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Iron as a Therapeutic Target in Intracerebral Hemorrhage: Preclinical Testing of Deferoxamine

  • Ya Hua
  • Richard F. Keep
  • Yuxiang Gu
  • Guohua Xi
Chapter
Part of the Springer Series in Translational Stroke Research book series (SSTSR)

Abstract

Intracerebral hemorrhage (ICH) is a subtype of stroke with high mortality. Experimental studies have found that brain iron overload occurs after ICH and iron has a key role in ICH-induced brain injuiry. Deferoxamine, an iron chelator, reduces hematoma-induced brain edema, neuronal death, brain atrophy and neurological deficits. Iron chelation with deferoxamine could be a new therapy for ICH.

Keywords

Iron Overload Brain Edema Iron Chelator Brain Atrophy Edema Formation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Kase CS, Caplan LR. Intracerebral hemorrhage. Boston: Butterworth-Heinemann; 1994.Google Scholar
  2. 2.
    Broderick JP, Brott T, Tomsick T, Miller R, Huster G. Intracerebral hemorrhage more than twice as common as subarachnoid hemorrhage. J Neurosurg. 1993;78:188–91.PubMedCrossRefGoogle Scholar
  3. 3.
    Chiueh CC. Iron overload, oxidative stress, and axonal dystrophy in brain disorders. Pediatr Neurol. 2001;25:138–47.PubMedCrossRefGoogle Scholar
  4. 4.
    Thompson KJ, Shoham S, Connor JR. Iron and neurodegenerative disorders. Brain Res Bull. 2001;55:155–64.PubMedCrossRefGoogle Scholar
  5. 5.
    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;34:2964–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Xi G, Keep RF, Hoff JT. Mechanisms of brain injury after intracerebral hemorrhage. Lancet Neurol. 2006;5:53–63.PubMedCrossRefGoogle Scholar
  7. 7.
    Xi G, Keep RF, Hoff JT. Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats. J Neurosurg. 1998;89:991–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Huang F, Xi G, Keep RF, Hua Y, Nemoianu A, Hoff JT. Brain edema after experimental intracerebral hemorrhage: Role of hemoglobin degradation products. J Neurosurg. 2002;96:287–93.PubMedCrossRefGoogle Scholar
  9. 9.
    Nakamura T, Keep R, Hua Y, Schallert T, Hoff J, Xi G. Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage. J Neurosurg. 2004;100:672–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Palmer C, Roberts RL, Bero C. Deferoxamine posttreatment reduces ischemic brain injury in neonatal rats. Stroke. 1994;25:1039–45.PubMedCrossRefGoogle Scholar
  11. 11.
    Keberle H. The biochemistry of desferrioxamine and its relation to iron metabolism. Ann NY Acad Sci. 1964;119:758–68.PubMedCrossRefGoogle Scholar
  12. 12.
    Porter JB. Deferoxamine pharmacokinetics. Semin Hematol. 2001;38 Suppl 1:63–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Sadrzadeh SM, Anderson DK, Panter SS, Hallaway PE, Eaton JW. Hemoglobin potentiates central nervous system damage. J Clin Invest. 1987;79:662–4.PubMedCrossRefGoogle Scholar
  14. 14.
    Regan RF, Panter SS. Neurotoxicity of hemoglobin in cortical cell culture. Neurosci Lett. 1993;153:219–22.PubMedCrossRefGoogle Scholar
  15. 15.
    Guo Y, Regan RF. Delayed therapy of hemoglobin neurotoxicity. Acad Emerg Med. 2001;8:510.Google Scholar
  16. 16.
    Hurn PD, Koehler RC, Blizzard KK, Traystman RJ. Deferoxamine reduces early metabolic failure associated with severe cerebral ischemic acidosis in dogs. Stroke. 1995;26:688–94. discussion 694–685.PubMedCrossRefGoogle Scholar
  17. 17.
    Liachenko S, Tang P, Xu Y. Deferoxamine improves early postresuscitation reperfusion after prolonged cardiac arrest in rats. J Cereb Blood Flow Metab. 2003;23:574–81.PubMedCrossRefGoogle Scholar
  18. 18.
    Prass K, Ruscher K, Karsch M, Isaev N, Megow D, Priller J, Scharff A, Dirnagl U, Meisel A. Desferrioxamine induces delayed tolerance against cerebral ischemia in vivo and in vitro. J Cereb Blood Flow Metab. 2002;22:520–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Whisnant JP, Sayer GP, Millikan CH. Experimental intracerebral hematoma. Arch Neurol. 1963;9:586–92.CrossRefGoogle Scholar
  20. 20.
    Sussman BJ, Barber JB, Goald H. Experimental intracerebral hematoma. Reduction of oxygen tension in brain and cerebrospinal fluid. J Neurosurg. 1974;41:177–86.PubMedCrossRefGoogle Scholar
  21. 21.
    Takasugi S, Ueda S, Matsumoto K. Chronological changes in spontaneous intracerebral hematoma–an experimental and clinical study. Stroke. 1985;16:651–8.PubMedCrossRefGoogle Scholar
  22. 22.
    Wagner KR, Xi G, Hua Y, Kleinholz M, de Courten-Myers GM, Myers RE, Broderick JP, Brott TG. Lobar intracerebral hemorrhage model in pigs: Rapid edema development in perihematomal white matter. Stroke. 1996;27:490–7.PubMedCrossRefGoogle Scholar
  23. 23.
    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;81:93–102.PubMedCrossRefGoogle Scholar
  24. 24.
    Xi G, Wagner KR, Keep RF, Hua Y, de Courten-Myers GM, Broderick JP, Brott TG, Hoff JT. The role of blood clot formation on early edema development following experimental intracerebral hemorrhage. Stroke. 1998;29:2580–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Xi G, Hua Y, Keep RF, Younger JG, Hoff JT. Systemic complement depletion diminishes perihematomal brain edema. Stroke. 2001;32:162–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Hua Y, Xi G, Keep RF, Hoff JT. Complement activation in the brain after experimental intracerebral hemorrhage. J Neurosurg. 2000;92:1016–22.PubMedCrossRefGoogle Scholar
  27. 27.
    Rosenberg GA, Mun-Bryce S, Wesley M, Kornfeld M. Collagenase-induced intracerebral hemorrhage in rats. Stroke. 1990;21:801–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Rosenberg GA, Navratil M. Metalloproteinase inhibition blocks edema in intracerebral hemorrhage in the rat. Neurology. 1997;48:921–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Xi G, Hua Y, Bhasin RR, Ennis SR, Keep RF, Hoff JT. Mechanisms of edema formation after intracerebral hemorrhage: effects of extravasated red blood cells on blood flow and blood–brain barrier integrity. Stroke. 2001;32:2932–8.PubMedCrossRefGoogle Scholar
  30. 30.
    Zazulia AR, Diringer MN, Videen TO, Adams RE, Tundt K, Aiyagari V, Grubb Jr RL, Powers WJ. Hypoperfusion without ischemia surrounding acute intracerebral hemorrhage. J Cereb Blood Flow Metab. 2001;21:804–10.PubMedCrossRefGoogle Scholar
  31. 31.
    Gong Y, Hua Y, Keep RF, Hoff JT, Xi G. Intracerebral hemorrhage: effects of aging on brain edema and neurological deficits. Stroke. 2004;35:2571–5.PubMedCrossRefGoogle Scholar
  32. 32.
    Ropper AH. Lateral displacement of the brain and level of consciousness in patients with an acute hemispheral mass. N Engl J Med. 1986;314:953–8.PubMedCrossRefGoogle Scholar
  33. 33.
    Clasen RA, Huckman MS, Von Roenn KA, Pandolfi S, Laing I, Clasen JR. Time course of cerebral swelling in stroke: a correlative autopsy and ct study. Adv Neurol. 1980;28: 395–412.PubMedGoogle Scholar
  34. 34.
    Zazulia AR, Diringer MN, Derdeyn CP, Powers WJ. Progression of mass effect after intracerebral hemorrhage. Stroke. 1999;30:1167–73.PubMedCrossRefGoogle Scholar
  35. 35.
    Xi G, Keep RF, Hoff JT. Pathophysiology of brain edema formation. Neurosurg Clin N Am. 2002;13:371–83.PubMedCrossRefGoogle Scholar
  36. 36.
    Enzmann DR, Britt RH, Lyons BE, Buxton JL, Wilson DA. Natural history of experimental intracerebral hemorrhage: sonography, computed tomography and neuropathology. AJNR Am J Neuroradiol. 1981;2:517–26.PubMedGoogle Scholar
  37. 37.
    Tomita H, Ito U, Ohno K, Hirakawa K. Chronological changes in brain edema induced by experimental intracerebral hematoma in cats. Acta Neurochir Suppl. 1994;60:558–60.Google Scholar
  38. 38.
    Skriver EB, Olsen TS. Tissue damage at computed tomography following resolution of intracerebral hematomas. Acta Radiol Diagn (Stockh). 1986;27:495–500.Google Scholar
  39. 39.
    Felberg RA, Grotta JC, Shirzadi AL, Strong R, Narayana P, Hill-Felberg SJ, Aronowski J. Cell death in experimental intracerebral hemorrhage: the “black hole” model of hemorrhagic damage. Ann Neurol. 2002;51:517–24.PubMedCrossRefGoogle Scholar
  40. 40.
    Xi G, Fewel ME, Hua Y, Thompson BG, Hoff J, Keep R. Intracerebral hemorrhage: pathophysiology and therapy. Neurocrit Care. 2004;1:5–18.PubMedCrossRefGoogle Scholar
  41. 41.
    Hua Y, Nakamura T, Keep RF, Wu J, Schallert T, Hoff JT, Xi G. Long-term effects of experimental intracerebral hemorrhage: the role of iron. J Neurosurg. 2006;104:305–12.PubMedCrossRefGoogle Scholar
  42. 42.
    Hua Y, Schallert T, Keep RF, Wu J, Hoff JT, Xi G. Behavioral tests after intracerebral hemorrhage in the rat. Stroke. 2002;33:2478–84.PubMedCrossRefGoogle Scholar
  43. 43.
    Hua Y, Wu J, Pecina S, Yang S, Schallert T, Keep R, Xi G. Ischemic preconditioning procedure induces behavioral deficits in the absence of brain injury? Neurol Res. 2005;27:261–7.PubMedCrossRefGoogle Scholar
  44. 44.
    Schallert T, Fleming SM, Leasure JL, Tillerson JL, Bland ST. Cns plasticity and assessment of forelimb sensorimotor outcome in unilateral rat models of stroke, cortical ablation, parkinsonism and spinal cord injury. Neuropharmacology. 2000;39:777–87.PubMedCrossRefGoogle Scholar
  45. 45.
    Okauchi M, Hua Y, Keep RF, Morgenstern LB, Xi G. Effects of deferoxamine on intracerebral hemorrhage-induced brain injury in aged rats. Stroke. 2009;40:1858–63.PubMedCrossRefGoogle Scholar
  46. 46.
    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;41:375–82.PubMedCrossRefGoogle Scholar
  47. 47.
    Gu Y, Hua Y, Keep RF, Morgenstern LB, Xi G. Deferoxamine reduces intracerebral hematoma-induced iron accumulation and neuronal death in piglets. Stroke. 2009;40:2241–3.PubMedCrossRefGoogle Scholar
  48. 48.
    Selim M. Deferoxamine mesylate: a new hope for intracerebral hemorrhage: from bench to clinical trials. Stroke. 2009;40:S90–1.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Ya Hua
    • 1
  • Richard F. Keep
    • 1
  • Yuxiang Gu
    • 1
  • Guohua Xi
    • 1
  1. 1.Department of NeurosurgeryUniversity of MichiganAnn ArborUSA

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