Translational Stroke Research

, Volume 5, Issue 4, pp 429–441 | Cite as

Iron and Intracerebral Hemorrhage: From Mechanism to Translation

  • Xiao-Yi Xiong
  • Jian Wang
  • Zhong-Ming Qian
  • Qing-Wu Yang
Review Article

Abstract

Intracerebral hemorrhage (ICH) is a leading cause of morbidity and mortality around the world. Currently, there is no effective medical treatment available to improve functional outcomes in patients with ICH due to its unknown mechanisms of damage. Increasing evidence has shown that the metabolic products of erythrocytes are the key contributor of ICH-induced secondary brain injury. Iron, an important metabolic product that accumulates in the brain parenchyma, has a detrimental effect on secondary injury following ICH. Because the damage mechanism of iron during ICH-induced secondary injury is clear, iron removal therapy research on animal models is effective. Although many animal and clinical studies have been conducted, the exact metabolic pathways of iron and the mechanisms of iron removal treatments are still not clear. This review summarizes recent progress concerning the iron metabolism mechanisms underlying ICH-induced injury. We focus on iron, brain iron metabolism, the role of iron in oxidative injury, and iron removal therapy following ICH, and we suggest that further studies focus on brain iron metabolism after ICH and the mechanism for iron removal therapy.

Keywords

Intracerebral hemorrhage Iron Brain iron metabolism Iron-handling proteins Hepcidin 

Notes

Acknowledgments

This work was supported by the National “973” project of China (no. 2014CB541605).

Conflict of Interest

The authors declare no conflict of interest.

References

  1. 1.
    Wang J. Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol. 2010;92(4):463–77.PubMedCentralPubMedGoogle Scholar
  2. 2.
    Mayer SA, Rincon F. Treatment of intracerebral haemorrhage. Lancet Neurol. 2005;4(10):662–72.PubMedGoogle Scholar
  3. 3.
    Sutherland GR, Auer RN. Primary intracerebral hemorrhage. J Clin Neurosci. 2006;13(5):511–7.PubMedGoogle Scholar
  4. 4.
    Chaudhary N, Gemmete JJ, Thompson BG, Xi G, Pandey AS. Iron-potential therapeutic target in hemorrhagic stroke. World Neurosurg. 2013;79(1):7–9.PubMedGoogle Scholar
  5. 5.
    Ke Y, Qian ZM. Brain iron metabolism: neurobiology and neurochemistry. Prog Neurobiol. 2007;83(3):149–73.PubMedGoogle Scholar
  6. 6.
    Hua Y, Nakamura T, Keep RF, Wu J, Schallert T, Hoff JT, et al. Long-term effects of experimental intracerebral hemorrhage: the role of iron. J Neurosurg. 2006;104(2):305–12.PubMedGoogle Scholar
  7. 7.
    Wu J, Hua Y, Keep RF, Nakamura T, Hoff JT, Xi G. Iron and iron-handling proteins in the brain after intracerebral hemorrhage. Stroke. 2003;34(12):2964–9.PubMedGoogle Scholar
  8. 8.
    Wang J, Doré S. Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage. Brain. 2007;130(6):1643–52.PubMedCentralPubMedGoogle Scholar
  9. 9.
    Maines MD. The heme oxygenase system: a regulator of second messenger gases. Annu Rev Pharmacol Toxicol. 1997;37(1):517–54.PubMedGoogle Scholar
  10. 10.
    Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol. 2006;5(1):53–63.PubMedGoogle Scholar
  11. 11.
    Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol. 2012;11(8):720–31.PubMedGoogle Scholar
  12. 12.
    Jin H, Wu G, Hu S, Hua Y, Keep RF, Wu J, et al. T2 and T2* magnetic resonance imaging sequences predict brain injury after intracerebral hemorrhage in rats. Acta Neurochir Suppl. 2013;18:151–5.Google Scholar
  13. 13.
    Wang W, Di X, D'Agostino RB, Torti SV, Torti FM. Excess capacity of the iron regulatory protein system. J Biol Chem. 2007;282(34):24650–9.PubMedGoogle Scholar
  14. 14.
    Crichton RR, Wilmet S, Legssyer R, Ward RJ. Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells. J Inorg Biochem. 2002;91(1):9–18.PubMedGoogle Scholar
  15. 15.
    Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochimica et biophysica acta. 2012;1823(9):1434–43.PubMedCentralPubMedGoogle Scholar
  16. 16.
    Galy B, Ferring-Appel D, Becker C, Gretz N, Gröne H-J, Schümann K, et al. Iron regulatory proteins control a mucosal block to intestinal iron absorption. Cell Rep. 2013;3(3):844–57.PubMedGoogle Scholar
  17. 17.
    Anderson GJ, Frazer DM, McLaren GD. Iron absorption and metabolism. Curr Opin Gastroenterol. 2009;25(2):129–35.PubMedGoogle Scholar
  18. 18.
    Knutson MD. Iron-sensing proteins that regulate hepcidin and enteric iron absorption. Annu Rev Nutr. 2010;30:149–71.PubMedGoogle Scholar
  19. 19.
    Schümann K, Moret R, Künzle H, Kühn LC. Iron regulatory protein as an endogenous sensor of iron in rat intestinal mucosa. EurJ Biochem. 1999;260(2):362–72.Google Scholar
  20. 20.
    Mastrogiannaki M, Matak P, Keith B, Simon MC, Vaulont S, Peyssonnaux C. HIF-2α, but not HIF-1α, promotes iron absorption in mice. J Clin Invest. 2009;119(5):1159.PubMedCentralPubMedGoogle Scholar
  21. 21.
    Shah YM, Matsubara T, Ito S, Yim S-H, Gonzalez FJ. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell Metab. 2009;9(2):152–64.PubMedCentralPubMedGoogle Scholar
  22. 22.
    Taylor M, Qu A, Anderson ER, Matsubara T, Martin A, Gonzalez FJ, et al. Hypoxia-inducible factor-2α mediates the adaptive increase of intestinal ferroportin during iron deficiency in mice. Gastroenterology. 2011;140(7):2044–55.PubMedCentralPubMedGoogle Scholar
  23. 23.
    Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004;306(5704):2090–3.PubMedGoogle Scholar
  24. 24.
    Rolfs A, Hediger MA. Metal ion transporters in mammals: structure, function and pathological implications. J Physiol. 1999;518(1):1–12.PubMedCentralPubMedGoogle Scholar
  25. 25.
    Goldman BS, Kranz RG. ABC transporters associated with cytochrome c biogenesis. Res microbiol. 2001;152(3):323–9.PubMedGoogle Scholar
  26. 26.
    Malecki EA, Devenyi AG, Beard JL, Connor JR. Existing and emerging mechanisms for transport of iron and manganese to the brain. J Neurosci Res. 1999;56(2):113.PubMedGoogle Scholar
  27. 27.
    Moos T, Morgan EH. Transferrin and transferrin receptor function in brain barrier systems. Cell Mol Neurobiol. 2000;20(1):77–95.PubMedGoogle Scholar
  28. 28.
    Bradbury M. Transport of iron in the blood–brain–cerebrospinal fluid system. J Neurochem. 1997;69(2):443–54.PubMedGoogle Scholar
  29. 29.
    Talukder M, Takeuchi T, Harada E. Receptor-mediated transport of lactoferrin into the cerebrospinal fluid via plasma in young calves. J Vet Med Sci. 2003;65(9):957–64.PubMedGoogle Scholar
  30. 30.
    Ji B, Maeda J, Higuchi M, Inoue K, Akita H, Harashima H, et al. Pharmacokinetics and brain uptake of lactoferrin in rats. Life Sci. 2006;78(8):851–5.PubMedGoogle Scholar
  31. 31.
    Qian ZM, Morgan EH. Changes in the uptake of transferrin-free and transferrin-bound iron during reticulocyte maturation in vivo and in vitro. Biochim Biophys Acta. 1992;1135(1):35–43.PubMedGoogle Scholar
  32. 32.
    Qian ZM, Tang PL, Morgan EH. Effect of lipid peroxidation on transferrin-free iron uptake by rabbit reticulocytes. Biochim Biophys Acta. 1996;1310(3):293–302.PubMedGoogle Scholar
  33. 33.
    Deane R, Zheng W, Zlokovic BV. Brain capillary endothelium and choroid plexus epithelium regulate transport of transferrin-bound and free iron into the rat brain. J Neurochem. 2004;88(4):813–20.PubMedCentralPubMedGoogle Scholar
  34. 34.
    Li H, Qian ZM. Transferrin/transferrin receptor-mediated drug delivery. Med Res Rev. 2002;22(3):225–50.PubMedGoogle Scholar
  35. 35.
    Rouault TA, Cooperman S. Brain iron metabolism. Semin pediatr neurol. 2006;13(3):142–8.PubMedGoogle Scholar
  36. 36.
    Hahn P, Qian Y, Dentchev T, Chen L, Beard J, Harris ZL, et al. Disruption of ceruloplasmin and hephaestin in mice causes retinal iron overload and retinal degeneration with features of age-related macular degeneration. Proc Natl Acad Sci U S A. 2004;101(38):13850–5.PubMedCentralPubMedGoogle Scholar
  37. 37.
    Qian ZM, Chang YZ, Zhu L, Yang L, Du JR, Ho KP, et al. Development and iron‐dependent expression of hephaestin in different brain regions of rats. J Cell Biochem. 2007;102(5):1225–33.PubMedGoogle Scholar
  38. 38.
    Moos T. Brain iron homeostasis. Dan Med Bull. 2002;49(4):279.PubMedGoogle Scholar
  39. 39.
    los Monteros D, Espinosa A, Kumar S, Scully S, Cole R, de Vellis J. Transferrin gene expression and secretion by rat brain cells in vitro. J Neurosci Res. 1990;25(4):576–80.Google Scholar
  40. 40.
    Moos T, Morgan EH. Evidence for low molecular weight, non-transferrin-bound iron in rat brain and cerebrospinal fluid. J Neurosci Res. 1998;54(4):486–94.PubMedGoogle Scholar
  41. 41.
    Qian ZM, Shen X. Brain iron transport and neurodegeneration. Trends Mol Med. 2001;7(3):103–8.PubMedGoogle Scholar
  42. 42.
    Attieh ZK, Mukhopadhyay CK, Seshadri V, Tripoulas NA, Fox PL. Ceruloplasmin ferroxidase activity stimulates cellular iron uptake by a trivalent cation-specific transport mechanism. J Biol Chem. 1999;274(2):1116–23.PubMedGoogle Scholar
  43. 43.
    Hulet S, Hess E, Debinski W, Arosio P, Bruce K, Powers S, et al. Characterization and distribution of ferritin binding sites in the adult mouse brain. J Neurochem. 1999;72(2):868–74.PubMedGoogle Scholar
  44. 44.
    Hulet S, Heyliger S, Powers S, Connor J. Oligodendrocyte progenitor cells internalize ferritin via clathrin-dependent receptor mediated endocytosis. J Neurosci Res. 2000;61(1):52–60.PubMedGoogle Scholar
  45. 45.
    Ke Y, Qian ZM. Iron misregulation in the brain: a primary cause of neurodegenerative disorders. Lancet Neurol. 2003;2(4):246–53.PubMedGoogle Scholar
  46. 46.
    Rouault TA. Systemic iron metabolism: a review and implications for brain iron metabolism. Pediatr Neurol. 2001;25(2):130–7.PubMedGoogle Scholar
  47. 47.
    Crowe A, Morgan EH. Iron and transferrrin uptake by brain and cerebrospinal fluid in the rat. Brain Res. 1992;592(1):8–16.PubMedGoogle Scholar
  48. 48.
    Descamps L, Dehouck M-P, Torpier G, Cecchelli R. Receptor-mediated transcytosis of transferrin through blood–brain barrier endothelial cells. Am J Physiol. 1996;270(4):H1149–58.PubMedGoogle Scholar
  49. 49.
    REGAN RF, PANTER S. Hemoglobin potentiates excitotoxic injury in cortical cell culture. J Neurotrauma. 1996;13(4):223–31.PubMedGoogle Scholar
  50. 50.
    Goldstein L, Teng ZP, Zeserson E, Patel M, Regan RF. Hemin induces an iron-dependent, oxidative injury to human neuron-like cells. J Neurosci Res. 2003;73(1):113–21.PubMedGoogle Scholar
  51. 51.
    Cooper CE. Nitric oxide and iron proteins. Biochim Biophys Acta. 1999;1411(2):290–309.PubMedGoogle Scholar
  52. 52.
    Nakamura T, Keep RF, Hua Y, Hoff JT, Xi G. Oxidative DNA injury after experimental intracerebral hemorrhage. Brain Res. 2005;1039(1):30–6.PubMedGoogle Scholar
  53. 53.
    Zaman K, Ryu H, Hall D, O'Donovan K, Lin K-I, Miller MP, et al. Protection from oxidative stress–induced apoptosis in cortical neuronal cultures by iron chelators is associated with enhanced dna binding of hypoxia-inducible factor-1 and atf-1/creb and increased expression of glycolytic enzymes, p21waf1/cip1, and erythropoietin. J Neurosci. 1999;19(22):9821–30.PubMedGoogle Scholar
  54. 54.
    Tanji K, Imaizumi T, Matsumiya T, Itaya H, Fujimoto K, Cui X-F, et al. Desferrioxamine, an iron chelator, upregulates cyclooxygenase-2 expression and prostaglandin production in a human macrophage cell line. Biochim Biophys Acta. 2001;1530(2):227–35.PubMedGoogle Scholar
  55. 55.
    Willmore JL, Ballinger Jr WE, Boggs W, Sypert GW, Rubin JJ. Dendritic alterations in rat isocortex within an iron-induced chronic epileptic focus. Neurosurg. 1980;7(2):142–6.Google Scholar
  56. 56.
    Reid SA, Sypert GW, Boggs WM, Willmore LJ. Histopathology of the ferric-induced chronic epileptic focus in cat: a Golgi study. Exp Neurol. 1979;66(2):205–19.PubMedGoogle Scholar
  57. 57.
    Connor JR, Menzies SL. Relationship of iron to oligondendrocytes and myelination. Glia. 1996;17(2):83–93.PubMedGoogle Scholar
  58. 58.
    Kondo Y, Ogawa N, Asanuma M, Ota Z, Mori A. Regional differences in late-onset iron deposition, ferritin, transferrin, astrocyte proliferation, and microglial activation after transient forebrain ischemia in rat brain. J Cereb Blood Flow Metab. 1995;15(2):216–26.PubMedGoogle Scholar
  59. 59.
    Dwork A, Schon E, Herbert J. Nonidentical distribution of transferrin and ferric iron in human brain. Neuroscience. 1988;27(1):333–45.PubMedGoogle Scholar
  60. 60.
    Wagner KR, Sharp FR, Ardizzone TD, Lu A, Clark JF. Heme and iron metabolism: role in cerebral hemorrhage. J Cereb Blood Flow Metab. 2003;23(6):629–52.PubMedGoogle Scholar
  61. 61.
    Connor JR, Menzies SL. Cellular management of iron in the brain. J Neurol Sci. 1995;134:33–44.PubMedGoogle Scholar
  62. 62.
    Connor JR, Menzies SL, Burdo JR, Boyer PJ. Iron and iron management proteins in neurobiology. Pediatr Neurol. 2001;25(2):118–29.PubMedGoogle Scholar
  63. 63.
    Zhao F, Hua Y, He Y, Keep RF, Xi G. Minocycline-induced attenuation of iron overload and brain injury after experimental intracerebral hemorrhage. Stroke. 2011;42(12):3587–93.PubMedCentralPubMedGoogle Scholar
  64. 64.
    Kaur C, Ling E. Increased expression of transferrin receptors and iron in amoeboid microglial cells in postnatal rats following an exposure to hypoxia. Neurosci Lett. 1999;262(3):183–6.PubMedGoogle Scholar
  65. 65.
    Djeha A, Perez-Arellano J-L, Hayes SL, Oria R, Simpson RJ, Raja KB, et al. Cytokine-mediated regulation of transferrin synthesis in mouse macrophages and human T lymphocytes. Blood. 1995;85(4):1036–42.PubMedGoogle Scholar
  66. 66.
    She H, Xiong S, Lin M, Zandi E, Giulivi C, Tsukamoto H. Iron activates NF-κB in Kupffer cells. Am J Physiol Gastrointest Liver Physiol. 2002;283(3):G719–26.PubMedGoogle Scholar
  67. 67.
    Mehdiratta M, Kumar S, Hackney D, Schlaug G, Selim M. Association between serum ferritin level and perihematoma edema volume in patients with spontaneous intracerebral hemorrhage. Stroke. 2008;39(4):1165–70.PubMedGoogle Scholar
  68. 68.
    de la Ossa NP, Sobrino T, Silva Y, Blanco M, Millán M, Gomis M, et al. Iron-related brain damage in patients with intracerebral hemorrhage. Stroke. 2010;41(4):810–3.Google Scholar
  69. 69.
    Ghosh S, Hevi S, Chuck SL. Regulated secretion of glycosylated human ferritin from hepatocytes. Blood. 2004;103(6):2369–76.PubMedGoogle Scholar
  70. 70.
    Tran TN, Eubanks SK, Schaffer KJ, Zhou CY, Linder MC. Secretion of ferritin by rat hepatoma cells and its regulation by inflammatory cytokines and iron. Blood. 1997;90(12):4979–86.PubMedGoogle Scholar
  71. 71.
    Sibille JC, Kondo H, Aisen P. Interactions between isolated hepatocytes and Kupffer cells in iron metabolism: a possible role for ferritin as an iron carrier protein. Hepatology. 1988;8(2):296–301.PubMedGoogle Scholar
  72. 72.
    Cohen LA, Gutierrez L, Weiss A, Leichtmann-Bardoogo Y, Zhang D-L, Crooks DR, et al. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood. 2010;116(9):1574–84.PubMedGoogle Scholar
  73. 73.
    Gutteridge J. Hydroxyl radicals, iron, oxidative stress, and neurodegeneration. Ann NY Acad Sci. 1994;738(1):201–13.PubMedGoogle Scholar
  74. 74.
    Thompson KJ, Shoham S, Connor JR. Iron and neurodegenerative disorders. Brain Res Bull. 2001;55(2):155–64.PubMedGoogle Scholar
  75. 75.
    Zecca L, Youdim MB, Riederer P, Connor JR, Crichton RR. Iron, brain ageing and neurodegenerative disorders. Nat Rev Neurosci. 2004;5(11):863–73.PubMedGoogle Scholar
  76. 76.
    Gu Y, Hua Y, Keep RF, Morgenstern LB, Xi G. Deferoxamine reduces intracerebral hematoma-induced iron accumulation and neuronal death in piglets. Stroke. 2009;40(6):2241–3.PubMedCentralPubMedGoogle Scholar
  77. 77.
    Nakamura T, Keep RF, Hua Y, Schallert T, Hoff JT, Xi G. Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage. J Neurosurg. 2004;100(4):672–8.PubMedGoogle Scholar
  78. 78.
    Warkentin LM, Auriat AM, Wowk S, Colbourne F. Failure of deferoxamine, an iron chelator, to improve outcome after collagenase-induced intracerebral hemorrhage in rats. Brain Res. 2010;1309:95–103.PubMedGoogle Scholar
  79. 79.
    Auriat AM, Silasi G, Wei Z, Paquette R, Paterson P, Nichol H, et al. Ferric iron chelation lowers brain iron levels after intracerebral hemorrhage in rats but does not improve outcome. Exp Neurol. 2012;234(1):136–43.PubMedGoogle Scholar
  80. 80.
    Selim M. Deferoxamine mesylate: a new hope for intracerebral hemorrhage: from bench to clinical trials. Stroke. 2009;40(3 suppl 1):S90–1.PubMedGoogle Scholar
  81. 81.
    Regan RF, Rogers B. Delayed treatment of hemoglobin neurotoxicity. J neurotrauma. 2003;20(1):111–20.PubMedGoogle Scholar
  82. 82.
    Okauchi M, Hua Y, Keep RF, Morgenstern LB, Xi G. Effects of deferoxamine on intracerebral hemorrhage-induced brain injury in aged rats. Stroke. 2009;40(5):1858–63.PubMedCentralPubMedGoogle Scholar
  83. 83.
    Song S, Hua Y, Keep R, He Y, Wang J, Wu J. Deferoxamine reduces brain swelling in a rat model of hippocampal intracerebral hemorrhage. Acta Neurochir Suppl. 2008;105:13–8.PubMedGoogle Scholar
  84. 84.
    Wu H, Wu T, Xu X, Wang J, Wang J. Iron toxicity in mice with collagenase-induced intracerebral hemorrhage. J Cereb Blood Flow Metab. 2010;31(5):1243–50.PubMedCentralPubMedGoogle Scholar
  85. 85.
    Wan S, Hua Y, Keep R, Hoff J, Xi G. Deferoxamine reduces CSF free iron levels following intracerebral hemorrhage. Acta Neurochir Suppl. 2006;96:199–202.PubMedGoogle Scholar
  86. 86.
    Rosenberg GA, Mun-Bryce S, Wesley M, Kornfeld M. Collagenase-induced intracerebral hemorrhage in rats. Stroke. 1990;21(5):801–7.PubMedGoogle Scholar
  87. 87.
    Paraskevaidis IA, Iliodromitis EK, Vlahakos D, Tsiapras DP, Nikolaidis A, Marathias A, et al. Deferoxamine infusion during coronary artery bypass grafting ameliorates lipid peroxidation and protects the myocardium against reperfusion injury: immediate and long-term significance. Eur Heart J. 2005;26(3):263–70.PubMedGoogle Scholar
  88. 88.
    Selim M, Yeatts S, Goldstein J, Gomes J, Greenberg S, Morgenstern L, et al. Deferoxamine Mesylate in Intracerebral Hemorrhage Investigators. Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage. Stroke. 2011;42:3067–74.PubMedCentralPubMedGoogle Scholar
  89. 89.
    Grenier D, Huot M-P, Mayrand D. Iron-chelating activity of tetracyclines and its impact on the susceptibility of Actinobacillus actinomycetemcomitans to these antibiotics. Antimicrob Agents Ch. 2000;44(3):763–6.Google Scholar
  90. 90.
    Chen-Roetling J, Chen L, Regan RF. Minocycline attenuates iron neurotoxicity in cortical cell cultures. Biochem Biophys Res Commun. 2009;386(2):322–6.PubMedCentralPubMedGoogle Scholar
  91. 91.
    Murata Y, Rosell A, Scannevin RH, Rhodes KJ, Wang X, Lo EH. Extension of the thrombolytic time window with minocycline in experimental stroke. Stroke. 2008;39(12):3372–7.PubMedCentralPubMedGoogle Scholar
  92. 92.
    Alano CC, Kauppinen TM, Valls AV, Swanson RA. Minocycline inhibits poly (ADP-ribose) polymerase-1 at nanomolar concentrations. Proc Natl Acad Sci U S A. 2006;103(25):9685–90.PubMedCentralPubMedGoogle Scholar
  93. 93.
    Wasserman JK, Schlichter LC. Minocycline protects the blood–brain barrier and reduces edema following intracerebral hemorrhage in the rat. Exp Neurol. 2007;207(2):227–37.PubMedGoogle Scholar
  94. 94.
    Power C, Henry S, Del Bigio MR, Larsen PH, Corbett D, Imai Y, et al. Intracerebral hemorrhage induces macrophage activation and matrix metalloproteinases. Ann Neurol. 2003;53(6):731–42.PubMedGoogle Scholar
  95. 95.
    Arosio P, Levi S. Ferritin, iron homeostasis, and oxidative damage. Free Radical Bio Med. 2002;33(4):457–63.Google Scholar
  96. 96.
    Meyron-Holtz EG, Ghosh MC, Iwai K, LaVaute T, Brazzolotto X, Berger UV, et al. Genetic ablations of iron regulatory proteins 1 and 2 reveal why iron regulatory protein 2 dominates iron homeostasis. EMBO J. 2004;23(2):386–95.PubMedCentralPubMedGoogle Scholar
  97. 97.
    Hu J, Connor JR. Demonstration and characterization of the iron regulatory protein in human brain. J Neurochem. 1996;67(2):838–44.PubMedGoogle Scholar
  98. 98.
    Pantopoulos K. Iron metabolism and the IRE/IRP regulatory system: an update. Ann N Y Acad Sci. 2004;1012(1):1–13.PubMedGoogle Scholar
  99. 99.
    Hentze MW, Caughman SW, Rouault TA, Barriocanal JG, Dancis A, Harford JB, et al. Identification of the iron-responsive element for the translational regulation of human ferritin mRNA. Science. 1987;238(4833):1570–3.PubMedGoogle Scholar
  100. 100.
    Casey JL, Hentze MW, Koeller DM, Caughman SW, Rouault TA, Klausner RD, et al. Iron-responsive elements: regulatory RNA sequences that control mRNA levels and translation. Science. 1988;240(4854):924–8.PubMedGoogle Scholar
  101. 101.
    Gunshin H, Allerson CR, Polycarpou-Schwarz M, Rofts A, Rogers JT, Kishi F, et al. Iron-dependent regulation of the divalent metal ion transporter. FEBS Lett. 2001;509(2):309–16.PubMedGoogle Scholar
  102. 102.
    Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, et al. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000;403(6771):776–81.PubMedGoogle Scholar
  103. 103.
    Guo B, Phillips JD, Yu Y, Leibold EA. Iron regulates the intracellular degradation of iron regulatory protein 2 by the proteasome. J Biol Chem. 1995;270(37):21645–51.PubMedGoogle Scholar
  104. 104.
    Galy B, Ferring-Appel D, Kaden S, Gröne H-J, Hentze MW. Iron regulatory proteins are essential for intestinal function and control key iron absorption molecules in the duodenum. Cell Metab. 2008;7(1):79–85.PubMedGoogle Scholar
  105. 105.
    Smith SR, Ghosh MC, Ollivierre-Wilson H, Hang Tong W, Rouault TA. Complete loss of iron regulatory proteins 1 and 2 prevents viability of murine zygotes beyond the blastocyst stage of embryonic development. Blood Cells Mol Dis. 2006;36(2):283–7.PubMedGoogle Scholar
  106. 106.
    Chen M, Awe OO, Chen-Roetling J, Regan RF. Iron regulatory protein-2 knockout increases perihematomal ferritin expression and cell viability after intracerebral hemorrhage. Brain Res. 2010;1337:95–103.PubMedCentralPubMedGoogle Scholar
  107. 107.
    Regan RF, Chen M, Li Z, Zhang X, Benvenisti-Zarom L, Chen-Roetling J. Neurons lacking iron regulatory protein-2 are highly resistant to the toxicity of hemoglobin. Neurobiol Dis. 2008;31(2):242–9.PubMedCentralPubMedGoogle Scholar
  108. 108.
    Santamaria R, Irace C, Festa M, Maffettone C, Colonna A. Induction of ferritin expression by oxalomalate. Biochim Biophys Acta. 2004;1691(2):151–9.PubMedGoogle Scholar
  109. 109.
    LaVaute T, Smith S, Cooperman S, Iwai K, Land W, Meyron-Holtz E, et al. Targeted deletion of the gene encoding iron regulatory protein-2 causes misregulation of iron metabolism and neurodegenerative disease in mice. Nat Genet. 2001;27(2):209–14.PubMedGoogle Scholar
  110. 110.
    Festa M, Colonna A, Pietropaolo C, Ruffo A. Oxalomalate, a competitive inhibitor of aconitase, modulates the RNA-binding activity of iron-regulatory proteins. Biochem J. 2000;348:315–20.PubMedCentralPubMedGoogle Scholar
  111. 111.
    Schroeder SE, Reddy MB, Schalinske KL. Retinoic acid modulates hepatic iron homeostasis in rats by attenuating the RNA-binding activity of iron regulatory proteins. J Nutr. 2007;137(12):2686–90.PubMedGoogle Scholar
  112. 112.
    Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet. 2009;373(9675):1632–44.PubMedCentralPubMedGoogle Scholar
  113. 113.
    Allkemper T, Tombach B, Schwindt W, Kugel H, Schilling M, Debus O, et al. Acute and subacute intracerebral hemorrhages: comparison of MR imaging at 1.5 and 3.0 T—initial experience. Radiology. 2004;232(3):874–81.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Xiao-Yi Xiong
    • 1
  • Jian Wang
    • 2
  • Zhong-Ming Qian
    • 3
  • Qing-Wu Yang
    • 1
  1. 1.Department of NeurologyXinqiao Hospital & the Second Affiliated Hospital, the Third Military Medical UniversityChongqingChina
  2. 2.Department of Anesthesiology/Critical Care Medicine, School of MedicineJohns Hopkins UniversityBaltimoreUSA
  3. 3.Department of NeurosurgerySouthwest Hospital, the Third Military Medical UniversityChongqingChina

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