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Rationale and Current Evidence for Testing Iron Chelators for Treating Stroke

  • Stroke (JF Meschia, Section Editor)
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Abstract

Purpose of Review

To discuss the mechanisms of iron regulation in the brain and the pathophysiological role of deregulation of iron homeostasis following a stroke, and to review existing evidence supporting the potential role of iron chelators in the treatment of ischemic and hemorrhagic stroke.

Recent Findings

In recent years, accumulating evidence has highlighted the role of neuroinflammation in neurological injury after ischemic and hemorrhagic stroke, and that free iron is central to this process. Via the Fenton reaction, free iron catalyzes the conversion of superoxide ion and hydrogen peroxide into hydroxyl radicals, which promote oxidative stress.

Summary

Advances in our understanding of changes in brain iron metabolism and its relationship to neuronal injury in stroke could provide new therapeutic strategies to improve the outcome of stroke patients. Pharmacological agents targeting brain iron regulation hold promise as potentially effective treatments in both ischemic and hemorrhagic stroke.

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References

Papers of particular interest, published recently, have been highlighted as: •• Of major importance

  1. Haase VH. HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial Int. 2017;21(Suppl 1):S110–24.

    Article  Google Scholar 

  2. Gerlach M, Ben-Shachar D, Riederer P, Youdim MB. Altered brain metabolism of iron as a cause of neurodegenerative diseases? J Neurochem. 1994;63(3):793–807.

    Article  CAS  Google Scholar 

  3. Morris CM, Candy JM, Keith AB, Oakley AE, Taylor GA, Pullen RG, et al. Brain iron homeostasis. J Inorg Biochem. 1992;47(3–4):257–65.

    Article  CAS  Google Scholar 

  4. Kowal K, Silver R, Sławińska E, Bielecki M, Chyczewski L, Kowal-Bielecka O. CD163 and its role in inflammation. Folia Histochem Cytobiol. 2011;49(3):365–74.

    Article  CAS  Google Scholar 

  5. Wang G, Wang L, Sun X-G, Tang J. Haematoma scavenging in intracerebral haemorrhage: from mechanisms to the clinic. J Cell Mol Med. 2018;22:768–77.

    CAS  PubMed  Google Scholar 

  6. Hanafy KA. The role of microglia and the TLR4 pathway in neuronal apoptosis and vasospasm after subarachnoid hemorrhage. J Neuroinflammation. 2013;10:83.

    Article  CAS  Google Scholar 

  7. Wang Y, Ge P, Zhu Y. TLR2 and TLR4 in the brain injury caused by cerebral ischemia and reperfusion. Mediat Inflamm. 2013;2013:124614.

    Google Scholar 

  8. Fang H, Wang P-F, Zhou Y, Wang Y-C, Yang Q-W. Toll-like receptor 4 signaling in intracerebral hemorrhage-induced inflammation and injury. J Neuroinflammation. 2013;10:27.

    Article  CAS  Google Scholar 

  9. Aisen P. Entry of iron into cells: a new role for the transferrin receptor in modulating iron release from transferrin. Ann Neurol. 1992;32(Suppl):S62–8.

    Article  CAS  Google Scholar 

  10. Jefferies WA, Brandon MR, Hunt SV, Williams AF, Gatter KC, Mason DY. Transferrin receptor on endothelium of brain capillaries. Nature. 1984;312(5990):162–3.

    Article  CAS  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. Bartlett WP, Li XS, Connor JR. Expression of transferrin mRNA in the CNS of normal and jimpy mice. J Neurochem. 1991;57(1):318–22.

    Article  CAS  Google Scholar 

  13. Connor JR, Menzies SL, St Martin SM, Mufson EJ. Cellular distribution of transferrin, ferritin, and iron in normal and aged human brains. J Neurosci Res. 1990;27(4):595–611.

    Article  CAS  Google Scholar 

  14. Kissel K, Hamm S, Schulz M, Vecchi A, Garlanda C, Engelhardt B. Immunohistochemical localization of the murine transferrin receptor (TfR) on blood-tissue barriers using a novel anti-TfR monoclonal antibody. Histochem Cell Biol. 1998;110(1):63–72.

    Article  CAS  Google Scholar 

  15. Dickinson TK, Connor JR. Immunohistochemical analysis of transferrin receptor: regional and cellular distribution in the hypotransferrinemic (hpx) mouse brain. Brain Res. 1998;801(1–2):171–81.

    Article  CAS  Google Scholar 

  16. Montosi G, Donovan A, Totaro A, Garuti C, Pignatti E, Cassanelli S, et al. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene. J Clin Invest. 2001;108(4):619–23.

    Article  CAS  Google Scholar 

  17. Chiabrando D, Marro S, Mercurio S, Giorgi C, Petrillo S, Vinchi F, et al. The mitochondrial heme exporter FLVCR1b mediates erythroid differentiation. J Clin Invest. 2012;122:4569–79.

    Article  CAS  Google Scholar 

  18. •• Lehmann C, Islam S, Jarosch S, Zhou J, Hoskin D, Greenshields A, et al. The utility of iron chelators in the management of inflammatory disorders. Mediat Inflamm. 2015;2015:516740 This article provides a review of the mechanisms of iron regulation and iron chelation strategies, and their impact in the management of several inflammatory disorders.

    Article  CAS  Google Scholar 

  19. Stockwell BR, Friedmann Angeli JP, Bayir H, Bush AI, Conrad M, Dixon SJ, et al. Ferroptosis: a regulated cell death nexus linking metabolism, redox biology, and disease. Cell. 2017;171(2):273–85.

    Article  CAS  Google Scholar 

  20. Coucha M, Li W, Johnson MH, Fagan SC, Ergul A. Protein nitration impairs the myogenic tone of rat middle cerebral arteries in both ischemic and nonischemic hemispheres after ischemic stroke. Am J Physiol Heart Circ Physiol. 2013;305:H1726–35.

    Article  CAS  Google Scholar 

  21. Knox R, Brennan-Minnella AM, Lu F, Yang D, Nakazawa T, Yamamoto T, et al. NR2B phosphorylation at tyrosine 1472 contributes to brain injury in a rodent model of neonatal hypoxia-ischemia. Stroke. 2014;45:3040–7.

    Article  CAS  Google Scholar 

  22. Jiang X, Mu D, Biran V, Faustino J, Chang S, Rincón CM, et al. Activated Src kinases interact with the N-methyl-D-aspartate receptor after neonatal brain ischemia. Ann Neurol. 2008;63(5):632–41.

    Article  CAS  Google Scholar 

  23. Sen CK, Khanna S, Roy S, Packer L. Molecular basis of vitamin E action. Tocotrienol potently inhibits glutamate-induced pp60(c-Src) kinase activation and death of HT4 neuronal cells. J Biol Chem. 2000;275(17):13049–55.

    Article  CAS  Google Scholar 

  24. Adgent MA, Squadrito GL, Ballinger CA, Krzywanski DM, Lancaster JR, Postlethwait EM. Desferrioxamine inhibits protein tyrosine nitration: mechanisms and implications. Free Radic Biol Med. 2012;53(4):951–61.

    Article  CAS  Google Scholar 

  25. Tuo Q-Z, Lei P, Jackman KA, Li X-L, Xiong H, Li X-L, et al. Tau-mediated iron export prevents ferroptotic damage after ischemic stroke. Mol Psychiatry. 2017;22:1520–30.

    Article  CAS  Google Scholar 

  26. •• Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol. 2006;5:53–63 This article provides a thorough review of the underlying mechanisms of ICH-induced brain injury including the role of inflammation and iron-mediated neuronal toxicity.

    Article  Google Scholar 

  27. Leclerc JL, Lampert AS, Loyola Amador C, Schlakman B, Vasilopoulos T, Svendsen P, et al. The absence of the CD163 receptor has distinct temporal influences on intracerebral hemorrhage outcomes. J Cereb Blood Flow Metab. 2018;38:262–73.

    Article  CAS  Google Scholar 

  28. Cao S, Zheng M, Hua Y, Chen G, Keep RF, Xi G. Hematoma changes during clot resolution after experimental intracerebral hemorrhage. Stroke. 2016;47:1626–31.

    Article  Google Scholar 

  29. Liu R, Cao S, Hua Y, Keep RF, Huang Y, Xi G. CD163 expression in neurons after experimental intracerebral hemorrhage. Stroke. 2017;48:1369–75.

    Article  CAS  Google Scholar 

  30. Hanafy KA, Oh J, Otterbein LE. Carbon monoxide and the brain: time to rethink the dogma. Curr Pharm Des. 2013;19(15):2771–5.

    Article  CAS  Google Scholar 

  31. Ma B, Day JP, Phillips H, Slootsky B, Tolosano E, Doré S. Deletion of the hemopexin or heme oxygenase-2 gene aggravates brain injury following stroma-free hemoglobin-induced intracerebral hemorrhage. J Neuroinflammation. 2016;13:26.

    Article  Google Scholar 

  32. Chen-Roetling J, Song W, Schipper HM, Regan CS, Regan RF. Astrocyte overexpression of heme oxygenase-1 improves outcome after intracerebral hemorrhage. Stroke. 2015;46:1093–8.

    Article  CAS  Google Scholar 

  33. Zhao X, Ting S-M, Liu C-H, Sun G, Kruzel M, Roy-O’Reilly M, et al. Neutrophil polarization by IL-27 as a therapeutic target for intracerebral hemorrhage. Nat Commun. 2017;8(1):602.

    Article  Google Scholar 

  34. Schallner N, Pandit R, LeBlanc R, Thomas AJ, Ogilvy CS, Zuckerbraun BS, et al. Microglia regulate blood clearance in subarachnoid hemorrhage by heme oxygenase-1. J Clin Invest. 2015;125:2609–25.

    Article  Google Scholar 

  35. He X-F, Lan Y, Zhang Q, Liu D-X, Wang Q, Liang F-Y, et al. Deferoxamine inhibits microglial activation, attenuates blood-brain barrier disruption, rescues dendritic damage, and improves spatial memory in a mouse model of microhemorrhages. J Neurochem. 2016;138(3):436–47.

    Article  CAS  Google Scholar 

  36. LeBlanc RH, Chen R, Selim MH, Hanafy KA. Heme oxygenase-1-mediated neuroprotection in subarachnoid hemorrhage via intracerebroventricular deferoxamine. J Neuroinflammation. 2016;13(1):244.

    Article  Google Scholar 

  37. Li Q, Wan J, Lan X, Han X, Wang Z, Wang J. Neuroprotection of brain-permeable iron chelator VK-28 against intracerebral hemorrhage in mice. J Cereb Blood Flow Metab. 2017;37(9):3110–23.

    Article  CAS  Google Scholar 

  38. Li Y, Yang H, Ni W, Gu Y. Effects of deferoxamine on blood-brain barrier disruption after subarachnoid hemorrhage. PLoS One. 2017;12(3):e0172784.

    Article  Google Scholar 

  39. Sun YM, Wang YT, Jiang L, Xue MZ. The effects of deferoxamine on inhibition for microglia activation and protection of secondary nerve injury after intracerebral hemorrhage in rats. Pak J Pharm Sci. 2016;29(3 Suppl):1087–93.

    CAS  PubMed  Google Scholar 

  40. Xing Y, Hua Y, Keep RF, Xi G. Effects of deferoxamine on brain injury after transient focal cerebral ischemia in rats with hyperglycemia. Brain Res. 2009;1291:113–21.

    Article  CAS  Google Scholar 

  41. Li Y-X, Ding S-J, Xiao L, Guo W, Zhan Q. Desferoxamine preconditioning protects against cerebral ischemia in rats by inducing expressions of hypoxia inducible factor 1 alpha and erythropoietin. Neurosci Bull. 2008;24(2):89–95.

    Article  Google Scholar 

  42. Oses C, Olivares B, Ezquer M, Acosta C, Bosch P, Donoso M, et al. Preconditioning of adipose tissue-derived mesenchymal stem cells with deferoxamine increases the production of pro-angiogenic, neuroprotective and anti-inflammatory factors: potential application in the treatment of diabetic neuropathy. PLoS One. 2017;12:e0178011.

    Article  Google Scholar 

  43. Selim M. Treatment with the iron chelator, deferoxamine mesylate, alters serum markers of oxidative stress in stroke patients. Transl Stroke Res. 2010;1(1):35–9.

    Article  CAS  Google Scholar 

  44. 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;39:1165–70.

    Article  CAS  Google Scholar 

  45. Gomes JA, Selim M, Cotleur A, Hussain MS, Toth G, Koffman L, et al. Brain iron metabolism and brain injury following subarachnoid hemorrhage: iCeFISH-pilot (CSF iron in SAH). Neurocrit Care. 2014;21(2):285–93.

    Article  CAS  Google Scholar 

  46. Yu J, Yuan Q, Sun Y-R, Wu X, Du Z-Y, Li Z-Q, et al. Effects of deferoxamine mesylate on hematoma and perihematoma edema after traumatic intracerebral hemorrhage. J Neurotrauma. 2017;34(19):2753–9.

    Article  Google Scholar 

  47. Selim M, Yeatts S, Goldstein JN, Gomes J, Greenberg S, Morgenstern LB, et al. Safety and tolerability of deferoxamine mesylate in patients with acute intracerebral hemorrhage. Stroke. 2011;42:3067–74.

    Article  CAS  Google Scholar 

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Funding

Dr. Hanafy receives support from the National Institute of Neurological Disorders and Stroke (R21NS099606) and the American Heart Association Grant in Aid (17GRNT33670058). Dr. Selim is partly supported by the National Institute of Neurological Disorders and Stroke (U01NS 074425).

Author information

Authors and Affiliations

  1. Beth Israel Deaconess Medical Center, Department of Neurology, Division of Stroke & Cerebrovascular Disease, Harvard Medical School, 330 Brookline Avenue – Palmer 127, Boston, MA, 02215, USA

    Khalid A. Hanafy & Magdy Selim

  2. Cerebrovascular Center, Cleveland Clinic, Cleveland, OH, USA

    Joao A. Gomes

Authors
  1. Khalid A. Hanafy
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Correspondence to Magdy Selim.

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Conflict of Interest

Khalid A. Hanafy, Joao A. Gomes, and Magdy Selim declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This is a review article so we have referenced studies done in humans and animals, but these studies were not done as part of this article, and they are just referenced here. For those studies performed by the authors, all procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. And all applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Hanafy, K.A., Gomes, J.A. & Selim, M. Rationale and Current Evidence for Testing Iron Chelators for Treating Stroke. Curr Cardiol Rep 21, 20 (2019). https://doi.org/10.1007/s11886-019-1106-z

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