curr. Neuropharmacol."},{"key":"ref_192","first-page":"684","article-title":"Endogenous Melatonin Increases in Cerebrospinal Fluid of Patients after Severe Traumatic Brain Injury and Correlates with Oxidative Stress and Metabolic Disarray","volume":"28","author":"Seifman","year":"2008","journal-title":"Br. J. Pharmacol."},{"key":"ref_193","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.comppsych.2016.03.005","article-title":"Differential melatonin alterations in cerebrospinal fluid and serum of patients with major depressive disorder and bipolar disorder","volume":"68","author":"Bumb","year":"2016","journal-title":"Compr. Psychiatry"},{"key":"ref_194","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/j.slsci.2016.08.001","article-title":"Loss of melatonin daily rhythmicity is asociated with delirium development in hospitalized older adults","volume":"9","author":"Escobar","year":"2016","journal-title":"Sleep Sci."},{"key":"ref_195","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.expneurol.2012.11.018","article-title":"Normobaric hyperoxia combined with minocycline provides greater neuroprotection than either alone in transient focal cerebral ischemia","volume":"240","author":"Jin","year":"2012","journal-title":"Exp. Neurol."},{"key":"ref_196","doi-asserted-by":"crossref","first-page":"31638","DOI":"10.18632\/oncotarget.15780","article-title":"Melatonin protects against blood-brain barrier damage by inhibiting the TLR4\/ NF-\u03baB signaling pathway after LPS treatment in neonatal rats","volume":"8","author":"Hu","year":"2017","journal-title":"Oncotarget"},{"key":"ref_197","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1111\/jpi.12254","article-title":"Melatonin alleviates brain injury in mice subjected to cecal ligation and puncture via attenuating inflammation, apoptosis, and oxidative stress: The role of SIRT1 signaling","volume":"59","author":"Zhao","year":"2015","journal-title":"J. Pineal Res."},{"key":"ref_198","first-page":"623","article-title":"Melatonin restores the mitochondrial production of ATP in septic mice","volume":"27","author":"Escames","year":"2006","journal-title":"Neuro Endocrinol. Lett."},{"key":"ref_199","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1111\/jpi.12099","article-title":"The beneficial effects of melatonin against heart mitochondrial impairment during sepsis: Inhibition of iNOS and preservation of nNOS","volume":"56","author":"Ortiz","year":"2013","journal-title":"J. Pineal Res."},{"key":"ref_200","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1007\/s00395-015-0526-1","article-title":"Melatonin attenuates sepsis-induced cardiac dysfunction via a PI3K\/Akt-dependent mechanism","volume":"111","author":"An","year":"2015","journal-title":"Basic Res. Cardiol."},{"key":"ref_201","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/S0165-1781(97)00128-5","article-title":"Melatonin treatment of winter depression: A pilot study","volume":"77","author":"Lewy","year":"1998","journal-title":"Psychiatry Res. Neuroimaging"},{"key":"ref_202","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1080\/07420520500398064","article-title":"Melatonin Entrains Free-running Blind People According to a Physiological Dose-response Curve","volume":"22","author":"Lewy","year":"2005","journal-title":"Chrono Int."},{"key":"ref_203","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1017\/S0029665100000434","article-title":"The hypothalamus and the regulation of energy homeostasis: Lifting the lid on a black box","volume":"59","author":"Williams","year":"2000","journal-title":"Proc. Nutr. Soc."},{"key":"ref_204","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1385\/ENDO:27:2:149","article-title":"Physiological ischemia\/reperfusion phenomena and their relation to endogenous melatonin production","volume":"27","author":"Tan","year":"2005","journal-title":"Endocrine"},{"key":"ref_205","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1111\/jpi.12010","article-title":"On the free radical scavenging activities of melatonin\u2019s metabolites, AFMK and AMK","volume":"54","author":"Galano","year":"2012","journal-title":"J. Pineal Res."},{"key":"ref_206","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1159\/000227465","article-title":"A Randomized Study of Low-Dose Subcutaneous lnterleukin-2 Plus Melatonin versus Supportive Care Alone in Metastatic Colorectal Cancer Patients Progressing under 5-Fluorouracil and Folates","volume":"52","author":"Barni","year":"1995","journal-title":"Oncology"},{"key":"ref_207","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1038\/bjc.1995.164","article-title":"Modulation of cancer endocrine therapy by melatonin: A phase II study of tamoxifen plus melatonin in metastatic breast cancer patients progressing under tamoxifen alone","volume":"71","author":"Lissoni","year":"1995","journal-title":"Br. J. Cancer"},{"key":"ref_208","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1016\/S0959-8049(99)00159-8","article-title":"Decreased toxicity and increased efficacy of cancer chemotherapy using the pineal hormone melatonin in metastatic solid tumour patients with poor clinical status","volume":"35","author":"Lissoni","year":"1999","journal-title":"Eur. J. Cancer"},{"key":"ref_209","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1034\/j.1600-079X.2003.00032.x","article-title":"Five years survival in metastatic non-small cell lung cancer patients treated with chemotherapy alone or chemotherapy and melatonin: A randomized trial","volume":"35","author":"Lissoni","year":"2003","journal-title":"J. Pineal Res."},{"key":"ref_210","first-page":"1951","article-title":"Biomodulation of cancer chemotherapy for metastatic colorectal cancer: A randomized study of weekly low-dose irinotecan alone versus irinotecan plus the oncostatic pineal hormone melatonin in metastatic colorectal cancer patients progressing on 5-fluorouracil-containing combinations","volume":"23","author":"Cerea","year":"2003","journal-title":"Anticancer. Res."},{"key":"ref_211","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1177\/1534735411425484","article-title":"Melatonin as adjuvant cancer care with and without chemotherapy: A systematic review and meta-analysis of randomized trials","volume":"11","author":"Seely","year":"2012","journal-title":"Integr. Cancer Ther."},{"key":"ref_212","doi-asserted-by":"crossref","first-page":"7895","DOI":"10.2147\/OTT.S174100","article-title":"Therapeutic strategies of melatonin in cancer patients: A systematic review and meta-analysis","volume":"11","author":"Wang","year":"2018","journal-title":"Onco Targets Ther."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/6\/1567\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:38:44Z","timestamp":1760175524000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/6\/1567"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,6,13]]},"references-count":212,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2020,6]]}},"alternative-id":["cancers12061567"],"URL":"https:\/\/doi.org\/10.3390\/cancers12061567","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,6,13]]}}}