Delivery of pineal melatonin to the brain and SCN: role of canaliculi, cerebrospinal fluid, tanycytes and Virchow–Robin perivascular spaces

Brain Structure and Function

Volumn 219, Issue 6, 2014, Pages 1873-1887

  Reiter, Russel J ^a   Tan, Dun Xian ^a   Kim, Seok Joong ^a   Cruz, Maria Helena C ^a  

^a Mays Cancer Center at UT Health San Antonio   (United States)

Author keywords

Canaliculi; Cerebrospinal fluid; Melatonin; Oxidative damage; Pineal gland; Suprachiasmatic nucleus; Tanycytes; Virchow Robin space

Indexed keywords

MELATONIN;

BIOLOGICAL RHYTHM; BRAIN; BRAIN NERVE CELL; BRAIN THIRD VENTRICLE; CEREBROSPINAL FLUID; CEREBROSPINAL FLUID FLOW; CHOROID PLEXUS; CIRCADIAN RHYTHM; CORPUS CALLOSUM; DARKNESS; DIENCEPHALON; EPENDYMA CELL; EPITHALAMUS; GALEN VEIN; GLIA CELL; HEART CYCLE; HUMAN; LATERAL BRAIN VENTRICLE; LIGHT DARK CYCLE; NITROSATIVE STRESS; NONHUMAN; OXIDATIVE STRESS; PERIVASCULAR SPACE; PINEAL BODY; PINEALOCYTE; PRIORITY JOURNAL; REVIEW; SUBARACHNOID SPACE; SUPRACHIASMATIC NUCLEUS; SYMPATHETIC INNERVATION; TANYCYTE; ANIMAL; BRAIN CHEMISTRY; CHEMISTRY; MACROGLIA; PHYSIOLOGY; SECRETION (PROCESS); VASCULARIZATION;

ANIMALS; BRAIN CHEMISTRY; CIRCADIAN RHYTHM; EPENDYMOGLIAL CELLS; HUMANS; MELATONIN; PINEAL GLAND; SUBARACHNOID SPACE; SUPRACHIASMATIC NUCLEUS; THIRD VENTRICLE;

EID: 84936077755     PISSN: 18632653     EISSN: 18632661     Source Type: Journal    
DOI: 10.1007/s00429-014-0719-7     Document Type: Review

References (144)

1. Acuna-Castroviejo D, Lopez LC, Escames G, Lopez A, Garcia JA, Reiter RJ (2011) Melatonin-mitochondria interplay in health and disease. Curr Top Med Chem 11:221–240
2. Agez L, Laurent V, Pevet P, Masson-Pevet M, Gauer F (2007) Melatonin affects nuclear orphan receptors mRNA in the rat suprachiasmatic nuclei. Neuroscience 144:522–530
3. Agez L, Laurent V, Guerrero HY, Pevet P, Masson-Pevet M, Gauer F (2009) Endogenous melatonin provides an effective circadian message to both the suprachiasmatic nuclei and the pars tuberalis of the rat. J Pineal Res 46:95–105
4. Arendt J, Wirz-Justice A, Bradtke J (1978) Annual rhythm of serum melatonin in man. Neurosci Lett 7:327–330
5. Barlow-Walden LR, Reiter RJ, Abe M, Pablos MI, Menendez-Pelaez A, Chen LD, Poeggeler B (1995) Melatonin stimulates brain glutathione peroxidase activity. Neurochem Int 26:497–502
6. Barrett P, Bolborea M (2012) Molecular pathways involved in seasonal body weight and reproductive responses governed by melatonin. J Pineal Res 52:376–388
7. Bolborea M, Dale N (2013) Hypothalamic tanycytes: potential roles in the control of feeding and energy balance. Trends Neurosci 36:91–100
8. Borison HL, Borison R, McCarthy LE (1980) Brain stem penetration by horseradish peroxidase from cerebrospinal fluid spaces in the cat. Exp Neurol 69:271–289
9. Bothorel B, Barassin S, Saboureau M, Perreau S, Vivien-Roels B, Malan A, Pevet P (2002) In the rat, exogenous melatonin increases the amplitude of pineal melatonin secretion by a direct action on the circadian clock. Eur J Neurosci 16:1090–1098
10. Brightman MW (1968) The intracerebral movement of proteins injected into the blood and cerebrospinal fluid of mice. Prog Brain Res 29:19–37
11. Brightman MW, Reese TS (1969) Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol 40:648–677
12. Brown GM, Young SN, Gauthier H, Tsiu H, Grota LJ (1979) Melatonin in human cerebrospinal fluid in daytime: its origin and variation with age. Life Sci 25:936–979
13. Bruce J, Tamarkin L, Riedel C, Markey S, Oldfield E (1991) Sequential cerebrospinal fluid and plasma sampling in humans: 24-hour melatonin measurements in normal subjects and after peripheral sympathectomy. J Clin Endocrinol Metab 72:819–823
14. Cabrera J, Reiter RJ, Tan DX, Qi W, Sainz RM, Mayo JC, Garcia JJ, Kim SJ, El-Sakkary G (2000) Melatonin reduces oxidative neurotoxicity due to quinolinic acid: in vitro and in vivo findings. Neuropharmacology 39:507–514
15. Cardinali DP (1981) Melatonin: a mammalian pineal hormone. Endocr Rev 2:327–346
16. Cardinali DP, Srinivasan V, Brzezinski A, Brown GM (2012a) Melatonin and its analogs in insomnia and depression. J Pineal Res 52:365–374
17. Cardinali DP, Vigo DE, Olivar N, Vidal MF, Furio AM, Brusco LI (2012b) Therapeutic application in mild cognitive impairment. Am J Neurodegener Dis 1:280–291
18. Corrales A, Martinez P, Garcia S, Vidal V, Garcia E, Florez J, Sanchez-Barcelo EJ, Martinez-Cue C, Rueda N (2013) Long-term oral administration of melatonin improve special learning and memory and protects against cholinergic degeneration in middle-aged Ts65Dn mice, a model of Down syndrome. J Pineal Res 54:346–358
19. 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
20. de Oliveira Silva S, Ximenes VF, Livramento JA, Catalani LH, Campa A (2005) High concentrations of the melatonin metabolite, N1-acetyl-N2-formyl-5-methoxykynuramine, in cerebrospinal fluid of patients with meningitis: a possible immunomodulatory mechanism. J Pineal Res 39:302–306
21. Debus OM, Lerchl A, Bothe HW, Bremer J, Fiedler B, Franssen M, Koehring J, Steils M, Kurlemann G (2002) Spontaneous central melatonin secretion and resorption kinetics of exogenous melatonin: a ventricular CSF study. J Pineal Res 33:213–217
22. Dochi M, Suwazono Y, Sakata K, Okubo Y, Oishi M, Tanaka K, Kobayashi E, Nogawa K (2009) Shift work is a risk factor for increased cholesterol level: a 14-year prospective cohort study in 6886 male workers. Occup Environ Med 66:592–597
23. Dubocovich ML (2007) Melatonin receptors: role on sleep and circadian rhythm regulation. Sleep Med 8(Supplement 3):34–42
24. Dubocovich ML, Hudson RL, Sumaya IC, Masana MI, Manna E (2005) Effect of MT1 melatonin receptor deletion on melatonin-mediated phase shift of circadian rhythms in C57BL/6 mouse. J Pineal Res 39:113–120
25. Elliott HW, Sutherland VC (1952) The oxygen uptake of human cerebral cortex slices and the effects of some inhibitors. J Cell Physiol 40:221–241
26. Filipski E, Levi F (2009) Circadian disruption in experimental cancer processes. Integr Cancer Ther 8:298–302
27. Fonken LK, Aubrecht TG, Melendez-Fernandez OH, Weil ZM, Nelson RJ (2013) Dim light at night disturbs molecular circadian rhythms and increases body weight. J Biol Rhythms 28:262–271
28. Fulia F, Gitto E, Cuzzocrea S, Reiter RJ, Dugo L, Gitto P, Barberi S, Cordaro S, Barber I (2001) Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: reduction by melatonin. J Pineal Res 31:343–349
29. Galano A, Tan DX, Reiter RJ (2011) Melatonin as a natural ally against oxidative stress: a physicochemical examination. J Pineal Res 51:1–16
30. Galano A, Tan DX, Reiter RJ (2013) On the free radical scavenging activities of melatonin’s metabolites, AFMK and AMK. J Pineal Res 54:245–257
31. Gillette MU, McArthur AJ (1996) Circadian actions of melatonin at the suprachiasmatic nucleus. Behav Brain Res 73:135–138
32. Gitto E, Karbownik M, Reiter RJ, Tan DX, Cuzzocrea S, Chiurazzi P, Cordaro S, Corona G, Trimarchi G, Barberi I (2001) Effects of melatonin treatment in septic newborns. Pediatr Res 50:756–760
33. Hardeland R (2013) Melatonin and the theories of aging: a critical appraisal of melatonin’s role in anti-aging mechanisms. J Pineal Res 55:325–356
34. Hardeland R, Poeggeler B (2003) Non-vertebrate melatonin. J Pineal Res 34:233–241
35. Hardeland R, Madrid JA, Tan DX, Reiter RJ (2012) Melatonin, the circadian multioscillator system and health: the need for detailed analyses of peripheral melatonin signaling. J Pineal Res 52:139–166
36. Hedlund L, Lischko MM, Rollag MD, Niswender GD (1977) Melatonin: daily cycle in plasma and cerebrospinal fluid in calves. Science 195:686–687
37. Hoffman RA (1970) The epiphyseal complex of fish and reptiles. Am Zool 10:191–199
38. Hong Y, Palaksha JJ, Park K, Park S, Kim HD, Reiter RJ, Chang KT (2010) Melatonin plus exercise-based neurorehabilitative therapy for spinal cord injury. J Pineal Res 49:201–209
39. Hunt AE, Al-Ghoul WM, Gillete MJ, Dubocovich ML (2001) Activation of MT(2) melatonin receptors in rat suprachiasmatic nucleus phase advances the circadian clock. Am J Physiol Cell Physiol 260:C110–C118
40. Hutchinson AJ, Hudson RL, Dubocovich ML (2012) Genetic deletion of MT1 and MT2 melatonin receptors differentially abrogates the development and expression of methamphetamine-induced locomotor sensitization during the day and the night in C3H/HeN mice. J Pineal Res 53:399–409
41. Inyushkin AN, Bhumbra GS, Gonzalez JA, Dyball RE (2007) Melatonin modulates spike coding in the rat suprachiasmatic nucleus. J Neuroendocrinol 19:671–681
42. Jaychandra Babu R, Dayal PP, Pawar K, Singh M (2011) Nose-to-brain transport of melatonin from polymer gel suspension: a microdialysis study in rats. J Drug Target 19:731–740
43. Kanematsu N, Mori Y, Hayashi S, Hoshitio K (1989) Presence of a distinct 24-hour melatonin rhythm in the ventricular cerebrospinal fluid of the goat. J Pineal Res 7:143–152
44. Karlsson BH, Knutsson AK, Lindahle BO, Alfredsson LS (2003) Metabolic disturbances in male workers with rotating three-shift work. Results of the WOLF study. Int Arch Occup Environ Health 76:424–430
45. Kelleher FC, Rao A, Maguire A (2014) Circadian molecular clocks and cancer. Cancer Lett 342:9–18
46. Kilic U, Yilmaz B, Ugur M, Yuksel A, Reiter RJ, Hermann DM, Kilic E (2012) 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
47. Kilic U, Yilmaz B, Reiter RJ, Yuksel A, Kilic E (2013) Effects of memantine and melatonin on signal transduction pathways, vascular leakage and brain injury after focal cerebral ischemia in mice. Neuroscience 237:268–276
48. Knott AB, Perkins G, Schwarzenbacher R, Bossy-Wetzel E (2008) Mitochondrial fragmentation in neurodegeneration. Nat Rev Neurosci 9:505–518
49. Knowles F (1972) Ependyma of the third ventricle in relation to pituitary function. Prog Brain Res 38:355–370
50. Koh PO (2012) Melatonin attenuates decrease of protein phosphatase 2A subunit B in ischemic brain injury. J Pineal Res 52:57–61
51. Krstic R (1975) Scanning electron microscope observations on the canaliculi in the rat pineal gland. Experientia 31:1072–1073
52. Krstic RV (1979) Scanning electron microscopic study of the freeze-fractured pineal body of the rat. Cell Tissue Res 201:129–135
53. Kurtcuoglu V, Soellinger M, Summers P, Boomsma K, Poulikakos D, Boesiger P, Ventikos Y (2007) Computational investigation of subject-specific cerebrospinal fluid flow in the third ventricle and aqueduct of Sylvius. J Biomech 40:1235–1245
54. Kwee RM, Kwee TG (2007) Virchow–Robin spaces at MR imaging. Radiographics 27:1071–1086
55. Leston J, Harthe C, Brun J, Mottolese C, Mertens P, Sindou M, Claustrat B (2010) Melatonin is released in the third ventricle in humans: a study in movement disorders. Neurosci Lett 469:294–297
56. Liu C, Weaver DR, Jin X, Shearman LP, Pieschl RL, Gribkoff VK, Reppert SM (1997) Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron 19:91–102
57. Liu RY, Zhou JN, van Heerikhulze J, Hofman MA, Swaab DF (1999) Decreased melatonin levels in postmortem cerebrospinal in relation to aging, Alzheimer’s disease, and apolipoprotein E-epsilon 4/4 genotype. J Clin Endocrinol Metab 84:323–327
58. Liu J, Somera-Molina KC, Hudson RL, Dubocovich ML (2013) Melatonin potentials running wheel-induced neurogenesis in the dentate gyrus of adult C3H/HeN mice hippocampus. J Pineal Res 54:222–231
59. Lockley SW, Dijk DJ, Kosti O, Skene DJ, Arendt J (2008) Alertness, mood and performance rhythm disturbances associated with circadian sleep disorders in the blind. J Sleep Res 17:207–216
60. Longatti P, Perin A, Rizzo V, Comai S, Giusti P, Costa CV (2007) Ventricular cerebrospinal fluid melatonin concentrations investigated with an endoscopic technique. J Pineal Res 42:113–118
61. Lovell MA, Markesbery WR (2007) Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer’s disease. Nucleic Acids Res 35:7497–7504
62. Maldonado MD, Murillo-Cabezas F, Terron MP, Flores LJ, Tan DX, Manchester LC, Reiter RJ (2007) The potential of melatonin in reducing morbidity-mortality after craniocerebral trauma. J Pineal Res 42:1–11
63. Malpaux B, Thiery JC, Chemineau P (1999) Melatonin and the seasonal control of reproduction. Reprod Nutr Dev 39:355–366
64. Matsushima S, Sakai Y, Hira Y (1989) Twenty-four-hour changes in pinealocytes, capillary endothelial cells and pericapillary and intercellular spaces in the pineal gland of mouse: semiquantitative electron-microscopic observations. Cell Tissue Res 255:323–332
65. Matthew TC (2008) Regional analysis of the ependyma of the third ventricle of rat by light and electron microscopy. Anat Histol Embryol 37:9–18
66. Maurizi CP (1991) Recirculation of cerebrospinal fluid through the tela choroidea is why high levels of melatonin can be found in the lateral ventricles. Med Hypotheses 35:154–158
67. Maurizi CP (2010) Choroid plexus portals and a deficiency of melatonin can explain the neuropathology of Alzheimer’s disease. Med Hypotheses 74:1059–1066
68. Naskar A, Manivasagam T, Chakraborty J, Singh R, Thomas B, Dhanasekaran M, Mohanakumar KP (2013) Melatonin synergizes with low doses of l-DOPA to improve dendritic spine density in the mouse striatum in experimental Parkinsonism. J Pineal Res 55:304–312
69. Neikrug AB, Ancoli-Israel S (2010) Sleep disorders in the older adult—a mini-review. Gerontology 56:181–189
70. Pablos MI, Reiter RJ, Ortiz GG, Guerrero JM, Agapito MT, Chuang JI, Sewerynek E (1998) Rhythms of glutathione peroxidase and glutathione reductase in the brain of the chick and their inhibition by light. Neurochem Int 32:69–75
71. Pappolla MA, Sas 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 17:1670–1683
72. Park S, Lee SK, Park K, Lee Y, Hong Y, Lee S, Jeon JC, Kim JH, Lee SR, Chang KT, Hong Y (2012) Beneficial effects of endogenous and exogenous melatonin on neural reconstruction and functional recovery in an animal model of spinal cord injury. J Pineal Res 52:107–119
73. Paul MA, Gray GW, Lieberman HR, Love RJ, Miller JC, Trouborst M, Arendt J (2011) Phase advance with separate and combined melatonin and light treatment. Psychopharmacology 214:515–523
74. Pelham RW (1975) A serum melatonin rhythm in chickens and its abolition by pinealectomy. Endocrinology 96:543–546
75. Perlow MJ, Reppert SM, Tamarkin L, Wyatt RJ, Klein DL (1980) Photic regulation of the melatonin rhythm: monkey and man are not the same. Brain Res 182:211–216
76. Perlow MJ, Reppert SM, Boyar RM, Klein DC (1981) Daily rhythms in cortisol and melatonin in primate cerebrospinal fluid. Neuroendocrinology 32:193–196
77. Pevet P (2003) Melatonin: from seasonal to circadian signal. J Neuroendocrinol 15:1–5
78. Pevet P, Challet E (2011) Melatonin: both master clock output and internal time-giver in the circadian clocks network. J Physiol (Paris) 105:170–182
79. Picinato MC, Haber EP, Carpinelli AR, Cipolloa-Neto J (2002) Daily rhythms of glucose-induced insulin secretion by isolated islets from intact and pinealectomized rate. J Pineal Res 33:172–177
80. Poeggeler B, Balzer I, Hardeland R, Lerchl A (1991) Pineal hormone melatonin: oscillates also in the dinoflagellate Gonyaulax polyedra. Naturwissenschaften 78:268–269
81. Poeggeler B, Reiter RJ, Tan DX, Chen LD, Manchester LC (1993) Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis. J Pineal Res 14:141–168
82. Quay WB (1970) Endocrine aspects of the mammalian pineal gland. Am Zool 10:287–402
83. Quay WB (1973) Retrograde perfusion of the pineal region and the question of pineal vascular routes to the brain and choroid plexus. Am J Anat 137:387–402
84. Quay WB (1974) Pineal canaliculi: demonstration, twenty-four-hour rhythmicity and experimental modification. Am J Anat 139:81–93
85. Reiter RJ (1971) Physiologic role of the pineal gland. In: Foa PO (ed) The action of hormones. Charles Thomas, Springfield, pp 283–314
86. Reiter RJ (1986) Normal patterns of melatonin levels in the pineal gland and body fluids of humans and experimental animals. J Neural Transm 21(Supplement):35–54
87. Reiter RJ, Fraschini F (1969) Endocrine aspects of the mammalian pineal gland: a review. Neuroendocrinology 5:219–255
88. Reiter RJ, Tan DX (2003) What constitutes a physiological concentration of melatonin. J Pineal Res 34:79–80
89. Reiter RJ, Vaughan MK, Blask DE (1975) Possible role of the cerebrospinal fluid in the transport of pineal hormones in mammals. In: Knigge KM, Scott DE (eds) Brain-endocrine interaction II. Karger, Basel, pp 337–354
90. Reiter RJ, Cabrera J, Sainz RM, Mayos JC, Manchester LC, Tan DX (1999) Melatonin as a pharmacological agent against neuronal loss in experimental models of Huntington’s disease, Alzheimer’s disease and Parkinsonism. Ann NY Acad Sci 890:471–485
91. Reiter RJ, Acuna-Castroviejo D, Tan DX, Burkhardt S (2001) Free radical-mediated molecular damage: mechanisms for the protective actions of melatonin in the central nervous system. Am NY Acad Sci 939:200–215
92. Reiter RJ, Tan DX, Leon J, Kilic U, Kilic E (2005) When melatonin gets on your nerves: its beneficial actions in experimental models of stroke. Exp Biol Med 230:104–117
93. Reiter RJ, Tan DX, Manchester LC, Terron MP, Flores LJ, Koppisepi S (2007) Medical implications of melatonin: receptor-mediated and receptor-independent actions. Adv Med Sci 52:11–28
94. Reiter RJ, Tan DX, Rosales-Corral SA, Manchester LC (2013) The universal nature, unequal distribution and antioxidant functions of melatonin and its derivatives. Mini-Rev Med Chem 13:373–384
95. Rennels ML, Gregory TF, Blaumanis OR, Fujimoto K, Grady PA (1985) Evidence for a “paravascular” fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space. Brain Res 326:47–63
96. Reppert SM, Perlow MJ, Tamarkin L, Orloff D, Klein DC (1981) The effects of environmental lighting on the daily melatonin rhythm in primate cerebrospinal fluid. Brain Res 223:313–323
97. Riederer BM, Leuba G, ElHajj Z (2013) Oxidation and ubiquitination in neurodegeneration. Exp Biol Med 238:519–524
98. Rodriguez 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
99. Rodriguez EM, Blazquez JL, Pastor FE, Pelaez B, Pena P, Peruzzo B, Amat P (2005) Hypothalamic tanycytes: a key component of brain-endocrine interaction. Int Rev Cytol 247:89–164
100. Roopin M, Yacobi YZ, Levy O (2013) Occurrence, diel patterns, and the influence of melatonin on the photosynthetic performance of cultured Symbiodinium. J Pineal Res 55:89–100
101. Rosales-Corral SA, Acuna-Castroveijo D, Cato-Montes A, Boga JA, Manchester LC, Fuentes-Broto L, Korkmaz A, Ma S, Tan DX, Reiter RJ (2012) Alzheimer’s disease: pathological mechanisms and the beneficial role of melatonin. J Pineal Res 52:167–202
102. Rousseau A, Petren S, Plannthin J, Eklundh T, Nordin C (1999) Serum and cerebrospinal fluid concentrations of melatonin: a pilot study in healthy male volunteers. J Neural Transm 106:883–888
103. Santhi N, Thorne HC, van der Veen DR, Johnson S, Mills SC, Hommes V, Schlangen LJM, Archer SN, Dijk DJ (2012) The spectral composition of evening light and individual differences in the suppression of melatonin and delay of sleep in humans. J Pineal Res 53:47–59
104. Saper CB (2013) The central circadian timing system. Curr Opin Neurobiol 23:747–751
105. Scheinberg P (1950) Simultaneous bilateral determinations of cerebral blood flow and arterial-cerebral venous oxygen and glucose differences. Proc Soc Exp Biol Med 74:575–578
106. Schroeder AM, Colwell CS (2013) How to fix a broken clock. Trends Pharmacol Sci 34:605–619
107. Scott FF, Belle MD, Delagrange P, Piggins HD (2010) Electrophysiological effects of melatonin on mouse Per1 and non-Per1 suprachiasmatic nuclei neurones in vitro. J Neuroendocrinol 22:1148–1156
108. Seifman MA, Adamides AA, Nguyen PN, Vallance SA, Cooper DJ, Kossman T, Rosenfeld JV, Morganti-Kossman MC (2008) Endogenous melatonin increases in cerebrospinal fluid of patients after severe traumatic brain injury and correlates with oxidative stress and metabolic disarray. J Cereb Blood Flow Metab 28:684–696
109. Shaw PF, Kennaway DJ, Seamark RF (1989) Evidence of high concentrations of melatonin in lateral ventricular cerebrospinal fluid of sheep. J Pineal Res 6:201–208
110. Sheridan MN, Reiter RJ (1970) Observations on the pineal system of the hamster. I. Relationship of the superficial and deep pineal to the epithalamus. J Morphol 131:153–161
111. Sheridan MN, Reiter RJ, Jacobs JJ (1969) An interesting anatomical relationship between the hamster pineal gland and the ventricular system of the brain. J Endocr 45:131–132
112. 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
113. Skinner DC, Malpaux B (1999) High melatonin concentrations in third ventricular cerebrospinal fluid are not due to Galen vein blood recirculating through the choroid plexus. Endocrinology 140:4399–4405
114. Symington RB, Hayes MMM, Knight BK, Grizic A (1973) Histological studies of the ependymal cells of the human third ventricle. S Afr Med J 47:2273–2278
115. Tan DX, Chen LD, Poeggeler B, Manchester LC, Reiter RJ (1993) Melatonin: a potent, endogenous hydroxyl radical scavenger. Endocr J 1:57–60
116. Tan DX, Reiter RJ, Manchester LC, Yan MT, El-Sawi M, Sainz RM, Mayo JC, Kohen R, Allegra M, Hardeland R (2002) Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2:181–198
117. Tan DX, Manchester LC, Sanchez-Barcelo E, Mediavilla MD, Reiter RJ (2010a) Significance of high levels of endogenous melatonin in mammalian cerebrospinal fluid and in the central nervous system. Curr Neuropharmacol 8:163–167
118. Tan DX, Hardeland R, Manchester LC, Paredes SD, Korkmaz A, Sainz RM, Mayo JC, Fuentes-Broto L, Reiter RJ (2010b) The changing biological roles of melatonin during evolution: from an antioxidant to signals of darkness, sexual selection and fitness. Biol Rev Camb Philos Soc 85:607–623
119. Tolleson CM, Feng JY (2013) Advances in the mechanisms of Parkinson’s disease. Discov Med 15:61–66
120. Tombaugh GC, Sapolsky RM (1993) Evolving concepts about the role of acidosis in ischemic neuropathology. J Neurochem 61:793–803
121. Tricoire H, Locatelli A, Chemineau P, Malpaux B (2002) Melatonin enters the cerebrospinal fluid through the pineal recess. Endocrinology 143:84–90
122. Tricoire H, Malpaux B, Moller M (2003) Cellular lining of the sheep pineal recess studied by light-, transmission-, and scanning electron microscopy: morphologic indications for a direct secretion of melatonin from the pineal gland to the cerebrospinal fluid. J Comp Neurol 456:39–47
123. Tsutsumi S, Ito M, Yasumoto Y, Tabuchi T, Ogino I (2011) The Virchow–Robins spaces: delineation by magnetic resonance imaging with consideration on anatomofunctional implications. Childs Nerv Syst 27:2057–2066
124. Tu PH, Gurney ME, Julien JP, Lee VM, Trojanowski JQ (1997) Oxidative stress, mutant SOD1, and neurofilament pathology in transgenic mouse models of human motor neurone disease. Lab Investig 76:441–450
125. Van den Berg MP, Merkus P, Romeijn SG, Verhoef JC, Merkus FW (2004) Uptake of melatonin into the cerebrospinal fluid after nasal and intravenous delivery: studies in rats in comparison with a human study. Pharm Res 21:799–802
126. Vaughan GM, Pelham RW, Pang SF, Laughlin LL, Wilson KW, Sandock KL, Vaughan MK, Koslow SH, Reiter RJ (1976) Nocturnal elevation of plasma melatonin and urinary 5-hydroxyindole-acetic acid in young men: attempts at modification by brief changes in environmental lighting and sleep and by autonomic drugs. J Clin Endocrinol Metab 42:752–764
127. Venegas C, Garcia JA, Escames G, Ortiz F, Lopez A, Doerrier L, Garcia-Corzo L, Lopez LC, Reiter RJ, Acuna-Castroviejo D (2012) Extrapineal melatonin: analysis of its subcellular distribution and daily fluctuations. J Pineal Res 52:217–227
128. Vitte PA, Harthe C, Lestage P, Claustrat B, Bobillier P (1988) Plasma, cerebrospinal fluid, and brain distribution of 14C-melatonin in rat: a biochemical and autoradiographic study. J Pineal Res 5:437–453
129. Vollrath L (1981) The pineal organ. Springer, Berlin
130. von Bernhardi R, Tichauer JE, Eugenin J (2010) Aging-dependent changes in microglial cells and their relevance for neurodegenerative disorders. J Neurochem 112:1099–1114
131. Wagner HJ, Pilgrim CH, Bradl J (1974) Penetration and removal of horseradish peroxidase injected into the cerebrospinal fluid: role of cerebral perivascular spaces, endothelium and microglia. Acta Neuropathol 27:299–315
132. Wang X, Figueroa BE, Stavrovskaya IG, Zhang Y, Sirianni AC, Zhu S, Day RL, Kristal BS, Friedlander RM (2009) Methazolamide and melatonin inhibit mitochondrial cytochrome C release and are neuroprotective in experimental models of ischemic injury. Stroke 40:1877–1885
133. Wang X, Sirianni A, Pei Z, Cormier K, Smith K, Jaing 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
134. Wang Z, Liu D, Wang J, Liu S, Gao M, Ling EA, Hao A (2012) Cytoprotective effects of melatonin astroglial cells subjected to palmitic acid treatment in vitro. J Pineal Res 52:253–264
135. 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
136. Wolff G, Duncan MJ, Esser KA (2013) Chronic phase advance alters circadian physiological rhythms and peripheral molecular clocks. J Appl Physiol 115:373–382
137. Yoo DY, Kim W, Lee CH, Shin BN, Nam SM, Choi JH, Won MH, Yoon YS, Hwang IK (2012) Melatonin improves d-galactose-induced aging effects on behavior, neurogenesis, and lipid peroxidation in the mouse dentate gyrus via increasing pCREB expression. J Pineal Res 52:21–28
138. Young SN, Gauthier S, Kiely ME, Lai S, Brown GM (1984) Effect of oral melatonin administration on melatonin, 5-hydroxyindoleacetic acid, indoleacetic acid, and cyclic nucleotides in human cerebrospinal fluid. Neuroendocrinology 39:87–92
139. Yun HY, Dawson VL, Dawson TM (1996) Neurobiology of NO·. Crit Rev Neurobiol 10:291–316
140. Zhang ET, Inman CB, Weller RO (1990) Interrelationships of the pia mater and the perivascular (Virchow–Robin) spaces in the human cerebrum. J Anat 170:111–123
141. Zhang Y, Cook A, Kim J, Baranov SV, Jiang J, Smith K, Cormier K, Bennett E, Browser RP, Day DL, Carlisle DL, Ferrante RJ, Wang X, Friedlander RM (2013a) Melatonin inhibits the caspase-1/cytochrome c/caspase-3 cell death pathway, inhibits MT1 receptor loss and delays disease progression in a mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 55:26–35
142. Zhang Y, Liu Q, Wang F, Liu S, Wang L, Yang Y, Yao L, Chen X, Wang F, Shi W, Gao M, Hao A (2013b) Melatonin antagonizes hypoxia-mediated glioblastoma cell migration and invasion via inhibition of HIF-1α. J Pineal Res 55:121–130
143. Zhao Y, Zhao B (2012) Natural antioxidants in prevention and management of Alzheimer’s disease. Front Biosci 4:794–808
144. 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 32:125–136