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Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets

NeuroRX volume 3, pages 143–153 (2006)Cite this article

Summary

Traumatic brain injury (TBI) is the leading cause of morbidity and mortality among children and both clinical and experimental data reveal that the immature brain is unique in its response and vulnerability to TBI compared to the adult brain. Current therapies for pediatric TBI focus on physiologic derangements and are based primarily on adult data. However, it is now evident that secondary biochemical perturbations play an important role in the pathobiology of pediatric TBI and may provide specific therapeutic targets for the treatment of the head-injured child. In this review, we discuss three specific components of the secondary pathogenesis of pediatric TBI — inflammation, oxidative injury, and iron-induced damage — and potential therapeutic strategies associated with each. The inflammatory response in the immature brain is more robust than in the adult and characterized by greater disruption of the blood-brain barrier and elaboration of cytokines. The immature brain also has a muted response to oxidative stress compared to the adult due to inadequate expression of certain antioxidant molecules. In addition, the developing brain is less able to detoxify free iron after TBI-induced hemorrhage and cell death. These processes thus provide potential therapeutic targets that may be tailored to pediatric TBI, including anti-inflammatory agents such as minocycline, antioxidants such as glutathione peroxidase, and the iron chelator deferoxamine.

References

  1. Langlois J, Rutland-Brown W, Thomas K: Traumatic brain injury in the United States: Emergency department visits, hospitalizations, and deaths. Atlanta (GA): Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, 2004.

  2. Mazzola CA, Adelson PD. Critical care management of head trauma in children.Crit Care Med 30: S393–401, 2002.

    PubMed  Article  Google Scholar 

  3. Costeff H, Groswasser Z, Goldstein R. Long-term follow-up review of 31 children with severe closed head trauma.J Neurosurg 73: 684–687, 1990.

    PubMed  CAS  Article  Google Scholar 

  4. Salmond CH, Sahakian BJ. Cognitive outcome in traumatic brain injury survivors.Curr Opin Crit Care 11: 111–116, 2005.

    PubMed  Article  Google Scholar 

  5. Levin HS, Aldrich EF, Saydjari C, Eisenberg HM, Foulkes MA, Bellefleur M, et al. Severe head injury in children: experience of the Traumatic Coma Data Bank.Neurosurgery 31: 435–443; discussion 443-434, 1992.

    PubMed  CAS  Article  Google Scholar 

  6. Khoshyomn S, Tranmer BI. Diagnosis and management of pediatric closed head injury.Semin Pediatr Surg 13: 80–86, 2004.

    PubMed  Article  Google Scholar 

  7. Adelson PD, Clyde B, Kochanek PM, Wisniewski SR, Marion DW, Yonas H. Cerebrovascular response in infants and young children following severe traumatic brain injury: a preliminary report.Pediatr Neurosurg 26: 200–207, 1997.

    PubMed  CAS  Article  Google Scholar 

  8. Koskiniemi M, Kyykka T, Nybo T, Jarho L. Long-term outcome after severe brain injury in preschoolers is worse than expected.Arch Pediatr Adolesc Med 149: 249–254, 1995.

    PubMed  CAS  Article  Google Scholar 

  9. Bittigau P, Sifringer M, Felderhoff-Mueser U, Ikonomidou C. Apoptotic neurodegeneration in the context of traumatic injury to the developing brain.Exp Toxicol Pathol 56: 83–89, 2004.

    PubMed  Article  Google Scholar 

  10. Adelson PD, Bratton SL, Carney NA, Chesnut RM, du Coudray HE, Goldstein B, et al. Guidelines for the acute medical management of severe traumatic brain injury in infants, children, and adolescents.Pediatr Crit Care Med 4: S2–75, 2003.

    PubMed  Article  Google Scholar 

  11. Carmody DP, Dunn SM, Boddie-Willis AS, DeMarco JK, Lewis M. A quantitative measure of myelination development in infants, using MR images.Neuroradiology 46: 781–786, 2004.

    PubMed  Article  Google Scholar 

  12. Koizumi H. The concept of ‘developing the brain’: a new natural science for learning and education.Brain Dev 26: 434–441, 2004.

    PubMed  Article  Google Scholar 

  13. Haynes RL, Borenstein NS, Desilva TM, Folkerth RD, Liu LG, Volpe JJ, et al. Axonal development in the cerebral white matter of the human fetus and infant.J Comp Neurol 484: 156–167. 2005.

    PubMed  Article  Google Scholar 

  14. Chambers IR, Jones PA, Lo TY, Forsyth RJ, Fulton B, Andrews PJ, et al. Critical thresholds of intracranial pressure and cerebral perfusion pressure related to age in paediatric head injury.J Neurol Neurosurg Psychiatry, 2005.

  15. Durkin MS, Olsen S, Barlow B, Virella A, Connolly ES, Jr. The epidemiology of urban pediatric neurological trauma: evaluation of, and implications for, injury prevention programs.Neurosurgery 42: 300–310, 1998.

    PubMed  CAS  Article  Google Scholar 

  16. Pigula FA, Wald SL, Shackford SR, Vane DW. The effect of hypotension and hypoxia on children with severe head injuries.J Pediatr Surg 28: 310–314; discussion 315–316, 1993.

    PubMed  CAS  Article  Google Scholar 

  17. Natale JE, Joseph JG, Helfaer MA, Shaffner DH. Early hyperthermia after traumatic brain injury in children: risk factors, influence on length of stay, and effect on short-term neurologic status.Crit Care Med 28: 2608–2615, 2000.

    PubMed  CAS  Article  Google Scholar 

  18. Ylvisaker M, Adelson PD, Braga LW, Burnett SM, Glang A, Feeney T, et al. Rehabilitation and ongoing support after pediatric TBI: twenty years of progress.J Head Trauma Rehabil 20: 95–109, 2005.

    PubMed  Article  Google Scholar 

  19. Bayir H, Kochanek PM, Clark RS. Traumatic brain injury in infants and children: mechanisms of secondary damage and treatment in the intensive care unit.Crit Care Clin 19: 529–549, 2003.

    PubMed  Article  Google Scholar 

  20. Kreutzberg G. Microglia: a sensor for pathological events in the CNS.Trends in Neuroscience 19: 312–318, 1996.

    CAS  Article  Google Scholar 

  21. Gao H-M, Hong J-S. Critical role of microglial NADPH oxidase in rotenone-induced degeneration of dopaminergic neurons.J Neuroscience 23: 6181–6187, 2002.

    Google Scholar 

  22. Hudome S, Palmer C, Roberts RL, Mauger D, Housman C, Towfighi J. The role of neutrophils in the production of hypoxic-ischemic brain injury in the neonatal rat.Pediatr Res 41: 607–616, 1997.

    PubMed  CAS  Article  Google Scholar 

  23. Kawabata K, Hagio T, Matsuoka S. The role of neutrophil elastase in acute lung injury.Eur J Pharmacol 451: 1–10, 2002.

    PubMed  CAS  Article  Google Scholar 

  24. Lee W, Downey G. Leukocyte elastase: physiological functions and role in acute lung injury.Am J Respir Crit Care Med 164: 896–904, 2001.

    PubMed  CAS  Google Scholar 

  25. Owen C, Campbell E. The cell biology of leukocyte-mediated proteolysis.J Leukoc Biol 1999 Feb; 65(2):137-50. 65: 137–150. 1999.

    PubMed  CAS  Google Scholar 

  26. DeWitt DS, Plough DS. Traumatic cerebral vascular injury: the effects of concussive brain injury on the cerebral vasculature.J Neurotrauma 20: 795–825, 2003.

    PubMed  Article  Google Scholar 

  27. Morganti-Kossmann MC, Rancan M, Stahel PF, Kossmann T. Inflammatory response in acute traumatic brain injury: a double-edged sword.Curr Opin Crit Care 8: 101–105, 2002.

    PubMed  Article  Google Scholar 

  28. Rothwall N. Interleukin-1 and neuronal injury: mechanisms, modification, and therapeutic potential.Brain, Behavior, and Immunity 17: 152–157, 2003.

    Article  Google Scholar 

  29. Sherwood ER, Prough DS. Interleukin-8, neuroinflammation, and secondary brain injury.Crit Care Med 28: 1221–1223, 2000.

    PubMed  CAS  Article  Google Scholar 

  30. Shohami E, Bass R, Wallach D, Yamin A, Gallily R. Inhibition of tumor necrosis factor alpha (TNFalpha) activity in rat brain is associated with cerebroprotection after closed head injury. JCereb Blood Flow Metab 16: 378–384, 1996.

    PubMed  CAS  Article  Google Scholar 

  31. Scherbel U, Raghupathi R, Nakamura M, Saatman KE, Trojanowski JQ, Neugebauer E, et al. Differential acute and chronic responses of tumor necrosis factor-deficient mice to experimental brain injury.Proc Natl Acad Sci U S A 96: 8721–8726, 1999.

    PubMed  CAS  Article  Google Scholar 

  32. Toulmond S, Rothwell NJ. Interleukin-1 receptor antagonist inhibits neuronal damage caused by fluid percussion injury in the rat.Brain Res 671: 261–266, 1995.

    PubMed  CAS  Article  Google Scholar 

  33. DeKosky ST, Styren SD, O’Malley ME, Goss JR, Kochanek P, Marion D, et al. Interleukin-1 receptor antagonist suppresses neurotrophin response in injured rat brain.Ann Neurol 39: 123–127, 1996.

    PubMed  CAS  Article  Google Scholar 

  34. Yang K, Mu XS, Hayes RL. Increased cortical nuclear factor-kappa B (NF-kappa B) DNA binding activity after traumatic brain injury in rats.Neurosci Lett 197: 101–104, 1995.

    PubMed  CAS  Article  Google Scholar 

  35. Nonaka M, Chen XH, Pierce JE, Leoni MJ, McIntosh TK, Wolf JA, et al. Prolonged activation of NF-kappaB following traumatic brain injury in rats.J Neurotrauma 16: 1023–1034, 1999.

    PubMed  CAS  Article  Google Scholar 

  36. Bell MJ, Kochanek PM, Doughty LA, Carcillo JA, Adelson PD, Clark RS, et al. Interleukin-6 and interleukin-10 in cerebrospinal fluid after severe traumatic brain injury in children.J Neurotrauma 14: 451–457, 1997.

    PubMed  CAS  Article  Google Scholar 

  37. Bell MJ, Kochanek PM, Doughty LA, Carcillo JA, Adelson PD, Clark RS, et al. Comparison of the interleukin-6 and interleukin-10 response in children after severe traumatic brain injury or septic shock.Acta Neurochir Suppl (Wien) 70: 96–97, 1997.

    CAS  Google Scholar 

  38. Bajetto A, Bonavai R, S. B, G. S. Characterization of chemokines and their receptors in the central nervous system: physiopathological implications.J Neurochem. 82: 1311–1329, 2002.

    PubMed  CAS  Article  Google Scholar 

  39. Bell MD, Taub DD, Perry VH. Overriding the brain’s intrinsic resistance to leukocyte recruitment with intraparenchymal injections of recombinant chemokines.Neuroscience 74: 283–292, 1996.

    PubMed  CAS  Article  Google Scholar 

  40. Whalen MJ, Carlos TM, Kochanek PM, Wisniewski SR, Bell MJ, Clark RS, et al. Interleukin-8 is increased in cerebrospinal fluid of children with severe head injury.Crit Care Med 28: 929–934, 2000.

    PubMed  CAS  Article  Google Scholar 

  41. Vane JR, Botting RM. Mechanism of action of antiinflammatory drugs.Int J Tissue React 20: 3–15, 1998.

    PubMed  CAS  Google Scholar 

  42. Willard LB, Hauss-Wegrzyniak B, Danysz W, Wenk GL. The cytotoxicity of chronic neuroinflammation upon basal forebrain cholinergic neurons of rats can be attenuated by glutamatergic antagonism or cyclooxygenase-2 inhibition.Exp Brain Res 134: 58–65, 2000.

    PubMed  CAS  Article  Google Scholar 

  43. Dunon D, Piali L, Imhof B. To stick or not to stick: the new leukocyte homing paradigm.Curr Opin Cell Biol 8: 714–723. 1996.

    PubMed  CAS  Article  Google Scholar 

  44. Whalen MJ, Carlos TM, Dixon CE, Schiding JK, Clark RS, Baum E, et al. Effect of traumatic brain injury in mice deficient in intercellular adhesion molecule-1: assessment of histopathologic and functional outcome.J Neurotrauma 16: 299–309, 1999.

    PubMed  CAS  Article  Google Scholar 

  45. Knoblach S, Faden AI. Administration of either anti-intercellular adhesion molecule-1 or a nonspecific control antibody improves recovery after traumatic brain injury in the rat.J Neurotrauma 19: 1039–1049, 2002.

    PubMed  CAS  Article  Google Scholar 

  46. Balabanov R, Goldman H, Murphy S, Pellizon G, Owen C, Rafols J, et al. Endothelial cell activation following moderate traumatic brain injury.Neurol Res 23: 175–182, 2001.

    PubMed  CAS  Article  Google Scholar 

  47. Whalen MJ, Carlos TM, Kochanek PM, Wisniewski SR, Bell MJ, Carcillo JA, et al. Soluble adhesion molecules in CSF are increased in children with severe head injury.J Neurotrauma 15: 777–787, 1998.

    PubMed  CAS  Article  Google Scholar 

  48. Lawson LJ, Perry VH. The unique characteristics of inflammatory responses in mouse brain are acquired during postnatal development.Eur J Neurosci 7: 1584–1595, 1995.

    PubMed  CAS  Article  Google Scholar 

  49. Anthony DC, Bolton SJ, Feam S, Perry VH. Age-related effects of interleukin-1 beta on polymorphonuclear neutrophil-dependent increases in blood-brain barrier permeability in rats.Brain 120 (Pt 3): 435–444, 1997.

    PubMed  Article  Google Scholar 

  50. Anthony D, Dempster R, Fearn S, Clements J, Wells G, Perry VH, et al. CXC chemokines generate age-related increases in neutrophil-mediated brain inflammation and blood-brain barrier breakdown.Curr Biol 8: 923–926, 1998.

    PubMed  CAS  Article  Google Scholar 

  51. Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH. Koistinaho J. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window.PNAS 96: 13496–13500, 1999.

    PubMed  CAS  Article  Google Scholar 

  52. Tikka T, Fiebich B, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia.J Neuroscience 21: 2580–2588, 2001.

    CAS  Google Scholar 

  53. Popovic N, Schubart A, Goetz B, Zhang S, Linington C, Duncan ID. Inhibition of autoimmune encephalomyelitis by a tetracycline.Ann Neurol 51: 215–223, 2002.

    PubMed  CAS  Article  Google Scholar 

  54. Thomas M, Le WD, Jankovic J. Minocycline and other tetracycline derivatives: a neuroprotective strategy in Parkinson’s disease and Huntington’s disease.Clin Neuropharmacol 26: 18–23, 2003.

    PubMed  Article  Google Scholar 

  55. Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice.Nature 417: 74–78, 2002.

    PubMed  CAS  Article  Google Scholar 

  56. Saccani S, Pantano S, Natoli G. p38-Dependent marking of inflammatory genes for increased NF-kappa B recruitment.Nat Immunol 3: 69–75, 2002.

    PubMed  CAS  Article  Google Scholar 

  57. Sanchez Mejia R, Ona V, Li M, Friedlander RM. Minocycline reduces traumatic brain injury-mediated caspase-1 activation, tissue damage, and neurological dysfunction.Neurosurgery 48: 1293–1298, 2001.

    Google Scholar 

  58. Arvin KL, Han BH, Du Y, Lin SZ, Paul SM, Holtzman DM. Minocycline markedly protects the neonatal brain against hypoxic-ischemic injury.Ann Neurol 52: 54–61, 2002.

    PubMed  CAS  Article  Google Scholar 

  59. Fox C, Dingman A, Derugin N, Wendland MF, Manabat C, Ji S, et al. Minocycline confers early but transient protection in the immature brain following focal cerebral ischemia-reperfusion.J Cereb Blood Flow Metab 25: 1138–1149, 2005.

    PubMed  CAS  Article  Google Scholar 

  60. Kontos HA, Wei EP. Superoxide production in experimental brain injury.J Neurosurg 64: 803–807, 1986.

    PubMed  CAS  Article  Google Scholar 

  61. Hall ED, Braughler JM. Free radicals in CNS injury.Res Publ Assoc Res Nerv Ment Dis 71: 81–105, 1993.

    PubMed  CAS  Google Scholar 

  62. Smith SL, Andrus PK, Zhang JR, Hall ED. Direct measurement of hydroxyl radicals, lipid peroxidation, and blood-brain barrier disruption following unilateral cortical impact head injury in the rat.J Neurotrauma 11: 393–404., 1994.

    PubMed  CAS  Article  Google Scholar 

  63. Lewen A, Matz P, Chan PH. Free radical pathways in CNS injury.J Neurotrauma 17: 871–890, 2000.

    PubMed  CAS  Article  Google Scholar 

  64. Shohami E, Beit-Yannai E, Horowitz M, Kohen R. Oxidative stress in closed-head injury: brain antioxidant capacity as an indicator of functional outcome.J Cereb Blood Flow Metab 17: 1007–1019, 1997.

    PubMed  CAS  Article  Google Scholar 

  65. Warner DS, Sheng H, Batinic-Haberle I. Oxidants, antioxidants and the ischemic brain.J Exp Biol 207: 3221–3231, 2004.

    PubMed  CAS  Article  Google Scholar 

  66. Lifshitz J, Sullivan PG, Hovda DA, Wieloch T, McIntosh TK. Mitochondrial damage and dysfunction in traumatic brain injury.Mitochondrion 4: 705–713, 2004.

    PubMed  CAS  Article  Google Scholar 

  67. Dietrich WD, Chatzipanteli K, Vitarbo E, Wada K, Kinoshita K. The role of inflammatory processes in the pathophysiology and treatment of brain and spinal cord trauma.Acta Neurochir Suppl 89: 69–74, 2004.

    PubMed  CAS  Article  Google Scholar 

  68. Feuerstein GZ, Wang X, Barone FC. Inflammatory gene expression in cerebral ischemia and trauma. Potential new therapeutic targets.Ann N Y Acad Sci 825: 179–193, 1997.

    PubMed  CAS  Article  Google Scholar 

  69. Floyd RA, Camey JM. Age influence on oxidative events during brain ischemia/reperfusion.Arch Gerontol Geriatr 12: 155–177. 1991.

    PubMed  CAS  Article  Google Scholar 

  70. Bayir H, Kagan VE, Tyurina YY, Tyurin V, Ruppel RA, Adelson PD, et al. Assessment of antioxidant reserves and oxidative stress in cerebrospinal fluid after severe traumatic brain injury in infants and children.Pediatr Res 51: 571–578, 2002.

    PubMed  Article  Google Scholar 

  71. Sheldon RA, Jiang X, Francisco C, Christen S, Vexler ZS, Tauber MG, et al. Manipulation of antioxidant pathways in neonatal murine brain.Pediatr Res 56: 656–662, 2004.

    PubMed  CAS  Article  Google Scholar 

  72. Natale JE, Knight JB, Cheng Y, Rome JE, Gallo V. Metallothionein I and II mitigate age-dependent secondary brain injury.J Neurosci Res 78: 303–314, 2004.

    PubMed  CAS  Article  Google Scholar 

  73. Mavelli I, Rigo A, Federico R, Ciriolo MR, Rotilio G. Superoxide dismutase, glutathione peroxidase and catalase in developing rat brain.Biochem J 204: 535–540, 1982.

    PubMed  CAS  Google Scholar 

  74. Mikawa S, Kinouchi H, Kamii H, Gobbel GT, Chen SF, Carlson E, et al. Attenuation of acute and chronic damage following traumatic brain injury in copper, zinc-superoxide dismutase transgenic mice.J Neurosurg 85: 885–891, 1996.

    PubMed  CAS  Article  Google Scholar 

  75. McIntosh TK, Juhler M, Wieloch T. Novel pharmacologic strategies in the treatment of experimental traumatic brain injury: 1998.J Neurotrauma 15: 731–769, 1998.

    PubMed  CAS  Article  Google Scholar 

  76. Kinouchi H, Epstein CJ, Mizui T, Carlson E, Chen SF, Chan PH. Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn Superoxide dismutase.Proc Natl Acad Sci U S A 88: 11158–11162, 1991.

    PubMed  CAS  Article  Google Scholar 

  77. Ditelberg JS, Sheldon RA, Epstein CJ, Ferriero DM. Brain injury after perinatal hypoxia-ischemia is exacerbated in copper/zinc Superoxide dismutase transgenic mice.Pediatr Res 39: 204–208, 1996.

    PubMed  CAS  Article  Google Scholar 

  78. Fullerton HJ, Ditelberg JS, Chen SF, Sarco DP, Chan PH, Epstein CJ, et al. Copper/zinc Superoxide dismutase transgenic brain accumulates hydrogen peroxide after perinatal hypoxia ischemia.Ann Neurol 44: 357–364, 1998.

    PubMed  CAS  Article  Google Scholar 

  79. Mischel RE, Kim YS, Sheldon RA, Ferriero DM. Hydrogen peroxide is selectively toxic to immature murine neurons in vitro.Neurosci Lett 231: 17–20, 1997.

    PubMed  CAS  Article  Google Scholar 

  80. Lewen A, Fujimura M, Sugawara T, Matz P, Copin JC, Chan PH. Oxidative stress-dependent release of mitochondrial cytochrome c after traumatic brain injury.J Cereb Blood Flow Metab 21: 914–920, 2001.

    PubMed  CAS  Article  Google Scholar 

  81. Sheng H, Bart RD, Oury TD, Pearlstein RD, Crapo JD, Warner DS. Mice overexpressing extracellular Superoxide dismutase have increased resistance to focal cerebral ischemia.Neuroscience 88: 185–191, 1999.

    PubMed  CAS  Article  Google Scholar 

  82. Sheng H, Kudo M, Mackensen GB, Pearlstein RD, Crapo JD, Warner DS. Mice overexpressing extracellular Superoxide dismutase have increased resistance to global cerebral ischemia.Exp Neurol 163: 392–398, 2000.

    PubMed  CAS  Article  Google Scholar 

  83. Sheng H, Brady TC, Pearlstein RD, Crapo JD, Warner DS. Extracellular Superoxide dismutase deficiency worsens outcome from focal cerebral ischemia in the mouse.Neurosci Lett 267: 13–16, 1999.

    PubMed  CAS  Article  Google Scholar 

  84. Hamm RJ, Temple MD, Pike BR, Ellis EF. The effect of postinjury administration of polyethylene glycol-conjugated Superoxide dismutase (pegorgotein, Dismutec) or lidocaine on behavioral function following fluid-percussion brain injury in rats.J Neurotrauma 13: 325–332, 1996.

    PubMed  CAS  Article  Google Scholar 

  85. Yunoki M, Kawauchi M, Ukita N, Noguchi Y, Nishio S, Ono Y, et al. Effects of lecithinized Superoxide dismutase on traumatic brain injury in rats.J Neurotrauma 14: 739–746, 1997.

    PubMed  CAS  Article  Google Scholar 

  86. Yunoki M, Kawauchi M, Ukita N, Sugiura T, Ohmoto T. Effects of lecithinized Superoxide dismutase on neuronal cell loss in CA3 hippocampus after traumatic brain injury in rats.Surg Neurol 59: 156–160; discussion 160-151, 2003.

    PubMed  Article  Google Scholar 

  87. Kesner RP, Lee I, Gilbert P. A behavioral assessment of hippocampal function based on a subregional analysis.Rev Neurosci 15: 333–351, 2004.

    PubMed  Google Scholar 

  88. Marklund SL, Westman NG, Lundgren E, Roos G. Copper- and zinc-containing Superoxide dismutase, manganese-containing superoxide dismutase, catalase, and glutathione peroxidase in normal and neoplastic human cell lines and normal human tissues.Cancer Res 42: 1955–1961, 1982.

    PubMed  CAS  Google Scholar 

  89. Fan P, Yamauchi T, Noble LJ, Ferriero DM. Age-dependent differences in glutathione peroxidase activity after traumatic brain injury.J Neurotrauma 20: 437–445, 2003.

    PubMed  Article  Google Scholar 

  90. Royo NC, Shimizu S, Schouten JW, Stover JF, McIntosh TK. Pharmacology of traumatic brain injury.Curr Opin Pharmacol 3: 27–32, 2003.

    PubMed  CAS  Article  Google Scholar 

  91. Marklund N, Clausen F, McIntosh TK, Hillered L. Free radical scavenger posttreatment improves functional and morphological outcome after fluid percussion injury in the rat.J Neurotrauma 18: 821–832, 2001.

    PubMed  CAS  Article  Google Scholar 

  92. Hall ED, Yonkers PA, McCall JM, Braughler JM. Effects of the 21-aminosteroid U74006F on experimental head injury in mice.J Neurosurg 68: 456–461, 1988.

    PubMed  CAS  Article  Google Scholar 

  93. McIntosh TK, Thomas M, Smith D, Banbury M. The novel 21-aminosteroid U74006F attenuates cerebral edema and improves survival after brain injury in the rat.J Neurotrauma 9: 33–46, 1992.

    PubMed  CAS  Article  Google Scholar 

  94. Sanada T, Nakamura T, Nishimura MC, Isayama K, Pitts LH. Effect of U74006F on neurologic function and brain edema after fluid percussion injury in rats.J Neurotrauma 10: 65–71, 1993.

    PubMed  CAS  Article  Google Scholar 

  95. Mathew P, Bullock R, Teasdale G, McCulloch J. Changes in local microvascular permeability and in the effect of intervention with 21-aminosteroid (Tirilazad) in a new experimental model of focal cortical injury in the rat.J Neurotrauma 13: 465–472, 1996.

    PubMed  CAS  Article  Google Scholar 

  96. Wei EP, Kontos HA, Dietrich WD, Povlishock JT, Ellis EF. Inhibition by free radical scavengers and by cyclooxygenase inhibitors of pial arteriolar abnormalities from concussive brain injury in cats.Circ Res 48: 95–103, 1981.

    PubMed  CAS  Article  Google Scholar 

  97. Hall ED. Beneficial effects of acute intravenous ibuprofen on neurologic recovery of head-injured mice: comparison of cyclooxygenase inhibition with inhibition of thromboxane A2 synthetase or 5-lipoxygenase.Cent Nerv Syst Trauma 2: 75–83, 1985.

    PubMed  CAS  Google Scholar 

  98. Kim HJ, Levasseur JE, Patterson JL, Jr., Jackson GF, Madge GE, Povlishock JT, et al. Effect of indomethacin pretreatment on acute mortality in experimental brain injury.J Neurosurg 71: 565–572, 1989.

    PubMed  CAS  Article  Google Scholar 

  99. Jafarian-Tehrani M, Louin G, Royo NC, Besson VC, Bohme GA, Plotkine M, et al. 1400W, a potent selective inducible NOS inhibitor, improves histopathological outcome following traumatic brain injury in rats.Nitric Oxide 12: 61–69, 2005.

    PubMed  CAS  Article  Google Scholar 

  100. Clifton GL, Lyeth BG, Jenkins LW, Taft WC, DeLorenzo RJ, Hayes RL. Effect of D, alpha-tocopheryl succinate and polyethylene glycol on performance tests after fluid percussion brain injury.J Neurotrauma 6: 71–81, 1989.

    PubMed  CAS  Article  Google Scholar 

  101. Inci S, Ozcan OE, Kilinc K. Time-level relationship for lipid peroxidation and the protective effect of alpha-tocopherol in experimental mild and severe brain injury.Neurosurgery 43: 330–335; discussion 335–336, 1998.

    PubMed  CAS  Article  Google Scholar 

  102. Beit-Yannai E, Zhang R, Trembovler V, Samuni A, Shohami E. Cerebroprotective effect of stable nitroxide radicals in closed head injury in the rat.Brain Res 717: 22–28, 1996.

    PubMed  CAS  Article  Google Scholar 

  103. Zhang R, Shohami E, Beit-Yannai E, Bass R, Trembovler V, Samuni A. Mechanism of brain protection by nitroxide radicals in experimental model of closed-head injury.Free Radic Biol Med 24: 332–340, 1998.

    PubMed  CAS  Article  Google Scholar 

  104. Sarrafzadeh AS, Thomale UW, Kroppenstedt SN, Unterberg AW. Neuroprotective effect of melatonin on cortical impact injury in the rat.Acta Neurochir (Wien) 142: 1293–1299, 2000.

    CAS  Article  Google Scholar 

  105. Ozdemir D, Tugyan K, Uysal N, Sonmez U, Sonmez A, Acikgoz O, et al. Protective effect of melatonin against head trauma-induced hippocampal damage and spatial memory deficits in immature rats.Neurosci Lett 385: 234–239, 2005.

    PubMed  CAS  Article  Google Scholar 

  106. Shohami E, Novikov M, Bass R. Long-term effect of HU-211, a novel non-competitive NMDA antagonist, on motor and memory functions after closed head injury in the rat.Brain Res 674: 55–62, 1995.

    PubMed  CAS  Article  Google Scholar 

  107. Nadler V, Biegon A, Beit-Yannai E, Adamchik J, Shohami E. 45Ca accumulation in rat brain after closed head injury; attenuation by the novel neuroprotective agent HU-211.Brain Res 685: 1–11, 1995.

    PubMed  CAS  Article  Google Scholar 

  108. Aoyama N, Katayama Y, Kawamata T, Maeda T, Mori T, Yamamoto T, et al. Effects of antioxidant, OPC-14117, on secondary cellular damage and behavioral deficits following cortical contusion in the rat.Brain Res 934: 117–124, 2002.

    PubMed  CAS  Article  Google Scholar 

  109. Xiong Y, Peterson PL, Muizelaar JP, Lee CP. Amelioration of mitochondrial function by a novel antioxidant U-101033E following traumatic brain injury in rats.J Neurotrauma 14: 907–917. 1997.

    PubMed  CAS  Article  Google Scholar 

  110. Wada K, Alonso OF, Busto R, Panetta J, Clemens JA, Ginsberg MD, et al. Early treatment with a novel inhibitor of lipid peroxidation (LY341122) improves histopathological outcome after moderate fluid percussion brain injury in rats.Neurosurgery 45: 601–608, 1999.

    PubMed  CAS  Article  Google Scholar 

  111. Hall ED, Andrus PK, Smith SL, Fleck TJ, Scherch HM, Lutzke BS, et al. Pyrrolopyrimidines: novel brain-penetrating antioxidants with neuroprotective activity in brain injury and ischemia models.J Pharmacol Exp Ther 281: 895–904, 1997.

    PubMed  CAS  Google Scholar 

  112. Muizelaar JP, Marmarou A, Young HF, Choi SC, Wolf A, Schneider RL, et al. Improving the outcome of severe head injury with the oxygen radical scavenger polyethylene glycol-conjugated Superoxide dismutase: a phase II trial.J Neurosurg 78: 375–382, 1993.

    PubMed  CAS  Article  Google Scholar 

  113. Young B, Runge JW, Waxman KS, Harrington T, Wilberger J, Muizelaar JP, et al. Effects of pegorgotein on neurologic outcome of patients with severe head injury. A multicenter, randomized controlled trial.Jama 276: 538–543, 1996.

    PubMed  CAS  Article  Google Scholar 

  114. Marshall LF, Maas AI, Marshall SB, Bricolo A, Feamside M, Iannotti F, et al. A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury.J Neurosurg 89: 519–525, 1998.

    PubMed  CAS  Article  Google Scholar 

  115. Knoller N, Levi L, Shoshan I, Reichenthal E, Razon N, Rappaport ZH, et al. Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled, phase II clinical trial.Crit Care Med 30: 548–554, 2002.

    PubMed  CAS  Article  Google Scholar 

  116. Yamaguchi T, Sano K, Takakura K, Saito I, Shinohara Y, Asano T, et al. Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group.Stroke 29: 12–17, 1998.

    PubMed  CAS  Article  Google Scholar 

  117. Saito I, Asano T, Sano K, Takakura K, Abe H, Yoshimoto T, et al. Neuroprotective effect of an antioxidant, ebselen, in patients with delayed neurological deficits after aneurysmal subarachnoid hemorrhage.Neurosurgery 42: 269–277; discussion 277-268, 1998.

    PubMed  CAS  Article  Google Scholar 

  118. Ogawa A, Yoshimoto T, Kikuchi H, Sano K, Saito I, Yamaguchi T, et al. Ebselen in acute middle cerebral artery occlusion: a placebo-controlled, double-blind clinical trial.Cerebrovasc Dis 9: 112–118, 1999.

    PubMed  CAS  Article  Google Scholar 

  119. Chang EF, Claus CP, Vreman HJ, Wong RJ, Noble-Haeusslein LJ. Heme regulation in traumatic brain injury: relevance to the adult and developing brain.J Cereb Blood Flow Metab, 2005

  120. Connor JR, Menzies SL, Burdo JR, Boyer PJ. Iron and iron management proteins in neurobiology.Pediatr Neurol 25: 118–129, 2001.

    PubMed  CAS  Article  Google Scholar 

  121. Roskams AJ, Connor JR. Iron, transferrin, and ferritin in the rat brain during development and aging.J Neurochem 63: 709–716, 1994.

    PubMed  CAS  Article  Google Scholar 

  122. Berger HM, Mumby S, Gutteridge JM. Ferrous ions detected in iron-overloaded cord blood plasma from preterm and term babies: implications for oxidative stress.Free Radic Res 22: 555–559, 1995.

    PubMed  CAS  Article  Google Scholar 

  123. Gutteridge JM, Mumby S, Koizumi M, Taniguchi N. “Free” iron in neonatal plasma activates aconitase: evidence for biologically reactive iron.Biochem Biophys Res Commun 229: 806–809, 1996.

    PubMed  CAS  Article  Google Scholar 

  124. Gutteridge JM. Ferrous ions detected in cerebrospinal fluid by using bleomycin and DNA damage.Clin Sci (Lond) 82: 315–320. 1992.

    CAS  Google Scholar 

  125. Dietrich RB, Bradley WG, Jr. Iron accumulation in the basal ganglia following severe ischemic-anoxic insults in children.Radiology 168: 203–206, 1988.

    PubMed  CAS  Google Scholar 

  126. Cheepsunthorn P, Palmer C, Menzies S, Roberts RL, Connor JR. Hypoxic/ischemic insult alters ferritin expression and myelination in neonatal rat brains.J Comp Neurol 431: 382–396, 2001.

    PubMed  CAS  Article  Google Scholar 

  127. Palmer C, Menzies SL, Roberts RL, Pavlick G, Connor JR. Changes in iron histochemistry after hypoxic-ischemic brain injury in the neonatal rat.J Neurosci Res 56: 60–71, 1999.

    PubMed  CAS  Article  Google Scholar 

  128. 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 15: 216–226, 1995.

    PubMed  CAS  Article  Google Scholar 

  129. Fredriksson A, Schroder N, Eriksson P, Izquierdo I, Archer T. Neonatal iron exposure induces neurobehavioural dysfunctions in adult mice.Toxicol Appl Pharmacol 159: 25–30, 1999.

    PubMed  CAS  Article  Google Scholar 

  130. Connor JR, Menzies SL. Relationship of iron to oligodendrocytes and myelination.Glia 17: 83–93, 1996.

    PubMed  CAS  Article  Google Scholar 

  131. Connor JR, Pavlick G, Karli D, Menzies SL, Palmer C. A histochemical study of iron-positive cells in the developing rat brain.J Comp Neurol 355: 111–123, 1995.

    PubMed  CAS  Article  Google Scholar 

  132. Ikeda Y, Ikeda K, Long DM. Comparative study of different iron-chelating agents in cold-induced brain edema.Neurosurgery 24: 820–824, 1989.

    PubMed  CAS  Article  Google Scholar 

  133. Regan RF, Rogers B. Delayed treatment of hemoglobin neurotoxicity.J Neurotrauma 20: 111–120, 2003.

    PubMed  Article  Google Scholar 

  134. Bergeron M, Gidday JM, Yu AY, Semenza GL, Ferriero DM, Sharp FR. Role of hypoxia-inducible factor-1 in hypoxia-induced ischemic tolerance in neonatal rat brain.Ann Neurol 48: 285–296, 2000.

    PubMed  CAS  Article  Google Scholar 

  135. Hamrick SE, McQuillen PS, Jiang X, Mu D, Madan A, Ferriero DM. A role for hypoxia-inducible factor-1 alpha in desferoxamine neuroprotection.Neurosci Lett 379: 96–100, 2005.

    PubMed  CAS  Article  Google Scholar 

  136. Long DA, Ghosh K, Moore AN, Dixon CE, Dash PK. Deferoxamine improves spatial memory performance following experimental brain injury in rats.Brain Res 717: 109–117, 1996.

    PubMed  CAS  Article  Google Scholar 

  137. Panter SS, Braughler JM, Hall ED. Dextran-coupled deferoxamine improves outcome in a murine model of head injury.J Neurotrauma 9: 47–53, 1992.

    PubMed  CAS  Article  Google Scholar 

  138. Nakamura T, Keep RF, Hua Y, Schauert T, Hoff JT, Xi G. Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage.J Neurosurg 100: 672–678, 2004.

    PubMed  CAS  Article  Google Scholar 

  139. Groenendaal F, Shadid M, McGowan JE, Mishra OP, van Bel F. Effects of deferoxamine, a chelator of free iron, on NA(+), K(+)-ATPase activity of cortical brain cell membrane during early reperfusion after hypoxia-ischemia in newborn lambs.Pediatr Res 48: 560–564, 2000.

    PubMed  CAS  Article  Google Scholar 

  140. Peeters-Scholte C, Braun K, Koster J, Kops N, Blomgren K, Buonocore G, et al. Effects of allopurinol and deferoxamine on reperfusion injury of the brain in newborn piglets after neonatal hypoxia-ischemia.Pediatr Res 54: 516–522, 2003.

    PubMed  CAS  Article  Google Scholar 

  141. Pettus EH, Wright DW, Stein DG, Hoffman SW. Progesterone treatment inhibits the inflammatory agents that accompany traumatic brain injury.Brain Res 1049: 112–119, 2005.

    PubMed  CAS  Article  Google Scholar 

  142. He J, Evans CO, Hoffman SW, Oyesiku NM, Stein DG. Progesterone and allopregnanolone reduce inflammatory cytokines after traumatic brain injury.Exp Neurol 189: 404–412, 2004.

    PubMed  CAS  Article  Google Scholar 

  143. Truettner JS, Suzuki T, Dietrich WD. The effect of therapeutic hypothermia on the expression of inflammatory response genes following moderate traumatic brain injury in the rat.Brain Res Mol Brain Res 138: 124–134, 2005.

    PubMed  CAS  Article  Google Scholar 

  144. Lynch JR, Wang H, Mace B, Leinenweber S, Warner DS, Bennett ER, et al. A novel therapeutic derived from apolipoprotein E reduces brain inflammation and improves outcome after closed head injury.Exp Neurol 192: 109–116, 2005.

    PubMed  CAS  Article  Google Scholar 

  145. Marklund N, Keck C, Hoover R, Soltesz K, Millard M, LeBold D, et al. Administration of monoclonal antibodies neutralizing the inflammatory mediators tumor necrosis factor alpha and interleukin -6 does not attenuate acute behavioral deficits following experimental traumatic brain injury in the rat.Restor Neurol Neurosci 23: 31–42, 2005.

    PubMed  CAS  Google Scholar 

  146. Gopez JJ, Yue H, Vasudevan R, Malik AS, Fogelsanger LN, Lewis S, et al. Cyclooxygenase-2-specific inhibitor improves functional outcomes, provides neuroprotection, and reduces inflammation in a rat model of traumatic brain injury.Neurosurgery 56: 590–604, 2005.

    PubMed  Article  Google Scholar 

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Affiliations

  1. Department of Neurological Surgery, University of California, 94143, San Francisco, California

    Mathew B. Potts, Seong-Eun Koh, Tomoko Yoneyama, Catherine P. Claus, Hovhannes M. Manvelyan & Linda J. Noble-Haeusslein

  2. Department of Medicine (Division of Emergency Medicine), University of California, 94143, San Francisco, California

    William D. Whetstone & Breset A. Walker

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  1. Mathew B. Potts
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  2. Seong-Eun Koh
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  8. Linda J. Noble-Haeusslein
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Correspondence to Linda J. Noble-Haeusslein.

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Potts, M.B., Koh, SE., Whetstone, W.D. et al. Traumatic injury to the immature brain: Inflammation, oxidative injury, and iron-mediated damage as potential therapeutic targets. NeuroRX 3, 143–153 (2006). https://doi.org/10.1016/j.nurx.2006.01.006

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Key Words

  • Traumatic brain injury
  • immature brain
  • inflammation
  • oxidative damage
  • iron