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Diagnostics and Treatments of Iron-Related CNS Diseases

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Brain Iron Metabolism and CNS Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1173))

Abstract

Iron has been proposed to be responsible for neuronal loss in several diseases of the central nervous system, including Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, Friedreich’s ataxia (FRDA), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS). In many diseases, abnormal accumulation of brain iron in disease-affected area has been observed, without clear knowledge of the contribution of iron overload to pathogenesis. Recent evidences implicate that key proteins involved in the disease pathogenesis may also participate in cellular iron metabolism, suggesting that the imbalance of brain iron homeostasis is associated with the diseases. Considering the complicated regulation of iron homeostasis within the brain, a thorough understanding of the molecular events leading to this phenotype is still to be investigated. However, current understanding has already provided the basis for the diagnosis and treatment of iron-related CNS diseases, which will be reviewed here.

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References

  1. Crichton RR, Boelaert JR (2001) Inorganic biochemistry of iron metabolism: from molecular mechanisms to clinical consequences. 2nd edn. Wiley

    Google Scholar 

  2. Rouault TA (2013) Iron metabolism in the CNS: implications for neurodegenerative diseases. Nat Rev Neurosci 14:551–564. https://doi.org/10.1038/nrn3453

    Article  CAS  PubMed  Google Scholar 

  3. Crichton RR, Ward RJ (2008) Metal-based neurodegeneration: from molecular mechanisms to therapeutic strategies. 2nd edn

    Google Scholar 

  4. Hentze MW, Muckenthaler MU, Galy B, Camaschella C (2010) Two to tango: regulation of mammalian iron metabolism. Cell 142:24–38. https://doi.org/10.1016/j.cell.2010.06.028

    Article  CAS  PubMed  Google Scholar 

  5. Wang J, Pantopoulos K (2011) Regulation of cellular iron metabolism. Biochem J 434:365–381. https://doi.org/10.1042/BJ20101825

    Article  CAS  PubMed  Google Scholar 

  6. Catala A (2009) Lipid peroxidation of membrane phospholipids generates hydroxy-alkenals and oxidized phospholipids active in physiological and/or pathological conditions. Chem Phys Lipids 157:1–11. https://doi.org/10.1016/j.chemphyslip.2008.09.004

    Article  CAS  PubMed  Google Scholar 

  7. Dalle-Donne I, Giustarini D, Colombo R, Rossi R, Milzani A (2003) Protein carbonylation in human diseases. Trends Mol Med 9:169–176

    Article  CAS  PubMed  Google Scholar 

  8. Perluigi M, Coccia R, Butterfield DA (2012) 4-Hydroxy-2-nonenal, a reactive product of lipid peroxidation, and neurodegenerative diseases: a toxic combination illuminated by redox proteomics studies. Antioxid Redox Signal 17:1590–1609. https://doi.org/10.1089/ars.2011.4406

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Raha S, Robinson BH (2000) Mitochondria, oxygen free radicals, disease and ageing. Trends Biochem Sci 25:502–508

    Article  CAS  PubMed  Google Scholar 

  10. Ott M, Gogvadze V, Orrenius S, Zhivotovsky B (2007) Mitochondria, oxidative stress and cell death. Apoptosis 12:913–922. https://doi.org/10.1007/s10495-007-0756-2

    Article  CAS  PubMed  Google Scholar 

  11. Stockwell BR et al (2017) Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell 171:273–285. https://doi.org/10.1016/j.cell.2017.09.021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Dixon SJ et al (2012) Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149:1060–1072. https://doi.org/10.1016/j.cell.2012.03.042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR (2004) Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci 5:863–873. https://doi.org/10.1038/nrn1537 [pii]

    Article  CAS  PubMed  Google Scholar 

  14. Ward RJ, Zucca FA, Duyn JH, Crichton RR, Zecca L (2014) The role of iron in brain ageing and neurodegenerative disorders. Lancet Neurol 13:1045–1060. https://doi.org/10.1016/S1474-4422(14)70117-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lei P et al (2012) Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export. Nat Med 18:291–295. https://doi.org/10.1038/nm.2613

    Article  CAS  PubMed  Google Scholar 

  16. Duce JA et al (2010) Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease. Cell 142:857–867. https://doi.org/10.1016/j.cell.2010.08.014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Dietrich RB, Bradley WG Jr (1988) Iron accumulation in the basal ganglia following severe ischemic-anoxic insults in children. Radiology 168:203–206. https://doi.org/10.1148/radiology.168.1.3380958

    Article  CAS  PubMed  Google Scholar 

  18. Waldvogel D, van Gelderen P, Hallett M (1999) Increased iron in the dentate nucleus of patients with Friedrich’s ataxia. Ann Neurol 46:123–125

    Article  CAS  PubMed  Google Scholar 

  19. Kwan JY et al (2012) Iron accumulation in deep cortical layers accounts for MRI signal abnormalities in ALS: correlating 7 tesla MRI and pathology. PLoS ONE 7:e35241. https://doi.org/10.1371/journal.pone.0035241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Ropele S et al (2011) MRI assessment of iron deposition in multiple sclerosis. J Magn Reson Imaging 34:13–21. https://doi.org/10.1002/jmri.22590

    Article  PubMed  Google Scholar 

  21. Allen RP, Barker PB, Wehrl FW, Song HK, Earley CJ (2001) MRI measurement of brain iron in patients with restless legs syndrome. Neurology 56:263–265

    Article  CAS  PubMed  Google Scholar 

  22. Knopman DS et al (2001) Practice parameter: diagnosis of dementia (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56:1143–1153

    Article  CAS  PubMed  Google Scholar 

  23. Sperling RA et al (2011) Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7:280–292. https://doi.org/10.1016/j.jalz.2011.03.003

    Article  PubMed  PubMed Central  Google Scholar 

  24. Dubois B et al (2014) Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol 13:614–629. https://doi.org/10.1016/S1474-4422(14)70090-0

    Article  PubMed  Google Scholar 

  25. Dubois B et al (2016) Preclinical Alzheimer’s disease: definition, natural history, and diagnostic criteria. Alzheimers Dement 12:292–323. https://doi.org/10.1016/j.jalz.2016.02.002

    Article  PubMed  PubMed Central  Google Scholar 

  26. Zhu WZ et al (2009) Quantitative MR phase-corrected imaging to investigate increased brain iron deposition of patients with Alzheimer disease. Radiology 253:497–504. https://doi.org/10.1148/radiol.2532082324

    Article  PubMed  Google Scholar 

  27. Ayton S et al (2017) Cerebral quantitative susceptibility mapping predicts amyloid-beta-related cognitive decline. Brain 140:2112–2119. https://doi.org/10.1093/brain/awx137

    Article  PubMed  Google Scholar 

  28. Ayton S, Faux NG, Bush AI, Alzheimer’s Disease Neuroimaging I (2015) Ferritin levels in the cerebrospinal fluid predict Alzheimer’s disease outcomes and are regulated by APOE. Nat Commun 6:6760. https://doi.org/10.1038/ncomms7760

  29. de Lau LM, Breteler MM (2006) Epidemiology of Parkinson’s disease. Lancet Neurol 5:525–535. https://doi.org/10.1016/S1474-4422(06)70471-9

    Article  PubMed  Google Scholar 

  30. Powers KM et al (2009) Dietary fats, cholesterol and iron as risk factors for Parkinson’s disease. Parkinsonism Relat Disord 15:47–52. https://doi.org/10.1016/j.parkreldis.2008.03.002

    Article  PubMed  Google Scholar 

  31. Pichler I et al (2013) Serum iron levels and the risk of Parkinson disease: a Mendelian randomization study. PLoS Med 10:e1001462. https://doi.org/10.1371/journal.pmed.1001462

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jimenez-Jimenez FJ et al (1998) Cerebrospinal fluid levels of transition metals in patients with Parkinson’s disease. J Neural Transm (Vienna) 105:497–505. https://doi.org/10.1007/s007020050073

    Article  CAS  Google Scholar 

  33. Zecca L et al (2005) In vivo detection of iron and neuromelanin by transcranial sonography: a new approach for early detection of substantia nigra damage. Mov Disord 20:1278–1285. https://doi.org/10.1002/mds.20550

    Article  PubMed  Google Scholar 

  34. Becker G, Seufert J, Bogdahn U, Reichmann H, Reiners K (1995) Degeneration of substantia nigra in chronic Parkinson’s disease visualized by transcranial color-coded real-time sonography. Neurology 45:182–184

    Article  CAS  PubMed  Google Scholar 

  35. Prestel J, Schweitzer KJ, Hofer A, Gasser T, Berg D (2006) Predictive value of transcranial sonography in the diagnosis of Parkinson’s disease. Mov Disord 21:1763–1765. https://doi.org/10.1002/mds.21054

    Article  PubMed  Google Scholar 

  36. Zhang J et al (2010) Characterizing iron deposition in Parkinson’s disease using susceptibility-weighted imaging: an in vivo MR study. Brain Res 1330:124–130. https://doi.org/10.1016/j.brainres.2010.03.036

    Article  CAS  PubMed  Google Scholar 

  37. Wypijewska A et al (2010) Iron and reactive oxygen species activity in parkinsonian substantia nigra. Parkinsonism Relat Disord 16:329–333. https://doi.org/10.1016/j.parkreldis.2010.02.007

    Article  PubMed  Google Scholar 

  38. Curtis AR et al (2001) Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 28:350–354. https://doi.org/10.1038/ng571

    Article  CAS  PubMed  Google Scholar 

  39. Maciel P et al (2005) Neuroferritinopathy: missense mutation in FTL causing early-onset bilateral pallidal involvement. Neurology 65:603–605. https://doi.org/10.1212/01.wnl.0000178224.81169.c2

    Article  CAS  PubMed  Google Scholar 

  40. Osaki S, Johnson DA, Frieden E (1966) The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J Biol Chem 241:2746–2751

    CAS  PubMed  Google Scholar 

  41. McNeill A, Pandolfo M, Kuhn J, Shang H, Miyajima H (2008) The neurological presentation of ceruloplasmin gene mutations. Eur Neurol 60:200–205. https://doi.org/10.1159/000148691

    Article  PubMed  Google Scholar 

  42. Swaiman KF (1991) Hallervorden-Spatz syndrome and brain iron metabolism. Arch Neurol 48:1285–1293

    Article  CAS  PubMed  Google Scholar 

  43. Alberca R, Rafel E, Chinchon I, Vadillo J, Navarro A (1987) Late onset parkinsonian syndrome in Hallervorden-Spatz disease. J Neurol Neurosurg Psychiatry 50:1665–1668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Krishnamurthi RV et al (2013) Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990–2010: findings from the global burden of disease study 2010. Lancet Global Health 1:E259–E281

    Article  PubMed  Google Scholar 

  45. Langhorne P, Bernhardt J, Kwakkel G (2011) Stroke rehabilitation. Lancet 377:1693–1702. https://doi.org/10.1016/S0140-6736(11)60325-5

    Article  PubMed  Google Scholar 

  46. Altamura C et al (2009) Ceruloplasmin/transferrin system is related to clinical status in acute stroke. Stroke: J Cereb Circ 40:1282–1288. https://doi.org/10.1161/STROKEAHA.108.536714

    Article  CAS  Google Scholar 

  47. Davalos A et al (1994) Iron-related damage in acute ischemic stroke. Stroke: J Cereb Circ 25:1543–1546

    Article  CAS  Google Scholar 

  48. Davalos A et al (2000) Body iron stores and early neurologic deterioration in acute cerebral infarction. Neurology 54:1568–1574

    Article  CAS  PubMed  Google Scholar 

  49. Mehdiratta M, Kumar S, Hackney D, Schlaug G, Selim M (2008) Association between serum ferritin level and perihematoma edema volume in patients with spontaneous intracerebral hemorrhage. Stroke: J Cereb Circ 39:1165–1170. https://doi.org/10.1161/STROKEAHA.107.501213

    Article  CAS  Google Scholar 

  50. Perez de la Ossa, N et al (2010) Iron-related brain damage in patients with intracerebral hemorrhage. Stroke: J Cereb Circ 41:810–813. https://doi.org/10.1161/strokeaha.109.570168

    Article  PubMed  Google Scholar 

  51. Xiong XY, Wang J, Qian ZM, Yang QW (2014) Iron and intracerebral hemorrhage: from mechanism to translation. Transl Stroke Res 5:429–441. https://doi.org/10.1007/s12975-013-0317-7

    Article  CAS  PubMed  Google Scholar 

  52. Lou M, Lieb K, Selim M (2009) The relationship between hematoma iron content and perihematoma edema: an MRI study. CerebVascular Dis 27:266–271. https://doi.org/10.1159/000199464

    Article  CAS  Google Scholar 

  53. Wu JR, Tuo QZ, Lei P (2018) Ferroptosis, a recent defined form of critical cell death in neurological disorders. J Mol Neurosci: MN. https://doi.org/10.1007/s12031-018-1155-6

    Article  CAS  PubMed  Google Scholar 

  54. Li K, Reichmann H (2016) Role of iron in neurodegenerative diseases. J Neural Transm 123:389–399. https://doi.org/10.1007/s00702-016-1508-7

    Article  CAS  PubMed  Google Scholar 

  55. Boddaert N et al (2007) Selective iron chelation in Friedreich ataxia: biologic and clinical implications. Blood 110:401–408. https://doi.org/10.1182/blood-2006-12-065433

    Article  CAS  PubMed  Google Scholar 

  56. Koeppen AH, Morral JA, McComb RD, Feustel PJ (2011) The neuropathology of late-onset Friedreich’s ataxia. Cerebellum 10:96–103. https://doi.org/10.1007/s12311-010-0235-0

    Article  PubMed  PubMed Central  Google Scholar 

  57. Koeppen AH et al (2007) The dentate nucleus in Friedreich’s ataxia: the role of iron-responsive proteins. Acta Neuropathol 114:163–173. https://doi.org/10.1007/s00401-007-0220-y

    Article  CAS  PubMed  Google Scholar 

  58. Rotig A et al (1997) Aconitase and mitochondrial iron-sulphur protein deficiency in Friedreich ataxia. Nat Genet 17:215–217. https://doi.org/10.1038/ng1097-215

    Article  CAS  PubMed  Google Scholar 

  59. Codazzi F et al (2016) Friedreich ataxia-induced pluripotent stem cell-derived neurons show a cellular phenotype that is corrected by a benzamide HDAC inhibitor. Hum Mol Genet 25:4847–4855. https://doi.org/10.1093/hmg/ddw308

    Article  CAS  PubMed  Google Scholar 

  60. Auchere F, Santos R, Planamente S, Lesuisse E, Camadro JM (2008) Glutathione-dependent redox status of frataxin-deficient cells in a yeast model of Friedreich’s ataxia. Hum Mol Genet 17:2790–2802. https://doi.org/10.1093/hmg/ddn178

    Article  CAS  PubMed  Google Scholar 

  61. Wijemanne S, Ondo W (2017) Restless Legs Syndrome: clinical features, diagnosis and a practical approach to management. Pract Neurol 17:444–452. https://doi.org/10.1136/practneurol-2017-001762

    Article  PubMed  Google Scholar 

  62. Earley CJ, Barker PB, Horska A, Allen RP (2006) MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome. Sleep Med 7:458–461. https://doi.org/10.1016/j.sleep.2005.11.009

    Article  PubMed  Google Scholar 

  63. Rizzo G et al (2013) Low brain iron content in idiopathic restless legs syndrome patients detected by phase imaging. Mov Disord: Off J Mov Disord Soc 28:1886–1890. https://doi.org/10.1002/mds.25576

    Article  CAS  Google Scholar 

  64. Haba-Rubio J et al (2005) Restless legs syndrome and low brain iron levels in patients with haemochromatosis. J Neurol Neurosurg Psychiatry 76:1009–1010. https://doi.org/10.1136/jnnp.2003.030536

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Earley CJ et al (2000) Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology 54:1698–1700

    Article  CAS  PubMed  Google Scholar 

  66. Ge Y et al (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. https://doi.org/10.3174/ajnr.A0646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Haacke EM et al (2009) Characterizing iron deposition in multiple sclerosis lesions using susceptibility weighted imaging. J Magn Reson Imaging: JMRI 29:537–544. https://doi.org/10.1002/jmri.21676

    Article  PubMed  Google Scholar 

  68. Hametner S et al (2013) Iron and neurodegeneration in the multiple sclerosis brain. Ann Neurol 74:848–861. https://doi.org/10.1002/ana.23974

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Stephenson E, Nathoo N, Mahjoub Y, Dunn JF, Yong VW (2014) Iron in multiple sclerosis: roles in neurodegeneration and repair. Nat Rev Neurol 10:459–468. https://doi.org/10.1038/nrneurol.2014.118

    Article  CAS  PubMed  Google Scholar 

  70. Weigel KJ, Lynch SG, LeVine SM (2014) Iron chelation and multiple sclerosis. ASN Neuro 6:e00136. https://doi.org/10.1042/AN20130037

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Benkler C et al (2010) Recent advances in amyotrophic lateral sclerosis research: perspectives for personalized clinical application. EPMA J 1:343–361. https://doi.org/10.1007/s13167-010-0026-1

    Article  PubMed  PubMed Central  Google Scholar 

  72. Kasarskis EJ, Tandon L, Lovell MA, Ehmann WD (1995) Aluminum, calcium, and iron in the spinal cord of patients with sporadic amyotrophic lateral sclerosis using laser microprobe mass spectroscopy: a preliminary study. J Neurol Sci 130:203–208

    Article  CAS  PubMed  Google Scholar 

  73. Ignjatovic A et al (2012) Inappropriately chelated iron in the cerebrospinal fluid of amyotrophic lateral sclerosis patients. Amyotroph Lateral Scler 13:357–362. https://doi.org/10.3109/17482968.2012.665929

    Article  CAS  PubMed  Google Scholar 

  74. Golko-Perez S, Amit T, Bar-Am O, Youdim MB, Weinreb O (2017) A novel iron chelator-radical scavenger ameliorates motor dysfunction and improves life span and mitochondrial biogenesis in SOD1(G93A) ALS Mice. Neurotox Res 31:230–244. https://doi.org/10.1007/s12640-016-9677-6

    Article  CAS  PubMed  Google Scholar 

  75. Li X, Jankovic J, Le W (2011) Iron chelation and neuroprotection in neurodegenerative diseases. J Neural Transm (Vienna) 118:473–477. https://doi.org/10.1007/s00702-010-0518-0

    Article  CAS  Google Scholar 

  76. Siciliano G et al (2007) Antioxidant capacity and protein oxidation in cerebrospinal fluid of amyotrophic lateral sclerosis. J Neurol 254:575–580. https://doi.org/10.1007/s00415-006-0301-1

    Article  CAS  PubMed  Google Scholar 

  77. Goodall EF, Haque MS, Morrison KE (2008) Increased serum ferritin levels in amyotrophic lateral sclerosis (ALS) patients. J Neurol 255:1652–1656. https://doi.org/10.1007/s00415-008-0945-0

    Article  CAS  PubMed  Google Scholar 

  78. Mizuno Y et al (2006) Transferrin localizes in Bunina bodies in amyotrophic lateral sclerosis. Acta Neuropathol 112:597–603. https://doi.org/10.1007/s00401-006-0122-4

    Article  CAS  PubMed  Google Scholar 

  79. Wang XS et al (2004) Increased incidence of the Hfe mutation in amyotrophic lateral sclerosis and related cellular consequences. J Neurol Sci 227:27–33. https://doi.org/10.1016/j.jns.2004.08.003

    Article  CAS  PubMed  Google Scholar 

  80. Perls T (2004) Dementia-free centenarians. Exp Gerontol 39:1587–1593. https://doi.org/10.1016/j.exger.2004.08.015

    Article  PubMed  Google Scholar 

  81. Bush AI (2008) Drug development based on the metals hypothesis of Alzheimer’s disease. J Alzheimers Dis 15:223–240

    Article  CAS  PubMed  Google Scholar 

  82. Ayton S, Lei P, Bush AI (2015) Biometals and their therapeutic implications in Alzheimer’s disease. Neurotherapeutics 12:109–120. https://doi.org/10.1007/s13311-014-0312-z

    Article  CAS  PubMed  Google Scholar 

  83. Crapper McLachlan DR et al (1991) Intramuscular desferrioxamine in patients with Alzheimer’s disease. Lancet 337:1304–1308

    Article  Google Scholar 

  84. Fine JM et al (2012) Intranasal deferoxamine improves performance in radial arm water maze, stabilizes HIF-1alpha, and phosphorylates GSK3beta in P301L tau transgenic mice. Exp Brain Res 219:381–390. https://doi.org/10.1007/s00221-012-3101-0

    Article  CAS  PubMed  Google Scholar 

  85. Guo C et al (2013) Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer’s disease. Neurobiol Aging 34:562–575. https://doi.org/10.1016/j.neurobiolaging.2012.05.009

    Article  CAS  PubMed  Google Scholar 

  86. Guo C et al (2015) Intranasal deferoxamine attenuates synapse loss via up-regulating the P38/HIF-1alpha pathway on the brain of APP/PS1 transgenic mice. Front Aging Neurosci 7:104. https://doi.org/10.3389/fnagi.2015.00104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Di Vaira M et al (2004) Clioquinol, a drug for Alzheimer’s disease specifically interfering with brain metal metabolism: structural characterization of its zinc(II) and copper(II) complexes. Inorg Chem 43:3795–3797. https://doi.org/10.1021/ic0494051

    Article  CAS  PubMed  Google Scholar 

  88. LeVine H 3rd, Ding Q, Walker JA, Voss RS, Augelli-Szafran CE (2009) Clioquinol and other hydroxyquinoline derivatives inhibit Abeta(1-42) oligomer assembly. Neurosci Lett 465:99–103. https://doi.org/10.1016/j.neulet.2009.08.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Mancino AM, Hindo SS, Kochi A, Lim MH (2009) Effects of clioquinol on metal-triggered amyloid-beta aggregation revisited. Inorg Chem 48:9596–9598. https://doi.org/10.1021/ic9014256

    Article  CAS  PubMed  Google Scholar 

  90. Stoppelkamp S et al (2011) In vitro modelling of Alzheimer’s disease: degeneration and cell death induced by viral delivery of amyloid and tau. Exp Neurol 229:226–237. https://doi.org/10.1016/j.expneurol.2011.01.018

    Article  CAS  PubMed  Google Scholar 

  91. Cherny RA et al (2001) Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 30:665–676

    Article  CAS  PubMed  Google Scholar 

  92. Grossi C et al (2009) Clioquinol decreases amyloid-beta burden and reduces working memory impairment in a transgenic mouse model of Alzheimer’s disease. J Alzheimers Dis 17:423–440. https://doi.org/10.3233/JAD-2009-1063

    Article  CAS  PubMed  Google Scholar 

  93. Ritchie CW et al (2003) Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Archives of neurology 60:1685–1691. https://doi.org/10.1001/archneur.60.12.1685/12/1685

  94. Adlard PA et al (2008) Rapid restoration of cognition in Alzheimer’s transgenic mice with 8-hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron 59:43–55. https://doi.org/10.1016/j.neuron.2008.06.018

    Article  CAS  PubMed  Google Scholar 

  95. Adlard PA et al (2011) Metal ionophore treatment restores dendritic spine density and synaptic protein levels in a mouse model of Alzheimer’s disease. PLoS ONE 6:e17669. https://doi.org/10.1371/journal.pone.0017669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Crouch PJ et al (2011) The Alzheimer’s therapeutic PBT2 promotes amyloid-beta degradation and GSK3 phosphorylation via a metal chaperone activity. J Neurochem 119:220–230. https://doi.org/10.1111/j.1471-4159.2011.07402.x

    Article  CAS  PubMed  Google Scholar 

  97. Lannfelt L et al (2008) Safety, efficacy, and biomarker findings of PBT2 in targeting Abeta as a modifying therapy for Alzheimer’s disease: a phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurol 7:779–786. https://doi.org/10.1016/S1474-4422(08)70167-4

    Article  CAS  PubMed  Google Scholar 

  98. Faux NG et al (2010) PBT2 rapidly improves cognition in Alzheimer’s Disease: additional phase II analyses. J Alzheimers Dis 20:509–516. https://doi.org/10.3233/JAD-2010-1390

    Article  CAS  PubMed  Google Scholar 

  99. Kwiatkowski A et al (2012) Long-term improvement under deferiprone in a case of neurodegeneration with brain iron accumulation. Parkinsonism Relat Disord 18:110–112. https://doi.org/10.1016/j.parkreldis.2011.06.024

    Article  CAS  PubMed  Google Scholar 

  100. Grolez G et al (2015) Ceruloplasmin activity and iron chelation treatment of patients with Parkinson’s disease. BMC Neurol 15:74. https://doi.org/10.1186/s12883-015-0331-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Devos D et al (2014) Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid Redox Signal 21:195–210. https://doi.org/10.1089/ars.2013.5593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Lei P et al (2015) Clioquinol rescues Parkinsonism and dementia phenotypes of the tau knockout mouse. Neurobiol Dis 81:168

    Article  CAS  PubMed  Google Scholar 

  103. Ayton S et al (2013) Ceruloplasmin dysfunction and therapeutic potential for Parkinson disease. Ann Neurol 73:554–559. https://doi.org/10.1002/ana.23817

    Article  CAS  PubMed  Google Scholar 

  104. Bar-Am O et al (2015) Neuroprotective and neurorestorative activities of a novel iron chelator-brain selective monoamine oxidase-A/monoamine oxidase-B inhibitor in animal models of Parkinson’s disease and aging. Neurobiol Aging 36:1529–1542. https://doi.org/10.1016/j.neurobiolaging.2014.10.026

    Article  CAS  PubMed  Google Scholar 

  105. Gal S, Zheng H, Fridkin M, Youdim MB (2005) Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases. In vivo selective brain monoamine oxidase inhibition and prevention of MPTP-induced striatal dopamine depletion. J Neurochem 95:79–88. https://doi.org/10.1111/j.1471-4159.2005.03341.x

    Article  CAS  PubMed  Google Scholar 

  106. Zheng H et al (2005) Novel multifunctional neuroprotective iron chelator-monoamine oxidase inhibitor drugs for neurodegenerative diseases: in vitro studies on antioxidant activity, prevention of lipid peroxide formation and monoamine oxidase inhibition. J Neurochem 95:68–78. https://doi.org/10.1111/j.1471-4159.2005.03340.x

    Article  CAS  PubMed  Google Scholar 

  107. Shachar DB, Kahana N, Kampel V, Warshawsky A, Youdim MB (2004) Neuroprotection by a novel brain permeable iron chelator, VK-28, against 6-hydroxydopamine lession in rats. Neuropharmacology 46:254–263. https://doi.org/10.1016/S002839080300354X [pii]

  108. Kaur D et al (2003) Genetic or pharmacological iron chelation prevents MPTP-induced neurotoxicity in vivo: a novel therapy for Parkinson’s disease. Neuron 37:899–909. https://doi.org/10.1016/S0896627303001260 [pii]

  109. Hasan TF et al (2018) Diagnosis and management of acute ischemic stroke. Mayo Clin Proc 93:523–538. https://doi.org/10.1016/j.mayocp.2018.02.013

    Article  PubMed  Google Scholar 

  110. Iadecola C, Anrather J (2011) Stroke research at a crossroad: asking the brain for directions. Nat Neurosci 14:1363–1368. https://doi.org/10.1038/nn.2953

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Selim M (2010) Treatment with the iron chelator, deferoxamine mesylate, alters serum markers of oxidative stress in stroke patients. Transl Stroke Res 1:35–39. https://doi.org/10.1007/s12975-009-0001-0

    Article  CAS  PubMed  Google Scholar 

  112. Investigators TR (1996) A randomized trial of tirilazad mesylate in patients with acute stroke (RANTTAS). Stroke: J Cereb Circ 27:1453–1458

    Google Scholar 

  113. Haley EC Jr (1998) High-dose tirilazad for acute stroke (RANTTAS II). Stroke: J Cereb Circ 29:1256–1257

    Article  Google Scholar 

  114. Hanson LR et al (2009) Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke. J Pharmacol Exp Ther 330:679–686. https://doi.org/10.1124/jpet.108.149807

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Tuo QZ et al (2017) Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry 22:1520–1530. https://doi.org/10.1038/mp.2017.171

    Article  CAS  PubMed  Google Scholar 

  116. Jang YG, Ilodigwe D, Macdonald RL (2009) Metaanalysis of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage. Neurocrit Care 10:141–147. https://doi.org/10.1007/s12028-008-9147-y

    Article  CAS  PubMed  Google Scholar 

  117. Burk K (2017) Friedreich Ataxia: current status and future prospects. Cerebellum & Ataxias 4. https://doi.org/10.1186/s40673-017-0062-x

  118. Voncken M, Ioannou P, Delatycki MB (2004) Friedreich ataxia-update on pathogenesis and possible therapies. Neurogenetics 5:1–8. https://doi.org/10.1007/s10048-003-0170-z

    Article  PubMed  Google Scholar 

  119. Pandolfo M et al (2014) Deferiprone in Friedreich ataxia: a 6-month randomized controlled trial. Ann Neurol 76:509–521. https://doi.org/10.1002/ana.24248

    Article  CAS  PubMed  Google Scholar 

  120. Velasco-Sanchez D et al (2011) Combined therapy with idebenone and deferiprone in patients with Friedreich’s ataxia. Cerebellum 10:1–8. https://doi.org/10.1007/s12311-010-0212-7

    Article  CAS  PubMed  Google Scholar 

  121. Earley CJ, Heckler D, Allen RP (2004) The treatment of restless legs syndrome with intravenous iron dextran. Sleep Med 5:231–235. https://doi.org/10.1016/j.sleep.2004.03.002

    Article  PubMed  Google Scholar 

  122. Earley CJ et al (2009) A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome. Sleep Med 10:206–211. https://doi.org/10.1016/j.sleep.2007.12.006

    Article  PubMed  Google Scholar 

  123. Pedchenko TV, LeVine SM (1998) Desferrioxamine suppresses experimental allergic encephalomyelitis induced by MBP in SJL mice. J Neuroimmunol 84:188–197

    Article  CAS  PubMed  Google Scholar 

  124. Lynch SG, Peters K, LeVine SM (1996) Desferrioxamine in chronic progressive multiple sclerosis: a pilot study. Mult Scler 2:157–160. https://doi.org/10.1177/135245859600200306

    Article  CAS  PubMed  Google Scholar 

  125. Lynch SG, Fonseca T, LeVine SM (2000) A multiple course trial of desferrioxamine in chronic progressive multiple sclerosis. Cell Mol Biol (Noisy-le-grand) 46:865–869

    Google Scholar 

  126. Creange A, Lefaucheur JP, Balleyguier MO, Galacteros F (2013) Iron depletion induced by bloodletting and followed by rhEPO administration as a therapeutic strategy in progressive multiple sclerosis: a pilot, open-label study with neurophysiological measurements. Neurophysiol Clin = Clin Neurophysiol 43:303–312. https://doi.org/10.1016/j.neucli.2013.09.004

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Sichuan, 610041, China

    Huan Xiong, Qing-zhang Tuo & Peng Lei

  2. West China School of Basic Medical Sciences and Forensic Medicine, Sichuan University, Sichuan, 610041, China

    Yu-jie Guo & Peng Lei

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  1. Huan Xiong
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  2. Qing-zhang Tuo
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  3. Yu-jie Guo
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  4. Peng Lei
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Correspondence to Peng Lei .

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  1. College of Life Sciences, Hebei Normal University , Shijiazhuang, Hebei, China

    Yan-Zhong Chang

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Xiong, H., Tuo, Qz., Guo, Yj., Lei, P. (2019). Diagnostics and Treatments of Iron-Related CNS Diseases. In: Chang, YZ. (eds) Brain Iron Metabolism and CNS Diseases. Advances in Experimental Medicine and Biology, vol 1173. Springer, Singapore. https://doi.org/10.1007/978-981-13-9589-5_10

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