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Melatonin Supplementation in Neurodegenerative Diseases: Current Status

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Melatonin, Neuroprotective Agents and Antidepressant Therapy

Abstract

Neurodegenerative diseases are chronic and progressive disorders characterized by selective destruction of neurons in motor, sensory, and cognitive systems. Despite their different origins, the majority of central and peripheral nervous system degenerative diseases (including Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), and amyotrophic lateral sclerosis) share the reduced capacity to maintain the balance between free radical formation and antioxidative mechanisms as a common critical factor [1].

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References

  1. Reiter RJ, Tan DX, Manchester LC, Tamura H. Melatonin defeats neurally-derived free radicals and reduces the associated neuromorphological and neurobehavioral damage. J Physiol Pharmacol. 2007;58:5–22.

    PubMed  Google Scholar 

  2. Cuzzocrea S, Zingarelli B, Gilad E, Hake P, Salzman AL, Szabo C. Protective effect of melatonin in carrageenan-induced models of local inflammation: relationship to its inhibitory effect on nitric oxide production and its peroxynitrite scavenging activity. J Pineal Res. 1997;23:106–16.

    Article  CAS  PubMed  Google Scholar 

  3. Cuzzocrea S, Zingarelli B, Costantino G, Caputi AP. Protective effect of melatonin in a non-septic shock model induced by zymosan in the rat. J Pineal Res. 1998;25:24–33.

    Article  CAS  PubMed  Google Scholar 

  4. Cuzzocrea S, Costantino G, Mazzon E, Micali A, De Sarro A, Caputi AP. Beneficial effects of melatonin in a rat model of splanchnic artery occlusion and reperfusion. J Pineal Res. 2000;28:52–63.

    Article  CAS  PubMed  Google Scholar 

  5. Cuzzocrea S, Mazzon E, Serraino I, Lepore V, Terranova ML, Ciccolo A, Caputi AP. Melatonin reduces dinitrobenzene sulfonic acid-induced colitis. J Pineal Res. 2001;30:1–12.

    Article  CAS  PubMed  Google Scholar 

  6. Dugo L, Serraino I, Fulia F, De Sarro A, Caputi AP, Cuzzocrea S. Effect of melatonin on cellular energy depletion mediated by peroxynitrite and poly (ADP-ribose) synthetase activation in an acute model of inflammation. J Pineal Res. 2001;31:76–84.

    Article  CAS  PubMed  Google Scholar 

  7. Cuzzocrea S, Reiter RJ. Pharmacological actions of melatonin in acute and chronic inflammation. Curr Top Med Chem. 2002;2:153–65.

    Article  CAS  PubMed  Google Scholar 

  8. MohanKumar SM, Campbell A, Block M, Veronesi B. Particulate matter, oxidative stress and neurotoxicity. Neurotoxicology. 2008;29:479–88.

    Article  CAS  PubMed  Google Scholar 

  9. Lin AM, Ho LT. Melatonin suppresses iron-induced neurodegeneration in rat brain. Free Radic Biol Med. 2000;28:904–11.

    Article  CAS  PubMed  Google Scholar 

  10. Emerit J, Edeas M, Bricaire F. Neurodegenerative diseases and oxidative stress. Biomed Pharmacother. 2004;58:39–46.

    Article  CAS  PubMed  Google Scholar 

  11. Campbell A, Smith MA, Sayre LM, Bondy SC, Perry G. Mechanisms by which metals promote events connected to neurodegenerative diseases. Brain Res Bull. 2001;55:125–32.

    Article  CAS  PubMed  Google Scholar 

  12. Gegg ME, Beltran B, Salas-Pino S, Bolanos JP, Clark JB, Moncada S, Heales SJ. Differential effect of nitric oxide on glutathione metabolism and mitochondrial function in astrocytes and neurones: implications for neuroprotection/neurodegeneration? J Neurochem. 2003;86:228–37.

    Article  CAS  PubMed  Google Scholar 

  13. Eddleston M, Mucke L. Molecular profile of reactive astrocytes-implications for their role in neurologic disease. Neuroscience. 1993;54:15–36.

    Article  CAS  PubMed  Google Scholar 

  14. Minagar A, Shapshak P, Fujimura R, Ownby R, Heyes M, Eisdorfer C. The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis. J Neurol Sci. 2002;202:13–23.

    Article  CAS  PubMed  Google Scholar 

  15. Yun HY, Dawson VL, Dawson TM. Nitric oxide in health and disease of the nervous system. Mol Psychiatry. 1997;2:300–10.

    Article  CAS  PubMed  Google Scholar 

  16. Antolin I, Mayo JC, Sainz RM, del Brio Mde L, Herrera F, Martin V, Rodriguez C. Protective effect of melatonin in a chronic experimental model of Parkinson’s disease. Brain Res. 2002;943:163–73.

    Article  CAS  PubMed  Google Scholar 

  17. Shen YX, Xu SY, Wei W, Wang XL, Wang H, Sun X. Melatonin blocks rat hippocampal neuronal apoptosis induced by amyloid beta-peptide 25–35. J Pineal Res. 2002;32:163–7.

    Article  CAS  PubMed  Google Scholar 

  18. Lin MT, Beal MF. Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature. 2006;443:787–95.

    Article  CAS  PubMed  Google Scholar 

  19. Reiter RJ, Tan DX, Gitto E, Sainz RM, Mayo JC, Leon J, Manchester LC, Vijayalaxmi, Kilic E, Kilic U. Pharmacological utility of melatonin in reducing oxidative cellular and molecular damage. Pol J Pharmacol. 2004;56:159–70.

    CAS  PubMed  Google Scholar 

  20. Tricoire H, Locatelli A, Chemineau P, Malpaux B. Melatonin enters the cerebrospinal fluid through the pineal recess. Endocrinology. 2002;143:84–90.

    Article  CAS  PubMed  Google Scholar 

  21. Andrabi SA, Sayeed I, Siemen D, Wolf G, Horn TF. Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti-apoptotic effects of melatonin. FASEB J. 2004;18:869–71.

    CAS  PubMed  Google Scholar 

  22. Cardinali DP, Pagano ES, Scacchi Bernasconi PA, Reynoso R, Scacchi P. Melatonin and mitochondrial dysfunction in the central nervous system. Horm Behav. 2013;63:322–30.

    Article  CAS  PubMed  Google Scholar 

  23. Kilic E, Kilic U, Yulug B, Hermann DM, Reiter RJ. Melatonin reduces disseminate neuronal death after mild focal ischemia in mice via inhibition of caspase-3 and is suitable as an add-on treatment to tissue-plasminogen activator. J Pineal Res. 2004;36:171–6.

    Article  CAS  PubMed  Google Scholar 

  24. Leon J, Acuna-Castroviejo D, Escames G, Tan DX, Reiter RJ. Melatonin mitigates mitochondrial malfunction. J Pineal Res. 2005;38:1–9.

    Article  CAS  PubMed  Google Scholar 

  25. Esposito E, Iacono A, Muia C, Crisafulli C, Mattace Raso G, Bramanti P, Meli R, Cuzzocrea S. Signal transduction pathways involved in protective effects of melatonin in C6 glioma cells. J Pineal Res. 2008;44:78–87.

    CAS  PubMed  Google Scholar 

  26. Wang X. The antiapoptotic activity of melatonin in neurodegenerative diseases. CNS Neurosci Ther. 2009;15:345–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Medeiros CA, Carvalhedo de Bruin PF, Lopes LA, Magalhaes MC, de Lourdes Seabra M, de Bruin VM. Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson’s disease. A randomized, double blind, placebo-controlled study. J Neurol. 2007;254:459–64.

    Article  CAS  PubMed  Google Scholar 

  28. Sharma R, McMillan CR, Tenn CC, Niles LP. Physiological neuroprotection by melatonin in a 6-hydroxydopamine model of Parkinson’s disease. Brain Res. 2006;1068:230–6.

    Article  CAS  PubMed  Google Scholar 

  29. Yang X, Yang Y, Fu Z, Li Y, Feng J, Luo J, Zhang Q, Wang Q, Tian Q. Melatonin ameliorates alzheimer-like pathological changes and spatial memory retention impairment induced by calyculin A. J Psychopharmacol. 2011;25:1118–25.

    Article  CAS  PubMed  Google Scholar 

  30. Olcese JM, Cao C, Mori T, Mamcarz MB, Maxwell A, Runfeldt MJ, Wang L, Zhang C, Lin X, Zhang G, Arendash GW. 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. 2009;47:82–96.

    Article  CAS  PubMed  Google Scholar 

  31. Weishaupt JH, Bartels C, Polking E, Dietrich J, Rohde G, Poeggeler B, Mertens N, Sperling S, Bohn M, Huther G, Schneider A, Bach A, Siren AL, Hardeland R, Bahr M, Nave KA, Ehrenreich H. Reduced oxidative damage in ALS by high-dose enteral melatonin treatment. J Pineal Res. 2006;41:313–23.

    Article  CAS  PubMed  Google Scholar 

  32. Jacob S, Poeggeler B, Weishaupt JH, Siren AL, Hardeland R, Bahr M, Ehrenreich H. Melatonin as a candidate compound for neuroprotection in amyotrophic lateral sclerosis (ALS): high tolerability of daily oral melatonin administration in ALS patients. J Pineal Res. 2002;33:186–7.

    Article  CAS  PubMed  Google Scholar 

  33. Daglioglu E, Serdar Dike M, Kilinc K, Erdogan D, Take G, Ergungor F, Okay O, Biyikli Z. Neuroprotective effect of melatonin on experimental peripheral nerve injury: an electron microscopic and biochemical study. Cen Eur Neurosurg. 2009;70:109–14.

    Article  CAS  Google Scholar 

  34. Genovese T, Mazzon E, Muia C, Bramanti P, De Sarro A, Cuzzocrea S. Attenuation in the evolution of experimental spinal cord trauma by treatment with melatonin. J Pineal Res. 2005;38:198–208.

    Article  CAS  PubMed  Google Scholar 

  35. Reiter RJ, Paredes SD, Manchester LC, Tan DX. Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin. Crit Rev Biochem Mol Biol. 2009;44:175–200.

    Article  CAS  PubMed  Google Scholar 

  36. Jan JE, Hamilton D, Seward N, Fast DK, Freeman RD, Laudon M. Clinical trials of controlled-release melatonin in children with sleep-wake cycle disorders. J Pineal Res. 2000;29:34–9.

    Article  CAS  PubMed  Google Scholar 

  37. Seabra ML, Bignotto M, Pinto Jr LR, Tufik S. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res. 2000;29:193–200.

    Article  CAS  PubMed  Google Scholar 

  38. Kelley BJ, Petersen RC. Alzheimer’s disease and mild cognitive impairment. Neurol Clin. 2007;25:577–609.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Selkoe DJ. The molecular pathology of Alzheimer’s disease. Neuron. 1991;6:487–98.

    Article  CAS  PubMed  Google Scholar 

  40. Pappolla MA, Omar RA, Kim KS, Robakis NK. Immunohistochemical evidence of oxidative [corrected] stress in Alzheimer’s disease. Am J Pathol. 1992;140:621–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Balazs L, Leon M. Evidence of an oxidative challenge in the Alzheimer’s brain. Neurochem Res. 1994;19:1131–7.

    Article  CAS  PubMed  Google Scholar 

  42. Pamplona R, Dalfo E, Ayala V, Bellmunt MJ, Prat J, Ferrer I, Portero-Otin M. Proteins in human brain cortex are modified by oxidation, glycoxidation, and lipoxidation. Effects of Alzheimer disease and identification of lipoxidation targets. J Biol Chem. 2005;280:21522–30.

    Article  CAS  PubMed  Google Scholar 

  43. Liu Q, Smith MA, Avila J, DeBernardis J, Kansal M, Takeda A, Zhu X, Nunomura A, Honda K, Moreira PI, Oliveira CR, Santos MS, Shimohama S, Aliev G, de la Torre J, Ghanbari HA, Siedlak SL, Harris PL, Sayre LM, Perry G. Alzheimer-specific epitopes of tau represent lipid peroxidation-induced conformations. Free Radic Biol Med. 2005;38:746–54.

    Article  CAS  PubMed  Google Scholar 

  44. Weldon DT, Rogers SD, Ghilardi JR, Finke MP, Cleary JP, O’Hare E, Esler WP, Maggio JE, Mantyh PW. Fibrillar beta-amyloid induces microglial phagocytosis, expression of inducible nitric oxide synthase, and loss of a select population of neurons in the rat CNS in vivo. J Neurosci. 1998;18:2161–73.

    CAS  PubMed  Google Scholar 

  45. Selkoe DJ. Alzheimer’s disease is a synaptic failure. Science. 2002;298:789–91.

    Article  CAS  PubMed  Google Scholar 

  46. Saragoni L, Hernandez P, Maccioni RB. Differential association of tau with subsets of microtubules containing posttranslationally-modified tubulin variants in neuroblastoma cells. Neurochem Res. 2000;25:59–70.

    Article  CAS  PubMed  Google Scholar 

  47. Brion JP, Anderton BH, Authelet M, Dayanandan R, Leroy K, Lovestone S, Octave JN, Pradier L, Touchet N, Tremp G. Neurofibrillary tangles and tau phosphorylation. Biochem Soc Symp. 2001;67:81–8.

    Article  CAS  Google Scholar 

  48. Dragicevic N, Mamcarz M, Zhu Y, Buzzeo R, Tan J, Arendash GW, Bradshaw PC. Mitochondrial amyloid-beta levels are associated with the extent of mitochondrial dysfunction in different brain regions and the degree of cognitive impairment in Alzheimer’s transgenic mice. J Alzheimers Dis. 2010;20:S535–50.

    PubMed  Google Scholar 

  49. Swerdlow RH, Burns JM, Khan SM. The Alzheimer’s disease mitochondrial cascade hypothesis. J Alzheimers Dis. 2010;20:S265–79.

    PubMed  Google Scholar 

  50. Ozcankaya R, Delibas N. Malondialdehyde, superoxide dismutase, melatonin, iron, copper, and zinc blood concentrations in patients with Alzheimer disease: cross-sectional study. Croat Med J. 2002;43:28–32.

    PubMed  Google Scholar 

  51. Magri F, Locatelli M, Balza G, Molla G, Cuzzoni G, Fioravanti M, Solerte SB, Ferrari E. Changes in endocrine circadian rhythms as markers of physiological and pathological brain aging. Chronobiol Int. 1997;14:385–96.

    Article  CAS  PubMed  Google Scholar 

  52. Wu YH, Feenstra MG, Zhou JN, Liu RY, Torano JS, Van Kan HJ, Fischer DF, Ravid R, Swaab DF. Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages. J Clin Endocrinol Metab. 2003;88:5898–906.

    Article  CAS  PubMed  Google Scholar 

  53. Ferrari E, Arcaini A, Gornati R, Pelanconi L, Cravello L, Fioravanti M, Solerte SB, Magri F. Pineal and pituitary-adrenocortical function in physiological aging and in senile dementia. Exp Gerontol. 2000;35:1239–50.

    Article  CAS  PubMed  Google Scholar 

  54. Zhou JN, Liu RY, Kamphorst W, Hofman MA, Swaab DF. Early neuropathological Alzheimer’s changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels. J Pineal Res. 2003;35:125–30.

    Article  CAS  PubMed  Google Scholar 

  55. Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR. Melatonin-a pleiotropic, orchestrating regulator molecule. Prog Neurobiol. 2011;93:3–84.

    Google Scholar 

  56. Pappolla MA, Sos M, Omar RA, Bick RJ, Hickson-Bick DL, Reiter RJ, Efthimiopoulos S, Robakis NK. Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide. J Neurosci. 1997;17:1683–90.

    CAS  PubMed  Google Scholar 

  57. Li XC, Wang ZF, Zhang JX, Wang Q, Wang JZ. Effect of melatonin on calyculin A-induced tau hyperphosphorylation. Eur J Pharmacol. 2005;510:25–30.

    Article  CAS  PubMed  Google Scholar 

  58. Cheng Y, Feng Z, Zhang QZ, Zhang JT. Beneficial effects of melatonin in experimental models of Alzheimer disease. Acta Pharmacol Sin. 2006;27:129–39.

    Article  CAS  PubMed  Google Scholar 

  59. Srinivasan V, Pandi-Perumal SR, Maestroni GJ, Esquifino AI, Hardeland R, Cardinali DP. Role of melatonin in neurodegenerative diseases. Neurotox Res. 2005;7:293–318.

    Article  CAS  PubMed  Google Scholar 

  60. Pappolla MA, Simovich MJ, Bryant-Thomas T, Chyan YJ, Poeggeler B, Dubocovich M, Bick R, Perry G, Cruz-Sanchez F, Smith MA. The neuroprotective activities of melatonin against the Alzheimer beta-protein are not mediated by melatonin membrane receptors. J Pineal Res. 2002;32:135–42.

    Article  CAS  PubMed  Google Scholar 

  61. Jesudason EP, Baben B, Ashok BS, Masilamoni JG, Kirubagaran R, Jebaraj WC, Jayakumar R. Anti-inflammatory effect of melatonin on A beta vaccination in mice. Mol Cell Biochem. 2007;298:69–81.

    Article  CAS  PubMed  Google Scholar 

  62. Pappolla MA, Chyan YJ, Poeggeler B, Frangione B, Wilson G, Ghiso J, Reiter RJ. An assessment of the antioxidant and the antiamyloidogenic properties of melatonin: implications for Alzheimer’s disease. J Neural Transm. 2000;107:203–31.

    Article  CAS  PubMed  Google Scholar 

  63. Pappolla M, Bozner P, Soto C, Shao H, Robakis NK, Zagorski M, Frangione B, Ghiso J. Inhibition of Alzheimer beta-fibrillogenesis by melatonin. J Biol Chem. 1998;273:7185–8.

    Article  CAS  PubMed  Google Scholar 

  64. Quinn J, Kulhanek D, Nowlin J, Jones R, Pratico D, Rokach J, Stackman R. Chronic melatonin therapy fails to alter amyloid burden or oxidative damage in old Tg2576 mice: implications for clinical trials. Brain Res. 2005;1037:209–13.

    Article  CAS  PubMed  Google Scholar 

  65. Feng Z, Qin C, Chang Y, Zhang JT. Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer’s disease. Free Radic Biol Med. 2006;40:101–9.

    Article  CAS  PubMed  Google Scholar 

  66. Zhou J, Zhang S, Zhao X, Wei T. Melatonin impairs NADPH oxidase assembly and decreases superoxide anion production in microglia exposed to amyloid-beta1-42. J Pineal Res. 2008;45:157–65.

    Article  CAS  PubMed  Google Scholar 

  67. Poeggeler B, Miravalle L, Zagorski MG, Wisniewski T, Chyan YJ, Zhang Y, Shao H, Bryant-Thomas T, Vidal R, Frangione B, Ghiso J, Pappolla MA. Melatonin reverses the profibrillogenic activity of apolipoprotein E4 on the Alzheimer amyloid Abeta peptide. Biochemistry. 2001;40:14995–5001.

    Article  CAS  PubMed  Google Scholar 

  68. Deng YQ, Xu GG, Duan P, Zhang Q, Wang JZ. Effects of melatonin on wortmannin-induced tau hyperphosphorylation. Acta Pharmacol Sin. 2005;26:519–26.

    Article  CAS  PubMed  Google Scholar 

  69. Feng Z, Chang Y, Cheng Y, Zhang BL, Qu ZW, Qin C, Zhang JT. Melatonin alleviates behavioral deficits associated with apoptosis and cholinergic system dysfunction in the APP 695 transgenic mouse model of Alzheimer’s disease. J Pineal Res. 2004;37:129–36.

    Article  CAS  PubMed  Google Scholar 

  70. Feng Z, Zhang JT. Protective effect of melatonin on beta-amyloid-induced apoptosis in rat astroglioma C6 cells and its mechanism. Free Radic Biol Med. 2004;37:1790–801.

    Article  CAS  PubMed  Google Scholar 

  71. Feng Z, Cheng Y, Zhang JT. Long-term effects of melatonin or 17 beta-estradiol on improving spatial memory performance in cognitively impaired, ovariectomized adult rats. J Pineal Res. 2004;37:198–206.

    Article  CAS  PubMed  Google Scholar 

  72. Veneroso C, Tunon MJ, Gonzalez-Gallego J, Collado PS. Melatonin reduces cardiac inflammatory injury induced by acute exercise. J Pineal Res. 2009;47:184–91.

    Article  CAS  PubMed  Google Scholar 

  73. Song W, Lahiri DK. Melatonin alters the metabolism of the beta-amyloid precursor protein in the neuroendocrine cell line PC12. J Mol Neurosci. 1997;9:75–92.

    Article  CAS  PubMed  Google Scholar 

  74. Matsubara E, Bryant-Thomas T, Pacheco Quinto J, Henry TL, Poeggeler B, Herbert D, Cruz-Sanchez F, Chyan YJ, Smith MA, Perry G, Shoji M, Abe K, Leone A, Grundke-Ikbal I, Wilson GL, Ghiso J, Williams C, Refolo LM, Pappolla MA, Chain DG, Neria E. Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer’s disease. J Neurochem. 2003;85:1101–8.

    Article  CAS  PubMed  Google Scholar 

  75. García-Mesa Y, Giménez-Llort L, López LC, Venegas C, Cristòfol R, Escames G, Acuña-Castroviejo D, Sanfeliu C. Melatonin plus physical exercise are highly neuroprotective in the 3xTg-AD mouse. Neurobiol Aging. 2012;33:1124.e13–29.

    Article  CAS  Google Scholar 

  76. Kostrzewa RM, Segura-Aguilar J. Novel mechanisms and approaches in the study of neurodegeneration and neuroprotection. a review. Neurotox Res. 2003;5:375–83.

    Article  PubMed  Google Scholar 

  77. Olivieri G, Otten U, Meier F, Baysang G, Dimitriades-Schmutz B, Muller-Spahn F, Savaskan E. Beta-amyloid modulates tyrosine kinase B receptor expression in SHSY5Y neuroblastoma cells: influence of the antioxidant melatonin. Neuroscience. 2003;120:659–65.

    Article  CAS  PubMed  Google Scholar 

  78. Crespo E, Macias M, Pozo D, Escames G, Martin M, Vives F, Guerrero JM, Acuna-Castroviejo D. Melatonin inhibits expression of the inducible NO synthase II in liver and lung and prevents endotoxemia in lipopolysaccharide-induced multiple organ dysfunction syndrome in rats. FASEB J. 1999;13:1537–46.

    CAS  PubMed  Google Scholar 

  79. Escames G, Leon J, Macias M, Khaldy H, Acuna-Castroviejo D. Melatonin counteracts lipopolysaccharide-induced expression and activity of mitochondrial nitric oxide synthase in rats. FASEB J. 2003;17:932–4.

    CAS  PubMed  Google Scholar 

  80. Garcia JJ, Reiter RJ, Pie J, Ortiz GG, Cabrera J, Sainz RM, Acuna-Castroviejo D. Role of pinoline and melatonin in stabilizing hepatic microsomal membranes against oxidative stress. J Bioenerg Biomembr. 1999;31:609–16.

    Article  CAS  PubMed  Google Scholar 

  81. Brusco LI, Marquez M, Cardinali DP. Monozygotic twins with Alzheimer’s disease treated with melatonin: case report. J Pineal Res. 1998;25:260–3.

    Article  CAS  PubMed  Google Scholar 

  82. Brunner P, Sozer-Topcular N, Jockers R, Ravid R, Angeloni D, Fraschini F, Eckert A, Muller-Spahn F, Savaskan E. Pineal and cortical melatonin receptors MT1 and MT2 are decreased in Alzheimer’s disease. Eur J Histochem. 2006;50:311–6.

    CAS  PubMed  Google Scholar 

  83. Cardinali DP, Brusco LI, Liberczuk C, Furio AM. The use of melatonin in Alzheimer’s disease. Neuro Endocrinol Lett. 2002;23:20–3.

    CAS  PubMed  Google Scholar 

  84. Asayama K, Yamadera H, Ito T, Suzuki H, Kudo Y, Endo S. Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. J Nippon Med Sch. 2003;70:334–41.

    Article  PubMed  Google Scholar 

  85. Jean-Louis G, Zizi F, von Gizycki H, Taub H. Effects of melatonin in two individuals with Alzheimer’s disease. Percept Mot Skills. 1998;87:331–9.

    Article  CAS  PubMed  Google Scholar 

  86. Linert W, Jameson GN. Redox reactions of neurotransmitters possibly involved in the progression of Parkinson’s disease. J Inorg Biochem. 2000;79:319–26.

    Article  CAS  PubMed  Google Scholar 

  87. Calne DB. The nature of Parkinson’s disease. Neurochem Int. 1992;20:1S–3.

    Article  CAS  PubMed  Google Scholar 

  88. Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature. 1998;392:605–8.

    Article  CAS  PubMed  Google Scholar 

  89. Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT. Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nat Neurosci. 2000;3:1301–6.

    Article  CAS  PubMed  Google Scholar 

  90. Di Monte D, Lawler CP. Mechanisms of parkinsonism: session X summary and research needs. Neurotoxicology. 2001;22:853–4.

    Article  PubMed  Google Scholar 

  91. Collins MA, Neafsey EJ. Potential neurotoxic “agents provocateurs” in Parkinson’s disease. Neurotoxicol Teratol. 2002;24:571–7.

    Article  CAS  PubMed  Google Scholar 

  92. Fahn S, Cohen G. The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it. Ann Neurol. 1992;32:804–12.

    Article  CAS  PubMed  Google Scholar 

  93. Olanow CW. Oxidation reactions in Parkinson’s disease. Neurology. 1990;40:32–7; discussion 37–9.

    Google Scholar 

  94. Alam ZI, Jenner A, Daniel SE, Lees AJ, Cairns N, Marsden CD, Jenner P, Halliwell B. Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J Neurochem. 1997;69:1196–203.

    Article  CAS  PubMed  Google Scholar 

  95. Dexter DT, Carter CJ, Wells FR, Javoy-Agid F, Agid Y, Lees A, Jenner P, Marsden CD. Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J Neurochem. 1989;52:381–9.

    Article  CAS  PubMed  Google Scholar 

  96. Perry TL, Yong VW. Idiopathic Parkinson’s disease, progressive supranuclear palsy and glutathione metabolism in the substantia nigra of patients. Neurosci Lett. 1986;67:269–74.

    Article  CAS  PubMed  Google Scholar 

  97. Lotharius J, O’Malley KL. The parkinsonism-inducing drug 1-methyl-4-phenylpyridinium triggers intracellular dopamine oxidation. A novel mechanism of toxicity. J Biol Chem. 2000;275:38581–8.

    Article  CAS  PubMed  Google Scholar 

  98. Langston JW, Ballard P, Tetrud JW, Irwin I. Chronic Parkinsonism in humans due to a product of meperidine-analog synthesis. Science. 1983;219:979–80.

    Article  CAS  PubMed  Google Scholar 

  99. Nicklas WJ, Vyas I, Heikkila RE. Inhibition of NADH-linked oxidation in brain mitochondria by 1-methyl-4-phenyl-pyridine, a metabolite of the neurotoxin, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. Life Sci. 1985;36:2503–8.

    Article  CAS  PubMed  Google Scholar 

  100. Zhang Y, Dawson VL, Dawson TM. Oxidative stress and genetics in the pathogenesis of Parkinson’s disease. Neurobiol Dis. 2000;7:240–50.

    Article  CAS  PubMed  Google Scholar 

  101. Adams Jr JD, Chang ML, Klaidman L. Parkinson’s disease – redox mechanisms. Curr Med Chem. 2001;8:809–14.

    Article  CAS  PubMed  Google Scholar 

  102. Hantraye P, Varastet M, Peschanski M, Riche D, Cesaro P, Willer JC, Maziere M. Stable parkinsonian syndrome and uneven loss of striatal dopamine fibres following chronic MPTP administration in baboons. Neuroscience. 1993;53:169–78.

    Article  CAS  PubMed  Google Scholar 

  103. Chen LJ, Gao YQ, Li XJ, Shen DH, Sun FY. Melatonin protects against MPTP/MPP+ -induced mitochondrial DNA oxidative damage in vivo and in vitro. J Pineal Res. 2005;39:34–42.

    Article  CAS  PubMed  Google Scholar 

  104. Benitez-King G, Ramirez-Rodriguez G, Ortiz L, Meza I. The neuronal cytoskeleton as a potential therapeutical target in neurodegenerative diseases and schizophrenia. Curr Drug Targets CNS Neurol Disord. 2004;3:515–33.

    Article  CAS  PubMed  Google Scholar 

  105. Dabbeni-Sala F, Di Santo S, Franceschini D, Skaper SD, Giusti P. Melatonin protects against 6-OHDA-induced neurotoxicity in rats: a role for mitochondrial complex I activity. FASEB J. 2001;15:164–70.

    Article  CAS  PubMed  Google Scholar 

  106. Mayo JC, Sainz RM, Uria H, Antolin I, Esteban MM, Rodriguez. Inhibition of cell proliferation: a mechanism likely to mediate the prevention of neuronal cell death by melatonin. J Pineal Res. 1998;25:12–8.

    Article  CAS  PubMed  Google Scholar 

  107. Bolitho SJ, Naismith SL, Rajaratnam SM, Grunstein RR, Hodges JR, Terpening Z, Rogers N, Lewis SJ. Disturbances in melatonin secretion and circadian sleep-wake regulation in Parkinson disease. Sleep Med. 2014;15:342–7.

    Article  CAS  PubMed  Google Scholar 

  108. Kim JS, Bailey MJ, Weller JL, Sugden D, Rath MF, Moller M, et al. Thyroid hormone and adrenergic signaling interact to control pineal expression of the dopamine receptor D4 gene (Drd4). Mol Cell Endocrinol. 2010;314:128–35.

    Article  CAS  PubMed  Google Scholar 

  109. Gonzalez S, Moreno-Delgado D, Moreno E, Perez-Capote K, Franco R, Mallol J, et al. Circadian-related heterodimerization of adrenergic and dopamine D4 receptors modulates melatonin synthesis and release in the pineal gland. Plos Biol. 2012;10:e1001347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Dowling GA, Mastick J, Colling E, Carter JH, Singer CM, Aminoff MJ. Melatonin for sleep disturbances in Parkinson’s disease. Sleep Med. 2005;6:459–66.

    Article  PubMed  Google Scholar 

  111. Shamir E, Barak Y, Shalman I, Laudon M, Zisapel N, Tarrasch R, Elizur A, Weizman R. Melatonin treatment for tardive dyskinesia: a double-blind, placebo-controlled, crossover study. Arch Gen Psychiatry. 2001;58:1049–52.

    Article  CAS  PubMed  Google Scholar 

  112. Srinivasan V, Cardinali DP, Srinivasan US, Kaur C, Brown GM, Spence DW, Hardeland R, Pandi-Perumal SR. Therapeutic potential of melatonin and its analogs in Parkinson’s disease: focus on sleep and neuroprotection. Ther Adv Neurol Disord. 2011;4:297–317.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Hughes RJ, Sack RL, Lewy AJ. The role of melatonin and circadian phase in age-related sleep-maintenance insomnia: assessment in a clinical trial of melatonin replacement. Sleep. 1998;21:52–68.

    CAS  PubMed  Google Scholar 

  114. Mishima K, Okawa M, Shimizu T, Hishikawa Y. Diminished melatonin secretion in the elderly caused by insufficient environmental illumination. J Clin Endocrinol Metab. 2001;86:129–34.

    CAS  PubMed  Google Scholar 

  115. Ross CA, Tabrizi SJ. Huntington’s disease: from molecular pathogenesis to clinical treatment. Lancet Neurol. 2011;10:83–98.

    Article  CAS  PubMed  Google Scholar 

  116. Walker FO. Huntington’s disease. Lancet. 2007;369:218–28.

    Article  CAS  PubMed  Google Scholar 

  117. Tobin AJ, Signer ER. Huntington’s disease: the challenge for cell biologists. Trends Cell Biol. 2000;10:531–6.

    Article  CAS  PubMed  Google Scholar 

  118. Arnulf I, Nielsen J, Lohmann E, Schiefer J, Wild E, Jennum P, Konofal E, Walker M, Oudiette D, Tabrizi S, Durr A. Rapid eye movement sleep disturbances in Huntington disease. Arch Neurol. 2008;65:482–8.

    Article  PubMed  Google Scholar 

  119. Bjorkqvist M, Wild EJ, Thiele J, Silvestroni A, Andre R, Lahiri N, Raibon E, Lee RV, Benn CL, Soulet D, Magnusson A, Woodman B, Landles C, Pouladi MA, Hayden MR, Khalili-Shirazi A, Lowdell MW, Brundin P, Bates GP, Leavitt BR, Moller T, Tabrizi SJ. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington’s disease. J Exp Med. 2008;205:1869–77.

    Google Scholar 

  120. van der Burg JM, Bjorkqvist M, Brundin P. Beyond the brain: widespread pathology in Huntington’s disease. Lancet Neurol. 2009;8:765–74.

    Article  PubMed  Google Scholar 

  121. Vonsattel JP. Huntington disease models and human neuropathology: similarities and differences. Acta Neuropathol. 2008;115:55–69.

    Article  PubMed  Google Scholar 

  122. Di Figlia M, Sena-Esteves M, Chase K, Sapp E, Pfister E, Sass M, Yoder J, Reeves P, Pandey RK, Rajeev KG, Manoharan M, Sah DW, Zamore PD, Aronin N. Therapeutic silencing of mutant huntingtin with siRNA attenuates striatal and cortical neuropathology and behavioral deficits. Proc Natl Acad Sci U S A. 2007;104:17204–9.

    Article  Google Scholar 

  123. Rowland LP, Shneider NA. Amyotrophic lateral sclerosis. N Engl J Med. 2001;344:1688–700.

    Article  CAS  PubMed  Google Scholar 

  124. Reiter RJ. Oxidative damage in the central nervous system: protection by melatonin. Prog Neurobiol. 1998;56:359–84.

    Article  CAS  PubMed  Google Scholar 

  125. Forrest CM, Mackay GM, Stoy N, Stone TW, Darlington LG. Inflammatory status and kynurenine metabolism in rheumatoid arthritis treated with melatonin. Br J Clin Pharmacol. 2007;64:517–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Sicilian Regional Centre of Pharmacovigilance, C/O Unit of Pharmacology, A.O.U. Policlinico “G. Martino”, Torre Biologica, Via Consolare Valeria - Gazzi, Messina, 98125, Italy

    Giovanni Polimeni Pharm D

  2. Department of Clinical Experimental Medicine, Section of Dermatology, The University of Messina C/O A.O.U. Policlinico “G. Martino”, Via Consolare Valeria - Gazzi, Messina, 98125, Italy

    Claudio Guarneri MD

  3. Department of Biological and Environmental Sciences, The University of Messina, viale Ferdinando Stagno D’Alcontres, 31, Messina, 98166, Italy

    Salvatore Cuzzocrea Pharm D

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  1. Giovanni Polimeni Pharm D
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  2. Claudio Guarneri MD
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  3. Salvatore Cuzzocrea Pharm D
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Correspondence to Claudio Guarneri MD .

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Editors and Affiliations

  1. Vice-Rectorate for Research and Sci, Camilo José Cela University Vice-Rectorate for Research and Sci, Madrid, Spain

    Francisco López-Muñoz

  2. International Medical Sciences Research Study Center, Sri Sathya Sai Medical Educational & Research Foundation, Coimbatore, India

    Venkataramanujam Srinivasan

  3. Department of Neurosciences and Ima, University of Chieti Department of Neurosciences and Ima, Italy, Italy

    Domenico de Berardis

  4. Department of Biomedical Sciences (Pharmacology Area), University of Alcalá, Madrid, Spain

    Cecilio Álamo

  5. Department of Neuropsychiatry, Kyushu University, Fukuoka, Japan

    Takahiro A. Kato

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Polimeni, G., Guarneri, C., Cuzzocrea, S. (2016). Melatonin Supplementation in Neurodegenerative Diseases: Current Status. In: López-Muñoz, F., Srinivasan, V., de Berardis, D., Álamo, C., Kato, T. (eds) Melatonin, Neuroprotective Agents and Antidepressant Therapy. Springer, New Delhi. https://doi.org/10.1007/978-81-322-2803-5_6

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