Consequences of iron accumulation in microglia and its implications in neuropathological conditions

CNS and Neurological Disorders - Drug Targets

Volumn 12, Issue 6, 2013, Pages 785-798

  Rathnasamy, Gurugirijha ^a   Ling, Eng Ang ^a   Kaur, Charanjit ^a  

^a NATIONAL UNIVERSITY OF SINGAPORE   (Singapore)

Author keywords

Free radicals; Inflammatory cytokines; Iron accumulation; Iron chelators; Iron transport; Microglia

Indexed keywords

GAMMA INTERFERON; INTERLEUKIN 1BETA; NATURAL RESISTANCE ASSOCIATED MACROPHAGE PROTEIN 2; TRANSFERRIN RECEPTOR; TUMOR NECROSIS FACTOR ALPHA;

5' UNTRANSLATED REGION; ALZHEIMER DISEASE; BLOOD BRAIN BARRIER; BRAIN HEMORRHAGE; DEMYELINATING DISEASE; DOWN REGULATION; HUMAN; IRON RESPONSIVE ELEMENT; IRON TRANSPORT; LIPID PEROXIDATION; LIVER CELL; MICROGLIA; NERVE DEGENERATION; NEUROPATHOLOGY; NEUROPROTECTION; NONHUMAN; OLIGODENDROGLIA; OXIDATIVE STRESS; PARKINSON DISEASE; PROTEIN EXPRESSION; PROTEIN PHOSPHORYLATION; REVIEW; UBIQUITINATION; UPREGULATION; WHITE MATTER INJURY;

ANIMALS; BIOLOGICAL TRANSPORT; BRAIN; CYTOKINES; HUMANS; IRON; IRON CHELATING AGENTS; MICROGLIA; NEURODEGENERATIVE DISEASES;

EID: 84888068219     PISSN: 18715273     EISSN: 19963181     Source Type: Journal    
DOI: 10.2174/18715273113126660169     Document Type: Review

References (169)

1. Pinero, D.J.; Connor, J.R. Iron in the Brain: An Important Contributor in Normal and Diseased States. Neuroscientist, 2000, 6(6), 435-453.
2. Beard, J. Iron deficiency alters brain development and functioning. J. Nutrition, 2003, 133(5 Suppl 1), 1468S-1472S.
3. Lozoff, B.; Georgieff, M.K. Iron deficiency and brain development. Semin. Pediatr. Neurol., 2006, 13(3), 158-165.
4. Halliwell, B. Use of desferrioxamine as a 'probe' for iron-dependent formation of hydroxyl radicals. Evidence for a direct reaction between desferal and the superoxide radical. Biochem. Pharmacol., 1985, 34(2), 229-233.
5. Halliwell, B. Reactive oxygen species and the central nervous system. J. Neurochem., 1992, 59(5), 1609-1623.
6. Oshiro, S.; Morioka, M.S.; Kikuchi, M. Dysregulation of iron metabolism in Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Adv. Pharmacol. Sci., 2011, 2011, 378278.
7. Kaur, C.; Dheen, S.T.; Ling, E.-A. From blood to brain: amoeboid microglial cell, a nascent macrophage and its functions in developing brain. Acta Pharmacol. Sin., 2007, 28(8), 1087-1096.
8. Checchin, D.; Sennlaub, F.; Levavasseur, E.; Leduc, M.; Chemtob, S. Potential role of microglia in retinal blood vessel formation. Invest. Ophthalmol. Vis. Sci., 2006, 47(8), 3595-3602.
9. Paolicelli, R.C.; Bolasco, G.; Pagani, F.; Maggi, L.; Scianni, M.; Panzanelli, P.; Giustetto, M.; Ferreira, T.A.; Guiducci, E.; Dumas, L.; Ragozzino, D.; Gross, C.T. Synaptic pruning by microglia is necessary for normal brain development. Science, 2011, 333(6048), 1456-1458.
10. Hamilton, S.P.; Rome, L.H. Stimulation of in vitro myelin synthesis by microglia. Glia, 1994, 11(4), 326-335.
11. Imamoto, K.; Leblond, C.P. Radioautographic investigation of gliogenesis in the corpus callosum of young rats. II. Origin of microglial cells. J Compar. Neurol., 1978, 180(1), 139-163.
12. Nimmerjahn, A.; Kirchhoff, F.; Helmchen, F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science, 2005, 308(5726), 1314-1318.
13. Vinet, J.; Weering, H.R.J.V.; Heinrich, A.; Kälin, R.E.; Wegner, A.; Brouwer, N.; Heppner, F.L.; Rooijen, N.V.; Boddeke, H.W.G.M.; Biber, K. Neuroprotective function for ramified microglia in hippocampal excitotoxicity. J. Neuroinflammation, 2012, 9, 27.
14. Ling, E.A.; Ng, Y.K.; Wu, C.H.; Kaur, C. Microglia: its development and role as a neuropathology sensor. Prog. Brain Res., 2001, 132, 61-79.
15. Davalos, D.; Grutzendler, J.; Yang, G.; Kim, J.V.; Zuo, Y.; Jung, S.; Littman, D.R.; Dustin, M.L.; Gan, W.-B. ATP mediates rapid microglial response to local brain injury in vivo. Nat. Neurosci., 2005, 8(6), 752-758.
16. Zhang, X.; Surguladze, N.; Slagle-Webb, B.; Cozzi, A.; Connor, J.R. Cellular iron status influences the functional relationship between microglia and oligodendrocytes. Glia, 2006, 54(8), 795-804.
17. Han, J.; Day, J.R.; Connor, J.R.; Beard, J.L. H and L ferritin subunit mRNA expression differs in brains of control and irondeficient rats. J. Nutrition, 2002, 132(9), 2769-2774.
18. Connor, J.R.; Boeshore, K.L.; Benkovic, S.A.; Menzies, S.L. Isoforms of ferritin have a specific cellular distribution in the brain. J. Neurosci. Res., 1994, 37(4), 461-465.
19. Cheepsunthorn, P.; Palmer, C.; Connor, J.R. Cellular distribution of ferritin subunits in postnatal rat brain. J. Compar. Neurol., 1998, 400(1), 73-86.
20. Kaur, C.; Ling, E.A. Increased expression of transferrin receptors and iron in amoeboid microglial cells in postnatal rats following an exposure to hypoxia. Neurosci. Lett., 1999, 262(3), 183-186.
21. McKie, A.T.; Barrow, D.; Latunde-Dada, G.O.; Rolfs, A.; Sager, G.; Mudaly, E.; Mudaly, M.; Richardson, C.; Barlow, D.; Bomford, A.; Peters, T.J.; Raja, K.B.; Shirali, S.; Hediger, M.A.; Farzaneh, F.; Simpson, R.J. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science, 2001, 291(5509), 1755-1759.
22. Knöpfel, M.; Solioz, M. Characterization of a cytochrome b(558) ferric/cupric reductase from rabbit duodenal brush border membranes. Biochem. Biophys. Res. Commun., 2002, 291(2), 220-225.
23. Latunde-Dada, G.O.; Simpson, R.J.; McKie, A.T. Duodenal cytochrome B expression stimulates iron uptake by human intestinal epithelial cells. J. Nutrition, 2008, 138(6), 991-995.
24. Gunshin, H.; Mackenzie, B.; Berger, U.V.; Gunshin, Y.; Romero, M.F.; Boron, W.F.; Nussberger, S.; Gollan, J.L.; Hediger, M.A. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature, 1997, 388(6641), 482-488.
25. Donovan, A.; Brownlie, A.; Zhou, Y.; Shepard, J.; Pratt, S.J.; Moynihan, J.; Paw, B.H.; Drejer, A.; Barut, B.; Zapata, A.; Law, T.C.; Brugnara, C.; Lux, S.E.; Pinkus, G.S.; Pinkus, J.L.; Kingsley, P.D.; Palis, J.; Fleming, M.D.; Andrews, N.C.; Zon, L.I. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature, 2000, 403(6771), 776-781.
26. Vulpe, C.D.; Kuo, Y.M.; Murphy, T.L.; Cowley, L.; Askwith, C.; Libina, N.; Gitschier, J.; Anderson, G.J. Hephaestin, a ceruloplasmin homologue implicated in intestinal iron transport, is defective in the sla mouse. Nat. Genet., 1999, 21(2), 195-199.
27. Harris, Z.L.; Durley, A.P.; Man, T.K.; Gitlin, J.D. Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc. Natl. Acad. Sci. USA, 1999, 96(19), 10812-10817.
28. De Domenico, I.; McVey Ward, D.; Kaplan, J. Regulation of iron acquisition and storage: consequences for iron-linked disorders. Nat. Rev. Mol. Cell Biol., 2008, 9(1), 72-81.
29. Takahashi, K.; Tavassoli, M. Internalization of iron-transferrin complex by murine L1210 leukemia cells and rat reticulocytes demonstrated by a minibead probe. J. Ultrastruct. Res., 1983, 82(3), 314-321.
30. Bucci, C.; Parton, R.G.; Mather, I.H.; Stunnenberg, H.; Simons, K.; Hoflack, B.; Zerial, M. The small GTPase rab5 functions as a regulatory factor in the early endocytic pathway. Cell, 1992, 70(5), 715-728.
31. Chavrier, P.; Parton, R.G.; Hauri, H.P.; Simons, K.; Zerial, M. Localization of low molecular weight GTP binding proteins to exocytic and endocytic compartments. Cell, 1990, 62(2), 317-329.
32. Ohgami, R.S.; Campagna, D.R.; Greer, E.L.; Antiochos, B.; McDonald, A.; Chen, J.; Sharp, J.J.; Fujiwara, Y.; Barker, J.E.; Fleming, M.D. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nat. Genet., 2005, 37(11), 1264-1269.
33. Trischler, M.; Stoorvogel, W.; Ullrich, O. Biochemical analysis of distinct Rab5-and Rab11-positive endosomes along the transferrin pathway. J. Cell Sci., 1999, 112(Pt 24), 4773-4783.
34. Shaw, G.C.; Cope, J.J.; Li, L.; Corson, K.; Hersey, C.; Ackermann, G.E.; Gwynn, B.; Lambert, A.J.; Wingert, R.A.; Traver, D.; Trede, N.S.; Barut, B.A.; Zhou, Y.; Minet, E.; Donovan, A.; Brownlie, A.; Balzan, R.; Weiss, M.J.; Peters, L.L.; Kaplan, J.; Zon, L.I.; Paw, B.H. Mitoferrin is essential for erythroid iron assimilation. Nature, 2006, 440(7080), 96-100.
35. MacKenzie, E.L.; Iwasaki, K.; Tsuji, Y. Intracellular iron transport and storage: from molecular mechanisms to health implications. Antioxidants Redox Signal., 2008, 10(6), 997-1030.
36. Gunshin, H.; Fujiwara, Y.; Custodio, A.O.; Direnzo, C.; Robine, S.; Andrews, N.C. Slc11a2 is required for intestinal iron absorption and erythropoiesis but dispensable in placenta and liver. J. Clin. Invest., 2005, 115(5), 1258-1266.
37. Dong, X.-P.; Cheng, X.; Mills, E.; Delling, M.; Wang, F.; Kurz, T.; Xu, H. The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel. Nature, 2008, 455(7215), 992-996.
38. Puertollano, R.; Kiselyov, K. TRPMLs: in sickness and in health. Am. J. Physiol. Renal Physiol., 2009, 296(6), F1245-1254.
39. Jabado, N.; Jankowski, A.; Dougaparsad, S.; Picard, V.; Grinstein, S.; Gros, P. Natural resistance to intracellular infections: natural resistance-associated macrophage protein 1 (Nramp1) functions as a pH-dependent manganese transporter at the phagosomal membrane. J. Exp. Med., 2000, 192(9), 1237-1248.
40. Andrews, N.C.; Levy, J.E. Iron is hot: an update on the pathophysiology of hemochromatosis. Blood, 1998, 92(6), 1845-1851.
41. Wang, C.-Y.; Jenkitkasemwong, S.; Duarte, S.; Sparkman, B.; Shawki, A.; Mackenzie, B.; Knutson, M.D. ZIP8 Is an Iron and Zinc Transporter Whose Cell-surface Expression Is Upregulated by Cellular Iron Loading. J. Biol. Chem., 2012.
42. Mills, E.; Dong, X.-P.; Wang, F.; Xu, H. Mechanisms of brain iron transport: insight into neurodegeneration and CNS disorders. Fut. Med. Chem., 2010, 2(1), 51-64.
43. Swaiman, K.F.; Machen, V.L. Iron uptake by mammalian cortical neurons. Ann. Neurol., 1984, 16(1), 66-70.
44. Pelizzoni, I.; Zacchetti, D.; Smith, C.P.; Grohovaz, F.; Codazzi, F. Expression of divalent metal transporter 1 in primary hippocampal neurons: reconsidering its role in non-transferrin-bound iron influx. J. Neurochem., 2012, 120(2), 269-278.
45. Salazar, J.; Mena, N.; Hunot, S.; Prigent, A.; Alvarez-Fischer, D.; Arredondo, M.; Duyckaerts, C.; Sazdovitch, V.; Zhao, L.; Garrick, L.M.; Nuñez, M.T.; Garrick, M.D.; Raisman-Vozari, R.; Hirsch, E.C. Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease. Proc. Natl. Acad. Sci. USA, 2008, 105(47), 18578-18583.
46. Ganz, T. Iron homeostasis: fitting the puzzle pieces together. Cell Metab., 2008, 7(4), 288-290.
47. Ganz, T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood, 2003, 102(3), 783-788.
48. De Domenico, I.; Ward, D.M.; Kaplan, J. Hepcidin regulation: ironing out the details. J. Clin. Invest., 2007, 117(7), 1755-1758.
49. Nemeth, E.; Tuttle, M.S.; Powelson, J.; Vaughn, M.B.; Donovan, A.; Ward, D.M.; Ganz, T.; Kaplan, J. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science, 2004, 306(5704), 2090-2093.
50. Rivera, S.; Nemeth, E.; Gabayan, V.; Lopez, M.A.; Farshidi, D.; Ganz, T. Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs. Blood, 2005, 106(6), 2196-2199.
51. Iwai, K.; Klausner, R.D.; Rouault, T.A. Requirements for ironregulated degradation of the RNA binding protein, iron regulatory protein 2. EMBO J., 1995, 14(21), 5350-5357.
52. Hirling, H.; Henderson, B.R.; Kühn, L.C. Mutational analysis of the [4Fe-4S]-cluster converting iron regulatory factor from its RNA-binding form to cytoplasmic aconitase. EMBO J., 1994, 13(2), 453-461.
53. Thomson, A.M.; Rogers, J.T.; Leedman, P.J. Iron-regulatory proteins, iron-responsive elements and ferritin mRNA translation. Intl. J. Biochem. Cell Biol., 1999, 31(10), 1139-1152.
54. Vashisht, A.A.; Zumbrennen, K.B.; Huang, X.; Powers, D.N.; Durazo, A.; Sun, D.; Bhaskaran, N.; Persson, A.; Uhlen, M.; Sangfelt, O.; Spruck, C.; Leibold, E.A.; Wohlschlegel, J.A. Control of iron homeostasis by an iron-regulated ubiquitin ligase. Science, 2009, 326(5953), 718-721.
55. Salahudeen, A.A.; Thompson, J.W.; Ruiz, J.C.; Ma, H.-W.; Kinch, L.N.; Li, Q.; Grishin, N.V.; Bruick, R.K. An E3 ligase possessing an iron-responsive hemerythrin domain is a regulator of iron homeostasis. Science, 2009, 326(5953), 722-726.
56. Moos, T.; Rosengren Nielsen, T.; Skjørringe, T.; Morgan, E.H. Iron trafficking inside the brain. J. Neurochem., 2007, 103(5), 1730-1740.
57. Bradbury, M.W. Transport of iron in the blood-brain-cerebrospinal fluid system. J. Neurochem., 1997, 69(2), 443-454.
58. Wu, L.J.-C.; Leenders, A.G.M.; Cooperman, S.; Meyron-Holtz, E.; Smith, S.; Land, W.; Tsai, R.Y.L.; Berger, U.V.; Sheng, Z.-H.; Rouault, T.A. Expression of the iron transporter ferroportin in synaptic vesicles and the blood-brain barrier. Brain Res., 2004, 1001(1-2), 108-117.
59. Jeong, S.Y.; David, S. Glycosylphosphatidylinositol-anchored ceruloplasmin is required for iron efflux from cells in the central nervous system. J. Biol. Chem., 2003, 278(29), 27144-27148.
60. Rouault, T.A.; Cooperman, S. Brain iron metabolism. Semin. Pediatr. Neurol., 2006, 13(3), 142-148.
61. Beard, J.L.; Wiesinger, J.A.; Li, N.; Connor, J.R. Brain iron uptake in hypotransferrinemic mice: influence of systemic iron status. J. Neurosci. Res., 2005, 79(1-2), 254-261.
62. Fillebeen, C.; Descamps, L.; Dehouck, M.P.; Fenart, L.; Benaïssa, M.; Spik, G.; Cecchelli, R.; Pierce, A. Receptor-mediated transcytosis of lactoferrin through the blood-brain barrier. J. Biol. Chem., 1999, 274(11), 7011-7017.
63. Rothenberger, S.; Food, M.R.; Gabathuler, R.; Kennard, M.L.; Yamada, T.; Yasuhara, O.; McGeer, P.L.; Jefferies, W.A. Coincident expression and distribution of melanotransferrin and transferrin receptor in human brain capillary endothelium. Brain Res., 1996, 712(1), 117-121.
64. Richardson, D.R.; Ponka, P. The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells. Biochim. Biophys. Acta, 1997, 1331(1), 1-40.
65. Takeda, A.; Devenyi, A.; Connor, J.R. Evidence for nontransferrin-mediated uptake and release of iron and manganese in glial cell cultures from hypotransferrinemic mice. J. Neurosci. Res., 1998, 51(4), 454-462.
66. Bennett, M.V.L.; Contreras, J.E.; Bukauskas, F.F.; Sáez, J.C. New roles for astrocytes: gap junction hemichannels have something to communicate. Trends Neurosci., 2003, 26(11), 610-617.
67. Li, J.Y.; Paragas, N.; Ned, R.M.; Qiu, A.; Viltard, M.; Leete, T.; Drexler, I.R.; Chen, X.; Sanna-Cherchi, S.; Mohammed, F.; Williams, D.; Lin, C.S.; Schmidt-Ott, K.M.; Andrews, N.C.; Barasch, J. Scara5 is a ferritin receptor mediating non-transferrin iron delivery. Dev. Cell, 2009, 16(1), 35-46.
68. Todorich, B.; Zhang, X.; Slagle-Webb, B.; Seaman, W.E.; Connor, J.R. Tim-2 is the receptor for H-ferritin on oligodendrocytes. J. Neurochem., 2008, 107(6), 1495-1505.
69. Dobbing, J. Undernutrition and the developing brain. The relevance of animal models to the human problem. Bibl. Nutr. Dieta, 1972, (17), 35-46.
70. Hallgren, B.; Sourander, P. The effect of age on the non-haemin iron in the human brain. J. Neurochem., 1958, 3(1), 41-51.
71. Bartzokis, G.; Beckson, M.; Hance, D.B.; Marx, P.; Foster, J.A.; Marder, S.R. MR evaluation of age-related increase of brain iron in young adult and older normal males. Magn. Reson. Imaging, 1997, 15(1), 29-35.
72. Roskams, A.J.; Connor, J.R. Iron, transferrin, and ferritin in the rat brain during development and aging. J. Neurochem., 1994, 63(2), 709-716.
73. Taylor, E.M.; Morgan, E.H. Developmental changes in transferrin and iron uptake by the brain in the rat. Brain Res. Dev. Brain Res., 1990, 55(1), 35-42.
74. Beard, J.L.; Connor, J.D.; Jones, B.C. Brain iron: location and function. Prog. Food Nutr. Sci., 1993, 17(3), 183-221.
75. Erikson, K.M.; Jones, B.C.; Hess, E.J.; Zhang, Q.; Beard, J.L. Iron deficiency decreases dopamine D1 and D2 receptors in rat brain. Pharmacol. Biochem. Behav., 2001, 69(3-4), 409-418.
76. Morse, A.C.; Beard, J.L.; Jones, B.C. A genetic developmental model of iron deficiency: biological aspects. Proc. Soc. Exper. Biol. Med. Soc. Exp. Biol. Med., 1999, 220(3), 147-152.
77. Cammer, W. Oligodendrocyte associated enzymes. In: Oligodendroglia; Norton WT, Ed.; Plenum Press: New York, 1984, pp. 199-232.
78. Oexle, H.; Gnaiger, E.; Weiss, G. Iron-dependent changes in cellular energy metabolism: influence on citric acid cycle and oxidative phosphorylation. Biochim. Biophys. Acta, 1999, 1413(3), 99-107.
79. de Deungria, M.; Rao, R.; Wobken, J.D.; Luciana, M.; Nelson, C.A.; Georgieff, M.K. Perinatal iron deficiency decreases cytochrome c oxidase (CytOx) activity in selected regions of neonatal rat brain. Pediatr. Res., 2000, 48(2), 169-176.
80. Beard, J.L.; Felt, B.; Schallert, T.; Burhans, M.; Connor, J.R.; Georgieff, M.K. Moderate iron deficiency in infancy: biology and behavior in young rats. Behav. Brain Res., 2006, 170(2), 224-232.
81. Felt, B.T.; Lozoff, B. Brain iron and behavior of rats are not normalized by treatment of iron deficiency anemia during early development. J. Nutrition, 1996, 126(3), 693-701.
82. McEchron, M.D.; Cheng, A.Y.; Liu, H.; Connor, J.R.; Gilmartin, M.R. Perinatal nutritional iron deficiency permanently impairs hippocampus-dependent trace fear conditioning in rats. Nutr. Neurosci., 2005, 8(3), 195-206.
83. Jorgenson, L.A.; Wobken, J.D.; Georgieff, M.K. Perinatal iron deficiency alters apical dendritic growth in hippocampal CA1 pyramidal neurons. Dev. Neurosci., 2003, 25(6), 412-420.
84. Jorgenson, L.A.; Sun, M.; O'Connor, M.; Georgieff, M.K. Fetal iron deficiency disrupts the maturation of synaptic function and efficacy in area CA1 of the developing rat hippocampus. Hippocampus, 2005, 15(8), 1094-1102.
85. Benkovic, S.A.; Connor, J.R. Ferritin, transferrin, and iron in selected regions of the adult and aged rat brain. J. Comp. Neurol., 1993, 338(1), 97-113.
86. Connor, J.R.; Menzies, S.L. Altered cellular distribution of iron in the central nervous system of myelin deficient rats. Neuroscience, 1990, 34(1), 265-271.
87. LeVine, S.M. Oligodendrocytes and myelin sheaths in normal, quaking and shiverer brains are enriched in iron. J. Neurosci. Res., 1991, 29(3), 413-419.
88. Nicholas, R.S.; Wing, M.G.; Compston, A. Nonactivated microglia promote oligodendrocyte precursor survival and maturation through the transcription factor NF-kappa B. Eur. J. Neurosci., 2001, 13(5), 959-967.
89. Diemel, L.T.; Copelman, C.A.; Cuzner, M.L. Macrophages in CNS remyelination: friend or foe? Neurochem. Res., 1998, 23(3), 341-347.
90. Lehnardt, S.; Lachance, C.; Patrizi, S.; Lefebvre, S.; Follett, P.L.; Jensen, F.E.; Rosenberg, P.A.; Volpe, J.J.; Vartanian, T. The tolllike receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J. Neurosci., 2002, 22(7), 2478-2486.
91. Rathore, K.I.; Redensek, A.; David, S. Iron homeostasis in astrocytes and microglia is differentially regulated by TNF-α and TGF-β1. Glia, 2012, 60(5), 738-750.
92. Saleppico, S.; Mazzolla, R.; Boelaert, J.R.; Puliti, M.; Barluzzi, R.; Bistoni, F.; Blasi, E. Iron regulates microglial cell-mediated secretory and effector functions. Cell. Immunol., 1996, 170(2), 251-259.
93. Wang, J.; Doré, S. Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage. Brain, 2007, 130(Pt 6), 1643-1652.
94. Min, K.-J.; Yang, M.-S.; Kim, S.-U.; Jou, I.; Joe, E.-h. Astrocytes induce hemeoxygenase-1 expression in microglia: a feasible mechanism for preventing excessive brain inflammation. J. Neurosci., 2006, 26(6), 1880-1887.
95. Yoshida, T.; Tanaka, M.; Sotomatsu, A.; Hirai, S. Activated microglia cause superoxide-mediated release of iron from ferritin. Neurosci. Lett., 1995, 190(1), 21-24.
96. Smith, M.A.; Harris, P.L.; Sayre, L.M.; Perry, G. Iron accumulation in Alzheimer disease is a source of redox-generated free radicals. Proc. Natl. Acad. Sci. USA, 1997, 94(18), 9866-9868.
97. Connor, J.R.; Menzies, S.L.; St Martin, S.M.; Mufson, E.J. A histochemical study of iron, transferrin, and ferritin in Alzheimer's diseased brains. J. Neurosci. Res., 1992, 31(1), 75-83.
98. Jefferies, W.A.; Food, M.R.; Gabathuler, R.; Rothenberger, S.; Yamada, T.; Yasuhara, O.; McGeer, P.L. Reactive microglia specifically associated with amyloid plaques in Alzheimer's disease brain tissue express melanotransferrin. Brain Res., 1996, 712(1), 122-126.
99. Yamada, T.; Tsujioka, Y.; Taguchi, J.; Takahashi, M.; Tsuboi, Y.; Moroo, I.; Yang, J.; Jefferies, W.A. Melanotransferrin is produced by senile plaque-associated reactive microglia in Alzheimer's disease. Brain Res., 1999, 845(1), 1-5.
100. Mairuae, N.; Connor, J.R.; Cheepsunthorn, P. Increased cellular iron levels affect matrix metalloproteinase expression and phagocytosis in activated microglia. Neurosci. Lett., 2011, 500(1), 36-40.
101. Stomrud, E.; Björkqvist, M.; Janciauskiene, S.; Minthon, L.; Hansson, O. Alterations of matrix metalloproteinases in the healthy elderly with increased risk of prodromal Alzheimer's disease. Alzheimers Res. Ther., 2010, 2(3), 20.
102. Lorenzl, S.; Albers, D.S.; Relkin, N.; Ngyuen, T.; Hilgenberg, S.L.; Chirichigno, J.; Cudkowicz, M.E.; Beal, M.F. Increased plasma levels of matrix metalloproteinase-9 in patients with Alzheimer's disease. Neurochem. Int., 2003, 43(3), 191-196.
103. Bruno, M.A.; Mufson, E.J.; Wuu, J.; Cuello, A.C. Increased matrix metalloproteinase 9 activity in mild cognitive impairment. J. Neuropathol. Exp. Neurol., 2009, 68(12), 1309-1318.
104. Lim, N.K.H.; Villemagne, V.L.; Soon, C.P.W.; Laughton, K.M.; Rowe, C.C.; McLean, C.A.; Masters, C.L.; Evin, G.; Li, Q.-X. Investigation of matrix metalloproteinases, MMP-2 and MMP-9, in plasma reveals a decrease of MMP-2 in Alzheimer's disease. J. Alzheimer's Dis., 2011, 26(4), 779-786.
105. Fearnley, J.M.; Lees, A.J. Striatonigral degeneration. A clinicopathological study. Brain, 1990, 113(Pt 6), 1823-1842.
106. Hirsch, E.C.; Brandel, J.P.; Galle, P.; Javoy-Agid, F.; Agid, Y. Iron and aluminum increase in the substantia nigra of patients with Parkinson's disease: an X-ray microanalysis. J. Neurochem., 1991, 56(2), 446-451.
107. Jellinger, K.; Kienzl, E.; Rumpelmair, G.; Riederer, P.; Stachelberger, H.; Ben-Shachar, D.; Youdim, M.B. Iron-melanin complex in substantia nigra of parkinsonian brains: an x-ray microanalysis. J. Neurochem., 1992, 59(3), 1168-1171.
108. Good, P.F.; Olanow, C.W.; Perl, D.P. Neuromelanin-containing neurons of the substantia nigra accumulate iron and aluminum in Parkinson's disease: a LAMMA study. Brain Res., 1992, 593(2), 343-346.
109. Jellinger, K.; Paulus, W.; Grundke-Iqbal, I.; Riederer, P.; Youdim, M.B. Brain iron and ferritin in Parkinson's and Alzheimer's diseases. J. Neural Transm. Parkinsons Dis. Dement., 1990, 2(4), 327-340.
110. Wilms, H.; Rosenstiel, P.; Sievers, J.; Deuschl, G.; Zecca, L.; Lucius, R. Activation of microglia by human neuromelanin is NFkappaB dependent and involves p38 mitogen-activated protein kinase: implications for Parkinson's disease. FASEB J., 2003, 17(3), 500-502.
111. Zecca, L.; Wilms, H.; Geick, S.; Claasen, J.-H.; Brandenburg, L.-O.; Holzknecht, C.; Panizza, M.L.; Zucca, F.A.; Deuschl, G.; Sievers, J.; Lucius, R. Human neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson's disease. Acta Neuropathol. (Berl.), 2008, 116(1), 47-55.
112. LeVine, S.M. Iron deposits in multiple sclerosis and Alzheimer's disease brains. Brain Res., 1997, 760(1-2), 298-303.
113. Adams, C.W. Perivascular iron deposition and other vascular damage in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry, 1988, 51(2), 260-265.
114. Craelius, W.; Migdal, M.W.; Luessenhop, C.P.; Sugar, A.; Mihalakis, I. Iron deposits surrounding multiple sclerosis plaques. Arch. Pathol. Lab. Med., 1982, 106(8), 397-399.
115. Forge, J.K.; Pedchenko, T.V.; LeVine, S.M. Iron deposits in the central nervous system of SJL mice with experimental allergic encephalomyelitis. Life Sci., 1998, 63(25), 2271-2284.
116. Pedchenko, T.V.; LeVine, S.M. Desferrioxamine suppresses experimental allergic encephalomyelitis induced by MBP in SJL mice. J. Neuroimmunol., 1998, 84(2), 188-197.
117. Rathnasamy, G.; Ling, E.-A.; Kaur, C. Iron and iron regulatory proteins in amoeboid microglial cells are linked to oligodendrocyte death in hypoxic neonatal rat periventricular white matter through production of proinflammatory cytokines and reactive oxygen/nitrogen species. J. Neurosci., 2011, 31(49), 17982-17995.
118. Deng, Y.; Lu, J.; Sivakumar, V.; Ling, E.A.; Kaur, C. Amoeboid microglia in the periventricular white matter induce oligodendrocyte damage through expression of proinflammatory cytokines via MAP kinase signaling pathway in hypoxic neonatal rats. Brain Pathol., 2008, 18(3), 387-400.
119. Waubant, E. Biomarkers indicative of blood-brain barrier disruption in multiple sclerosis. Dis. Markers, 2006, 22(4), 235-244.
120. Shinto, L.; Marracci, G.; Bumgarner, L.; Yadav, V. The effects of omega-3 Fatty acids on matrix metalloproteinase-9 production and cell migration in human immune cells: implications for multiple sclerosis. Autoimmune Dis., 2011, 2011, 134592.
121. Maeda, A.; Sobel, R.A. Matrix metalloproteinases in the normal human central nervous system, microglial nodules, and multiple sclerosis lesions. J. Neuropath. Exp. Neur., 1996, 55(3), 300-309.
122. Liuzzi, G.M.; Trojano, M.; Fanelli, M.; Avolio, C.; Fasano, A.; Livrea, P.; Riccio, P. Intrathecal synthesis of matrix metalloproteinase-9 in patients with multiple sclerosis: implication for pathogenesis. Mult. Scler., 2002, 8(3), 222-228.
123. Leppert, D.; Ford, J.; Stabler, G.; Grygar, C.; Lienert, C.; Huber, S.; Miller, K.M.; Hauser, S.L.; Kappos, L. Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. Brain, 1998, (Pt 12), 2327-2334.
124. Williams, R.; Buchheit, C.L.; Berman, N.E.J.; LeVine, S.M. Pathogenic implications of iron accumulation in multiple sclerosis. J. Neurochem., 2012, 120(1), 7-25.
125. Proost, P.; Van Damme, J.; Opdenakker, G. Leukocyte gelatinase B cleavage releases encephalitogens from human myelin basic protein. Biochem. Biophys. Res. Commun., 1993, 192(3), 1175-1181.
126. Casciola-Rosen, L.; Wigley, F.; Rosen, A. Scleroderma autoantigens are uniquely fragmented by metal-catalyzed oxidation reactions: implications for pathogenesis. J. Exper. Med., 1997, 185(1), 71-79.
127. Kalluri, R.; Cantley, L.G.; Kerjaschki, D.; Neilson, E.G. Reactive oxygen species expose cryptic epitopes associated with autoimmune goodpasture syndrome. J. Biol. Chem., 2000, 275(26), 20027-20032.
128. Trigwell, S.M.; Radford, P.M.; Page, S.R.; Loweth, A.C.; James, R.F.; Morgan, N.G.; Todd, I. Islet glutamic acid decarboxylase modified by reactive oxygen species is recognized by antibodies from patients with type 1 diabetes mellitus. Clin. Exp. Immunol., 2001, 126(2), 242-249.
129. Shouman, B.O.; Mesbah, A.; Aly, H. Iron metabolism and lipid peroxidation products in infants with hypoxic ischemic encephalopathy. J. Perinatol., 2008, 28(7), 487-491.
130. Palmer, C.; Menzies, S.L.; Roberts, R.L.; Pavlick, G.; Connor, J.R. Changes in iron histochemistry after hypoxic-ischemic brain injury in the neonatal rat. J. Neurosci. Res., 1999, 56(1), 60-71.
131. Zhou, B.; Westaway, S.K.; Levinson, B.; Johnson, M.A.; Gitschier, J.; Hayflick, S.J. A novel pantothenate kinase gene (PANK2) is defective in Hallervorden-Spatz syndrome. Nat. Genet., 2001, 28(4), 345-349.
132. Kruer, M.C.; Boddaert, N.; Schneider, S.A.; Houlden, H.; Bhatia, K.P.; Gregory, A.; Anderson, J.C.; Rooney, W.D.; Hogarth, P.; Hayflick, S.J. Neuroimaging features of neurodegeneration with brain iron accumulation. AJNR, 2012, 33(3), 407-414.
133. Dooling, E.C.; Schoene, W.C.; Richardson, E.P., Jr. Hallervorden-Spatz syndrome. Arch. Neurol., 1974, 30(1), 70-83.
134. Gregory, A.; Hayflick, S.J. Neurodegeneration with brain iron accumulation. Folia Neuropathol., 2005, 43(4), 286-296.
135. Gregory, A.; Hayflick, S.J. Pantothenate Kinase-Associated Neurodegeneration. 1993.
136. Swaiman, K.F.; Smith, S.A.; Trock, G.L.; Siddiqui, A.R. Sea-blue histiocytes, lymphocytic cytosomes, movement disorder and 59Feuptake in basal ganglia: Hallervorden-Spatz disease or ceroid storage disease with abnormal isotope scan? Neurology, 1983, 33(3), 301-305.
137. Nishiyama, K.; Murayama, S.; Nishimura, Y.; Asayama, K.; Kanazawa, I. Superoxide dismutase-like immunoreactivity in spheroids in Hallervorden-Spatz disease. Acta Neuropathol. (Berl.), 1997, 93(1), 19-23.
138. Halliday, W. The nosology of Hallervorden-spatz disease. J. Neurol. Sci., 1995, 134(Suppl), 84-91.
139. Hautot, D.; Pankhurst, Q.A.; Morris, C.M.; Curtis, A.; Burn, J.; Dobson, J. Preliminary observation of elevated levels of nanocrystalline iron oxide in the basal ganglia of neuroferritinopathy patients. Biochim. Biophys. Acta, 2007, 1772(1), 21-25.
140. Petrat, F.; de Groot, H.; Sustmann, R.; Rauen, U. The chelatable iron pool in living cells: a methodically defined quantity. Biol. Chem., 2002, 383(3-4), 489-502.
141. Halliwell, B.; Gutteridge, J.M. Role of free radicals and catalytic metal ions in human disease: an overview. Methods Enzymol., 1990, 186, 1-85.
142. Berg, D.; Gerlach, M.; Youdim, M.B.H.; Double, K.L.; Zecca, L.; Riederer, P.; Becker, G. Brain iron pathways and their relevance to Parkinson's disease. J. Neurochem., 2001, 79(2), 225-236.
143. Gorter, J.A.; Mesquita, A.R.M.; van Vliet, E.A.; da Silva, F.H.L.; Aronica, E. Increased expression of ferritin, an iron-storage protein, in specific regions of the parahippocampal cortex of epileptic rats. Epilepsia, 2005, 46(9), 1371-1379.
144. Mehlhase, J.; Sandig, G.; Pantopoulos, K.; Grune, T. Oxidationinduced ferritin turnover in microglial cells: role of proteasome. Free Radic. Biol. Med., 2005, 38(2), 276-285.
145. Alam, Z.I. DS E; Lees, A J; Marsden, D C; Jenner, P; Halliwell, B. A generalised increase in protein carbonyls in the brain in Parkinson's but not incidental Lewy body disease. J. Neurochem., 1997, 69(3), 1326-1329.
146. Kaur, D.; Yantiri, F.; Rajagopalan, S.; Kumar, J.; Mo, J.Q.; Boonplueang, R.; Viswanath, V.; Jacobs, R.; Yang, L.; Beal, M.F.; DiMonte, D.; Volitaskis, I.; Ellerby, L.; Cherny, R.A.; Bush, A.I.; Andersen, J.K. Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson's disease. Neuron, 2003, 37(6), 899-909.
147. Dexter, D.T.; Statton, S.A.; Whitmore, C.; Freinbichler, W.; Weinberger, P.; Tipton, K.F.; Della Corte, L.; Ward, R.J.; Crichton, R.R. Clinically available iron chelators induce neuroprotection in the 6-OHDA model of Parkinson's disease after peripheral administration. J. Neural Transm., 2011, 118(2), 223-231.
148. Cherny, R.A.; Atwood, C.S.; Xilinas, M.E.; Gray, D.N.; Jones, W.D.; McLean, C.A.; Barnham, K.J.; Volitakis, I.; Fraser, F.W.; Kim, Y.; Huang, X.; Goldstein, L.E.; Moir, R.D.; Lim, J.T.; Beyreuther, K.; Zheng, H.; Tanzi, R.E.; Masters, C.L.; Bush, A.I. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer's disease transgenic mice. Neuron, 2001, 30(3), 665-676.
149. Peeters-Scholte, C.; Braun, K.; Koster, J.; Kops, N.; Blomgren, K.; Buonocore, G.; van Buul-Offers, S.; Hagberg, H.; Nicolay, K.; van Bel, F.; Groenendaal, F. Effects of allopurinol and deferoxamine on reperfusion injury of the brain in newborn piglets after neonatal hypoxia-ischemia. Pediatr. Res., 2003, 54(4), 516-522.
150. Liachenko, S.; Tang, P.; Xu, Y. Deferoxamine improves early postresuscitation reperfusion after prolonged cardiac arrest in rats. J. Cereb. Blood Flow Metab., 2003, 23(5), 574-581.
151. Nayini, N.R.; White, B.C.; Aust, S.D.; Huang, R.R.; Indrieri, R.J.; Evans, A.T.; Bialek, H.; Jacobs, W.A.; Komara, J. Post resuscitation iron delocalization and malondialdehyde production in the brain following prolonged cardiac arrest. J. Free Radic. Biol. Med., 1985, 1(2), 111-116.
152. Nelson, C.W.; Wei, E.P.; Povlishock, J.T.; Kontos, H.A.; Moskowitz, M.A. Oxygen radicals in cerebral ischemia. Am. J. Physiol., 1992, 263(5 Pt 2), H1356-1362.
153. Palmer, C.; Roberts, R.L.; Bero, C. Deferoxamine posttreatment reduces ischemic brain injury in neonatal rats. Stroke, 1994, 25(5), 1039-1045.
154. Groenendaal, F.; Shadid, M.; McGowan, J.E.; Mishra, O.P.; van Bel, F. Effects of deferoxamine, a chelator of free iron, on NA(+), K(+)-ATPase activity of cortical brain cell membrane during early reperfusion after hypoxia-ischemia in newborn lambs. Pediatr. Res., 2000, 48(4), 560-564.
155. Wu, H.; Wu, T.; Xu, X.; Wang, J. Iron toxicity in mice with collagenase-induced intracerebral hemorrhage. J. Cereb. Blood Flow Metab., 2011, 31(5), 1243-1250.
156. Miao, X.Y.; Liu, X.B.; Yue, Q.; Qiu, N.; Huang, W.D.; Wang, J.J.; Xu, Y.G.; Zhang, Y.L.; Yang, J.; Chen, X.L. Deferoxamine suppresses microglia activation and protects against secondary neural injury after intracerebral hemorrhage in rats. Nan Fang Yi Ke Da Xue Xue Bao, 2012, 32(7), 970-975.
157. Huang, F.P.; Xi, G.; Keep, R.F.; Hua, Y.; Nemoianu, A.; Hoff, J.T. Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products. J. Neurosurg., 2002, 96(2), 287-293.
158. Tanaka, M.; Sotomatsu, A.; Yoshida, T.; Hirai, S.; Nishida, A. Detection of superoxide production by activated microglia using a sensitive and specific chemiluminescence assay and microgliamediated PC12h cell death. J. Neurochem., 1994, 63(1), 266-270.
159. Crapper McLachlan, D.R.; Dalton, A.J.; Kruck, T.P.; Bell, M.Y.; Smith, W.L.; Kalow, W.; Andrews, D.F. Intramuscular desferrioxamine in patients with Alzheimer's disease. Lancet, 1991, 337(8753), 1304-1308.
160. Fredenburg, A.M.; Sethi, R.K.; Allen, D.D.; Yokel, R.A. The pharmacokinetics and blood-brain barrier permeation of the chelators 1,2 dimethly-, 1,2 diethyl-, and 1-[ethan-1'ol]-2-methyl-3-hydroxypyridin-4-one in the rat. Toxicology, 1996, 108(3), 191-199.
161. Mitchell, K.M.; Dotson, A.L.; Cool, K.M.; Chakrabarty, A.; Benedict, S.H.; LeVine, S.M. Deferiprone, an orally deliverable iron chelator, ameliorates experimental autoimmune encephalomyelitis. Mult. Scler., 2007, 13(9), 1118-1126.
162. Song, D.; Song, Y.; Hadziahmetovic, M.; Zhong, Y.; Dunaief, J.L. Systemic administration of the iron chelator deferiprone protects against light-induced photoreceptor degeneration in the mouse retina. Free Radic. Biol. Med., 2012, 53(1), 64-71.
163. Liang, L.P.; Jarrett, S.G.; Patel, M. Chelation of mitochondrial iron prevents seizure-induced mitochondrial dysfunction and neuronal injury. J. Neurosci., 2008, 28(45), 11550-11556.
164. Kalivendi, S.V.; Kotamraju, S.; Cunningham, S.; Shang, T.; Hillard, C.J.; Kalyanaraman, B. 1-Methyl-4-phenylpyridinium (MPP+)-induced apoptosis and mitochondrial oxidant generation: role of transferrin-receptor-dependent iron and hydrogen peroxide. Biochem. J., 2003, 371(Pt 1), 151-164.
165. Weinreb, O.; Bar-Am, O.; Amit, T.; Chillag-Talmor, O.; Youdim, M.B. Neuroprotection via pro-survival protein kinase C isoforms associated with Bcl-2 family members. FASEB J., 2004, 18(12), 1471-1473.
166. Bar Am, O.; Amit, T.; Youdim, M.B. Contrasting neuroprotective and neurotoxic actions of respective metabolites of anti-Parkinson drugs rasagiline and selegiline. Neurosci. Lett., 2004, 355(3), 169-172.
167. Gal, S.; Zheng, H.; Fridkin, M.; Youdim, M.B. Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTPinduced striatal dopamine depletion. J. Neurochem., 2005, 95(1), 79-88.
168. Shachar, D.B.; Kahana, N.; Kampel, V.; Warshawsky, A.; Youdim, M.B. Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lession in rats. Neuropharmacology, 2004, 46(2), 254-263.
169. Mandel, S.; Weinreb, O.; Reznichenko, L.; Kalfon, L.; Amit, T. Green tea catechins as brain-permeable, non toxic iron chelators to "iron out iron" from the brain. J. Neural Transm. Suppl., 2006, (71), 249-257.