Pathogenic implications of iron accumulation in multiple sclerosis

Journal of Neurochemistry

Volumn 120, Issue 1, 2012, Pages 7-25

  Williams, Rachel ^a   Buchheit, Cassandra L ^a,b,c   Berman, Nancy E J ^a   Levine, Steven M ^a  

^a UNIVERSITY OF KANSAS SCHOOL OF MEDICINE   (United States)

^b ROCKHURST UNIVERSITY   (United States)

^c UNIVERSITY OF NOTRE DAME   (United States)

Author keywords

DMT1; experimental autoimmune encephalomyelitis; ferritin; neurodegeneration; reactive oxygen species; transferrin receptor

Indexed keywords

FERRITIN; GLUTAMIC ACID; INTERLEUKIN 1BETA; INTERLEUKIN 6; IRON; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; NATURAL RESISTANCE ASSOCIATED MACROPHAGE PROTEIN 1; NATURAL RESISTANCE ASSOCIATED MACROPHAGE PROTEIN 2; REACTIVE OXYGEN METABOLITE; TRANSFERRIN RECEPTOR; TUMOR NECROSIS FACTOR ALPHA; VASCULOTROPIN;

ALLERGIC ENCEPHALOMYELITIS; ALZHEIMER DISEASE; BLOOD BRAIN BARRIER; BRAIN ATROPHY; BRAIN BLOOD FLOW; DISEASE ACTIVITY; DISEASE DURATION; EXCITOTOXICITY; GRAY MATTER; HUMAN; IRON METABOLISM; IRON RESPONSIVE ELEMENT; IRON STORAGE; MACROPHAGE; MICROGLIA; MULTIPLE SCLEROSIS; NERVE DEGENERATION; NERVOUS SYSTEM INFLAMMATION; NEUROIMAGING; NONHUMAN; NUCLEAR MAGNETIC RESONANCE IMAGING; OLIGODENDROGLIA; OXIDATIVE STRESS; PARKINSON DISEASE; PATHOGENESIS; PRIORITY JOURNAL; REVIEW; WHITE MATTER;

ANIMALS; BLOOD VESSELS; BRAIN CHEMISTRY; DISEASE MODELS, ANIMAL; ENCEPHALOMYELITIS, AUTOIMMUNE, EXPERIMENTAL; GLUTAMIC ACID; HUMANS; IRON; IRON, DIETARY; MACROPHAGES; MAGNETIC RESONANCE IMAGING; MICROGLIA; MULTIPLE SCLEROSIS; NEURODEGENERATIVE DISEASES; NEUROTOXINS;

EID: 83855163999     PISSN: 00223042     EISSN: 14714159     Source Type: Journal    
DOI: 10.1111/j.1471-4159.2011.07536.x     Document Type: Review

References (281)

1. Abo-Krysha N., and, Rashed L., (2008) The role of iron dysregulation in the pathogenesis of multiple sclerosis: an Egyptian study. Mult. Scler. 14, 602-608. (Pubitemid 351954401)
2. Aboul-Enein F., Rauschka H., Kornek B., Stadelmann C., Stefferl A., Bruck W., Lucchinetti C., Schmidbauer M., Jellinger K., and, Lassmann H., (2003) Preferential loss of myelin-associated glycoprotein reflects hypoxia-like white matter damage in stroke and inflammatory brain diseases. J. Neuropathol. Exp. Neurol. 62, 25-33. (Pubitemid 36068890)
3. Adamo A. M., Paez P. M., Escobar Cabrera O. E., Wolfson M., Franco P. G., Pasquini J. M., and, Soto E. F., (2006) Remyelination after cuprizone-induced demyelination in the rat is stimulated by apotransferrin. Exp. Neurol. 198, 519-529.
4. Adams C. W. M., (1988) Perivascular iron deposition and other vascular damage in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 51, 260-265. (Pubitemid 18055135)
5. Adams C. W. M., (1989) A Color Atlas of Multiple Sclerosis and Other Myelin Disorders. Sheridan Medical Books, Dobbs Ferry, New York.
6. Adams C. W., Poston R. N., and, Buk S. J., (1989) Pathology, histochemistry and immunocytochemistry of lesions in acute multiple sclerosis. J. Neurol. Sci. 92, 291-306. (Pubitemid 19241812)
7. Alexander G. E., and, Crutcher M. D., (1990) Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci. 13, 266-271. (Pubitemid 20193456)
8. Algarín C., Peirano P., Garrido M., Pizarro F., and, Lozoff B., (2003) Iron deficiency anemia in infancy: long-lasting effects on auditory and visual system functioning. Pediatr. Res. 53, 217-223. (Pubitemid 36177116)
9. Andrews H., White K., Thomson C., Edgar J., Bates D., Griffiths I., Turnbull D., and, Nichols P., (2006) Increased axonal mitochondrial activity as an adaptation to myelin deficiency in the Shiverer mouse. J. Neurosci. Res. 83, 1533-1539. (Pubitemid 43844998)
10. Ates O., Kurt S., Bozkurt N., and, Karaer H., (2010) NRAMP1 (SLC11A1) variants: genetic susceptibility to multiple Sclerosis. J. Clin. Immunol. 30, 583-586.
11. Auriel E., Karni A., Bornstein N. M., Nissel T., Gadoth A., and, Hallevi H., (2011) Extra-cranial venous flow in patients with multiple sclerosis. J. Neurol. Sci. 309, 102-104.
12. Badaracco M. E., Ortiz E. H., Soto E. F., Connor J., and, Pasquini J. M., (2008) Effect of transferrin on hypomyelination induced by iron deficiency. J. Neurosci. Res. 86, 2663-2673.
13. Baeten K., Hendriks J. J., Hellings N., Theunissen E., Vanderlocht J., Ryck L. D., Gelan J., Stinissen P., and, Adriaensens P., (2008) Visualisation of the kinetics of macrophage infiltration during experimental autoimmune encephalomyelitis by magnetic resonance imaging. J. Neuroimmunol. 195, 1-6.
14. Bakshi R., Miletich R. S., Kinkel P. R., Emmet M. L., and, Kinkel W. R., (1998) High-resolution fluorodeoxyglucose positron emission tomography shows both global and regional cerebral hypometabolism in multiple sclerosis. J. Neuroimaging 8, 228-234. (Pubitemid 28457989)
15. Bakshi R., Shaikh Z. A., and, Janardhan V., (2000) MRI T2 shortening ('black T2') in multiple sclerosis: frequency, location, and clinical correlation. Neuroreport 11, 15-21. (Pubitemid 30053382)
16. Bakshi R., Benedict R. H., Bermel R. A., Caruthers S. D., Puli S. R., Tjoa C. W., Fabiano A. J., and, Jacobs L., (2002) T2 hypointensity in the deep gray matter of patients with multiple sclerosis, a quantitative magnetic resonance imaging study. Arch. Neurol. 59, 62-68. (Pubitemid 34052557)
17. Balla G., Jacob H. S., Balla J., Rosenberg M., Nath K., Apple F., Eaton J. W., and, Vercellotti G. M., (1992) Ferritin: a cytoprotective antioxidant strategem of endothelium. J. Biol. Chem. 267, 18148-18153.
18. Barbeito A. G., Garringer H. J., Baraibar M. A., Gao X., Arredondo M., Nunez M. T., Smith M. A., Ghetti B., and, Vidal R., (2009) Abnormal iron metabolism and oxidative stress in mice expressing a mutant form of the ferritin light polypeptide gene. J. Neurochem. 109, 1067-1078.
19. Bartnik B. L., Juurlink B. H., and, Devon R. M., (2000) Macrophages: their myelinotrophic or neurotoxic actions depend upon tissue oxidative stress. Mult. Scler. 6, 37-42. (Pubitemid 30175370)
20. Bartolome S., Dhillon N. K., Buch S., Casillan A. J., Wood J. G., and, O'Brien-Ladner A. R., (2009) Deferoxamine mimics the pattern of hypoxia-related injury at the microvasculature. Shock 31, 481-485.
21. Berg D., and, Youdim M. B., (2006) Role of iron in neurodegenerative disorders. Top. Magn. Reson. Imaging 17, 5-17. (Pubitemid 46672929)
22. Bermel R. A., Puli S. R., Rudick R. A., Weinstock-Guttman B., Fisher E., Munschauer 3rd F. E., and, Bakshi R., (2005) Prediction of longitudinal brain atrophy in multiple sclerosis by gray matter magnetic resonance imaging T2 hypointensity. Arch. Neurol. 62, 1371-1376. (Pubitemid 41352053)
23. Bertoni-Freddari C., Fattoretti P., Casoli T., Di Stefano G., Solazzi M., Perna E., and, De Angelis C., (2006) Reactive structural dynamics of synaptic mitochondria in ischemic delayed neuronal death. Ann. NY Acad. Sci. 1090, 26-34. (Pubitemid 47092105)
24. Bianchi L., Tacchini L., and, Cairo G., (1999) HIF-1-mediated activation of transferrin receptor gene transcription by iron chelation. Nucleic Acids Res. 27, 4223-4227. (Pubitemid 29500256)
25. Biswas S., Biesiada H., Williams T. D., and, LeVine S. M., (2002) Delayed clinical and pathological signs in twitcher (globoid cell leukodystrophy) mice on a C57BL/6 x CAST/Ei background. Neurobiol. Dis. 10, 344-357. (Pubitemid 35217586)
26. Bjartmar C., and, Trapp B. D., (2001) Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences. Curr. Opin. Neurol. 14, 271-278. (Pubitemid 32510589)
27. Blinkenberg M., Jensen C. V., Holm S., Paulson O. B., and, Sorensen P. S., (1999) A longitudinal study of cerebral glucose metabolism, MRI, and disability in patients with MS. Neurology 53, 149-153. (Pubitemid 29329663)
28. Bolton C., and, Paul C., (2006) Glutamate receptors in neuroinflammatory demyelinating disease. Mediators Inflamm. 2006, 93684.
29. Boretius S., Schmelting B., Watanabe T., Merkler D., Tammer R., Czeh B., Michaelis T., Frahm J., and, Fuchs E., (2006) Monitoring of EAE onset and progression in the common marmoset monkey by sequential high-resolution 3D MRI. NMR Biomed. 19, 41-49. (Pubitemid 43250788)
30. Bowern N., Ramshaw I. A., Clark I. A., and, Doherty P. C., (1984) Inhibition of autoimmune neuropathological process by treatment with an iron-chelating agent. J. Exp. Med. 160, 1532-1543. (Pubitemid 15220781)
31. Bowlus C. L., (2003) The role of iron in T cell development and autoimmunity. Autoimmun. Rev. 2, 73-78. (Pubitemid 37443858)
32. Brass S. D., Benedict R. H., Weinstock-Guttman B., Munschauer F., and, Bakshi R., (2006a) Cognitive impairment is associated with subcortical magnetic resonance imaging grey matter T2 hypointensity in multiple sclerosis. Mult. Scler. 12, 437-444. (Pubitemid 44132584)
33. Brass S. D., Chen N. K., Mulkern R. V., and, Bakshi R., (2006b) Magnetic resonance imaging of iron deposition in neurological disorders. Top. Magn. Reson. Imaging 17, 31-40. (Pubitemid 46672931)
34. Brett R., and, Rumsby M. G., (1993) Evidence of free radical damage in the central nervous system of guinea-pigs at the prolonged acute and early relapse stages of chronic relapsing experimental allergic encephalomyelitis. Neurochem. Int. 23, 35-44.
35. Brochet B., Deloire M. S., Touil T., Anne O., Caille J. M., Dousset V., and, Petry K. G., (2006) Early macrophage MRI of inflammatory lesions predicts lesion severity and disease development in relapsing EAE. Neuroimage 32, 266-274.
36. Brown G. C., and, Neher J. J., (2010) Inflammatory neurodegeneration and mechanisms of microglial killing of neurons. Mol. Neurobiol. 41, 242-247.
37. Burdo J. R., Menzies S. L., Simpson I. A., Garrick L. M., Garrick M. D., Dolan K. G., Haile D. J., Beard J. L., and, Connor J. R., (2001) Distribution of divalent metal transporter 1 and metal transport protein 1 in the normal and Belgrade rat. J. Neurosci. Res. 66, 1198-1207. (Pubitemid 33135606)
38. Burdo J. R., Antonetti D. A., Wolpert E. B., and, Connor J. R., (2003) Mechanisms and regulation of transferrin and iron transport in a model blood-brain barrier system. Neuroscience 121, 883-890. (Pubitemid 37324587)
39. Calabrese V., Scapagnini G., Ravagna A., Bella R., Butterfield D. A., Calvani M., Pennisi G., and, Giuffrida Stella A. M., (2003) Disruption of thiol homeostasis and nitrosative stress in the cerebrospinal fluid of patients with active multiple sclerosis: evidence for a protective role of acetylcarnitine. Neurochem. Res. 28, 1321-1328. (Pubitemid 38113060)
40. Carbonell T., and, Rama R., (2007) Iron, oxidative stress and early neurological deterioration in ischemic stroke. Curr. Med. Chem. 14, 857-874. (Pubitemid 46863616)
41. Casciola-Rosen L., Wigley F., and, Rosen A., (1997) Scleroderma autoantigens are uniquely fragmented by metal-catalyzed oxidation reactions: implications for pathogenesis. J. Exp. Med. 185, 71-79. (Pubitemid 27039442)
42. Cassan C., and, Liblau R. S., (2007) Immune tolerance and control of CNS autoimmunity: from animal models to MS patients. J. Neurochem. 100, 883-892. (Pubitemid 46213915)
43. Ceccarelli A., Filippi M., Neema M., Arora A., Valsasina P., Rocca M. A., Healy B. C., and, Bakshi R., (2009) T2 hypointensity in the deep gray matter of patients with benign multiple sclerosis. Mult. Scler. 15, 678-686.
44. Ceccarelli A., Rocca M. A., Neema M., Martinelli V., Arora A., Tauhid S., Ghezzi A., Comi G., Bakshi R., and, Filippi M., (2010) Deep gray matter T2 hypointensity is present in patients with clinically isolated syndromes suggestive of multiple sclerosis. Mult. Scler. 16, 39-44.
45. Ceccarelli A., Rocca M. A., Perego E., Moiola L., Ghezzi A., Martinelli V., Comi G., and, Filippi M., (2011) Deep grey matter T2 hypo-intensity in patients with paediatric multiple sclerosis. Mult. Scler. 17, 702-707.
46. Centonze D., Muzio L., Rossi S., Furlan R., Bernardi G., and, Martino G., (2010) The link between inflammation, synaptic transmission and neurodegeneration in multiple sclerosis. Cell Death Differ. 17, 1083-1091.
47. Chakrabarty A., Emerson M. R., and, LeVine S. M., (2003) Heme oxygenase-1 in SJL mice with experimental allergic encephalomyelitis. Mult. Scler. 9, 372-381. (Pubitemid 36958020)
48. Chakravarti S., Sabatos C. A., Xiao S., Illes Z., Cha E. K., Sobel R. A., Zheng X. X., Strom T. B., and, Kuchroo V. K., (2005) Tim-2 regulates T helper type 2 responses and autoimmunity. J. Exp. Med. 202, 437-444. (Pubitemid 41126961)
49. Cheah J. H., Kim S. F., Hester L. D., Clancy K. W., Patterson 3rd S. E., Papadopoulos V., and, Snyder S. H., (2006) NMDA receptor-nitric oxide transmission mediates neuronal iron homeostasis via the GTPase Dexras1. Neuron 51, 431-440. (Pubitemid 44209322)
50. Cheepsunthorn P., Palmer C., and, Connor J. R., (1998) Cellular distribution of ferritin subunits in postnatal rat brain. J. Comp. Neurol. 400, 73-86. (Pubitemid 28440754)
51. Chen-Roetling J., Chen L., and, Regan R. F., (2011) Apotransferrin protects cortical neurons from hemoglobin toxicity. Neuropharmacology 60, 423-431.
52. Chi S. I., Wang C. K., Chen J. J., Chau L. Y., and, Lin T. N., (2000) Differential regulation of H- and L-ferritin messenger RNA subunits, ferritin protein and iron following focal cerebral ischemia-reperfusion. Neuroscience 100, 475-484.
53. Chi O. Z., Hunter C., Liu X., and, Weiss H. R., (2008) Effects of deferoxamine on blood-brain barrier disruption and VEGF in focal cerebral ischemia. Neurol. Res. 30, 288-293. (Pubitemid 351769424)
54. Chin C. L., Pai M., Bousquet P. F., Schwartz A. J., O'Connor E. M., Nelson C. M., Hradil V. P., Cox B. F., McRae B. L., and, Fox G. B., (2009) Distinct spatiotemporal pattern of CNS lesions revealed by USPIO-enhanced MRI in MOG-induced EAE rats implicates the involvement of spino-olivocerebellar pathways. J. Neuroimmunol. 211, 49-55.
55. Choi I. Y., Lee S. P., Denney D. R., and, Lynch S. G., (2011) Lower levels of glutathione in the brains of secondary progressive multiple sclerosis patients measured by 1H magnetic resonance chemical shift imaging at 3 T. Mult. Scler. 17, 289-296.
56. Ciccarelli O., Altmann D. R., McLean M. A., Wheeler-Kingshott C. A., Wimpey K., Miller D. H., and, Thompson A. J., (2010) Spinal cord repair in MS: does mitochondrial metabolism play a role? Neurology 74, 721-727.
57. Comabella M., Altet L., Peris F., Villoslada P., Sánchez A., and, Montalban X., (2004) Genetic analysis of SLC11A1 polymorphisms in multiple sclerosis patients. Mult. Scler. 10, 618-620. (Pubitemid 39585238)
58. Connor J. R., and, Menzies S. L., (1990) Altered cellular distribution of iron in the central nervous system of myelin deficient rats. Neuroscience 34, 265-271. (Pubitemid 20097913)
59. Connor J. R., and, Menzies S. L., (1996) Relationship of iron to oligodendrocytes and myelination. Glia 17, 83-93. (Pubitemid 26309437)
60. Connor J. R., Menzies S. L., St Martin S. M., and, Mufson E. J., (1990) Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains. J. Neurosci. Res. 27, 595-611.
61. Connor J. R., Pavlick G., Karli D., Menzies S. L., and, Palmer C., (1995) A histochemical study of iron-positive cells in the developing rat brain. J. Comp. Neurol. 355, 111-123.
62. Connor J. R., Ponnuru P., Wang X. S., Patton S. M., Allen R. P., and, Earley C. J., (2011) Profile of altered brain iron acquisition in restless legs syndrome. Brain 134, 959-968.
63. Cooper C. E., Lynagh G. R., Hoyes K. P., Hider R. C., Cammack R., and, Porter J. B., (1996) The relationship of intracellular iron chelation to the inhibition and regeneration of human ribonucleotide reductase. J. Biol. Chem. 271, 20291-20299. (Pubitemid 26281794)
64. Craelius W., Migdal M. W., Luessenhop C. P., Sugar A., and, Mihalakis I., (1982) Iron deposits surrounding multiple sclerosis plaques. Arch. Pathol. Lab. Med. 106, 397-399.
65. Crichton R. R., Wilmet S., Legssyer R., and, Ward R. J., (2002) Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells. J. Inorg. Biochem. 91, 9-18. (Pubitemid 34727756)
66. Crichton R. R., Dexter D. T., and, Ward R. J., (2011) Brain iron metabolism and its perturbation in neurological diseases. J. Neural. Transm. 118, 301-314.
67. Crompton D. E., Chinnery P. F., Fey C., et al. (2002) Neuroferritinopathy: a window on the role of iron in neurodegeneration. Blood Cells Mol. Dis. 29, 522-531.
68. Cunnea P., Ni Mháille A., McQuaid S., Farrell M., McMahon J., and, FitzGerald U., (2011) Expression profiles of endoplasmic reticulum stress-related molecules in demyelinating lesions and multiple sclerosis. Mult. Scler. 17, 808-818.
69. De Stefano N., Narayanan S., Francis G. S., Arnaoutelis R., Tartaglia M. C., Antel J. P., Matthews P. M., and, Arnold D. L., (2001) Evidence of axonal damage in the early stages of multiple sclerosis and its relevance to disability. Arch. Neurol. 58, 65-70. (Pubitemid 32053209)
70. Deng X., Vidal R., and, Englander E. W., (2010) Accumulation of oxidative DNA damage in brain mitochondria in mouse model of hereditary ferritinopathy. Neurosci. Lett. 479, 44-48.
71. Doepp F., Paul F., Valdueza J. M., Schmierer K., and, Schreiber S. J., (2010) No cerebrocervical venous congestion in patients with multiple sclerosis. Ann. Neurol. 68, 173-183.
72. Domercq M., Sánchez-Gõmez M. V., Sherwin C., Etxebarria E., Fern R., and, Matute C., (2007) System xc- and glutamate transporter inhibition mediates microglial toxicity to oligodendrocytes. J. Immunol. 178, 6549-6556. (Pubitemid 46717438)
73. Dousset V., Ballarino L., Delalande C., Coussemacq M., Canioni P., Petry K. G., and, Caille J. M., (1999) Comparison of ultrasmall particles of iron oxide (USPIO)-enhanced T2-weighted, conventional T2-weighted, and gadolinium-enhanced T1-weighted MR images in rats with experimental autoimmune encephalomyelitis. AJNR Am. J. Neuroradiol. 20, 223-227. (Pubitemid 30418702)
74. Drayer B., Burger P., Hurwitz B., Dawson D., and, Cain J., (1987a) Reduced signal intensity on MR images of thalamus and putamen in multiple sclerosis: increased iron content? AJR Am. J. Roentgenol. 149, 357-363. (Pubitemid 17104997)
75. Drayer B. P., Burger P., Hurwitz B., Dawson D., Cain J., Leong J., Herfkens R., and, Johnson G. A., (1987b) Magnetic resonance imaging in multiple sclerosis: decreased signal in thalamus and putamen. Ann. Neurol. 22, 546-550. (Pubitemid 17164782)
76. Dunn L. L., Rahmanto Y. S., and, Richardson D. R., (2007) Iron uptake and metabolism in the new millennium. Trends Cell Biol. 17, 93-100. (Pubitemid 46199183)
77. Dutta R., and, Trapp B. D., (2007) Pathogenesis of axonal and neuronal damage in multiple sclerosis. Neurology 68, S22-S31. (Pubitemid 46848608)
78. Dutta R., and, Trapp B. D., (2011) Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog. Neurobiol. 93, 1-12.
79. Dwork A. J., Schon E. A., and, Herbert J., (1988) Nonidentical distribution of transferrin and ferric iron in human brain. Neuroscience 27, 333-345.
80. Erb G. L., Osterbur D. L., and, LeVine S. M., (1996) The distribution of iron in the brain: a phylogenetic analysis using iron histochemistry. Brain Res. Dev. Brain Res. 93, 120-128. (Pubitemid 26188238)
81. Espinosa-Jeffrey A., Kumar S., Zhao P. M., Awosika O., Agbo C., Huang A., Chang R., and, De Vellis J., (2002) Transferrin regulates transcription of the MBP gene and its action synergizes with IGF-1 to enhance myelinogenesis in the md rat. Dev. Neurosci. 24, 227-241. (Pubitemid 36151454)
82. Fan Y., Wang J., Wei L., He B., Wang C., and, Wang B., (2011) Iron deficiency activates pro-inflammatory signaling in macrophages and foam cells via the p38 MAPK-NF-kappaB pathway. Int. J. Cardiol. 152, 49-55.
83. Ferretti G., Bacchetti T., DiLudovico F., Viti B., Angeleri V. A., Danni M., and, Provinciali L., (2006) Intracellular oxidative activity and respiratory burst of leukocytes isolated from multiple sclerosis patients. Neurochem. Int. 48, 87-92. (Pubitemid 41832442)
84. Fisher M., Levine P. H., Weiner B. H., Vaudreuil C. H., Natale A., Johnson M. H., and, Hoogasian J. J., (1988) Monocyte and polymorphonuclear leukocyte toxic oxygen metabolite production in multiple sclerosis. Inflammation 12, 123-131.
85. Fisher J., Devraj K., Ingram J., Slagle-Webb B., Madhankumar A. B., Liu X., Klinger M., Simpson I. A., and, Connor J. R., (2007) Ferritin: a novel mechanism for delivery of iron to the brain and other organs. Am. J. Physiol. Cell Physiol. 293, C641-C649. (Pubitemid 47235186)
86. Floris S., Blezer E. L., Schreibelt G., Dopp E., van der Pol S. M., Schadee-Eestermans I. L., Nicolay K., Dijkstra C. D., and, de Vries H. E., (2004) Blood-brain barrier permeability and monocyte infiltration in experimental allergic encephalomyelitis: a quantitative MRI study. Brain 127, 616-627. (Pubitemid 38295477)
87. Forge J. K., Pedchenko T. V., and, LeVine S. M., (1998) Iron deposits in the central nervous system of SJL mice with experimental allergic encephalomyelitis. Life Sci. 63, 2271-2284. (Pubitemid 28551772)
88. Francois C., Nguyen-Legros J., and, Percheron G., (1981) Topographical and cytological localization of iron in rat and monkey brains. Brain Res. 215, 317-322. (Pubitemid 11123250)
89. Gaasch J. A., Geldenhuys W. J., Lockman P. R., Allen D. D., and, Van der Schyf C. J., (2007) Voltage-gated calcium channels provide an alternate route for iron uptake in neuronal cell cultures. Neurochem. Res. 32, 1686-1693. (Pubitemid 47428848)
90. Ganz T., (2009) Iron in innate immunity: starve the invaders. Curr. Opin. Immunol. 21, 63-67.
91. Gazouli M., Sechi L., Paccagnini D., Sotgiu S., Arru G., Nasioulas G., and, Vassilopoulos D., (2008) NRAMP1 polymorphism and viral factors in Sardinian multiple sclerosis patients. Can. J. Neurol. Sci. 35, 491-494.
92. Ge Y., Law M., Johnson G., Herbert J., Babb J. S., Mannon L. J., and, Grossman R. I., (2005) Dynamic susceptibility contrast perfusion MR imaging of multiple sclerosis lesions: characterizing hemodynamic impairment and inflammatory activity. AJNR Am. J. Neuroradiol. 26, 1539-1547. (Pubitemid 43733458)
93. Ge Y., Jensen J. H., Lu H., Helpern J. A., Miles L., Inglese M., Babb J. S., Herbert J., and, Grossman R. I., (2007) Quantitative assessment of iron accumulation in the deep gray matter of multiple sclerosis by magnetic field correlation imaging. AJNR Am. J. Neuroradiol. 28, 1639-1644. (Pubitemid 47598131)
94. Ge Y., Zohrabian V. M., Osa E. O., Xu J., Jaggi H., Herbert J., Haacke E. M., and, Grossman R. I., (2009) Diminished visibility of cerebral venous vasculature in multiple sclerosis by susceptibility-weighted imaging at 3.0 Tesla. J. Magn. Reson. Imaging 29, 1190-1194.
95. Gerber M. R., and, Connor J. R., (1989) Do oligodendrocytes mediate iron regulation in the human brain? Ann. Neurol. 26, 95-98.
96. Geurts J. J., and, van Horssen J., (2010) The brake on neurodegeneration: increased mitochondrial metabolism in the injured MS spinal cord. Neurology 74, 710-711.
97. Gille G., and, Reichmann H., (2011) Iron-dependent functions of mitochondria-relation to neurodegeneration. J. Neural. Transm. 118, 349-359.
98. Gotz M. E., Double K., Gerlach M., Youdim M. B., and, Riederer P., (2004) The relevance of iron in the pathogenesis of Parkinson's disease. Ann. NY Acad. Sci. 1012, 193-208. (Pubitemid 38455479)
99. Grant S. M., Wiesinger J. A., Beard J. L., and, Cantorna M. T., (2003) Iron-deficient mice fail to develop autoimmune encephalomyelitis. J. Nutr. 133, 2635-2638. (Pubitemid 36935983)
100. Grimaud J., Millar J., Thorpe J. W., Moseley I. F., McDonald W. I., and, Miller D. H., (1995) Signal intensity on MRI of basal ganglia in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 59, 306-308.
101. Gutsaeva D. R., Suliman H. B., Carraway M. S., Demchenko I. T., and, Piantadosi C. A., (2006) Oxygen-induced mitochondrial biogenesis in the rat hippocampus. Neuroscience 137, 493-504. (Pubitemid 43031515)
102. Haacke E. M., Makki M., Ge Y., et al. (2009) Characterizing iron deposition in multiple sclerosis lesions using susceptibility weighted imaging. J. Magn. Reson. Imaging 29, 537-544.
103. Haacke E. M., Garbern J., Miao Y., Habib C., and, Liu M., (2010a) Iron stores and cerebral veins in MS studied by susceptibility weighted imaging. Int. Angiol. 29, 149-157.
104. Haacke E. M., Miao Y., Liu M., Habib C. A., Katkuri Y., Liu T., Yang Z., Lang Z., Hu J., and, Wu J., (2010b) Correlation of putative iron content as represented by changes in R2* and phase with age in deep gray matter of healthy adults. J. Magn. Reson. Imaging 32, 561-576.
105. Hallgren B., and, Sourander P., (1958) The effect of age on the non-haemin iron in the human brain. J. Neurochem. 3, 41-51.
106. Hammann K. P., and, Hopf H. C., (1986) Monocytes constitute the only peripheral blood cell population showing an increased burst activity in multiple sclerosis patients. Int. Arch. Allergy Appl. Immunol. 81, 230-234. (Pubitemid 16004192)
107. Han J., Seaman W. E., Di X., Wang W., Willingham M., Torti F. M., and, Torti S. V., (2011) Iron Uptake Mediated by Binding of H-Ferritin to the TIM-2 Receptor in Mouse Cells. PLoS ONE 6 (8), e23800.
108. Harada T., Baba M., Torii I., and, Morikawa S., (1987) Ferritin selectively suppresses delayed-type hypersensitivity responses at induction or effector phase. Cell. Immunol. 109, 75-88. (Pubitemid 17155710)
109. Hill J. M., and, Switzer 3rd R. C., (1984) The regional distribution and cellular localization of iron in the rat brain. Neuroscience 11, 595-603. (Pubitemid 14155958)
110. Hill J. M., Ruff M. R., Weber R. J., and, Pert C. B., (1985) Transferrin receptors in rat brain: neuropeptide-like pattern and relationship to iron distribution. Proc. Natl Acad. Sci. USA 82, 4553-4557. (Pubitemid 15233159)
111. Hodges Y. K., Reese S. M., Pahl P. M., and, Horwitz L. D., (2005) Paradoxical effects of iron chelation on growth of vascular endothelial cells. J. Cardiovasc. Pharmacol. 45, 539-544. (Pubitemid 40734574)
112. Hogan V., White K., Edgar J., McGill A., Karim S., McLaughlin M., Griffiths I., Turnbull D., and, Nichols P., (2009) Increase in mitochondrial density within axons and supporting cells in response to demyelination in the Plp1 mouse model. J. Neurosci. Res. 87, 452-459.
113. Holley J. E., Newcombe J., Whatmore J. L., and, Gutowski N. J., (2010) Increased blood vessel density and endothelial cell proliferation in multiple sclerosis cerebral white matter. Neurosci. Lett. 470, 65-70.
114. Honegger C. G., Krenger W., and, Langemann H., (1989) Measurement of free radical scavengers in the spinal cord of rats with experimental autoimmune encephalomyelitis. Neurosci. Lett. 98, 327-332. (Pubitemid 19077421)
115. Huang E., Ong W. Y., Go M. L., and, Connor J. R., (2006) Upregulation of iron regulatory proteins and divalent metal transporter-1 isoforms in the rat hippocampus after kainate induced neuronal injury. Exp. Brain Res. 170, 376-386.
116. Hulet S. W., Hess E. J., Debinski W., Arosio P., Bruce K., Powers S., and, Connor J. R., (1999a) Characterization and distribution of ferritin binding sites in the adult mouse brain. J. Neurochem. 72, 868-874. (Pubitemid 29055254)
117. Hulet S. W., Powers S., and, Connor J. R., (1999b) Distribution of transferrin and ferritin binding in normal and multiple sclerotic human brains. J. Neurol. Sci. 165, 48-55. (Pubitemid 29298081)
118. Hulet S. W., Heyliger S. O., Powers S., and, Connor J. R., (2000) Oligodendrocyte progenitor cells internalize ferritin via clathrin-dependent receptor mediated endocytosis. J. Neurosci. Res. 61, 52-60. (Pubitemid 30436474)
119. Hulet S. W., Menzies S., and, Connor J. R., (2002) Ferritin binding in the developing mouse brain follows a pattern similar to myelination and is unaffected by the jimpy mutation. Dev. Neurosci. 24, 208-213. (Pubitemid 36151451)
120. Huynh C., and, Andrews N. W., (2008) Iron acquisition within host cells and the pathogenicity of Leishmania. Cell Microbiol. 10, 293-300.
121. Inglese M., Park S. J., Johnson G., Babb J. S., Miles L., Jaggi H., Herbert J., and, Grossman R. I., (2007) Deep gray matter perfusion in multiple sclerosis: dynamic susceptibility contrast perfusion magnetic resonance imaging at 3 T. Arch. Neurol. 64, 196-202.
122. Jiang H., Song N., Xu H., Zhang S., Wang J., and, Xie J., (2010) Up-regulation of divalent metal transporter 1 in 6-hydroxydopamine intoxication is IRE/IRP dependent. Cell Res. 20, 345-356.
123. Juckett M. B., Balla J., Balla G., Jessurun J., Jacob H. S., and, Vercellotti G. M., (1995) Ferritin protects endothelial cells from oxidized low density lipoprotein in vitro. Am. J. Pathol. 147, 782-789.
124. Kalluri R., Cantley L. G., Kerjaschki D., and, Neilson E. G., (2000) Reactive oxygen species expose cryptic epitopes associated with autoimmune goodpasture syndrome. J. Biol. Chem. 275, 20027-20032. (Pubitemid 30441611)
125. Kaneko Y., Kitamoto T., Tateishi J., and, Yamaguchi K., (1989) Ferritin immunohistochemistry as a marker for microglia. Acta Neuropathol. 79, 129-136. (Pubitemid 19286137)
126. Kaur C., and, Ling E. A., (1995) Transient expression of transferrin receptors and localisation of iron in amoeboid microglia in postnatal rats. J. Anat. 186, 165-173.
127. Kaur C., and, Ling E. A., (1999) Increased expression of transferrin receptors and iron in amoeboid microglial cells in postnatal rats following an exposure to hypoxia. Neurosci. Lett. 262, 183-1869.
128. Kaur C., and, Ling E. A., (2008) Blood brain barrier in hypoxic-ischemic conditions. Curr. Neurovasc. Res. 5, 71-81. (Pubitemid 351302657)
129. Kaur C., Sivakumar V., Ang L. S., and, Sundaresan A., (2006) Hypoxic damage to the periventricular white matter in neonatal brain: role of vascular endothelial growth factor, nitric oxide and excitotoxicity. J. Neurochem. 98, 1200-1216. (Pubitemid 44127795)
130. Keown P., and, Descamps-Latscha B., (1983) In vitro suppression of cell-mediated immunity by ferroproteins and ferric salts. Cell. Immunol. 80, 257-266. (Pubitemid 13005982)
131. Khalil M., Enzinger C., Langkammer C., Tscherner M., Wallner-Blazek M., Jehna M., Ropele S., Fuchs S., and, Fazekas F., (2009) Quantitative assessment of brain iron by R(2)* relaxometry in patients with clinically isolated syndrome and relapsing-remitting multiple sclerosis. Mult. Scler. 15, 1048-1054.
132. Knickelbein J. E., de Souza A. J., Tosti R., Narayan P., and, Kane L. P., (2006) Cutting edge: inhibition of T cell activation by TIM-2. J. Immunol. 177, 4966-4970. (Pubitemid 44527565)
133. Knutson M., and, Wessling-Resnick M., (2003) Iron metabolism in the reticuloendothelial system. Crit. Rev. Biochem. Mol. Biol. 38, 61-88. (Pubitemid 36308351)
134. Koeppen A. H., Dickson A. C., and, McEvoy J. A., (1995) The cellular reactions to experimental intracerebral hemorrhage. J. Neurol. Sci. 134 (Suppl), 102-112.
135. Kotze M. J., de Villiers J. N., Rooney R. N., Grobbelaar J. J., Mansvelt E. P., Bouwens C. S., Carr J., Stander I., and, du Plessis L., (2001) Analysis of the NRAMP1 gene implicated in iron transport: association with multiple sclerosis and age effects. Blood Cells Mol. Dis. 27, 44-53. (Pubitemid 32299753)
136. Kotze M. J., de Villiers J. N., Warnich L., Schmidt S., Carr J., Mansvelt E., Fourie E., and, van Rensburg S. J., (2006) Lack of clinical manifestation of hereditary haemochromatosis in South African patients with multiple sclerosis. Metab. Brain Dis. 21, 109-120.
137. Kuchroo V. K., Umetsu D. T., DeKruyff R. H., and, Freeman G. J., (2003) The TIM gene family: emerging roles in immunity and disease. Nat. Rev. Immunol. 3, 454-462. (Pubitemid 37339185)
138. Kupershmidt L., Weinreb O., Amit T., Mandel S., Bar-Am O., and, Youdim M. B., (2011) Novel molecular targets of the neuroprotective/neurorescue multimodal iron chelating drug M30 in the mouse brain. Neuroscience 189, 345-358.
139. Kutzelnigg A., and, Lassmann H., (2005) Cortical lesions and brain atrophy in MS. J. Neurol. Sci. 233, 55-59. (Pubitemid 40804816)
140. Lall M. M., Ferrell J., Nagar S., Fleisher L. N., and, McGahan M. C., (2008) Iron regulates L-cystine uptake and glutathione levels in lens epithelial and retinal pigment epithelial cells by its effect on cytosolic aconitase. Invest. Ophthalmol. Vis. Sci. 49, 310-419.
141. Langemann H., Kabiersch A., and, Newcombe J., (1992) Measurement of low-molecular-weight antioxidants, uric acid, tyrosine and tryptophan in plaques and white matter from patients with multiple sclerosis. Eur. Neurol. 32, 248-252.
142. Langkammer C., Krebs N., Goessler W., Scheurer E., Ebner F., Yen K., Fazekas F., and, Ropele S., (2010) Quantitative MR imaging of brain iron: a postmortem validation study. Radiology 257, 455-462.
143. Lassmann H., (2003) Hypoxia-like tissue injury as a component of multiple sclerosis lesions. J. Neurol. Sci. 206, 187-191. (Pubitemid 36143726)
144. Lassmann H., (2011) Mechanisms of neurodegeneration shared between multiple sclerosis and Alzheimer's disease. J. Neural. Transm. 118, 747-752.
145. Law M., Saindane A. M., Ge Y., Babb J. S., Johnson G., Mannon L. J., Herbert J., and, Grossman R. I., (2004) Microvascular abnormality in relapsing-remitting multiple sclerosis: perfusion MR imaging findings in normal-appearing white matter. Radiology 231, 645-652. (Pubitemid 38668078)
146. Leppert D., Ford J., Stabler G., Grygar C., Lienert C., Huber S., Miller K. M., Hauser S. L., and, Kappos L., (1998) Matrix metalloproteinase-9 (gelatinase B) is selectively elevated in CSF during relapses and stable phases of multiple sclerosis. Brain 121, 2327-2334. (Pubitemid 28552469)
147. LeVine S. M., (1991) Oligodendrocytes and myelin sheaths in normal,
148. LeVine S. M., (1997) Iron deposits in multiple sclerosis and Alzheimer's disease brains. Brain Res. 760, 298-303. (Pubitemid 27304170)
149. LeVine S. M., and, Brown D. C., (1997) IL-6 and TNFalpha expression in brains of twitcher, quaking and normal mice. J. Neuroimmunol. 73, 47-56. (Pubitemid 27105268)
150. LeVine S. M., and, Chakrabarty A., (2004) The role of iron in the pathogenesis of experimental allergic encephalomyelitis and multiple sclerosis. Ann. NY Acad. Sci. 1012, 252-266. (Pubitemid 38453530)
151. LeVine S. M., and, Macklin W. B., (1990) Iron-enriched oligodendrocytes: a reexamination of their spatial distribution. J. Neurosci. Res. 26, 508-512.
152. LeVine S. M., and, Torres M. V., (1992) Morphological features of degenerating oligodendrocytes in twitcher mice. Brain Res. 587, 348-352.
153. LeVine S. M., and, Wetzel D. L., (1998) Chemical analysis of multiple sclerosis lesions by FT-IR microspectroscopy. Free Radic. Biol. Med. 25, 33-41. (Pubitemid 28285268)
154. LeVine S. M., Lynch S. G., Ou C. N., Wulser M. J., Tam E., and, Boo N., (1999) Ferritin, transferrin and iron concentrations in the cerebrospinal fluid of multiple sclerosis patients. Brain Res. 821, 511-515. (Pubitemid 29222815)
155. LeVine S. M., Maiti S., Emerson M. R., and, Pedchenko T. V., (2002) Apoferritin attenuates experimental allergic encephalomyelitis in SJL mice. Dev. Neurosci. 24, 177-183. (Pubitemid 36151448)
156. Li H., Swiercz R., and, Englander E. W., (2009) Elevated metals compromise repair of oxidative DNA damage via the base excision repair pathway: implications of pathologic iron overload in the brain on integrity of neuronal DNA. J. Neurochem. 110, 1774-1783.
157. Li L., Fang C. J., Ryan J. C., et al. (2010) Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Proc. Natl Acad. Sci. USA 107, 3505-3510.
158. Lin H. H., and, Connor J. R., (1989) The development of the transferrin-transferrin receptor system in relation to astrocytes, MBP and galactocerebroside in normal and myelin-deficient rat optic nerves. Brain Res. Dev. Brain Res. 49, 281-293. (Pubitemid 19250379)
159. Liuzzi G. M., Trojano M., Fanelli M., Avolio C., Fasano A., Livrea P., and, Riccio P., (2002) Intrathecal synthesis of matrix metalloproteinase-9 in patients with multiple sclerosis: implication for pathogenesis. Mult. Scler. 8, 222-228. (Pubitemid 34654058)
160. Lok C. N., and, Ponka P., (1999) Identification of a hypoxia response element in the transferrin receptor gene. J. Biol. Chem. 274, 24147-24152.
161. Lucchinetti C., Brück W., Parisi J., Scheithauer B., Rodriguez M., and, Lassmann H., (1999) A quantitative analysis of oligodendrocytes in multiple sclerosis lesions. A study of 113 cases. Brain 122, 2279-2295.
162. Lynch S. G., Peters K., and, LeVine S. M., (1996) Desferrioxamine in chronic progressive multiple sclerosis: a pilot study. Mult. Scler. 2, 157-160.
163. Lynch S. G., Fonseca T., and, LeVine S. M., (2000) A multiple course trial of desferrioxamine in chronic progressive multiple sclerosis. Cell. Mol. Biol. (Noisy-le-grand) 46, 865-869.
164. Mackenzie B., and, Hediger M. A., (2004) SLC11 family of H+-coupled metal-ion transporters NRAMP1 and DMT1. Pflugers Arch. 447, 571-579. (Pubitemid 38258216)
165. MacMicking J. D., Willenborg D. O., Weidemann M. J., Rockett K. A., and, Cowden W. B., (1992) Elevated secretion of reactive nitrogen and oxygen intermediates by inflammatory leukocytes in hyperacute experimental autoimmune encephalomyelitis: enhancement by the soluble products of encephalitogenic T cells. J. Exp. Med. 176, 303-307.
166. Maeda A., and, Sobel R. A., (1996) Matrix metalloproteinases in the normal human central nervous system, microglial nodules, and multiple sclerosis lesions. J. Neuropathol. Exp. Neurol. 55, 300-309. (Pubitemid 26085579)
167. Mahad D., Lassmann H., and, Turnbull D., (2008a) Review: mitochondria and disease progression in multiple sclerosis. Neuropathol. Appl. Neurobiol. 34, 577-589.
168. Mahad D., Ziabreva I., Lassmann H., and, Turnbull D., (2008b) Mitochondrial defects in acute multiple sclerosis lesions. Brain 131, 1722-1735. (Pubitemid 351957459)
169. Mairuae N., Connor J. R., and, Cheepsunthorn P., (2011) Increased cellular iron levels affect matrix metalloproteinase expression and phagocytosis in activated microglia. Neurosci. Lett. 500, 36-40.
170. Mao P., and, Reddy P. H., (2010) Is multiple sclerosis a mitochondrial disease? Biochim. Biophys. Acta 1802, 66-79.
171. Marder E., Gupta P., Greenberg B. M., Frohman E. M., Awad A. M., Bagert B., and, Stüve O., (2011) No cerebral or cervical venous insufficiency in US veterans with multiple sclerosis. Arch. Neurol. (in press).
172. Mastroberardino P. G., Hoffman E. K., Horowitz M. P., et al. (2009) A novel transferrin/TfR2-mediated mitochondrial iron transport system is disrupted in Parkinson's disease. Neurobiol. Dis. 34, 417-431.
173. Matute C., (2011) Glutamate and ATP signalling in white matter pathology. J. Anat. 219, 53-64.
174. Matute C., Sánchez-Gõmez M. V., Martínez- Millán L., and, Miledi R., (1997) Glutamate receptor-mediated toxicity in optic nerve oligodendrocytes. Proc. Natl Acad. Sci. USA 94, 8830-8835. (Pubitemid 27335125)
175. Matzner Y., Hershko C., Polliack A., Konijn A. M., and, Izak G., (1979) Suppressive effect of ferritin on in vitro lymphocyte function. Br. J. Haematol. 42, 345-353. (Pubitemid 9221025)
176. McFarland H. F., and, Martin R., (2007) Multiple sclerosis: a complicated picture of autoimmunity. Nat. Immunol. 8, 913-919. (Pubitemid 47300005)
177. McGahan M. C., Harned J., Mukunnemkeril M., Goralska M., Fleisher L., and, Ferrell J. B., (2005) Iron alters glutamate secretion by regulating cytosolic aconitase activity. Am. J. Physiol. Cell Physiol. 288, C1117-1124. (Pubitemid 40559387)
178. Mehindate K., Sahlas D. J., Frankel D., Mawal Y., Liberman A., Corcos J., Dion S., and, Schipper H. M., (2001) Proinflammatory cytokines promote glial heme oxygenase-1 expression and mitochondrial iron deposition: implications for multiple sclerosis. J. Neurochem. 77, 1386-1395. (Pubitemid 32523691)
179. Mitchell K. M., Dotson A. L., Cool K. M., Chakrabarty A., Benedict S. H., and, LeVine S. M., (2007) Deferiprone, an orally deliverable iron chelator, ameliorates experimental autoimmune encephalomyelitis. Mult. Scler. 13, 1118-1126. (Pubitemid 351541415)
180. Miyachi S., Lu X., Imanishi M., Sawada K., Nambu A., and, Takada M., (2006) Somatotopically arranged inputs from putamen and subthalamic nucleus to primary motor cortex. Neurosci. Res. 56, 300-308. (Pubitemid 44572539)
181. Moos T., and, Morgan E. H., (2000) Transferrin and transferrin receptor function in brain barrier systems. Cell. Mol. Neurobiol. 20, 77-95. (Pubitemid 30090917)
182. Moos T., and, Morgan E. H., (2004) The metabolism of neuronal iron and its pathogenic role in neurological disease: review. Ann. NY Acad. Sci. 1012, 14-26. (Pubitemid 38453512)
183. Moos T., Trinder D., and, Morgan E. H., (2000) Cellular distribution of ferric iron, ferritin, transferrin and divalent metal transporter 1 (DMT1) in substantia nigra and basal ganglia of normal and beta2-microglobulin deficient mouse brain. Cell. Mol. Biol. (Noisy-le-grand) 46, 549-561.
184. Moos T., Rosengren Nielsen T., Skjorringe T., and, Morgan E. H., (2007) Iron trafficking inside the brain. J. Neurochem. 103, 1730-1740. (Pubitemid 350126643)
185. Neema M., Arora A., Healy B. C., et al. (2009) Deep gray matter involvement on brain MRI scans is associated with clinical progression in multiple sclerosis. J. Neuroimaging 19, 3-8.
186. Norstrand I. F., and, Craelius W., (1989) A trial of deferoxamine (Desferal) in the treatment of multiple sclerosis. A pilot study. Clinical Trials 26, 365-369. (Pubitemid 20069424)
187. Omori N., Maruyama K., Jin G., Li F., Wang S. J., Hamakawa Y., Sato K., Nagano I., Shoji M., and, Abe K., (2003) Targeting of post-ischemic cerebral endothelium in rat by liposomes bearing polyethylene glycol-coupled transferrin. Neurol. Res. 25, 275-279. (Pubitemid 36520484)
188. Ong W. Y., Ren M. Q., Makjanic J., Lim T. M., and, Watt F., (1999) A nuclear microscopic study of elemental changes in the rat hippocampus after kainate-induced neuronal injury. J. Neurochem. 72, 1574-1579. (Pubitemid 29140830)
189. Onyango I. G., Lu J., Rodova M., Lezi E., Crafter A. B., and, Swerdlow R. H., (2010) Regulation of neuron mitochondrial biogenesis and relevance to brain health. Biochim. Biophys. Acta 1802, 228-234.
190. Onyszchuk G., LeVine S. M., Brooks W. M., and, Berman N. E., (2009) Post-acute pathological changes in the thalamus and internal capsule in aged mice following controlled cortical impact injury: a magnetic resonance imaging, iron histochemical, and glial immunohistochemical study. Neurosci. Lett. 452, 204-208.
191. Oweida A. J., Dunn E. A., Karlik S. J., Dekaban G. A., and, Foster P. J., (2007) Iron-oxide labeling of hematogenous macrophages in a model of experimental autoimmune encephalomyelitis and the contribution to signal loss in fast imaging employing steady state acquisition (FIESTA) images. J. Magn. Reson. Imaging 26, 144-151. (Pubitemid 47235242)
192. Pampliega O., Domercq M., Soria F. N., Villoslada P., Rodríguez-Antigüedad A., and, Matute C., (2011) Increased expression of cystine/glutamate antiporter in multiple sclerosis. J. Neuroinflammation 8, 63.
193. Paradkar P. N., and, Roth J. A., (2006) Nitric oxide transcriptionally down-regulates specific isoforms of divalent metal transporter (DMT1) via NF-kappaB. J. Neurochem. 96, 1768-1777. (Pubitemid 43351634)
194. Pedchenko T. V., and, LeVine S. M., (1998) Desferrioxamine suppresses experimental allergic encephalomyelitis induced by MBP in SJL mice. J. Neuroimmunol. 84, 188-197. (Pubitemid 28248405)
195. Pelizzoni I., Macco R., Morini M. F., Zacchetti D., Grohovaz F., and, Codazzi F., (2011) Iron handling in hippocampal neurons: activity-dependent iron entry and mitochondria-mediated neurotoxicity. Aging Cell 10, 172-183.
196. Penkowa M., Espejo C., Martinez-Caceres E. M., Poulsen C. B., Montalban X., and, Hidalgo J., (2001) Altered inflammatory response and increased neurodegeneration in metallothionein I+II deficient mice during experimental autoimmune encephalomyelitis. J. Neuroimmunol. 119, 248-260. (Pubitemid 32918333)
197. Peterson J. W., Bö L., Mörk S., Chang A., and, Trapp B. D., (2001) Transected neurites, apoptotic neurons, and reduced inflammation in cortical multiple sclerosis lesions. Ann. Neurol. 50, 389-400. (Pubitemid 32848742)
198. Petzold A., Eikelenboom M. J., Gveric D., et al. (2002) Markers for different glial cell responses in multiple sclerosis: clinical and pathological correlations. Brain 125, 1462-1473. (Pubitemid 34755162)
199. Piñero D. J., and, Connor J. R., (2000) Iron in the brain: an important contributor in normal and diseased states. Neuroscientist 6, 435-453.
200. Pirko I., Johnson A. J., Lohrey A. K., Chen Y., and, Ying J., (2009) Deep gray matter T2 hypointensity correlates with disability in a murine model of MS. J. Neurol. Sci. 282, 34-38.
201. Pirko I., Johnson A. J., Chen Y., Lindquist D. M., Lohrey A. K., Ying J., and, Dunn R. S., (2011) Brain atrophy correlates with functional outcome in a murine model of multiple sclerosis. Neuroimage 54, 802-806.
202. Prinster A., Quarantelli M., Orefice G., et al. (2006) Grey matter loss in relapsing-remitting multiple sclerosis: a voxel-based morphometry study. Neuroimage 29, 859-867. (Pubitemid 43121211)
203. Proescholdt M. A., Jacobson S., Tresser N., Oldfield E. H., and, Merrill M. J., (2002) Vascular endothelial growth factor is expressed in multiple sclerosis plaques and can induce inflammatory lesions in experimental allergic encephalomyelitis rats. J. Neuropathol. Exp. Neurol. 61, 914-925.
204. Putnam T., (1937) Evidences of vascular occlusion in multiple sclerosis and "encephalomyelitis". Arch. Neurol. Psychiatry 37, 1298-1321.
205. Qian Z. M., Wu X. M., Fan M., Yang L., Du F., Yung W. H., and, Ke Y., (2011) Divalent metal transporter 1 is a hypoxia-inducible gene. J. Cell. Physiol. 226, 1596-1603.
206. Rajan K. S., Colburn R. W., and, Davis J. M., (1976) Distribution of metal ions in the subcellular fractions of several rat brain areas. Life Sci. 18, 423-431.
207. Ram M., Sherer Y., and, Shoenfeld Y., (2006) Matrix metalloproteinase-9 and autoimmune diseases. J. Clin. Immunol. 26, 299-307. (Pubitemid 44051377)
208. Ramagopalan S. V., Cukjati M., Cernilec M., DeLuca G. C., Dyment D. A., Degenhardt A., Sadovnick A. D., Serbec V. C., Ebers G. C., and, Duquette P., (2008) Mutations in the hemochromatosis gene and the clinical outcome of multiple sclerosis. J. Neuroimmunol. 203, 104-107.
209. Rausch M., Hiestand P., Foster C. A., Baumann D. R., Cannet C., and, Rudin M., (2004) Predictability of FTY720 efficacy in experimental autoimmune encephalomyelitis by in vivo macrophage tracking: clinical implications for ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging. J. Magn. Reson. Imaging 20, 16-24. (Pubitemid 38857512)
210. Recalcati S., Invernizzi P., Arosio P., and, Cairo G., (2008) New functions for an iron storage protein: the role of ferritin in immunity and autoimmunity. J. Autoimmun. 30, 84-89.
211. Richardson D. R., Lane D. J., Becker E. M., Huang M. L., Whitnall M., Rahmanto Y. S., Sheftel A. D., and, Ponka P., (2010) Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol. Proc. Natl Acad. Sci. USA 107, 10775-10782.
212. Risti S., Lovreci L., Brajenovi-Mili B., Starcevi-Cizmarevi N., Jazbec S. S., Sepci J., Kapovi M., and, Peterlin B., (2005) Mutations in the hemochromatosis gene (HFE) and multiple sclerosis. Neurosci. Lett. 383, 301-304. (Pubitemid 40805574)
213. Robb S. J., and, Connor J. R., (1998) An in vitro model for analysis of oxidative death in primary mouse astrocytes. Brain Res. 788, 125-132. (Pubitemid 28202152)
214. Robb S. J., Robb-Gaspers L. D., Scaduto Jr R. C., Thomas A. P., and, Connor J. R., (1999) Influence of calcium and iron on cell death and mitochondrial function in oxidatively stressed astrocytes. J. Neurosci. Res. 55, 674-686. (Pubitemid 29173482)
215. Roediger B., and, Armati P. J., (2003) Oxidative stress induces axonal beading in cultured human brain tissue. Neurobiol. Dis. 13, 222-229. (Pubitemid 36937205)
216. Rogers J. T., Bridges K. R., Durmowicz G. P., Glass J., Auron P. E., and, Munro H. N., (1990) Translational control during the acute phase response. Ferritin synthesis in response to interleukin-1. J. Biol. Chem. 265, 14572-14578.
217. Roscoe W. A., Welsh M. E., Carter D. E., and, Karlik S. J., (2009) VEGF and angiogenesis in acute and chronic MOG((35-55)) peptide induced EAE. J. Neuroimmunol. 209, 6-15.
218. Ruiz de Almodovar C., Lambrechts D., Mazzone M., and, Carmeliet P., (2009) Role and therapeutic potential of VEGF in the nervous system. Physiol. Rev. 89, 607-48.
219. Russo C., Smoker W. R., and, Kubal W., (1997) Cortical and subcortical T2 shortening in multiple sclerosis. AJNR Am. J. Neuroradiol. 18, 124-126. (Pubitemid 27036640)
220. Ruuls S. R., Bauer J., Sontrop K., Huitinga I., t Hart B. A., and, Dijkstra C. D., (1995) Reactive oxygen species are involved in the pathogenesis of experimental allergic encephalomyelitis in Lewis rats. J. Neuroimmunol. 56, 207-217.
221. Salazar J., Mena N., Hunot S., et al. (2008) Divalent metal transporter 1 (DMT1) contributes to neurodegeneration in animal models of Parkinson's disease. Proc. Natl Acad. Sci. USA 105, 18578-18583.
222. Saleh M. C., Espinosa de los Monteros A., de Arriba Zerpa G. A., et al. (2003) Myelination and motor coordination are increased in transferrin transgenic mice. J. Neurosci. Res. 72, 587-594. (Pubitemid 36578644)
223. Saleppico S., Mazzolla R., Boelaert J. R., Puliti M., Barluzzi R., Bistoni F., and, Blasi E., (1996) Iron regulates microglial cell-mediated secretory and effector functions. Cell. Immunol. 170, 251-259. (Pubitemid 26227851)
224. Sastry S., and, Arendash G. W., (1995) Time-dependent changes in iron levels and associated neuronal loss within the substantia nigra following lesions within the neostriatum/globus pallidus complex. Neuroscience 67, 649-666.
225. Sayre L. M., Moreira P. I., Smith M. A., and, Perry G., (2005) Metal ions and oxidative protein modification in neurological disease. Ann. Ist. Super. Sanita. 41, 143-164. (Pubitemid 43169859)
226. Seabrook T. J., Littlewood-Evans A., Brinkmann V., Pöllinger B., Schnell C., and, Hiestand P. C., (2010) Angiogenesis is present in experimental autoimmune encephalomyelitis and pro-angiogenic factors are increased in multiple sclerosis lesions. J. Neuroinflammation 7, 95.
227. Sfagos C., Makis A. C., Chaidos A., Hatzimichael E. C., Dalamaga A., Kosma K., and, Bourantas K. L., (2005) Serum ferritin, transferrin and soluble transferrin receptor levels in multiple sclerosis patients. Mult. Scler. 11, 272-275. (Pubitemid 40775181)
228. Sharp C. D., Hines I., Houghton J., et al. (2003) Glutamate causes a loss in human cerebral endothelial barrier integrity through activation of NMDA receptor. Am. J. Physiol. Heart Circ. Physiol. 285, H2592-H2598. (Pubitemid 37443078)
229. Sharp C. D., Houghton J., Elrod J. W., Warren A., Jackson 4th T. H., Jawahar A., Nanda A., Minagar A., and, Alexander J. S., (2005) N-methyl-D-aspartate receptor activation in human cerebral endothelium promotes intracellular oxidant stress. Am. J. Physiol. Heart Circ. Physiol. 288, H1893-H1899. (Pubitemid 40418018)
230. Shoham S., Wertman E., and, Ebstein R. P., (1992) Iron accumulation in the rat basal ganglia after excitatory amino acid injections - dissociation from neuronal loss. Exp. Neurol. 118, 227-241.
231. Silkis I., (2001) The cortico-basal ganglia-thalamocortical circuit with synaptic plasticity. II. Mechanism of synergistic modulation of thalamic activity via the direct and indirect pathways through the basal ganglia. Biosystems 59, 7-14. (Pubitemid 32156930)
232. Sindrilaru A., Peters T., Wieschalka S., et al. (2011) An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J. Clin. Invest. 121, 985-997.
233. Singh A. V., and, Zamboni P., (2009) Anomalous venous blood flow and iron deposition in multiple sclerosis. J. Cereb. Blood Flow Metab. 29, 1867-1878.
234. Sinor A. D., Irvin S. M., Cobbs C. S., Chen J., Graham S. H., and, Greenberg D. A., (1998) Hypoxic induction of vascular endothelial growth factor (VEGF) protein in astroglial cultures. Brain Res. 812, 289-291. (Pubitemid 29005363)
235. Smirnov I. M., Bailey K., Flowers C. H., Garrigues N. W., and, Wesselius L. J., (1999) Effects of TNF-alpha and IL-1beta on iron metabolism by A549 cells and influence on cytotoxicity. Am. J. Physiol. 277, L257-L263. (Pubitemid 29415082)
236. Srinivasan R., Sailasuta N., Hurd R., Nelson S., and, Pelletier D., (2005) Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T. Brain 128, 1016-1025. (Pubitemid 40675457)
237. Srinivasan R., Ratiney H., Hammond-Rosenbluth K. E., Pelletier D., and, Nelson S. J., (2010) MR spectroscopic imaging of glutathione in the white and gray matter at 7 T with an application to multiple sclerosis. Magn. Reson. Imaging 28, 163-170.
238. Stoll G., Wesemeier C., Gold R., Solymosi L., Toyka K. V., and, Bendszus M., (2004) In vivo monitoring of macrophage infiltration in experimental autoimmune neuritis by magnetic resonance imaging. J. Neuroimmunol. 149, 142-146. (Pubitemid 38352867)
239. Sun D., Tani M., Newman T. A., et al. (2000) Role of chemokines, neuronal projections, and the blood-brain barrier in the enhancement of cerebral EAE following focal brain damage. J. Neuropathol. Exp. Neurol. J. Neuropathol. Exp. Neurol. 59, 1031-1043. (Pubitemid 32006306)
240. Sundstrom P., Wahlin A., Ambarki K., Birgander R., Eklund A., and, Malm J., (2010) Venous and cerebrospinal fluid flow in multiple sclerosis: a case-control study. Ann. Neurol. 68, 255-259.
241. Sweeney M. E., Slusser J. G., Lynch S. G., Benedict S. H., Garcia S. L., Rues L., and, LeVine S. M., (2011) Deferiprone modulates in vitro responses by peripheral blood T cells from control and relapsing-remitting multiple sclerosis subjects. Int. Immunopharmacol. 11, 1796-1801.
242. Tacchini L., Gammella E., De Ponti C., Recalcati S., and, Cairo G., (2008) Role of HIF-1 and NF-kappaB transcription factors in the modulation of transferrin receptor by inflammatory and anti-inflammatory signals. J. Biol. Chem. 283, 20674-20686.
243. Takeuchi H., Mizuno T., Zhang G., Wang J., Kawanokuchi J., Kuno R., and, Suzumura A., (2005) Neuritic beading induced by activated microglia is an early feature of neuronal dysfunction toward neuronal death by inhibition of mitochondrial respiration and axonal transport. J. Biol. Chem. 280, 10444-10454. (Pubitemid 40395902)
244. Tanaka R., Iwasaki Y., and, Koprowski H., (1975) Ultrastructural studies of perivascular cuffing cells in multiple sclerosis brain. Am. J. Pathol. 81, 467-478.
245. Taylor M. C., and, Kelly J. M., (2010) Iron metabolism in trypanosomatids, and its crucial role in infection. Parasitology 137, 899-917.
246. Tjoa C. W., Benedict R. H., Weinstock-Guttman B., Fabiano A. J., and, Bakshi R., (2005) MRI T2 hypointensity of the dentate nucleus is related to ambulatory impairment in multiple sclerosis. J. Neurol. Sci. 234, 17-24. (Pubitemid 40910338)
247. Todorich B., Zhang X., Slagle-Webb B., Seaman W. E., and, Connor J. R., (2008) Tim-2 is the receptor for H-ferritin on oligodendrocytes. J. Neurochem. 107, 1495-1505.
248. Todorich B., Pasquini J. M., Garcia C. I., Paez P. M., and, Connor J. R., (2009) Oligodendrocytes and myelination: the role of iron. Glia 57, 467-478.
249. Todorich B., Zhang X., and, Connor J. R., (2011) H-ferritin is the major source of iron for oligodendrocytes. Glia 59, 927-935.
250. van Toorn R., Schoeman J. F., Solomons R., Rensburg M. A., and, van Rensburg S. J., (2010) Iron status in children with recurrent episodes of tumefactive cerebral demyelination. J. Child Neurol. 25, 1401-1407.
251. Tovar-Y-Romo L. B., and, Tapia R., (2010) VEGF protects spinal motor neurons against chronic excitotoxic degeneration in vivo by activation of PI3-K pathway and inhibition of p38MAPK. J. Neurochem. 115, 1090-1101.
252. Trapp B. D., and, Stys P. K., (2009) Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol. 8, 280-291.
253. Trapp B. D., Peterson J., Ransohoff R. M., Rudick R., Mork S., and, Bo L., (1998) Axonal transection in the lesions of multiple sclerosis. N. Engl. J. Med. 338, 278-285. (Pubitemid 28065253)
254. Trapp B. D., Ransohoff R., and, Rudick R., (1999) Axonal pathology in multiple sclerosis: relationship to neurologic disability. Curr. Opin. Neurol. 12, 295-302. (Pubitemid 29378163)
255. Trebst C., Staugaitis S. M., Tucky B., Wei T., Suzuki K., Aldape K. D., Pardo C. A., Troncoso J., Lassmann H., and, Ransohoff R. M., (2003) Chemokine receptors on infiltrating leucocytes in inflammatory pathologies of the central nervous system (CNS). Neuropathol. Appl. Neurobiol. 29, 584-595. (Pubitemid 37548353)
256. Trigwell S. M., Radford P. M., Page S. R., Loweth A. C., James R. F., Morgan N. G., and, Todd I., (2001) Islet glutamic acid decarboxylase modified by reactive oxygen species is recognized by antibodies from patients with type 1 diabetes mellitus. Clin. Exp. Immunol. 126, 242-249. (Pubitemid 32995138)
257. Tsuji Y., Miller L. L., Miller S. C., Torti S. V., and, Torti F. M., (1991) Tumor necrosis factor-alpha and interleukin 1-alpha regulate transferrin receptor in human diploid fibroblasts. Relationship to the induction of ferritin heavy chain. J. Biol. Chem. 266, 7257-7261. (Pubitemid 21906360)
258. Vercellino M., Plano F., Votta B., Mutani R., Giordana M. T., and, Cavalla P., (2005) Grey matter pathology in multiple sclerosis. J. Neuropathol. Exp. Neurol. 64, 1101-1107.
259. Vercellino M., Merola A., Piacentino C., Votta B., Capello E., Mancardi G. L., Mutani R., Giordana M. T., and, Cavalla P., (2007) Altered glutamate reuptake in relapsing-remitting and secondary progressive multiple sclerosis cortex: correlation with microglia infiltration, demyelination, and neuronal and synaptic damage. J. Neuropathol. Exp. Neurol. 66, 732-739. (Pubitemid 47344252)
260. Vercellino M., Masera S., Lorenzatti M., et al. (2009) Demyelination, inflammation, and neurodegeneration in multiple sclerosis deep gray matter. J. Neuropathol. Exp. Neurol. 68, 489-502.
261. Wakefield A. J., More L. J., Difford J., and, McLaughlin J. E., (1994) Immunohistochemical study of vascular injury in acute multiple sclerosis. J. Clin. Pathol. 47, 129-133. (Pubitemid 24095465)
262. Wang J., and, Pantopoulos K., (2011) Regulation of cellular iron metabolism. Biochem. J. 434, 365-381.
263. Wang X. S., Ong W. Y., and, Connor J. R., (2002) Increase in ferric and ferrous iron in the rat hippocampus with time after kainate-induced excitotoxic injury. Exp. Brain Res. 143, 137-148.
264. Warnke C., Meyer Zu Hörste G., Hartung H. P., Stüve O., and, Kieseier B. C., (2009) Review of teriflunomide and its potential in the treatment of multiple sclerosis. Neuropsychiatr. Dis. Treat. 5, 333-340.
265. Werner P., Pitt D., and, Raine C. S., (2001) Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage. Ann. Neurol. 50, 169-180. (Pubitemid 32738141)
266. Williams R., Rohr A. M., Wang W.-T., Choi I.-Y., Lee P., Berman N. E. J., Lynch S. G., and, LeVine S. M., (2011) Iron deposition is independent of cellular inflammation in a cerebral model of multiple sclerosis. BMC Neuroscience 12, 59.
267. Witte M. E., Bo L., Rodenburg R. J., et al. (2009) Enhanced number and activity of mitochondria in multiple sclerosis lesions. J. Pathol. 219, 193-204.
268. Wong R., (2006) NMDA receptors expressed in oligodendrocytes. Bioessays 28, 460-464. (Pubitemid 43668061)
269. Worthington V., Killestein J., Eikelenboom M. J., Teunissen C. E., Barkhof F., Polman C. H., Uitdehaag B. M., and, Petzold A., (2010) Normal CSF ferritin levels in MS suggest against etiologic role of chronic venous insufficiency. Neurol. 75, 1617-1622.
270. Xu X., Wang Q., and, Zhang M., (2008) Age, gender, and hemispheric differences in iron deposition in the human brain: an in vivo MRI study. Neuroimage 40, 35-42.
271. Yin W., Signore A. P., Iwai M., Cao G., Gao Y., and, Chen J., (2008) Rapidly increased neuronal mitochondrial biogenesis after hypoxic-ischemic brain injury. Stroke 39, 3057-3063.
272. Yu J., Guo Y., Sun M., Li B., Zhang Y., and, Li C., (2009) Iron is a potential key mediator of glutamate excitotoxicity in spinal cord motor neurons. Brain Res. 1257, 102-107.
273. Zamboni P., (2006) The big idea: iron-dependent inflammation in venous disease and proposed parallels in multiple sclerosis. J. R. Soc. Med. 99, 589-593. (Pubitemid 44876813)
274. Zamboni P., Scapoli G., Lanzara V., Izzo M., Fortini P., Legnaro R., Palazzo A., Tognazzo S., and, Gemmati D., (2005) Serum iron and matrix metalloproteinase-9 variations in limbs affected by chronic venous disease and venous leg ulcers. Dermatol. Surg. 31, 644-649. (Pubitemid 43093415)
275. Zamboni P., Menegatti E., Bartolomei I., Galeotti R., Malagoni A. M., Tacconi G., and, Salvi F., (2007) Intracranial venous haemodynamics in multiple sclerosis. Curr. Neurovasc. Res. 4, 252-258. (Pubitemid 350171825)
276. Zamboni P., Lanzara S., Mascoli F., Caggiati A., and, Liboni A., (2008) Inflammation in venous disease. Int. Angiol. 27, 361-369.
277. Zhang Z. G., Zhang L., Jiang Q., Zhang R., Davies K., Powers C., Bruggen N., and, Chopp M., (2000) VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J. Clin. Invest. 106, 829-838.
278. Zhang X., Haaf M., Todorich B., Grosstephan E., Schieremberg H., Surguladze N., and, Connor J. R., (2005) Cytokine toxicity to oligodendrocyte precursors is mediated by iron. Glia 52, 199-208. (Pubitemid 43078509)
279. Zhang X., Surguladze N., Slagle-Webb B., Cozzi A., and, Connor J. R., (2006) Cellular iron status influences the functional relationship between microglia and oligodendrocytes. Glia 54, 795-804. (Pubitemid 44671985)
280. Zhang Y., Zabad R. K., Wei X., Metz L. M., Hill M. D., and, Mitchell J. R., (2007) Deep grey matter "black T2" on 3 tesla magnetic resonance imaging correlates with disability in multiple sclerosis. Mult. Scler. 13, 880-883. (Pubitemid 351540859)
281. Zhang S., Wang J., Song N., Xie J., and, Jiang H., (2009) Up-regulation of divalent metal transporter 1 is involved in 1-methyl-4-phenylpyridinium (MPP(+))-induced apoptosis in MES23.5 cells. Neurobiol. Aging 30, 1466-1476.