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Current Cardiology Reports
Erschienen in: Current Cardiology Reports 4/2019

01.04.2019 | Stroke (JF Meschia, Section Editor)

Rationale and Current Evidence for Testing Iron Chelators for Treating Stroke

verfasst von: Khalid A. Hanafy, Joao A. Gomes, Magdy Selim

Erschienen in: Current Cardiology Reports | Ausgabe 4/2019

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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.
Literatur
1.
Haase VH. HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial Int. 2017;21(Suppl 1):S110–24.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.PubMed
6.
Hanafy KA. The role of microglia and the TLR4 pathway in neuronal apoptosis and vasospasm after subarachnoid hemorrhage. J Neuroinflammation. 2013;10:83.CrossRef
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.
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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. CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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. CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.PubMed
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
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.CrossRef
Metadaten
Titel
Rationale and Current Evidence for Testing Iron Chelators for Treating Stroke
verfasst von
Khalid A. Hanafy
Joao A. Gomes
Magdy Selim
Publikationsdatum
01.04.2019
Verlag
Springer US
Erschienen in
Current Cardiology Reports / Ausgabe 4/2019
Print ISSN: 1523-3782
Elektronische ISSN: 1534-3170
DOI
https://doi.org/10.1007/s11886-019-1106-z

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