Neurological Sciences

, Volume 34, Issue 7, pp 1173–1180 | Cite as

Increased expression of ferritin in cerebral cortex after human traumatic brain injury

  • Huan-Dong Liu
  • Wei Li
  • Zhen-Rui Chen
  • Meng-Liang Zhou
  • Zong Zhuang
  • Ding-Ding Zhang
  • Lin Zhu
  • Chun-Hua HangEmail author
Original Article


Despite numerous researches and improvements in the past few years, the precise mechanisms underlying secondary brain injury after trauma remain obscure. Iron is essential for almost all types of cells, including nerve cells. However, excess of iron has been proved to contribute to the brain injury following trauma in animal models. As a key iron-handling protein in the brain, ferritin might be involved in iron-induced pathophysiological process of various brain disorders. Therefore, the current study was aimed to investigate the expression of ferritin in the human contused brain. Nineteen contused brain samples were obtained from 19 patients undergoing surgery for brain contusions 3 h–17 d after trauma, and three normal temporal pole samples from 3 patients with petroclival meningioma were collected as controls. Expression of ferritin-H-chain was measured by quantitative real-time polymerase chain reaction (PCR), western blot and immunohistochemistry, respectively. Perl’s reaction was taken for iron staining. The results showed that human traumatic brain injury (TBI) could up-regulate ferritin-H-chain in pericontusional cortex. A marked increase of ferritin was detected in the early group (≤12 h), and remained elevated for a long time till after 48 h post-injury. The location of ferritin-H-chain was found mainly at the neuron-like cells and seldom at glia-like cells. Perl’s reaction showed that most of the iron-positive cells were glia-like cells. These findings suggested that iron and ferritin might be involved in the secondary brain injury and could be therapeutic targets for patients with TBI.


Ferritin Iron Traumatic brain injury Inflammation 



This study was supported by grants from National Natural Science Foundation, China (No. 81171170 for C.-H. Hang, No. 8100053 for M.-L. Zhou and No. 81271377 for L. Zhu) and Nature Science Foundation of Jiangsu Province, China (BK2010459).


  1. 1.
    Roth P, Farls K (2000) Pathophysiology of traumatic brain injury. Crit Care Nurs Q 23(3):14–25 quiz 65PubMedGoogle Scholar
  2. 2.
    Khoshyomn S, Tranmer BI (2004) Diagnosis and management of pediatric closed head injury. Semin Pediatr Surg 13(2):80–86PubMedCrossRefGoogle Scholar
  3. 3.
    Ziebell JM, Morganti-Kossmann MC (2010) Involvement of pro- and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics 7(1):22–30PubMedCrossRefGoogle Scholar
  4. 4.
    Bramlett HM, Dietrich WD (2007) Progressive damage after brain and spinal cord injury: pathomechanisms and treatment strategies. Prog Brain Res 161:125–141PubMedCrossRefGoogle Scholar
  5. 5.
    Helmy A, De Simoni MG, Guilfoyle MR, Carpenter KL, Hutchinson PJ (2011) Cytokines and innate inflammation in the pathogenesis of human traumatic brain injury. Prog Neurobiol 95(3):352–372PubMedCrossRefGoogle Scholar
  6. 6.
    Clausen F, Marklund N, Lewen A, Enblad P, Basu S, Hillered L (2012) Interstitial F(2)-isoprostane 8-iso-PGF(2alpha) as a biomarker of oxidative stress after severe human traumatic brain injury. J Neurotrauma 29(5):766–775PubMedCrossRefGoogle Scholar
  7. 7.
    Zhang QG, Laird MD, Han D, Nguyen K, Scott E, Dong Y, Dhandapani KM, Brann DW (2012) Critical role of NADPH oxidase in neuronal oxidative damage and microglia activation following traumatic brain injury. PLoS ONE 7(4):e34504PubMedCrossRefGoogle Scholar
  8. 8.
    Jin W, Wang H, Yan W, Zhu L, Hu Z, Ding Y, Tang K (2009) Role of Nrf2 in protection against traumatic brain injury in mice. J Neurotrauma 26(1):131–139PubMedCrossRefGoogle Scholar
  9. 9.
    Carbonell T, Rama R (2007) Iron, oxidative stress and early neurological deterioration in ischemic stroke. Curr Med Chem 14(8):857–874PubMedCrossRefGoogle Scholar
  10. 10.
    Connor JR, Menzies SL, Burdo JR, Boyer PJ (2001) Iron and iron management proteins in neurobiology. Pediatr Neurol 25(2):118–129PubMedCrossRefGoogle Scholar
  11. 11.
    Wagner KR, Sharp FR, Ardizzone TD, Lu A, Clark JF (2003) Heme and iron metabolism: role in cerebral hemorrhage. J Cereb Blood Flow Metab 23(6):629–652PubMedCrossRefGoogle Scholar
  12. 12.
    Dennery PA, Visner G, Weng YH, Nguyen X, Lu F, Zander D, Yang G (2003) Resistance to hyperoxia with heme oxygenase-1 disruption: role of iron. Free Radic Biol Med 34(1):124–133PubMedCrossRefGoogle Scholar
  13. 13.
    Chang EF, Claus CP, Vreman HJ, Wong RJ, Noble-Haeusslein LJ (2005) Heme regulation in traumatic brain injury: relevance to the adult and developing brain. J Cereb Blood Flow Metab 25(11):1401–1417PubMedCrossRefGoogle Scholar
  14. 14.
    Huang FP, Xi G, Keep RF, Hua Y, Nemoianu A, Hoff JT (2002) Brain edema after experimental intracerebral hemorrhage: role of hemoglobin degradation products. J Neurosurg 96(2):287–293PubMedCrossRefGoogle Scholar
  15. 15.
    Wu J, Hua Y, Keep RF, Schallert T, Hoff JT, Xi G (2002) Oxidative brain injury from extravasated erythrocytes after intracerebral hemorrhage. Brain Res 953(1–2):45–52PubMedCrossRefGoogle Scholar
  16. 16.
    Lee JY, Keep RF, He Y, Sagher O, Hua Y, Xi G (2010) Hemoglobin and iron handling in brain after subarachnoid hemorrhage and the effect of deferoxamine on early brain injury. J Cereb Blood Flow Metab 30(11):1793–1803PubMedCrossRefGoogle Scholar
  17. 17.
    Long DA, Ghosh K, Moore AN, Dixon CE, Dash PK (1996) Deferoxamine improves spatial memory performance following experimental brain injury in rats. Brain Res 717(1–2):109–117PubMedCrossRefGoogle Scholar
  18. 18.
    Panter SS, Braughler JM, Hall ED (1992) Dextran-coupled deferoxamine improves outcome in a murine model of head injury. J Neurotrauma 9(1):47–53PubMedCrossRefGoogle Scholar
  19. 19.
    Lovell MA, Robertson JD, Teesdale WJ, Campbell JL, Markesbery WR (1998) Copper, iron and zinc in Alzheimer’s disease senile plaques. J Neurol Sci 158(1):47–52PubMedCrossRefGoogle Scholar
  20. 20.
    Youdim MB, Ben-Shachar D, Riederer P (1991) Iron in brain function and dysfunction with emphasis on Parkinson’s disease. Eur Neurol 31(Suppl 1):34–40PubMedCrossRefGoogle Scholar
  21. 21.
    Chiueh CC (2001) Iron overload, oxidative stress, and axonal dystrophy in brain disorders. Pediatr Neurol 25(2):138–147PubMedCrossRefGoogle Scholar
  22. 22.
    Koeppen AH, Dickson AC, McEvoy JA (1995) The cellular reactions to experimental intracerebral hemorrhage. J Neurol Sci 134(Suppl):102–112PubMedCrossRefGoogle Scholar
  23. 23.
    Wu J, Hua Y, Keep RF, Nakamura T, Hoff JT, Xi G (2003) Iron and iron-handling proteins in the brain after intracerebral hemorrhage. Stroke 34(12):2964–2969PubMedCrossRefGoogle Scholar
  24. 24.
    Levi S, Yewdall SJ, Harrison PM, Santambrogio P, Cozzi A, Rovida E, Albertini A, Arosio P (1992) Evidence of H- and L-chains have co-operative roles in the iron-uptake mechanism of human ferritin. Biochem J 288(Pt 2):591–596PubMedGoogle Scholar
  25. 25.
    Hang CH, Chen G, Shi JX, Zhang X, Li JS (2006) Cortical expression of nuclear factor kappaB after human brain contusion. Brain Res 1109(1):14–21PubMedCrossRefGoogle Scholar
  26. 26.
    Li W, Ling HP, You WC, Ji XJ, Tang Y, Zhao JB, Su XF, Hang CH (2012) Recombinant high-mobility group box 1 protein (HMGB-1) promotes myeloid differentiation primary response protein 88 (Myd88) upregulation in mouse primary cortical neurons. Neurol SciGoogle Scholar
  27. 27.
    McIntosh TK, Thomas M, Smith D, Banbury M (1992) The novel 21-aminosteroid U74006F attenuates cerebral edema and improves survival after brain injury in the rat. J Neurotrauma 9(1):33–46PubMedCrossRefGoogle Scholar
  28. 28.
    Marklund N, Clausen F, Lewen A, Hovda DA, Olsson Y, Hillered L (2001) alpha-Phenyl-tert-N-butyl nitrone (PBN) improves functional and morphological outcome after cortical contusion injury in the rat. Acta Neurochir (Wien) 143(1):73–81CrossRefGoogle Scholar
  29. 29.
    Fukuda K, Richmon JD, Sato M, Sharp FR, Panter SS, Noble LJ (1996) Induction of heme oxygenase-1 (HO-1) in glia after traumatic brain injury. Brain Res 736(1–2):68–75PubMedCrossRefGoogle Scholar
  30. 30.
    Beschorner R, Adjodah D, Schwab JM, Mittelbronn M, Pedal I, Mattern R, Schluesener HJ, Meyermann R (2000) Long-term expression of heme oxygenase-1 (HO-1, HSP-32) following focal cerebral infarctions and traumatic brain injury in humans. Acta Neuropathol 100(4):377–384PubMedCrossRefGoogle Scholar
  31. 31.
    Chen Z, Gao C, Hua Y, Keep RF, Muraszko K, Xi G (2011) Role of iron in brain injury after intraventricular hemorrhage. Stroke 42(2):465–470PubMedCrossRefGoogle Scholar
  32. 32.
    Okauchi M, Hua Y, Keep RF, Morgenstern LB, Xi G (2009) Effects of deferoxamine on intracerebral hemorrhage-induced brain injury in aged rats. Stroke 40(5):1858–1863PubMedCrossRefGoogle Scholar
  33. 33.
    Zhang L, Hu R, Li M, Li F, Meng H, Zhu G, Lin J, Feng H (2012) Deferoxamine attenuates iron-induced long-term neurotoxicity in rats with traumatic brain injury. Neurol SciGoogle Scholar
  34. 34.
    Selim M (2009) Deferoxamine mesylate: a new hope for intracerebral hemorrhage: from bench to clinical trials. Stroke 40(3 Suppl):S90–S91PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Italia 2012

Authors and Affiliations

  • Huan-Dong Liu
    • 1
  • Wei Li
    • 2
  • Zhen-Rui Chen
    • 1
  • Meng-Liang Zhou
    • 2
  • Zong Zhuang
    • 2
  • Ding-Ding Zhang
    • 2
  • Lin Zhu
    • 2
  • Chun-Hua Hang
    • 1
    • 2
    Email author
  1. 1.Department of NeurosurgerySchool of Medicine, Southern Medical University (Guangzhou), Jinling HospitalNanjingPeople’s Republic of China
  2. 2.Department of NeurosurgeryJinling Hospital, School of Medicine, Nanjing UniversityNanjingPeople’s Republic of China

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