Melatonin Antioxidative Defense: Therapeutical Implications for Aging and Neurodegenerative Processes

Abstract

The pineal product melatonin has remarkable antioxidant properties. It is secreted during darkness and plays a key role in various physiological responses including regulation of circadian rhythms, sleep homeostasis, retinal neuromodulation, and vasomotor responses. It scavenges hydroxyl, carbonate, and various organic radicals as well as a number of reactive nitrogen species. Melatonin also enhances the antioxidant potential of the cell by stimulating the synthesis of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and glutathione reductase, and by augmenting glutathione levels. Melatonin preserves mitochondrial homeostasis, reduces free radical generation and protects mitochondrial ATP synthesis by stimulating Complexes I and IV activities. The decline in melatonin production in aged individuals has been suggested as one of the primary contributing factors for the development of age-associated neurodegenerative diseases. The efficacy of melatonin in preventing oxidative damage in either cultured neuronal cells or in the brains of animals treated with various neurotoxic agents, suggests that melatonin has a potential therapeutic value as a neuroprotective drug in treatment of Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), Huntington’s disease (HD), stroke, and brain trauma. Therapeutic trials with melatonin indicate that it has a potential therapeutic value as a neuroprotective drug in treatment of AD, ALS, and HD. In the case of other neurological conditions, like PD, the evidence is less compelling. Melatonin’s efficacy in combating free radical damage in the brain suggests that it can be a valuable therapeutic agent in the treatment of cerebral edema following traumatic brain injury or stroke. Clinical trials employing melatonin doses in the range of 50–100 mg/day are warranted before its relative merits as a neuroprotective agent is definitively established.

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Abbreviations

3xTg-AD:

Triple-Tg mouse model of Alzheimer’s disease

6-OHDA:

6-Hydroxydopamine

AANAT:

Arylalkylamine N-acetyltransferase

AD:

Alzheimer’s disease

AFMK:

N 1-acetyl-N 2-formyl-5-methoxykynuramine

AMK:

N 1-acetyl-5-methoxykynuramine

ALS:

Amyotrophic lateral sclerosis

apoE4:

Apolipoprotein E4

APP:

Amyloid protein precursor

ASMT:

Acetylserotonin O-methyltransferase

AVP:

Arginine vasopressin

Aβ:

Amyloid beta

BBB:

Blood brain barrier

Bcl-2:

B cell lymphoma proto-oncogene protein

c3OHM:

Cyclic 3-hydroxymelatonin

CaM:

Calmodulin

CSF:

Cerebrospinal fluid

DA:

Dopamine

ETC:

Electron transport chain

GABA:

γ-Aminobutyric acid

GH:

Growth hormone

GPx:

Glutathione peroxidase

GR:

Glutathione reductase

GSH:

Glutathione

GSK-3:

Glycogen synthase kinase 3

HD:

Huntington’s disease

HIOMT:

Hydroxyindole-O-methyl transferase

IL-1β:

Interleukin-1β

IL-R1 :

Interleukin-1 receptor 1

iNOS:

Inducible nitric oxide synthase

KA:

Kainic acid

MAO:

Monoamine oxidase

MAP:

Microtubule-associated protein

MCI:

Mild cognitive impairment

mHtt:

Mutated huntingtin gene

MPTP:

1-Methyl-4-phenyl-1,2,3,6 tetrahydropyridine

MT1 :

Melatonin receptor 1

MT2 :

Melatonin receptor 2

mtNOS:

Mitochondrial nitric oxide synthase

mtPTP:

Mitochondrial permeability transition pore

NMDA:

N-methyl-d-aspartate

nNOS:

Neuronal nitric oxide synthase

NOS:

Nitric oxide synthase

PD:

Parkinson’s disease

PP:

Protein phosphatase

PS1:

Presenilin 1

QR2:

Quinone reductase

RBD:

Rapid eye movement-associated sleep behavior disorder

RNS:

Reactive nitrogen species

ROS:

Reactive oxygen species

SCN:

Suprachiasmatic nuclei

SOD:

Superoxide dismutase

Tg:

Transgenic

TNF-R1 :

Tumor necrosis factor receptor 1

TNF-α:

Tumor necrosis factor-α

VEGF:

Vascular endothelial growth factor

VIP:

Vasoactive intestinal polypeptide

References

  1. Acuña-Castroviejo D, Coto-Montes A, Gaia MM, Ortiz GG, Reiter RJ (1997) Melatonin is protective against MPTP-induced striatal and hippocampal lesions. Life Sci 60:L23–L29

    Google Scholar 

  2. Acuña-Castroviejo CD, Escames G, Carazo A, León J, Khaldy H, Reiter RJ (2002) Melatonin, mitochondrial homeostasis and mitochondrial-related diseases. Curr Top Med Chem 2:133–151

    Google Scholar 

  3. Acuña-Castroviejo CD, Lopez LC, Escames G, Lopez A, García JA, Reiter RJ (2011) Melatonin-mitochondria interplay in health and disease. Curr Top Med Chem 11:221–240

    Google Scholar 

  4. Adi N, Mash DC, Ali Y, Singer C, Shehadeh L, Papapetropoulos S (2010) Melatonin MT1 and MT2 receptor expression in Parkinson’s disease. Med Sci Monit 16:61–67

    Google Scholar 

  5. Alam ZI, Jenner A, Daniel SE, Lees AJ, Cairns N, Marsden CD, Jenner P, Halliwell B (1997) Oxidative DNA damage in the parkinsonian brain: an apparent selective increase in 8-hydroxyguanine levels in substantia nigra. J Neurochem 69:1196–1203

    CAS  Google Scholar 

  6. Alders J, Smits M, Kremer B, Naarding P (2009) The role of melatonin in sleep disturbances in end-stage Huntington’s disease. J Neuropsychiatry Clin Neurosci 21:226–227

    Google Scholar 

  7. Aliev G, Li Y, Palacios HH, Obrenovich ME (2011) Oxidative stress induced mitochondrial DNA deletion as a hallmark for the drug development in the context of the cerebrovascular diseases. Recent Pat Cardiovasc Drug Discov 6:222–241

    CAS  Google Scholar 

  8. Anderson KN, Shneerson JM (2009) Drug treatment of REM sleep behavior disorder: the use of drug therapies other than clonazepam. J Clin Sleep Med 5:235–239

    Google Scholar 

  9. Anderson KN, Jamieson S, Graham AJ, Shneerson JM (2008) REM sleep behaviour disorder treated with melatonin in a patient with Alzheimer’s disease. Clin Neurol Neurosurg 110:492–495

    Google Scholar 

  10. Andrabi SA, Sayeed I, Siemen D, Wolf G, Horn TF (2004) Direct inhibition of the mitochondrial permeability transition pore: a possible mechanism responsible for anti-apoptotic effects of melatonin. FASEB J 18:869–871

    CAS  Google Scholar 

  11. Antolin I, Mayo JC, Sainz RM, del Brio ML, Herrera F, Martin V, Rodríguez C (2002) Protective effect of melatonin in a chronic experimental model of Parkinson’s disease. Brain Res 943:163–173

    CAS  Google Scholar 

  12. Arendt J, Skene DJ, Middleton B, Lockley SW, Deacon S (1997) Efficacy of melatonin treatment in jet lag, shift work, and blindness. J Biol Rhythms 12:604–617

    CAS  Google Scholar 

  13. Asayama K, Yamadera H, Ito T, Suzuki H, Kudo Y, Endo S (2003) Double blind study of melatonin effects on the sleep-wake rhythm, cognitive and non-cognitive functions in Alzheimer type dementia. J Nippon Med Sch 70:334–341

    Google Scholar 

  14. Atanassova PA, Terzieva DD, Dimitrov BD (2009) Impaired nocturnal melatonin in acute phase of ischaemic stroke: cross-sectional matched case-control analysis. J Neuroendocrinol 21:657–663

    CAS  Google Scholar 

  15. Aurora RN, Zak RS, Maganti RK, Auerbach SH, Casey KR, Chowdhuri S, Karippot A, Ramar K, Kristo DA, Morgenthaler TI (2010) Best practice guide for the treatment of REM sleep behavior disorder (RBD). J Clin Sleep Med 6:85–95

    Google Scholar 

  16. Aziz NA, Pijl H, Frolich M, Schroder-van der Elst JP, van der BC, Roelfsema F, Roos RA (2009) Delayed onset of the diurnal melatonin rise in patients with Huntington’s disease. J Neurol 256:1961–1965

    CAS  Google Scholar 

  17. Balzer I, Hardeland R (1991) Photoperiodism and effects of indoleamines in a unicellular alga, Gonyaulax polyedra. Science 253:795–797

    CAS  Google Scholar 

  18. Barzilai N, Gabriely I, Atzmon G, Suh Y, Rothenberg D, Bergman A (2010) Genetic studies reveal the role of the endocrine and metabolic systems in aging. J Clin Endocrinol Metab 95:4493–4500

    CAS  Google Scholar 

  19. Beatty S, Koh H, Phil M, Henson D, Boulton M (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 45:115–134

    CAS  Google Scholar 

  20. Beck-Friis J, Kjellman BF, Aperia B, Unden F, von Rosen D, Ljunggren JG, Wetterberg L (1985) Serum melatonin in relation to clinical variables in patients with major depressive disorder and a hypothesis of a low melatonin syndrome. Acta Psychiatr Scand 71:319–330

    CAS  Google Scholar 

  21. Bedrosian TA, Herring KL, Weil ZM, Nelson RJ (2011) Altered temporal patterns of anxiety in aged and amyloid precursor protein (APP) transgenic mice. Proc Natl Acad Sci USA 108:11686–11691

    CAS  Google Scholar 

  22. Behrends A, Hardeland R, Ness H, Grube S, Poeggeler B, Haldar C (2004) Photocatalytic actions of the pesticide metabolite 2-hydroxyquinoxaline: destruction of antioxidant vitamins and biogenic amines—implications of organic redox cycling. Redox Rep 9:279–288

    CAS  Google Scholar 

  23. Beni SM, Kohen R, Reiter RJ, Tan DX, Shohami E (2004) Melatonin-induced neuroprotection after closed head injury is associated with increased brain antioxidants and attenuated late-phase activation of NF-kappaB and AP-1. FASEB J 18:149–151

    CAS  Google Scholar 

  24. Benítez-King G, Rios A, Martinez A, Anton-Tay F (1996) In vitro inhibition of Ca2+/calmodulin-dependent kinase II activity by melatonin. Biochim Biophys Acta 1290:191–196

    Google Scholar 

  25. Benítez-King G, Tunez I, Bellon A, Ortiz GG, Anton-Tay F (2003) Melatonin prevents cytoskeletal alterations and oxidative stress induced by okadaic acid in N1E-115 cells. Exp Neurol 182:151–159

    Google Scholar 

  26. Benítez-King G, Ramirez-Rodríguez G, Ortiz L, Meza I (2004) The neuronal cytoskeleton as a potential therapeutical target in neurodegenerative diseases and schizophrenia. Curr Drug Targets CNS Neurol Disord 3:515–533

    Google Scholar 

  27. Bergiannaki JD, Soldatos CR, Paparrigopoulos TJ, Syrengelas M, Stefanis CN (1995) Low and high melatonin excretors among healthy individuals. J Pineal Res 18:159–164

    CAS  Google Scholar 

  28. Blackhall LJ (2012) Amyotrophic lateral sclerosis and palliative care: where we are, and the road ahead. Muscle Nerve 45:311–318

    Google Scholar 

  29. Blask DE, Hill SM, Dauchy RT, Xiang S, Yuan L, Duplessis T, Mao L, Dauchy E, Sauer LA (2011) Circadian regulation of molecular, dietary, and metabolic signaling mechanisms of human breast cancer growth by the nocturnal melatonin signal and the consequences of its disruption by light at night. J Pineal Res 51:259–269

    CAS  Google Scholar 

  30. Boeve BF, Silber MH, Ferman TJ (2003) Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med 4:281–284

    Google Scholar 

  31. Borah A, Mohanakumar KP (2009) Melatonin inhibits 6-hydroxydopamine production in the brain to protect against experimental parkinsonism in rodents. J Pineal Res 47:293–300

    CAS  Google Scholar 

  32. Bordet R, Devos D, Brique S, Touitou Y, Guieu JD, Libersa C, Destee A (2003) Study of circadian melatonin secretion pattern at different stages of Parkinson’s disease. Clin Neuropharmacol 26:65–72

    CAS  Google Scholar 

  33. Borlongan CV, Yamamoto M, Takei N, Kumazaki M, Ungsuparkorn C, Hida H, Sanberg PR, Nishino H (2000) Glial cell survival is enhanced during melatonin-induced neuroprotection against cerebral ischemia. FASEB J 14:1307–1317

    CAS  Google Scholar 

  34. Bouslama M, Renaud J, Olivier P, Fontaine RH, Matrot B, Gressens P, Gallego J (2007) Melatonin prevents learning disorders in brain-lesioned newborn mice. Neuroscience 150:712–719

    CAS  Google Scholar 

  35. Boveris DL, Boveris A (2007) Oxygen delivery to the tissues and mitochondrial respiration. Front Biosci 12:1014–1023

    CAS  Google Scholar 

  36. Braak H, Ghebremedhin E, Rub U, Bratzke H, Del Tredici K (2004) Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318:121–134

    Google Scholar 

  37. Brown GM, Young SN, Gauthier S, Tsui H, Grota LJ (1979) Melatonin in human cerebrospinal fluid in daytime; its origin and variation with age. Life Sci 25:929–936

    CAS  Google Scholar 

  38. Brown GM, Cardinali DP, Pandi-Perumal SR (2010) Melatonin and mental illness. In: Pandi-Perumal SR, Kramer M (eds) Sleep and Mental Illness. Cambridge University Press, Cambridge, pp 119–129

    Google Scholar 

  39. Brusco LI, Marquez M, Cardinali DP (1998) Monozygotic twins with Alzheimer’s disease treated with melatonin: case report. J Pineal Res 25:260–263

    CAS  Google Scholar 

  40. Brusco LI, Marquez M, Cardinali DP (2000) Melatonin treatment stabilizes chronobiologic and cognitive symptoms in Alzheimer’s disease. Neuroendocrinol Lett 21:39–42

    Google Scholar 

  41. Bubenik GA (2002) Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci 47:2336–2348

    CAS  Google Scholar 

  42. Bubenik GA, Konturek SJ (2011) Melatonin and aging: prospects for human treatment. J Physiol Pharmacol 62:13–19

    CAS  Google Scholar 

  43. Cai Y, Ding H, Li N, Chai Y, Zhang Y, Chan P (2010a) Oscillation development for neurotransmitter-related genes in the mouse striatum. NeuroReport 21:79–83

    CAS  Google Scholar 

  44. Cai Y, Liu S, Sothern RB, Xu S, Chan P (2010b) Expression of clock genes Per1 and Bmal1 in total leukocytes in health and Parkinson’s disease. Eur J Neurol 17:550–554

    CAS  Google Scholar 

  45. Cardinali DP (1983) Molecular mechanisms of neuroendocrine integration in the central nervous system: an approach through the study of the pineal gland and its innervating sympathetic pathway. Psychoneuroendocrinology 8:3–30

    CAS  Google Scholar 

  46. Cardinali DP, Freire F (1975) Melatonin effects on brain. Interaction with microtubule protein, inhibition of fast axoplasmic flow and induction of crystaloid and tubular formations in the hypothalamus. Mol Cell Endocrinol 2:317–330

    CAS  Google Scholar 

  47. Cardinali DP, Pévet P (1998) Basic aspects of melatonin action. Sleep Med Rev 2:175–190

    CAS  Google Scholar 

  48. Cardinali DP, Scacchi PA (2010) Chronophysiology of melatonin: therapeutical implications. Open Neuroendocrinol J 3:72–84

    CAS  Google Scholar 

  49. Cardinali DP, Brusco LI, Liberczuk C, Furio AM (2002) The use of melatonin in Alzheimer’s disease. Neuroendocrinol Lett 23(suppl. 1):20–23

    CAS  Google Scholar 

  50. Cardinali DP, Esquifino AI, Srinivasan V, Pandi-Perumal SR (2008) Melatonin and the immune system in aging. NeuroImmunoModulation 15:272–278

    CAS  Google Scholar 

  51. Cardinali DP, Furio AM, Brusco LI (2010) Clinical aspects of melatonin intervention in Alzheimer’s disease progression. Curr Neuropharmacol 8:218–227

    CAS  Google Scholar 

  52. Cardinali DP, Cano P, Jimenez-Ortega V, Esquifino AI (2011) Melatonin and the metabolic syndrome: physiopathologic and therapeutical implications. Neuroendocrinology 93:133–142

    CAS  Google Scholar 

  53. Cardinali DP, Srinivasan V, Brzezinski A, Brown GM (2012) Melatonin and its analogs in insomnia and depression. J Pineal Res 52:365–375

    CAS  Google Scholar 

  54. Carneiro RC, Reiter RJ (1998) Melatonin protects against lipid peroxidation induced by delta-aminolevulinic acid in rat cerebellum, cortex and hippocampus. Neuroscience 82:293–299

    CAS  Google Scholar 

  55. Carrillo-Vico A, Reiter RJ, Lardone PJ, Herrera JL, Fernandez-Montesinos R, Guerrero JM, Pozo D (2006) The modulatory role of melatonin on immune responsiveness. Curr Opin Investig Drugs 7:423–431

    CAS  Google Scholar 

  56. Catala MD, Canete-Nicolas C, Iradi A, Tarazona PJ, Tormos JM, Pascual-Leóne A (1997) Melatonin levels in Parkinson’s disease: drug therapy versus electrical stimulation of the internal globus pallidus. Exp Gerontol 32:553–558

    CAS  Google Scholar 

  57. Caumo W, Levandovski R, Hidalgo MP (2009) Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy: a double-blind, randomized, placebo-controlled study. J Pain 10:100–108

    CAS  Google Scholar 

  58. Cavallo A (1993) Melatonin and human puberty: current perspectives. J Pineal Res 15:115–121

    CAS  Google Scholar 

  59. Chahbouni M, Escames G, Venegas C, Sevilla B, García JA, Lopez LC, Munoz-Hoyos A, Molina-Carballo A, Acuña-Castroviejo D (2010) Melatonin treatment normalizes plasma pro-inflammatory cytokines and nitrosative/oxidative stress in patients suffering from Duchenne muscular dystrophy. J Pineal Res 48:282–289

    CAS  Google Scholar 

  60. Chance B, Sies H, Boveris A (1979) Hydroperoxide metabolism in mammalian organs. Physiol Rev 59:527–605

    CAS  Google Scholar 

  61. Chen CM (2011) Mitochondrial dysfunction, metabolic deficits, and increased oxidative stress in Huntington’s disease. Chang Gung Med J 34:135–152

    Google Scholar 

  62. Chen G, Huo Y, Tan DX, Liang Z, Zhang W, Zhang Y (2003) Melatonin in Chinese medicinal herbs. Life Sci 73:19–26

    CAS  Google Scholar 

  63. Cheung RT (2003) The utility of melatonin in reducing cerebral damage resulting from ischemia and reperfusion. J Pineal Res 34:153–160

    CAS  Google Scholar 

  64. Cho S, Joh TH, Baik HH, Dibinis C, Volpe BT (1997) Melatonin administration protects CA1 hippocampal neurons after transient forebrain ischemia in rats. Brain Res 755:335–338

    CAS  Google Scholar 

  65. Chuang YC (2010) Mitochondrial dysfunction and oxidative stress in seizure-induced neuronal cell death. Acta Neurol Taiwan 19:3–15

    Google Scholar 

  66. Chuang JI, Chen TH (2004) Effect of melatonin on temporal changes of reactive oxygen species and glutathione after MPP+ treatment in human astrocytoma U373MG cells. J Pineal Res 36:117–125

    CAS  Google Scholar 

  67. Cifra A, Mazzone GL, Nistri A (2012) Riluzole: What It Does to Spinal and Brainstem Neurons and How It Does It. Neuroscientist. http://dx.doi.org/10.1177/1073858412444932

  68. Claustrat B, Brun J, Chazot G (2005) The basic physiology and pathophysiology of melatonin. Sleep Med Rev 9:11–24

    Google Scholar 

  69. Cohen-Mansfield J, Garfinkel D, Lipson S (2000) Melatonin for treatment of sundowning in elderly persons with dementia—a preliminary study. Arch Gerontol Geriatr 31:65–76

    CAS  Google Scholar 

  70. Conti A, Conconi S, Hertens E, Skwarlo-Sonta K, Markowska M, Maestroni JM (2000) Evidence for melatonin synthesis in mouse and human bone marrow cells. J Pineal Res 28:193–202

    CAS  Google Scholar 

  71. Cunningham C (2011) Systemic inflammation and delirium: important co-factors in the progression of dementia. Biochem Soc Trans 39:945–953

    CAS  Google Scholar 

  72. Cuzzocrea S, Zingarelli B, Gilad E, Hake P, Salzman AL, Szabo C (1997) 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 23:106–116

    CAS  Google Scholar 

  73. Dabbeni-Sala F, Di Santo S, Franceschini D, Skaper SD, Giusti P (2001) Melatonin protects against 6-OHDA-induced neurotoxicity in rats: a role for mitochondrial complex I activity. FASEB J 15:164–170

    CAS  Google Scholar 

  74. Dardente H (2012) Melatonin-dependent timing of seasonal reproduction by the pars tuberalis: pivotal roles for long daylengths and thyroid hormones. J Neuroendocrinol 24:249–266

    CAS  Google Scholar 

  75. Das A, McDowell M, Pava MJ, Smith JA, Reiter RJ, Woodward JJ, Varma AK, Ray SK, Banik NL (2010) The inhibition of apoptosis by melatonin in VSC4.1 motoneurons exposed to oxidative stress, glutamate excitotoxicity, or TNF-alpha toxicity involves membrane melatonin receptors. J Pineal Res 48:157–169

    CAS  Google Scholar 

  76. Dawson D, Armstrong SM (1996) Chronobiotics—drugs that shift rhythms. Pharmacol Ther 69:15–36

    CAS  Google Scholar 

  77. de Jonghe A, Korevaar JC, van Munster BC, de Rooij SE (2010) Effectiveness of melatonin treatment on circadian rhythm disturbances in dementia. Are there implications for delirium? A systematic review. Int J Geriatr Psychiatry 25:1201–1208

    Google Scholar 

  78. Devore EE, Grodstein F, van Rooij FJ, Hofman A, Stampfer MJ, Witteman JC, Breteler MM (2010) Dietary antioxidants and long-term risk of dementia. Arch Neurol 67:819–825

    Google Scholar 

  79. Dexter DT, Carter CJ, Wells FR, Javoy-Agid F, Agid Y, Lees A, Jenner P, Marsden CD (1989) Basal lipid peroxidation in substantia nigra is increased in Parkinson’s disease. J Neurochem 52:381–389

    CAS  Google Scholar 

  80. Domínguez-Rodríguez A, Abreu-Gonzalez P, Sanchez–Sanchez JJ, Kaski JC, Reiter RJ (2010) Melatonin and circadian biology in human cardiovascular disease. J Pineal Res 49:14–22

    Google Scholar 

  81. Dori D, Casale G, Solerte SB, Fioravanti M, Migliorati G, Cuzzoni G, Ferrari E (1994) Chrono-neuroendocrinological aspects of physiological aging and senile dementia. Chronobiologia 21:121–126

    CAS  Google Scholar 

  82. Dowling GA, Mastick J, Colling E, Carter JH, Singer CM, Aminoff MJ (2005) Melatonin for sleep disturbances in Parkinson’s disease. Sleep Med 6:459–466

    Google Scholar 

  83. Dowling GA, Burr RL, Van Someren EJ, Hubbard EM, Luxenberg JS, Mastick J, Cooper BA (2008) Melatonin and bright-light treatment for rest-activity disruption in institutionalized patients with Alzheimer’s disease. J Am Geriatr Soc 56:239–246

    Google Scholar 

  84. Dragicevic N, Copes N, O’Neal-Moffitt G, Jin J, Buzzeo R, Mamcarz M, Tan J, Cao C, Olcese JM, Arendash GW, Bradshaw PC (2011) Melatonin treatment restores mitochondrial function in Alzheimer’s mice: a mitochondrial protective role of melatonin membrane receptor signaling. J Pineal Res 51:75–86

    CAS  Google Scholar 

  85. Dubbels R, Reiter RJ, Klenke E, Goebel A, Schnakenberg E, Ehlers C, Schiwara HW, Schloot W (1995) Melatonin in edible plants identified by radioimmunoassay and by high performance liquid chromatography-mass spectrometry. J Pineal Res 18:28–31

    CAS  Google Scholar 

  86. Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J (2010) International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacol Rev 62:343–380

    CAS  Google Scholar 

  87. Ehrnhoefer DE, Wong BK, Hayden MR (2011) Convergent pathogenic pathways in Alzheimer’s and Huntington’s diseases: shared targets for drug development. Nat Rev Drug Discov 10:853–867

    CAS  Google Scholar 

  88. Erol FS, Topsakal C, Ozveren MF, Kaplan M, Ilhan N, Ozercan IH, Yildiz OG (2004) Protective effects of melatonin and vitamin E in brain damage due to gamma radiation: an experimental study. Neurosurg Rev 27:65–69

    Google Scholar 

  89. Escames G, Acuña-Castroviejo CD, Vives F (1996) Melatonin–dopamine interaction in the striatal projection area of sensorimotor cortex in the rat. NeuroReport 7:597–600

    CAS  Google Scholar 

  90. Escames G, León J, Lopez LC, Acuña-Castroviejo D (2004) Mechanisms of N-methyl-d-aspartate receptor inhibition by melatonin in the rat striatum. J Neuroendocrinol 16:929–935

    CAS  Google Scholar 

  91. Esposito E, Cuzzocrea S (2010) Antiinflammatory activity of melatonin in central nervous system. Curr Neuropharmacol 8:228–242

    CAS  Google Scholar 

  92. Esquifino AI, Pandi-Perumal SR, Cardinali DP (2004) Circadian organization of the immune response: a role for melatonin. Clin Applied Immunol Rev 4:423–433

    CAS  Google Scholar 

  93. Fahn S, Cohen G (1992) The oxidant stress hypothesis in Parkinson’s disease: evidence supporting it. Ann Neurol 32:804–812

    CAS  Google Scholar 

  94. Fainstein I, Bonetto A, Brusco LI, Cardinali DP (1997) Effects of melatonin in elderly patients with sleep disturbance. A pilot study. Curr Ther Res 58:990–1000

    CAS  Google Scholar 

  95. Feng Z, Zhang JT (2004) Melatonin reduces amyloid beta-induced apoptosis in pheochromocytoma (PC12) cells. J Pineal Res 37:257–266

    CAS  Google Scholar 

  96. Feng Z, Qin C, Chang Y, Zhang JT (2006) Early melatonin supplementation alleviates oxidative stress in a transgenic mouse model of Alzheimer’s disease. Free Radic Biol Med 40:101–109

    CAS  Google Scholar 

  97. Ferrari E, Fioravanti M, Magri F, Solerte SB (2000) Variability of interactions between neuroendocrine and immunological functions in physiological aging and dementia of the Alzheimer’s type. Ann N Y Acad Sci 917:582–596

    CAS  Google Scholar 

  98. Ferrari E, Cravello L, Falvo F, Barili L, Solerte SB, Fioravanti M, Magri F (2008) Neuroendocrine features in extreme longevity. Exp Gerontol 43:88–94

    CAS  Google Scholar 

  99. Fertl E, Auff E, Doppelbauer A, Waldhauser F (1993) Circadian secretion pattern of melatonin in de novo parkinsonian patients: evidence for phase-shifting properties of l-dopa. J Neural Transm Park Dis Dement Sect 5:227–234

    CAS  Google Scholar 

  100. Floden AM, Li S, Combs CK (2005) Beta-amyloid-stimulated microglia induce neuron death via synergistic stimulation of tumor necrosis factor alpha and NMDA receptors. J Neurosci 25:2566–2575

    CAS  Google Scholar 

  101. Fourtillan JB, Brisson AM, Fourtillan M, Ingrand I, Decourt JP, Girault J (2001) Melatonin secretion occurs at a constant rate in both young and older men and women. Am J Physiol Endocrinol Metab 280:E11–E22

    CAS  Google Scholar 

  102. Fraser PA (2011) The role of free radical generation in increasing cerebrovascular permeability. Free Radic Biol Med 51:967–977

    CAS  Google Scholar 

  103. Furio AM, Cutrera RA, Castillo TV, Perez LS, Riccio P, Caccuri RL, Brusco LL, Cardinali DP (2002) Effect of melatonin on changes in locomotor activity rhythm of Syrian hamsters injected with beta amyloid peptide 25–35 in the suprachiasmatic nuclei. Cell Mol Neurobiol 22:699–709

    CAS  Google Scholar 

  104. Furio AM, Brusco LI, Cardinali DP (2007) Possible therapeutic value of melatonin in mild cognitive impairment: a retrospective study. J Pineal Res 43:404–409

    CAS  Google Scholar 

  105. Furio AM, Fontao R, Falco N, Ruiz JI, Caccuri RL, Cardinali DP (2008) Neuroprotective effect of melatonin on glucocorticoid toxicity in the rat hippocampus. Open Physiol J 1:23–27

    CAS  Google Scholar 

  106. Galano A, Tan DX, Reiter RJ (2011) Melatonin as a natural ally against oxidative stress: a physicochemical examination. J Pineal Res 51:1–16

    CAS  Google Scholar 

  107. Galecki P, Szemraj J, Bartosz G, Bienkiewicz M, Galecka E, Florkowski A, Lewinski A, Karbownik-Lewinska M (2010) Single-nucleotide polymorphisms and mRNA expression for melatonin synthesis rate-limiting enzyme in recurrent depressive disorder. J Pineal Res 48:311–317

    CAS  Google Scholar 

  108. García JJ, Reiter RJ, Pie J, Ortiz GG, Cabrera J, Sainz RM, Acuña-Castroviejo D (1999) Role of pinoline and melatonin in stabilizing hepatic microsomal membranes against oxidative stress. J Bioenerg Biomembr 31:609–616

    Google Scholar 

  109. García T, Ribes D, Colomina MT, Cabre M, Domingo JL, Gomez M (2009) Evaluation of the protective role of melatonin on the behavioral effects of aluminum in a mouse model of Alzheimer’s disease. Toxicology 265:49–55

    Google Scholar 

  110. García T, Esparza JL, Nogues MR, Romeu M, Domingo JL, Gomez M (2010) Oxidative stress status and RNA expression in hippocampus of an animal model of Alzheimer’s disease after chronic exposure to aluminum. Hippocampus 20:218–225

    Google Scholar 

  111. García-Mesa Y, Gimenez-Llort L, Lopez LC, Venegas C, Cristofol R, Escames G, Acuña-Castroviejo D, Sanfeliu C (2012) Melatonin plus physical exercise are highly neuroprotective in the 3xTg-AD mouse. Neurobiol Aging 33:1124–1129

    Google Scholar 

  112. Garzon C, Guerrero JM, Aramburu O, Guzman T (2009) Effect of melatonin administration on sleep, behavioral disorders and hypnotic drug discontinuation in the elderly: a randomized, double-blind, placebo-controlled study. Aging Clin Exp Res 21:38–42

    CAS  Google Scholar 

  113. Gauthier S, Reisberg B, Zaudig M, Petersen RC, Ritchie K, Broich K, Belleville S, Brodaty H, Bennett D, Chertkow H, Cummings JL, de León M, Feldman H, Ganguli M, Hampel H, Scheltens P, Tierney MC, Whitehouse P, Winblad B (2006) Mild cognitive impairment. Lancet 367:1262–1270

    Google Scholar 

  114. Gehrman PR, Connor DJ, Martin JL, Shochat T, Corey-Bloom J, Ancoli-Israel S (2009) Melatonin fails to improve sleep or agitation in double-blind randomized placebo-controlled trial of institutionalized patients with Alzheimer disease. Am J Geriatr Psychiatry 17:166–169

    Google Scholar 

  115. Genova ML, Pich MM, Bernacchia A, Bianchi C, Biondi A, Bovina C, Falasca AI, Formiggini G, Castelli GP, Lenaz G (2004) The mitochondrial production of reactive oxygen species in relation to aging and pathology. Ann N Y Acad Sci 1011:86–100

    CAS  Google Scholar 

  116. Ghanta S, Chattopadhyay S (2011) Glutathione as a signaling molecule: another challenge to pathogens. Plant Signal Behav 6:783–788

    CAS  Google Scholar 

  117. Gibson GE, Starkov A, Blass JP, Ratan RR, Beal MF (2010) Cause and consequence: mitochondrial dysfunction initiates and propagates neuronal dysfunction, neuronal death and behavioral abnormalities in age-associated neurodegenerative diseases. Biochim Biophys Acta 1802:122–134

    CAS  Google Scholar 

  118. Girotti L, Lago M, Ianovsky O, Carbajales J, Elizari MV, Brusco LI, Cardinali DP (2000) Low urinary 6-sulphatoxymelatonin levels in patients with coronary artery disease. J Pineal Res 29:138–142

    CAS  Google Scholar 

  119. Giusti P, Franceschini D, Petrone M, Manev H, Floreani M (1996a) In vitro and in vivo protection against kainate-induced excitotoxicity by melatonin. J Pineal Res 20:226–231

    CAS  Google Scholar 

  120. Giusti P, Lipartiti M, Franceschini D, Schiavo N, Floreani M, Manev H (1996b) Neuroprotection by melatonin from kainate-induced excitotoxicity in rats. FASEB J 10:891–896

    CAS  Google Scholar 

  121. Golombek DA, Pévet P, Cardinali DP (1996) Melatonin effects on behavior: possible mediation by the central GABAergic system. Neurosci Biobehav Rev 20:403–412

    CAS  Google Scholar 

  122. Gorgulu A, Palaoglu S, Ismailoglu O, Tuncel M, Surucu MT, Erbil M, Kilinc K (2001) Effect of melatonin on cerebral edema in rats. Neurosurgery 49:1434–1441

    CAS  Google Scholar 

  123. Green DR, Galluzzi L, Kroemer G (2011) Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333:1109–1112

    CAS  Google Scholar 

  124. Grinberg LT, Rueb U, Alho AT, Heinsen H (2010) Brainstem pathology and non-motor symptoms in PD. J Neurol Sci 289:81–88

    Google Scholar 

  125. Grof E, Grof P, Brown GM, Arato M, Lane J (1985) Investigations of melatonin secretion in man. Prog Neuropsychopharmacol Biol Psychiatry 9:609–612

    CAS  Google Scholar 

  126. Guerrero JM, Reiter RJ (2002) Melatonin-immune system relationships. Curr Top Med Chem 2:167–179

    CAS  Google Scholar 

  127. Guerrero JM, Reiter RJ, Ortiz GG, Pablos MI, Sewerynek E, Chuang JI (1997) Melatonin prevents increases in neural nitric oxide and cyclic GMP production after transient brain ischemia and reperfusion in the Mongolian gerbil (Meriones unguiculatus). J Pineal Res 23:24–31

    CAS  Google Scholar 

  128. Guido ME, Garbarino-Pico E, Contin MA, Valdez DJ, Nieto PS, Verra DM, Acosta-Rodríguez VA, de Zavalia N, Rosenstein RE (2010) Inner retinal circadian clocks and non-visual photoreceptors: novel players in the circadian system. Prog Neurobiol 92:484–504

    Google Scholar 

  129. Gupta M, Gupta YK, Agarwal S, Aneja S, Kalaivani M, Kohli K (2004) Effects of add-on melatonin administration on antioxidant enzymes in children with epilepsy taking carbamazepine monotherapy: a randomized, double-blind, placebo-controlled trial. Epilepsia 45:1636–1639

    CAS  Google Scholar 

  130. Hall ED (2011) Antioxidant therapies for acute spinal cord injury. Neurotherapeutics 8:152–167

    CAS  Google Scholar 

  131. Hall NF, Gale CR (2002) Prevention of age related macular degeneration. BMJ 325:1–2

    Google Scholar 

  132. Hall ED, Vaishnav RA, Mustafa AG (2010) Antioxidant therapies for traumatic brain injury. Neurotherapeutics 7:51–61

    CAS  Google Scholar 

  133. Harada S, Fujii C, Hayashi A, Ohkoshi N (2001) An association between idiopathic Parkinson’s disease and polymorphisms of phase II detoxification enzymes: glutathione S-transferase M1 and quinone oxidoreductase 1 and 2. Biochem Biophys Res Commun 288:887–892

    CAS  Google Scholar 

  134. Hardeland R (2005) Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine 27:119–130

    CAS  Google Scholar 

  135. Hardeland R (2008) Melatonin, hormone of darkness and more—occurrence, control mechanisms, actions and bioactive metabolites. Cell Mol Life Sci 65:2001–2018

    CAS  Google Scholar 

  136. Hardeland R (2009a) Melatonin: signaling mechanisms of a pleiotropic agent. BioFactors 35:183–192

    CAS  Google Scholar 

  137. Hardeland R (2009b) Neuroprotection by radical avoidance: search for suitable agents. Molecules 14:5054–5102

    CAS  Google Scholar 

  138. Hardeland R (2010a) Investigational melatonin receptor agonists. Expert Opin Investig Drugs 19:747–764

    CAS  Google Scholar 

  139. Hardeland R (2010b) Melatonin metabolism in the central nervous system. Curr Neuropharmacol 8:168–181

    CAS  Google Scholar 

  140. Hardeland R, Pandi-Perumal SR (2005) Melatonin, a potent agent in antioxidative defense: actions as a natural food constituent, gastrointestinal factor, drug and prodrug. Nutr Metab (Lond) 2:22

    Google Scholar 

  141. Hardeland R, Poeggeler B (2007) Actions of melatonin, its structural and functional analogs in the central nervous system and the significance of metabolism. Cent Nerv Syst Agents Med Chem 7:303

    Google Scholar 

  142. Hardeland R, Poeggeler B (2008) Melatonin beyond its classical functions. Open Physiol J 1:1–23

    CAS  Google Scholar 

  143. Hardeland R, Balzer I, Poeggeler B, Fuhrberg B, Uria H, Behrmann G, Wolf R, Meyer TJ, Reiter RJ (1995) On the primary functions of melatonin in evolution: mediation of photoperiodic signals in a unicell, photooxidation, and scavenging of free radicals. J Pineal Res 18:104–111

    CAS  Google Scholar 

  144. Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR (2011) Melatonin-A pleiotropic, orchestrating regulator molecule. Prog Neurobiol 93:350–384

    CAS  Google Scholar 

  145. Hausman DB, Fischer JG, Johnson MA (2011) Nutrition in centenarians. Maturitas 68:203–209

    Google Scholar 

  146. He H, Dong W, Huang F (2010) Anti-amyloidogenic and anti-apoptotic role of melatonin in Alzheimer disease. Curr Neuropharmacol 8:211–217

    CAS  Google Scholar 

  147. Heiser V, Scherzinger E, Boeddrich A, Nordhoff E, Lurz R, Schugardt N, Lehrach H, Wanker EE (2000) Inhibition of huntingtin fibrillogenesis by specific antibodies and small molecules: implications for Huntington’s disease therapy. Proc Natl Acad Sci USA 97:6739–6744

    CAS  Google Scholar 

  148. Hu K, Van Someren EJ, Shea SA, Scheer FA (2009) Reduction of scale invariance of activity fluctuations with aging and Alzheimer’s disease: involvement of the circadian pacemaker. Proc Natl Acad Sci USA 106:2490–2494

    CAS  Google Scholar 

  149. Huether G (1993) The contribution of extrapineal sites of melatonin synthesis to circulating melatonin levels in higher vertebrates. Experientia 49:665–670

    CAS  Google Scholar 

  150. Huether G (1994) Melatonin synthesis in the gastrointestinal tract and the impact of nutritional factors on circulating melatonin. Ann N Y Acad Sci 719:146–158

    CAS  Google Scholar 

  151. Huether G, Poeggeler B, Reimer A, George A (1992) Effect of tryptophan administration on circulating melatonin levels in chicks and rats: evidence for stimulation of melatonin synthesis and release in the gastrointestinal tract. Life Sci 51:945–953

    CAS  Google Scholar 

  152. Iguchi H, Kato KI, Ibayashi H (1982) Melatonin serum levels and metabolic clearance rate in patients with liver cirrhosis. J Clin Endocrinol Metab 54:1025–1027

    CAS  Google Scholar 

  153. Jean-Louis G, von Gizycki H, Zizi F (1998a) Melatonin effects on sleep, mood, and cognition in elderly with mild cognitive impairment. J Pineal Res 25:177–183

    CAS  Google Scholar 

  154. Jean-Louis G, Zizi F, von Gizycki H, Taub H (1998b) Effects of melatonin in two individuals with Alzheimer’s disease. Percept Mot Skills 87:331–339

    CAS  Google Scholar 

  155. Jiao S, Wu MM, Hu CL, Zhang ZH, Mei YA (2004) Melatonin receptor agonist 2-iodomelatonin prevents apoptosis of cerebellar granule neurons via K(+) current inhibition. J Pineal Res 36:109–116

    CAS  Google Scholar 

  156. Jimenez-Jorge S, Guerrero JM, Jimenez-Caliani AJ, Naranjo MC, Lardone PJ, Carrillo-Vico A, Osuna C, Molinero P (2007) Evidence for melatonin synthesis in the rat brain during development. J Pineal Res 42:240–246

    CAS  Google Scholar 

  157. Jiménez-Ortega V, Cano P, Scacchi PA, Cardinali DP, Esquifino AI (2011) Cadmium-induced disruption in 24-h expression of clock and redox enzyme genes in rat medial basal hypothalamus. Prevention by melatonin. Front Neurol 2:13

    Google Scholar 

  158. Jin BK, Shin DY, Jeong MY, Gwag MR, Baik HW, Yoon KS, Cho YH, Joo WS, Kim YS, Baik HH (1998) Melatonin protects nigral dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+) neurotoxicity in rats. Neurosci Lett 245:61–64

    CAS  Google Scholar 

  159. Jonsson L, Ljunggren E, Bremer A, Pedersen C, Landen M, Thuresson K, Giacobini M, Melke J (2010) Mutation screening of melatonin-related genes in patients with autism spectrum disorders. BMC Med Genomics 3:10

    Google Scholar 

  160. Jou MJ (2011) Melatonin preserves the transient mitochondrial permeability transition for protection during mitochondrial Ca2+ stress in astrocyte. J Pineal Res 50:427–435

    CAS  Google Scholar 

  161. Jucker M, Walker LC (2011) Pathogenic protein seeding in Alzheimer disease and other neurodegenerative disorders. Ann Neurol 70:532–540

    CAS  Google Scholar 

  162. Kabadi SV, Maher TJ (2010) Posttreatment with uridine and melatonin following traumatic brain injury reduces edema in various brain regions in rats. Ann N Y Acad Sci 1199:105–113

    CAS  Google Scholar 

  163. Karasek M, Reiter RJ (2002) Melatonin and aging. Neuroendocrinol Lett 23(Suppl 1):14–16

    CAS  Google Scholar 

  164. Kaur C, Sivakumar V, Zhang Y, Ling EA (2006) Hypoxia-induced astrocytic reaction and increased vascular permeability in the rat cerebellum. Glia 54:826–839

    CAS  Google Scholar 

  165. Kaur C, Sivakumar V, Ling EA (2007) Expression of transferrin receptors in the pineal gland of postnatal and adult rats and its alteration in hypoxia and melatonin treatment. Glia 55:263–273

    CAS  Google Scholar 

  166. Kaur C, Sivakumar V, Ling EA (2010) Melatonin protects periventricular white matter from damage due to hypoxia. J Pineal Res 48:185–193

    CAS  Google Scholar 

  167. Kaur C, Viswanathan S, Ling EA (2011) Hypoxia-induced cellular and vascular changes in the nucleus tractus solitarius and ventrolateral medulla. J Neuropathol Exp Neurol 70:201–217

    CAS  Google Scholar 

  168. Khandelwal PJ, Herman AM, Moussa CE (2011) Inflammation in the early stages of neurodegenerative pathology. J Neuroimmunol 238:1–11

    CAS  Google Scholar 

  169. Kilanczyk E, Bryszewska M (2003) The effect of melatonin on antioxidant enzymes in human diabetic skin fibroblasts. Cell Mol Biol Lett 8:333–336

    CAS  Google Scholar 

  170. Kilic E, Ozdemir YG, Bolay H, Kelestimur H, Dalkara T (1999) Pinealectomy aggravates and melatonin administration attenuates brain damage in focal ischemia. J Cereb Blood Flow Metab 19:511–516

    CAS  Google Scholar 

  171. Kilic U, Yilmaz B, Ugur M, Yuksel A, Reiter RJ, Hermann DM, Kilic E (2011) Evidence that membrane-bound G protein-coupled melatonin receptors MT1 and MT2 are not involved in the neuroprotective effects of melatonin in focal cerebral ischemia. J Pineal Res 52:228–235

    Google Scholar 

  172. Kitazawa M, Yamasaki TR, Laferla FM (2004) Microglia as a potential bridge between the amyloid {beta}-peptide and tau. Ann N Y Acad Sci 1035:85–103

    CAS  Google Scholar 

  173. Klein DC (2007) Arylalkylamine N-acetyltransferase: “the Timezyme”. J Biol Chem 282:4233–4237

    CAS  Google Scholar 

  174. Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD (1997) The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 275:1132–1136

    CAS  Google Scholar 

  175. Koh PO (2011) Melatonin prevents down-regulation of astrocytic phosphoprotein PEA-15 in ischemic brain injury. J Pineal Res 51:381–386

    CAS  Google Scholar 

  176. Koh PO (2012) Melatonin attenuates decrease of protein phosphatase 2A subunit B in ischemic brain injury. J Pineal Res 52:57–61

    CAS  Google Scholar 

  177. Koller WC (1996) Management of motor fluctuations in Parkinson’s disease. Eur Neurol 36(Suppl 1):43–48

    Google Scholar 

  178. Kunz D, Bes F (1997) Melatonin effects in a patient with severe REM sleep behavior disorder: case report and theoretical considerations. Neuropsychobiology 36:211–214

    CAS  Google Scholar 

  179. Kunz D, Bes F (1999) Melatonin as a therapy in REM sleep behavior disorder patients: an open-labeled pilot study on the possible influence of melatonin on REM-sleep regulation. Mov Disord 14:507–511

    CAS  Google Scholar 

  180. Kvetnoy IM, Ingel IE, Kvetnaia TV, Malinovskaya NK, Rapoport SI, Raikhlin NT, Trofimov AV, Yuzhakov VV (2002) Gastrointestinal melatonin: cellular identification and biological role. Neuro Endocrinol Lett 23:121–132

    CAS  Google Scholar 

  181. Lacza Z, Horn TF, Snipes JA, Zhang J, Roychowdhury S, Horvath EM, Figueroa JP, Kollai M, Szabo C, Busija DW (2004) Lack of mitochondrial nitric oxide production in the mouse brain. J Neurochem 90:942–951

    CAS  Google Scholar 

  182. Landau M, Zisapel N (2007) The low affinity binding of melatonin to calmodulin: use of computational methods to explain its physiological relevance. In: Cardinali DP, Pandi-Perumal SR (eds) Melatonin - From Molecules to Therapy. Nova Science, New York, pp 69–79

    Google Scholar 

  183. Lardone PJ, Guerrero JM, Fernandez-Santos JM, Rubio A, Martin-Lacave I, Carrillo-Vico A (2011) Melatonin synthesized by T lymphocytes as a ligand of the retinoic acid-related orphan receptor. J Pineal Res 51:454–462

    CAS  Google Scholar 

  184. Lee EJ, Wu TS, Lee MY, Chen TY, Tsai YY, Chuang JI, Chang GL (2004) Delayed treatment with melatonin enhances electrophysiological recovery following transient focal cerebral ischemia in rats. J Pineal Res 36:33–42

    CAS  Google Scholar 

  185. León-Blanco MM, Guerrero JM, Reiter RJ, Pozo D (2004) RNA expression of human telomerase subunits TR and TERT is differentially affected by melatonin receptor agonists in the MCF-7 tumor cell line. Cancer Lett 216:73–80

    Google Scholar 

  186. Levoye A, Dam J, Ayoub MA, Guillaume JL, Couturier C, Delagrange P, Jockers R (2006) The orphan GPR50 receptor specifically inhibits MT1 melatonin receptor function through heterodimerization. EMBO J 25:3012–3023

    CAS  Google Scholar 

  187. Lewy AJ, Sack RA, Singer CL (1984) Assessment and treatment of chronobiologic disorders using plasma melatonin levels and bright light exposure: the clock-gate model and the phase response curve. Psychopharmacol Bull 20:561–565

    CAS  Google Scholar 

  188. Lezoualc’h F, Skutella T, Widmann M, Behl C (1996) Melatonin prevents oxidative stress-induced cell death in hippocampal cells. NeuroReport 7:2071–2077

    Google Scholar 

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

    CAS  Google Scholar 

  190. Lieverse R, Van Someren EJ, Nielen MM, Uitdehaag BM, Smit JH, Hoogendijk WJ (2011) Bright light treatment in elderly patients with nonseasonal major depressive disorder: a randomized placebo-controlled trial. Arch Gen Psychiatry 68:61–70

    Google Scholar 

  191. Lin HW, Lee EJ (2009) Effects of melatonin in experimental stroke models in acute, sub-acute, and chronic stages. Neuropsychiatr Dis Treat 5:157–162

    CAS  Google Scholar 

  192. Ling ZQ, Tian Q, Wang L, Fu ZQ, Wang XC, Wang Q, Wang JZ (2009) Constant illumination induces Alzheimer-like damages with endoplasmic reticulum involvement and the protection of melatonin. J Alzheimers Dis 16:287–300

    CAS  Google Scholar 

  193. Liu T, Borjigin J (2005) N-acetyltransferase is not the rate-limiting enzyme of melatonin synthesis at night. J Pineal Res 39:91–96

    CAS  Google Scholar 

  194. Liu RY, Zhou JN, Van Heerikhuize J, Hofman MA, Swaab DF (1999) Decreased melatonin levels in postmortem cerebrospinal fluid in relation to aging, Alzheimer’s disease, and apolipoprotein E-ε 4/4 genotype. J Clin Endocrinol Metab 84:323–327

    CAS  Google Scholar 

  195. Louzada PR, Paula Lima AC, Mendonca-Silva DL, Noel F, De Mello FG, Ferreira ST (2004) Taurine prevents the neurotoxicity of beta-amyloid and glutamate receptor agonists: activation of GABA receptors and possible implications for Alzheimer’s disease and other neurological disorders. FASEB J 18:511–518

    CAS  Google Scholar 

  196. Luboshitzky R, Shen-Orr Z, Tzischichinsky O, Maldonado M, Herer P, Lavie P (2001) Actigraphic sleep–wake patterns and urinary 6-sulfatoxymelatonin excretion in patients with Alzheimer’s disease. Chronobiol Int 18:513–524

    CAS  Google Scholar 

  197. Macias M, Escames G, León J, Coto A, Sbihi Y, Osuna A, Acuña-Castroviejo D (2003) Calreticulin–melatonin. An unexpected relationship. Eur J Biochem 270:832–840

    CAS  Google Scholar 

  198. Macleod MR, O’Collins T, Horky LL, Howells DW, Donnan GA (2005) Systematic review and meta-analysis of the efficacy of melatonin in experimental stroke. J Pineal Res 38:35–41

    CAS  Google Scholar 

  199. Magri F, Sarra S, Cinchetti W, Guazzoni V, Fioravanti M, Cravello L, Ferrari E (2004) Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians. J Pineal Res 36:256–261

    CAS  Google Scholar 

  200. Maguire-Zeiss KA, Federoff HJ (2010) Future directions for immune modulation in neurodegenerative disorders: focus on Parkinson’s disease. J Neural Transm 117:1019–1025

    CAS  Google Scholar 

  201. Mahlberg R, Walther S (2007) Actigraphy in agitated patients with dementia: monitoring treatment outcomes. Z Gerontol Geriatr 40:178–184

    CAS  Google Scholar 

  202. Mahlberg R, Kunz D, Sutej I, Kuhl KP, Hellweg R (2004) Melatonin treatment of day–night rhythm disturbances and sundowning in Alzheimer disease: an open-label pilot study using actigraphy. J Clin Psychopharmacol 24:456–459

    Google Scholar 

  203. Mahlberg R, Kienast T, Hadel S, Heidenreich JO, Schmitz S, Kunz D (2009) Degree of pineal calcification (DOC) is associated with polysomnographic sleep measures in primary insomnia patients. Sleep Med 10:439–445

    Google Scholar 

  204. Manev H, Uz T, Kharlamov A, Joo JY (1996) Increased brain damage after stroke or excitotoxic seizures in melatonin-deficient rats. FASEB J 10:1546–1551

    CAS  Google Scholar 

  205. Maronde E, Stehle JH (2007) The mammalian pineal gland: known facts, unknown facets. Trends Endocrinol Metab 18:142–149

    CAS  Google Scholar 

  206. Martin M, Macias M, Escames G, Reiter RJ, Agapito MT, Ortiz GG, Acuña-Castroviejo D (2000) Melatonin-induced increased activity of the respiratory chain complexes I and IV can prevent mitochondrial damage induced by ruthenium red in vivo. J Pineal Res 28:242–248

    CAS  Google Scholar 

  207. Martin M, Macias M, León J, Escames G, Khaldy H, Acuña-Castroviejo D (2002) Melatonin increases the activity of the oxidative phosphorylation enzymes and the production of ATP in rat brain and liver mitochondria. Int J Biochem Cell Biol 34:348–357

    CAS  Google Scholar 

  208. Mathes AM, Kubulus D, Weiler J, Bentley A, Waibel L, Wolf B, Bauer I, Rensing H (2008) Melatonin receptors mediate improvements of liver function but not of hepatic perfusion and integrity after hemorrhagic shock in rats. Crit Care Med 36:24–29

    CAS  Google Scholar 

  209. Matsubara E, Bryant-Thomas T, Pacheco QJ, Henry TL, Poeggeler B, Herbert D, Cruz-Sanchez F, Chyan YJ, Smith MA, Perry G, Shoji M, Abe K, Leóne A, Grundke-Ikbal I, Wilson GL, Ghiso J, Williams C, Refolo LM, Pappolla MA, Chain DG, Neria E (2003) Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer’s disease. J Neurochem 85:1101–1108

    CAS  Google Scholar 

  210. Mayo JC, Sainz RM, Uria H, Antolin I, Esteban MM, Rodríguez C (1998) Melatonin prevents apoptosis induced by 6-hydroxydopamine in neuronal cells: implications for Parkinson’s disease. J Pineal Res 24:179–192

    CAS  Google Scholar 

  211. Mazzoccoli G, De Cata A, Carughi S, Greco A, Inglese M, Perfetto F, Tarquini R (2010a) A possible mechanism for altered immune response in the elderly. In Vivo (Athens, Greece) 24:471–487

    CAS  Google Scholar 

  212. Mazzoccoli G, Vendemiale G, Inglese M, De Cata A, Piepoli A, Pazienza V, Muscarella LA, Tarquini R (2010b) Neuroendocrine axes function in healthy aging: Evaluation of predictive and manipulable blood serum indexes. Biomed Pharmacother. http://dx.doi.org/10.1016/j.biopha.2010.09.001

  213. Medeiros CA, Carvalhedo de Bruin PF, Lopes LA, Magalhaes MC, de Lourdes SM, Sales dBV (2007) Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson’s disease: a randomized, double blind, placebo-controlled study. J Neurol 254:459–464

    CAS  Google Scholar 

  214. Mediavilla MD, Sanchez-Barcelo EJ, Tan DX, Manchester L, Reiter RJ (2010) Basic mechanisms involved in the anti-cancer effects of melatonin. Curr Med Chem 17:4462–4481

    CAS  Google Scholar 

  215. Melchiorri D, Reiter RJ, Chen LD, Sewerynek E, Nistico G (1996) Melatonin affords protection against kainate-induced in vitro lipid peroxidation in brain. Eur J Pharmacol 305:239–242

    CAS  Google Scholar 

  216. Melke J, Goubran BH, Chaste P, Betancur C, Nygren G, Anckarsater H, Rastam M, Stahlberg O, Gillberg IC, Delorme R, Chabane N, Mouren-Simeoni MC, Fauchereau F, Durand CM, Chevalier F, Drouot X, Collet C, Launay JM, Leboyer M, Gillberg C, Bourgeron T (2008) Abnormal melatonin synthesis in autism spectrum disorders. Mol Psychiatry 13:90–98

    CAS  Google Scholar 

  217. Menéndez-Pelaez A, Reiter RJ (1993) Distribution of melatonin in mammalian tissues: the relative importance of nuclear versus cytosolic localization. J Pineal Res 15:59–69

    Google Scholar 

  218. Mesenge C, Margaill I, Verrecchia C, Allix M, Boulu RG, Plotkine M (1998) Protective effect of melatonin in a model of traumatic brain injury in mice. J Pineal Res 25:41–46

    CAS  Google Scholar 

  219. Millan MJ, Gobert A, Lejeune F, Dekeyne A, Newman-Tancredi A, Pasteau V, Rivet JM, Cussac D (2003) The novel melatonin agonist agomelatine (S20098) is an antagonist at 5-hydroxytryptamine2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J Pharmacol Exp Ther 306:954–964

    CAS  Google Scholar 

  220. Mishima K, Tozawa T, Satoh K, Matsumoto Y, Hishikawa Y, Okawa M (1999) Melatonin secretion rhythm disorders in patients with senile dementia of Alzheimer’s type with disturbed sleep-waking. Biol Psychiatry 45:417–421

    CAS  Google Scholar 

  221. Mishima K, Okawa M, Hozumi S, Hishikawa Y (2000) Supplementary administration of artificial bright light and melatonin as potent treatment for disorganized circadian rest-activity and dysfunctional autonomic and neuroendocrine systems in institutionalized demented elderly persons. Chronobiol Int 17:419–432

    CAS  Google Scholar 

  222. Mishima K, Okawa M, Shimizu T, Hishikawa Y (2001) Diminished melatonin secretion in the elderly caused by insufficient environmental illumination. J Clin Endocrinol Metab 86:129–134

    CAS  Google Scholar 

  223. Miyamoto M (2009) Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS Neurosci Ther 15:32–51

    CAS  Google Scholar 

  224. Moller M, Baeres FM (2002) The anatomy and innervation of the mammalian pineal gland. Cell Tissue Res 309:139–150

    CAS  Google Scholar 

  225. Monti JM, Cardinali DP (2000) A critical assessment of the melatonin effect on sleep in humans. Biol Signals Recept 9:328–339

    CAS  Google Scholar 

  226. Monti JM, Alvarino F, Cardinali DP, Savio I, Pintos A (1999) Polysomnographic study of the effect of melatonin on sleep in elderly patients with chronic primary insomnia. Arch Gerontol Geriatr 28:85–98

    CAS  Google Scholar 

  227. Mukda S, Moller M, Ebadi M, Govitrapong P (2009) The modulatory effect of substance P on rat pineal norepinephrine release and melatonin secretion. Neurosci Lett 461:258–261

    CAS  Google Scholar 

  228. Mulchahey JJ, Goldwater DR, Zemlan FP (2004) A single blind, placebo controlled, across groups dose escalation study of the safety, tolerability, pharmacokinetics and pharmacodynamics of the melatonin analog beta-methyl 6 chloromelatonin. Life Sci 75:1843–1856

    CAS  Google Scholar 

  229. Nag S, Kapadia A, Stewart DJ (2011) Review: molecular pathogenesis of blood-brain barrier breakdown in acute brain injury. Neuropathol Appl Neurobiol 37:3–23

    CAS  Google Scholar 

  230. Nakazawa T, Nakazawa C, Matsubara A, Noda K, Hisatomi T, She H, Michaud N, Hafezi-Moghadam A, Miller JW, Benowitz LI (2006) Tumor necrosis factor-alpha mediates oligodendrocyte death and delayed retinal ganglion cell loss in a mouse model of glaucoma. J Neurosci 26:12633–12641

    CAS  Google Scholar 

  231. Nosjean O, Ferro M, Coge F, Beauverger P, Henlin JM, Lefoulon F, Fauchere JL, Delagrange P, Canet E, Boutin JA (2000) Identification of the melatonin-binding site MT3 as the quinone reductase 2. J Biol Chem 275:31311–31317

    CAS  Google Scholar 

  232. Ohashi Y, Okamoto N, Uchida K, Iyo M, Mori N, Morita Y (1999) Daily rhythm of serum melatonin levels and effect of light exposure in patients with dementia of the Alzheimer’s type. Biol Psychiatry 45:1646–1652

    CAS  Google Scholar 

  233. Okatani Y, Wakatsuki A, Reiter RJ, Miyahara Y (2002) Hepatic mitochondrial dysfunction in senescence-accelerated mice: correction by long-term, orally administered physiological levels of melatonin. J Pineal Res 33:127–133

    CAS  Google Scholar 

  234. Olanow CW (1990) Oxidation reactions in Parkinson’s disease. Neurology 40(Suppl):32–37

    Google Scholar 

  235. Olanow CW (1992) An introduction to the free radical hypothesis in Parkinson’s disease. Ann Neurol 32(Suppl):S2–S9

    CAS  Google Scholar 

  236. Olanow CW, Brin MF, Obeso JA (2000) The role of deep brain stimulation as a surgical treatment for Parkinson’s disease. Neurology 55:S60–S66

    CAS  Google Scholar 

  237. Olcese JM, Cao C, Mori T, Mamcarz MB, Maxwell A, Runfeldt MJ, Wang L, Zhang C, Lin X, Zhang G, Arendash GW (2009) Protection against cognitive deficits and markers of neurodegeneration by long-term oral administration of melatonin in a transgenic model of Alzheimer disease. J Pineal Res 47:82–96

    CAS  Google Scholar 

  238. Oliveira JM (2010) Nature and cause of mitochondrial dysfunction in Huntington’s disease: focusing on huntingtin and the striatum. J Neurochem 114:1–12

    CAS  Google Scholar 

  239. Onuki J, Almeida EA, Medeiros MH, Di Mascio P (2005) Inhibition of 5-aminolevulinic acid-induced DNA damage by melatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, quercetin or resveratrol. J Pineal Res 38:107–115

    CAS  Google Scholar 

  240. Pablos MI, Reiter RJ, Chuang JI, Ortiz GG, Guerrero JM, Sewerynek E, Agapito MT, Melchiorri D, Lawrence R, Deneke SM (1997) Acutely administered melatonin reduces oxidative damage in lung and brain induced by hyperbaric oxygen. J Appl Physiol 83:354–358

    CAS  Google Scholar 

  241. Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87:315–424

    CAS  Google Scholar 

  242. Pagan C, Goubran-Botros H, Poirier K, Dumaine A, Jamain S, Moreno S, de Brouwer A, Van Esch H, Delorme R, Launay JM, Tzschach A, Kalscheuer VM, Lacombe D, Briault S, Laumonnier F, Raynaud M, van Bon BW, Willemsen MH, Leboyer M, Chelly J, Bourgeron T (2011) Mutation screening of ASMT, the last enzyme of the melatonin pathway, in a large sample of patients with Intellectual Disability. BMC Med Genet 12:17

    CAS  Google Scholar 

  243. Pandi-Perumal SR, Seils LK, Kayumov L, Ralph MR, Lowe A, Moller H, Swaab DF (2002) Senescence, sleep, and circadian rhythms. Ageing Res Rev 1:559–604

    CAS  Google Scholar 

  244. Pandi-Perumal SR, Srinivasan V, Maestroni GJM, Cardinali DP, Poeggeler B, Hardeland R (2006) Melatonin: nature’s most versatile biological signal? FEBS J 273(13):2813–2838

    CAS  Google Scholar 

  245. Pappolla MA, Sos M, Omar RA, Bick RJ, Hickson-Bick DL, Reiter RJ, Efthimiopoulos S, Robakis NK (1997) Melatonin prevents death of neuroblastoma cells exposed to the Alzheimer amyloid peptide. J Neurosci 17:1683–1690

    CAS  Google Scholar 

  246. Pappolla MA, Chyan YJ, Poeggeler B, Bozner P, Ghiso J, LeDoux SP, Wilson GL (1999) Alzheimer beta protein mediated oxidative damage of mitochondrial DNA: prevention by melatonin. J Pineal Res 27:226–229

    CAS  Google Scholar 

  247. Pappolla MA, Chyan YJ, Poeggeler B, Frangione B, Wilson G, Ghiso J, Reiter RJ (2000) An assessment of the antioxidant and the antiamyloidogenic properties of melatonin: implications for Alzheimer’s disease. J Neural Transm 107:203–231

    CAS  Google Scholar 

  248. Payton A, Miyajima F, Ollier W, Rabbitt P, Pickles A, Weiss V, Pendleton N, Horan M (2010) Investigation of a functional quinine oxidoreductase (NQO2) polymorphism and cognitive decline. Neurobiol Aging 31:351–352

    CAS  Google Scholar 

  249. Peck JS, LeGoff DB, Ahmed I, Goebert D (2004) Cognitive effects of exogenous melatonin administration in elderly persons: a pilot study. Am J Geriatr Psychiatry 12:432–436

    Google Scholar 

  250. Pei Z, Cheung RT (2004) Pretreatment with melatonin exerts anti-inflammatory effects against ischemia/reperfusion injury in a rat middle cerebral artery occlusion stroke model. J Pineal Res 37:85–91

    Google Scholar 

  251. Peng TI, Hsiao CW, Reiter RJ, Tanaka M, Lai YK, Jou MJ (2012) mtDNA T8993G mutation-induced mitochondrial complex V inhibition augments cardiolipin-dependent alterations in mitochondrial dynamics during oxidative, Ca2+, and lipid insults in NARP cybrids: a potential therapeutic target for melatonin. J Pineal Res 52:93–106

    CAS  Google Scholar 

  252. Perez M, Hernandez F, Gomez-Ramos A, Smith M, Perry G, Avila J (2002) Formation of aberrant phosphotau fibrillar polymers in neural cultured cells. Eur J Biochem 269:1484–1489

    CAS  Google Scholar 

  253. 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 (2001) Melatonin reverses the profibrillogenic activity of apolipoprotein E4 on the Alzheimer amyloid Aβ peptide. Biochemistry 40:14995–15001

    CAS  Google Scholar 

  254. Poliandri AH, Esquifino AI, Cano P, Jimenez V, Lafuente A, Cardinali DP, Duvilanski BH (2006) In vivo protective effect of melatonin on cadmium-induced changes in redox balance and gene expression in rat hypothalamus and anterior pituitary. J Pineal Res 41:238–246

    CAS  Google Scholar 

  255. Princ FG, Juknat AA, Maxit AG, Cardalda C, Batlle A (1997) Melatonin’s antioxidant protection against delta-aminolevulinic acid-induced oxidative damage in rat cerebellum. J Pineal Res 23:40–46

    CAS  Google Scholar 

  256. Quinn J, Kulhanek D, Nowlin J, Jones R, Pratico D, Rokach J, Stackman R (2005) Chronic melatonin therapy fails to alter amyloid burden or oxidative damage in old Tg2576 mice: implications for clinical trials. Brain Res 1037:209–213

    CAS  Google Scholar 

  257. Radogna F, Diederich M, Ghibelli L (2010) Melatonin: a pleiotropic molecule regulating inflammation. Biochem Pharmacol 80:1844–1852

    CAS  Google Scholar 

  258. Rajaratnam SM, Polymeropoulos MH, Fisher DM, Roth T, Scott C, Birznieks G, Klerman EB (2009) Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials. Lancet 373:482–491

    CAS  Google Scholar 

  259. Reiter RJ (1980) The pineal and its hormones in the control of reproduction in mammals. Endocr Rev 1:109–131

    CAS  Google Scholar 

  260. Reiter RJ (1998) Oxidative damage in the central nervous system: protection by melatonin. Prog Neurobiol 56:359–384

    CAS  Google Scholar 

  261. Reiter RJ, Tan DX (2003) What constitutes a physiological concentration of melatonin? J Pineal Res 34:79–80

    CAS  Google Scholar 

  262. Reiter RJ, Manchester LC, Tan DX (2010) Neurotoxins: free radical mechanisms and melatonin protection. Curr Neuropharmacol 8:194–210

    CAS  Google Scholar 

  263. Reyes Toso C, Ricci C, de Mignone IR, Reyes P, Linares LM, Albornoz LE, Cardinali DP, Zaninovich AA (2003) In vitro effect of melatonin on oxygen consumption in liver mitochondria of rats. Neuroendocrinol Lett 24:341–344

    CAS  Google Scholar 

  264. Ribelayga C, Pévet P, Simonneaux V (2000) HIOMT drives the photoperiodic changes in the amplitude of the melatonin peak of the Siberian hamster. Am J Physiol Regul Integr Comp Physiol 278:R1339–R1345

    CAS  Google Scholar 

  265. Riemersma-van der Lek RF, Swaab DF, Twisk J, Hol EM, Hoogendijk WJ, van Someren EJ (2008) Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial. JAMA 299:2642–2655

    CAS  Google Scholar 

  266. Rod NH, Hansen J, Schernhammer E, Ritz B (2010) Major life events and risk of Parkinson’s disease. Mov Disord 25:1639–1645

    Google Scholar 

  267. Rodríguez C, Mayo JC, Sainz RM, Antolin I, Herrera F, Martin V, Reiter RJ (2004) Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 36:1–9

    Google Scholar 

  268. Rosales-Corral S, Tan DX, Reiter RJ, Valdivia-Velazquez M, Martinez-Barboza G, Acosta-Martinez JP, Ortiz GG (2003) Orally administered melatonin reduces oxidative stress and proinflammatory cytokines induced by amyloid-beta peptide in rat brain: a comparative, in vivo study versus vitamin C and E. J Pineal Res 35:80–84

    CAS  Google Scholar 

  269. Rosen R, Hu DN, Perez V, Tai K, Yu GP, Chen M, Tone P, McCormick SA, Walsh J (2009) Urinary 6-sulfatoxymelatonin level in age-related macular degeneration patients. Mol Vis 15:1673–1679

    CAS  Google Scholar 

  270. Rosenstein RE, Pandi-Perumal SR, Srinivasan V, Spence DW, Brown GM, Cardinali DP (2010) Melatonin as a therapeutic tool in ophthalmology: implication for glaucoma and uveitis. J Pineal Res 49:1–13

    CAS  Google Scholar 

  271. Rosenthal NE, Sack DA, Gillin JC, Lewy AJ, Goodwin FK, Davenport Y, Mueller PS, Newsome DA, Wehr TA (1984) Seasonal affective disorder. A description of the syndrome and preliminary findings with light therapy. Arch Gen Psychiatry 41:72–80

    CAS  Google Scholar 

  272. Sack RL, Lewy AJ, Erb DL, Vollmer WM, Singer CM (1986) Human melatonin production decreases with age. J Pineal Res 3:379–388

    CAS  Google Scholar 

  273. Sainz RM, Mayo JC, Rodríguez C, Tan DX, Lopez-Burillo S, Reiter RJ (2003) Melatonin and cell death: differential actions on apoptosis in normal and cancer cells. Cell Mol Life Sci 60:1407–1426

    CAS  Google Scholar 

  274. Saravanan KS, Sindhu KM, Mohanakumar KP (2007) Melatonin protects against rotenone-induced oxidative stress in a hemiparkinsonian rat model. J Pineal Res 42:247–253

    CAS  Google Scholar 

  275. Savaskan E, Ayoub MA, Ravid R, Angeloni D, Fraschini F, Meier F, Eckert A, Muller-Spahn F, Jockers R (2005) Reduced hippocampal MT2 melatonin receptor expression in Alzheimer’s disease. J Pineal Res 38:10–16

    CAS  Google Scholar 

  276. Scheer FA, Van Montfrans GA, Van Someren EJ, Mairuhu G, Buijs RM (2004) Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension 43:192–197

    CAS  Google Scholar 

  277. Scher J, Wankiewicz E, Brown GM, Fujieda H (2003) AII amacrine cells express the MT1 melatonin receptor in human and macaque retina. Exp Eye Res 77:375–382

    CAS  Google Scholar 

  278. Schernhammer E, Chen H, Ritz B (2006) Circulating melatonin levels: possible link between Parkinson’s disease and cancer risk? Cancer Causes Control 17:577–582

    Google Scholar 

  279. Serfaty M, Kennell-Webb S, Warner J, Blizard R, Raven P (2002) Double blind randomised placebo controlled trial of low dose melatonin for sleep disorders in dementia. Int J Geriatr Psychiatry 17:1120–1127

    Google Scholar 

  280. Shaikh AY, Xu J, Wu Y, He L, Hsu CY (1997) Melatonin protects bovine cerebral endothelial cells from hyperoxia-induced DNA damage and death. Neurosci Lett 229:193–197

    CAS  Google Scholar 

  281. Shirazi A, Mihandoost E, Mohseni M, Ghazi-Khansari M, Rabie MS (2011) Radio-protective effects of melatonin against irradiation-induced oxidative damage in rat peripheral blood. Phys Med. http://dx.doi.org/10.1016/j.ejmp.2011.11.007

  282. Siegrist C, Benedetti C, Orlando A, Beltran JM, Tuchscherr L, Noseda CM, Brusco LI, Cardinali DP (2001) Lack of changes in serum prolactin, FSH, TSH, and estradiol after melatonin treatment in doses that improve sleep and reduce benzodiazepine consumption in sleep-disturbed, middle-aged, and elderly patients. J Pineal Res 30:34–42

    CAS  Google Scholar 

  283. Silva SO, Rodrigues MR, Carvalho SR, Catalani LH, Campa A, Ximenes VF (2004) Oxidation of melatonin and its catabolites, N1-acetyl-N2-formyl-5-methoxykynuramine and N1-acetyl-5-methoxykynuramine, by activated leukocytes. J Pineal Res 37:171–175

    CAS  Google Scholar 

  284. Simonneaux V, Ribelayga C (2003) Generation of the melatonin endocrine message in mammals: a review of the complex regulation of melatonin synthesis by norepinephrine, peptides, and other pineal transmitters. Pharmacol Rev 55:325–395

    CAS  Google Scholar 

  285. Singer C, Tractenberg RE, Kaye J, Schafer K, Gamst A, Grundman M, Thomas R, Thal LJ (2003) A multicenter, placebo-controlled trial of melatonin for sleep disturbance in Alzheimer’s disease. Sleep 26:893–901

    Google Scholar 

  286. Singhal NK, Srivastava G, Patel DK, Jain SK, Singh MP (2011) Melatonin or silymarin reduces maneb- and paraquat-induced Parkinson’s disease phenotype in the mouse. J Pineal Res 50:97–109

    CAS  Google Scholar 

  287. Skene DJ, Swaab DF (2003) Melatonin rhythmicity: effect of age and Alzheimer’s disease. Exp Gerontol 38:199–206

    CAS  Google Scholar 

  288. Skene DJ, Vivien-Roels B, Sparks DL, Hunsaker JC, Pévet P, Ravid D, Swaab DF (1990) Daily variation in the concentration of melatonin and 5-methoxytryptophol in the human pineal gland: effect of age and Alzheimer’s disease. Brain Res 528:170–174

    CAS  Google Scholar 

  289. Southgate G, Daya S (1999) Melatonin reduces quinolinic acid-induced lipid peroxidation in rat brain homogenate. Metab Brain Dis 14:165–171

    CAS  Google Scholar 

  290. Spadoni G, Bedini A, Rivara S, Mor M (2011) Melatonin receptor agonists: new options for insomnia and depression treatment. CNS Neurosci Ther 17:733–741

    CAS  Google Scholar 

  291. Spuch C, Antequera D, Isabel Fernandez-Bachiller M, Isabel Rodríguez-Franco M, Carro E (2010) A new tacrine-melatonin hybrid reduces amyloid burden and behavioral deficits in a mouse model of Alzheimer’s disease. Neurotox Res 17:421–431

    CAS  Google Scholar 

  292. Srinivasan V, Singh J, Pandi-Perumal SR, Brown GM, Spence DW, Cardinali DP (2010) Jet lag, circadian rhythm sleep disturbances, and depression: the role of melatonin and its analogs. Adv Ther 27:796–813

    CAS  Google Scholar 

  293. Srinivasan V, Spence DW, Pandi-Perumal SR, Brown GM (2011) Cardinali DP (2011) Melatonin in mitochondrial dysfunction and related disorders. Int J Alzheimer′s Dis vol. doi:10.4061/2011/741974

    Google Scholar 

  294. Sterniczuk R, Dyck RH, Laferla FM, Antle MC (2010) Characterization of the 3xTg-AD mouse model of Alzheimer’s disease: part 1. Circadian changes. Brain Res 1348:139–148

    CAS  Google Scholar 

  295. Stevens RG, Hansen J, Costa G, Haus E, Kauppinen T, Aronson KJ, Castano-Vinyals G, Davis S, Frings-Dresen MH, Fritschi L, Kogevinas M, Kogi K, Lie JA, Lowden A, Peplonska B, Pesch B, Pukkala E, Schernhammer E, Travis RC, Vermeulen R, Zheng T, Cogliano V, Straif K (2011) Considerations of circadian impact for defining ‘shift work’ in cancer studies: IARC Working Group Report. Occup Environ Med 68:154–162

    Google Scholar 

  296. Stopa EG, Volicer L, Kuo-Leblanc V, Harper D, Lathi D, Tate B, Satlin A (1999) Pathologic evaluation of the human suprachiasmatic nucleus in severe dementia. J Neuropathol Exp Neurol 58:29–39

    CAS  Google Scholar 

  297. Subramanian P, Mirunalini S, Pandi-Perumal SR, Trakht I, Cardinali DP (2007) Melatonin treatment improves the antioxidant status and decreases lipid content in brain and liver of rats. Eur J Pharmacol 571:116–119

    CAS  Google Scholar 

  298. Swabb DF, Fliers E, Partiman TS (1985) The suprachiasmatic nucleus of the human brain in relation to sex, age and senile dementia. Brain Res 342:37–44

    Google Scholar 

  299. Swerdlow RH (2011) Brain aging, Alzheimer’s disease, and mitochondria. Biochim Biophys Acta 1812:1630–1639

    CAS  Google Scholar 

  300. Synofzik M, Ronchi D, Keskin I, Basak AN, Wilhelm C, Gobbi C, Birve A, Biskup S, Zecca C, Fernandez-Santiago R, Kaugesaar T, Schols L, Marklund SL, Andersen PM (2012) Mutant superoxide dismutase-1 indistinguishable from wild type causes ALS. Hum Mol Genet. http://dx.doi.org/10.1093/hmg/dds188

  301. Tai SH, Hung YC, Lee EJ, Lee AC, Chen TY, Shen CC, Chen HY, Lee MY, Huang SY, Wu TS (2011) Melatonin protects against transient focal cerebral ischemia in both reproductively active and estrogen-deficient female rats: the impact of circulating estrogen on its hormetic dose-response. J Pineal Res 50:292–303

    CAS  Google Scholar 

  302. Takeuchi N, Uchimura N, Hashizume Y, Mukai M, Etoh Y, Yamamoto K, Kotorii T, Ohshima H, Ohshima M, Maeda H (2001) Melatonin therapy for REM sleep behavior disorder. Psychiatry Clin Neurosci 55:267–269

    CAS  Google Scholar 

  303. Tan DX, Manchester LC, Reiter RJ, Plummer BF, Hardies LJ, Weintraub ST, Vijayalaxmi Shepherd AM (1998) A novel melatonin metabolite, cyclic 3-hydroxymelatonin: a biomarker of in vivo hydroxyl radical generation. Biochem Biophys Res Commun 253:614–620

    CAS  Google Scholar 

  304. Tan D, Manchester LC, Reiter RJ, Qi W, Hanes MA, Farley NJ (1999) High physiological levels of melatonin in the bile of mammals. Life Sci 65:2523–2529

    CAS  Google Scholar 

  305. Tan DX, Manchester LC, Hardeland R, Lopez-Burillo S, Mayo JC, Sainz RM, Reiter RJ (2003) Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin. J Pineal Res 34:75–78

    CAS  Google Scholar 

  306. Tan DX, Manchester LC, Sanchez-Barcelo E, Mediavilla MD, Reiter RJ (2010) Significance of high levels of endogenous melatonin in mammalian cerebrospinal fluid and in the central nervous system. Curr Neuropharmacol 8:162–167

    CAS  Google Scholar 

  307. Tansey MG, McCoy MK, Frank-Cannon TC (2007) Neuroinflammatory mechanisms in Parkinson’s disease: potential environmental triggers, pathways, and targets for early therapeutic intervention. Exp Neurol 208:1–25

    CAS  Google Scholar 

  308. Tapias V, Cannon JR, Greenamyre JT (2010) Melatonin treatment potentiates neurodegeneration in a rat rotenone Parkinson’s disease model. J Neurosci Res 88:420–427

    CAS  Google Scholar 

  309. Taysi S, Memisogullari R, Koc M, Yazici AT, Aslankurt M, Gumustekin K, Al B, Ozabacigil F, Yilmaz A, Tahsin OH (2008) Melatonin reduces oxidative stress in the rat lens due to radiation-induced oxidative injury. Int J Radiat Biol 84:803–808

    CAS  Google Scholar 

  310. Thomas B, Mohanakumar KP (2004) Melatonin protects against oxidative stress caused by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in the mouse nigrostriatum. J Pineal Res 36:25–32

    CAS  Google Scholar 

  311. Travis RC, Allen NE, Peeters PH, van Noord PA, Key TJ (2003) Reproducibility over 5 years of measurements of 6-sulphatoxymelatonin in urine samples from postmenopausal women. Cancer Epidemiol Biomarkers Prev 12:806–808

    CAS  Google Scholar 

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

    CAS  Google Scholar 

  313. Tsai MC, Chen WJ, Tsai MS, Ching CH, Chuang JI (2011) Melatonin attenuates brain contusion-induced oxidative insult, inactivation of signal transducers and activators of transcription 1, and upregulation of suppressor of cytokine signaling-3 in rats. J Pineal Res 51:233–245

    CAS  Google Scholar 

  314. Tunez I, Montilla P, Del Carmen MM, Feijoo M, Salcedo M (2004) Protective effect of melatonin on 3-nitropropionic acid-induced oxidative stress in synaptosomes in an animal model of Huntington’s disease. J Pineal Res 37:252–256

    CAS  Google Scholar 

  315. Turek FW, Gillette MU (2004) Melatonin, sleep, and circadian rhythms: rationale for development of specific melatonin agonists. Sleep Med 5:523–532

    Google Scholar 

  316. Uchida K, Okamoto N, Ohara K, Morita Y (1996) Daily rhythm of serum melatonin in patients with dementia of the degenerate type. Brain Res 717:154–159

    CAS  Google Scholar 

  317. Urata Y, Honma S, Goto S, Todoroki S, Iida T, Cho S, Honma K, Kondo T (1999) Melatonin induces gamma-glutamylcysteine synthetase mediated by activator protein-1 in human vascular endothelial cells. Free Radic Biol Med 27:838–847

    CAS  Google Scholar 

  318. Urbanski HF, Sorwell KG (2011) Age-related changes in neuroendocrine rhythmic function in the rhesus macaque. Age (Dordr ). http://dx.doi.org/10.1007/s11357-011-9352-z

  319. van Someren EJ (2000) Circadian and sleep disturbances in the elderly. Exp Gerontol 35:1229–1237

    Google Scholar 

  320. Vekrellis K, Xilouri M, Emmanouilidou E, Rideout HJ, Stefanis L (2011) Pathological roles of alpha-synuclein in neurological disorders. Lancet Neurol 10:1015–1025

    CAS  Google Scholar 

  321. Venegas C, García JA, Escames G, Ortiz F, Lopez A, Doerrier C, García-Corzo L, Lopez LC, Reiter RJ, Acuña-Castroviejo D (2012) Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. J Pineal Res 52:217–227

    CAS  Google Scholar 

  322. Voordouw BC, Euser R, Verdonk RE, Alberda BT, de Jong FH, Drogendijk AC, Fauser BC, Cohen M (1992) Melatonin and melatonin–progestin combinations alter pituitary-ovarian function in women and can inhibit ovulation. J Clin Endocrinol Metab 74:108–117

    CAS  Google Scholar 

  323. Wada K, Chatzipanteli K, Busto R, Dietrich WD (1998) Role of nitric oxide in traumatic brain injury in the rat. J Neurosurg 89:807–818

    CAS  Google Scholar 

  324. Wade AG, Ford I, Crawford G, McMahon AD, Nir T, Laudon M, Zisapel N (2007) Efficacy of prolonged release melatonin in insomnia patients aged 55–80 years: quality of sleep and next-day alertness outcomes. Curr Med Res Opin 23:2597–2605

    CAS  Google Scholar 

  325. Waldhauser F, Steger H (1986) Changes in melatonin secretion with age and pubescence. J Neural Transm Suppl 21:183–197

    CAS  Google Scholar 

  326. Waldhauser F, Waldhauser M, Lieberman HR, Deng MH, Lynch HJ, Wurtman RJ (1984) Bioavailability of oral melatonin in humans. Neuroendocrinology 39:307–313

    CAS  Google Scholar 

  327. Wang X (2009) The antiapoptotic activity of melatonin in neurodegenerative diseases. CNS Neurosci Ther 15:345–357

    CAS  Google Scholar 

  328. Wang X, Sirianni A, Pei Z, Cormier K, Smith K, Jiang J, Zhou S, Wang H, Zhao R, Yano H, Kim JE, Li W, Kristal BS, Ferrante RJ, Friedlander RM (2011) The melatonin MT1 receptor axis modulates mutant Huntingtin-mediated toxicity. J Neurosci 31:14496–14507

    CAS  Google Scholar 

  329. 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 (2006) Reduced oxidative damage in ALS by high-dose enteral melatonin treatment. J Pineal Res 41:313–323

    CAS  Google Scholar 

  330. Wiesenberg I, Missbach M, Kahlen JP, Schrader M, Carlberg C (1995) Transcriptional activation of the nuclear receptor RZR alpha by the pineal gland hormone melatonin and identification of CGP 52608 as a synthetic ligand. Nucleic Acids Res 23:327–333

    CAS  Google Scholar 

  331. Willis GL (2008) Parkinson’s disease as a neuroendocrine disorder of circadian function: dopamine-melatonin imbalance and the visual system in the genesis and progression of the degenerative process. Rev Neurosci 19:245–316

    CAS  Google Scholar 

  332. Willis GL, Armstrong SM (1999) A therapeutic role for melatonin antagonism in experimental models of Parkinson’s disease. Physiol Behav 66:785–795

    CAS  Google Scholar 

  333. Willis GL, Robertson AD (2004) Recovery of experimental Parkinson’s disease with the melatonin analogues ML-23 and S-20928 in a chronic, bilateral 6-OHDA model: a new mechanism involving antagonism of the melatonin receptor. Pharmacol Biochem Behav 79:413–429

    CAS  Google Scholar 

  334. Willis GL, Turner EJ (2007) Primary and secondary features of Parkinson’s disease improve with strategic exposure to bright light: a case series study. Chronobiol Int 24:521–537

    Google Scholar 

  335. Wilson SJ, Nutt DJ, Alford C, Argyropoulos SV, Baldwin DS, Bateson AN, Britton TC, Crowe C, Dijk DJ, Espie CA, Gringras P, Hajak G, Idzikowski C, Krystal AD, Nash JR, Selsick H, Sharpley AL, Wade AG (2010) British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. J Psychopharmacol 24:1577–1601

    CAS  Google Scholar 

  336. Wu YH, Swaab DF (2007) Disturbance and strategies for reactivation of the circadian rhythm system in aging and Alzheimer’s disease. Sleep Med 8:623–636

    Google Scholar 

  337. Wu YH, Feenstra MG, Zhou JN, Liu RY, Torano JS, Van Kan HJ, Fischer DF, Ravid R, Swaab DF (2003) Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages. J Clin Endocrinol Metab 88:5898–5906

    CAS  Google Scholar 

  338. Wu J, Seregard S, Algvere PV (2006a) Photochemical damage of the retina. Surv Ophthalmol 51:461–481

    Google Scholar 

  339. Wu YH, Zhou JN, Balesar R, Unmehopa U, Bao A, Jockers R, Van Heerikhuize J, Swaab DF (2006b) Distribution of MT1 melatonin receptor immunoreactivity in the human hypothalamus and pituitary gland: colocalization of MT1 with vasopressin, oxytocin, and corticotropin-releasing hormone. J Comp Neurol 499:897–910

    CAS  Google Scholar 

  340. Wu YH, Zhou JN, Van Heerikhuize J, Jockers R, Swaab DF (2007) Decreased MT1 melatonin receptor expression in the suprachiasmatic nucleus in aging and Alzheimer’s disease. Neurobiol Aging 28:1239–1247

    CAS  Google Scholar 

  341. Wurtman RJ, Zhdanova I (1995) Improvement of sleep quality by melatonin. Lancet 346:1491

    CAS  Google Scholar 

  342. Yang X, Yang Y, Fu Z, Li Y, Feng J, Luo J, Zhang Q, Wang Q, Tian Q (2011) Melatonin ameliorates Alzheimer-like pathological changes and spatial memory retention impairment induced by calyculin A. J Psychopharmacol 25:1118–1125

    CAS  Google Scholar 

  343. Yuan H, Pang SF (1991) [125I]Iodomelatonin-binding sites in the pigeon brain: binding characteristics, regional distribution and diurnal variation. J Endocrinol 128:475–482

    CAS  Google Scholar 

  344. Zeitzer JM, Daniels JE, Duffy JF, Klerman EB, Shanahan TL, Dijk DJ, Czeisler CA (1999) Do plasma melatonin concentrations decline with age? Am J Med 107:432–436

    CAS  Google Scholar 

  345. Zhang Y, Dawson VL, Dawson TM (2000) Oxidative stress and genetics in the pathogenesis of Parkinson’s disease. Neurobiol Dis 7:240–250

    CAS  Google Scholar 

  346. Zhang Q, Ding H, Li W, Fan Z, Sun A, Luo J, Ke ZJ (2009) Senescence accelerated mouse strain is sensitive to neurodegeneration induced by mild impairment of oxidative metabolism. Brain Res 1264:111–118

    CAS  Google Scholar 

  347. Zhong G, Naismith SL, Rogers NL, Lewis SJ (2011) Sleep-wake disturbances in common neurodegenerative diseases: a closer look at selected aspects of the neural circuitry. J Neurol Sci 307:9–14

    Google Scholar 

  348. Zhou JN, Liu RY, Kamphorst W, Hofman MA, Swaab DF (2003) Early neuropathological Alzheimer’s changes in aged individuals are accompanied by decreased cerebrospinal fluid melatonin levels. J Pineal Res 35:125–130

    CAS  Google Scholar 

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Disclosures

S.R. Pandi-Perumal is a stockholder and the President and Chief Executive Officer of Somnogen Canada Inc., a Canadian Corporation. He declares that he has no competing interests that might be perceived to influence the content of this article. All remaining authors declare that they have no proprietary, financial, professional, nor any other personal interest of any nature or kind in any product or services and/or company that could be construed or considered to be a potential conflict of interest that might have influenced the views expressed in this manuscript.

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Correspondence to Daniel P. Cardinali.

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Pandi-Perumal, S.R., BaHammam, A.S., Brown, G.M. et al. Melatonin Antioxidative Defense: Therapeutical Implications for Aging and Neurodegenerative Processes. Neurotox Res 23, 267–300 (2013). https://doi.org/10.1007/s12640-012-9337-4

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Keywords

  • Melatonin
  • Mitochondria
  • Free radicals
  • Oxidative stress
  • Aging
  • Parkinson’s disease
  • Alzheimer’s disease
  • Huntington’s disease
  • Amyotrophic lateral sclerosis
  • Stroke