Top

Published in:

01-10-2013 | Original Article

Deferoxamine Reduces Neuronal Death and Hematoma Lysis After Intracerebral Hemorrhage in Aged Rats

Authors: Tetsuhiro Hatakeyama, Masanobu Okauchi, Ya Hua, Richard F. Keep, Guohua Xi

Published in: Translational Stroke Research | Issue 5/2013

Abstract

Intracerebral hemorrhage (ICH) is primarily a disease of the elderly. Deferoxamine (DFX), an iron chelator, reduces long-term neurological deficits and brain atrophy after ICH in aged rats. In the present study, we investigated whether DFX can reduce acute ICH-induced neuronal death and whether it affects the endogenous response to ICH (ferritin upregulation and hematoma resolution) in aged rats. Male Fischer 344 rats (18 months old) had an intracaudate injection of 100 μL autologous whole blood into the right basal ganglia and were treated with DFX (100 mg/kg) or vehicle 2 h post-ICH and then every 12 h up to 7 days. Rats were euthanized 1, 3, or 7 days later for neuronal death and ferritin and hematoma size measurements. Plasma ferritin levels and behavioral outcome following ICH were also examined. DFX treatment significantly reduced ICH-induced neuronal death and neurological deficits. DFX also suppressed ferritin upregulation in the ipsilateral basal ganglia after ICH and hematoma lysis (hematoma volume at day 7, 13.2 ± 4.9 vs. 3.8 ± 1.2 mm³ in vehicle-treated group, p < 0.01). However, effects of DFX on plasma ferritin levels after ICH did not reach significance. In conclusion, DFX reduces neuronal death and neurological deficits after ICH in aged rats. It also affects the endogenous response to ICH.

Huang FP, Xi G, Keep RF, Hua Y, Nemoianu A, Hoff JT. Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products. J Neurosurg. 2002;96(2):287–93.PubMedCrossRef

Wagner KR, Dwyer BE. Hematoma removal, heme, and heme oxygenase following hemorrhagic stroke. Ann N Y Acad Sci. 2004;1012:237–51.PubMedCrossRef

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.PubMedCrossRef

Wu J, Hua Y, Keep RF, Schallert T, Hoff JT, Xi G. Oxidative brain injury from extravasated erythrocytes after intracerebral hemorrhage. Brain Res. 2002;953(1–2):45–52.PubMedCrossRef

Xi G, Keep RF, Hoff JT. Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurg. 1998;89(6):991–6.PubMedCrossRef

Rincon F, Mayer SA. Intracerebral hemorrhage: clinical overview and pathophysiologic concepts. Transl Stroke Res. 2012;3 Suppl 1:s10–24.CrossRef

Bodmer D, Vaughan KA, Zacharia BE, Hickman ZL, Connolly Jr ES. The molecular mechanisms that promote edema after intracerebral hemorrhage. Transl Stroke Res. 2012;3 suppl 1:s52–61.CrossRef

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.PubMedCrossRef

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.PubMedCrossRef

10.

Nakamura T, Keep RF, Hua Y, Hoff JT, Xi G. Oxidative DNA injury after experimental intracerebral hemorrhage. Brain Res. 2005;1039(1–2):30–6.PubMedCrossRef

11.

Song S, Hua Y, Keep RF, Hoff JT, Xi G. A new hippocampal model for examining intracerebral hemorrhage-related neuronal death: effects of deferoxamine on hemoglobin-induced neuronal death. Stroke. 2007;38(10):2861–3.PubMedCrossRef

12.

Keep RF, Hua Y, Xi G. Intracerebral haemorrhage: mechanisms of injury and therapeutic targets. Lancet Neurol. 2012;11(8):720–31.PubMedCrossRef

13.

Collins TC, Petersen NJ, Menke TJ, Souchek J, Foster W, Ashton CM. Short-term, intermediate-term, and long-term mortality in patients hospitalized for stroke. J Clin Epidemiol. 2003;56(1):81–7.PubMedCrossRef

14.

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.PubMedCrossRef

15.

Harrison PM, Arosio P. The ferritins: molecular properties, iron storage function and cellular regulation. Biochim Biophys Acta. 1996;1275(3):161–203.PubMedCrossRef

16.

Arosio P, Levi S. Ferritin, iron homeostasis, and oxidative damage. Free Radic Biol Med. 2002;33(4):457–63.PubMedCrossRef

17.

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.PubMedCrossRef

18.

Perez de la Ossa N, Sobrino T, Silva Y, Blanco M, Millan M, Gomis M, et al. Iron-related brain damage in patients with intracerebral hemorrhage. Stroke. 2010;41(4):810–3.PubMedCrossRef

19.

Xi G, Keep RF, Hua Y, Xiang J, Hoff JT. Attenuation of thrombin-induced brain edema by cerebral thrombin preconditioning. Stroke. 1999;30(6):1247–55.PubMedCrossRef

20.

Hua Y, Xi G, Keep RF, Wu J, Jiang Y, Hoff JT. Plasminogen activator inhibitor-1 induction after experimental intracerebral hemorrhage. J Cereb Blood Flow Metab. 2002;22(1):55–61.PubMedCrossRef

21.

Hua Y, Schallert T, Keep RF, Wu J, Hoff JT, Xi G. Behavioral tests after intracerebral hemorrhage in the rat. Stroke. 2002;33(10):2478–84.PubMedCrossRef

22.

Schmued LC, Albertson C, Slikker Jr W. Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration. Brain Res. 1997;751(1):37–46.PubMedCrossRef

23.

Wasserman JK, Yang H, Schlichter LC. Glial responses, neuron death and lesion resolution after intracerebral hemorrhage in young vs. aged rats. Eur J Neurosci. 2008;28(7):1316–28.PubMedCrossRef

24.

MacLellan CL, Silasi G, Poon CC, Edmundson CL, Buist R, Peeling J, et al. Intracerebral hemorrhage models in rat: comparing collagenase to blood infusion. J Cereb Blood Flow Metab. 2008;28(3):516–25.PubMedCrossRef

25.

Okauchi M, Hua Y, Keep RF, Morgenstern LB, Schallert T, Xi G. Deferoxamine treatment for intracerebral hemorrhage in aged rats: therapeutic time window and optimal duration. Stroke. 2010;41(2):375–82.PubMedCrossRef

26.

Nakamura T, Xi G, Park JW, Hua Y, Hoff JT, Keep RF. Holo-transferrin and thrombin can interact to cause brain damage. Stroke. 2005;36(2):348–52.PubMedCrossRef

27.

Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol. 2006;5(1):53–63.PubMedCrossRef

28.

Aruoma OI, Halliwell B, Dizdaroglu M. Iron ion-dependent modification of bases in DNA by the superoxide radical-generating system hypoxanthine/xanthine oxidase. J Biol Chem. 1989;264(22):13024–8.PubMed

29.

Keberle H. The biochemistry of desferrioxamine and its relation to iron metabolism. Ann N Y Acad Sci. 1964;119:758–68.PubMedCrossRef

30.

Palmer C, Roberts RL, Bero C. Deferoxamine posttreatment reduces ischemic brain injury in neonatal rats. Stroke. 1994;25(5):1039–45.PubMedCrossRef

31.

Connor JR, Menzies SL, Burdo JR, Boyer PJ. Iron and iron management proteins in neurobiology. Pediatr Neurol. 2001;25(2):118–29.PubMedCrossRef

32.

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.PubMedCrossRef

33.

Perez de la Ossa N, Sobrino T, Silva Y, Blanco M, Millan M, Gomis M, et al. Iron-related brain damage in patients with intracerebral hemorrhage. Stroke. 2010;41(4):810–3.PubMedCrossRef

34.

Masuda T, Dohrmann GJ, Kwaan HC, Erickson RK, Wollman RL. Fibrinolytic activity in experimental intracerebral hematoma. J Neurosurg. 1988;68(2):274–8.PubMedCrossRef

35.

Yang GY, Betz AL, Chenevert TL, Brunberg JA, Hoff JT. Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood–brain barrier permeability in rats. J Neurosurg. 1994;81(1):93–102.PubMedCrossRef

36.

Naff NJ, Williams MA, Rigamonti D, Keyl PM, Hanley DF. Blood clot resolution in human cerebrospinal fluid: evidence of first-order kinetics. Neurosurgery. 2001;49(3):614–9. discussion 9–21.PubMed

37.

Detraglia M, Cook FB, Stasiw DM, Cerny LC. Erythrocyte fragility in aging. Biochim Biophys Acta. 1974;345(2):213–9.PubMedCrossRef

38.

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.PubMedCrossRef

39.

Sullivan SG, Baysal E, Stern A. Inhibition of hemin-induced hemolysis by desferrioxamine: binding of hemin to red cell membranes and the effects of alteration of membrane sulfhydryl groups. Biochim Biophys Acta. 1992;1104(1):38–44.PubMedCrossRef

40.

Franke CL, van Swieten JC, van Gijn J. Residual lesions on computed tomography after intracerebral hemorrhage. Stroke. 1991;22(12):1530–3.PubMedCrossRef

41.

Castillo-Ruiz MM, Campuzano O, Acarin L, Castellano B, Gonzalez B. Delayed neurodegeneration and early astrogliosis after excitotoxicity to the aged brain. Exp Gerontol. 2007;42(4):343–54.PubMedCrossRef

42.

Zhao X, Sun G, Zhang J, Strong R, Song W, Gonzales N, et al. Hematoma resolution as a target for intracerebral hemorrhage treatment: role for peroxisome proliferator-activated receptor gamma in microglia/macrophages. Ann Neurol. 2007;61(4):352–62.PubMedCrossRef

Title: Deferoxamine Reduces Neuronal Death and Hematoma Lysis After Intracerebral Hemorrhage in Aged Rats
Authors: Tetsuhiro Hatakeyama
Masanobu Okauchi
Ya Hua
Richard F. Keep
Guohua Xi
Publication date: 01-10-2013
Publisher: Springer US
Published in: Translational Stroke Research / Issue 5/2013
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI: https://doi.org/10.1007/s12975-013-0270-5

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Deferoxamine Reduces Neuronal Death and Hematoma Lysis After Intracerebral Hemorrhage in Aged Rats

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 5/2013

Phenotypic Changes in Immune Cell Subsets Reflect Increased Infarct Volume in Male vs. Female Mice

P2X7 Receptor Inhibition Increases CNTF in the Subventricular Zone, But Not Neurogenesis or Neuroprotection After Stroke in Adult Mice

Transgene Delivery to Endothelial Cultures Derived from Porcine Carotid Artery Ex Vivo

A Model of Rat Embolic Cerebral Infarction with a Quantifiable, Autologous Arterial Blood Clot

Heart Rate Variability in Stroke Patients Submitted to an Acute Bout of Aerobic Exercise

Role of the Sphingosine Metabolism Pathway on Neurons Against Experimental Cerebral Ischemia in Rats