Skip to main content
SpringerLink
Log in

Time course of heme oxygenase-1 and oxidative stress after experimental intracerebral hemorrhage

  • Experimental research
  • Published:
Acta Neurochirurgica Aims and scope Submit manuscript

Abstract

Background

Heme oxygenase-1 (HO-1), the rate-limiting enzyme for heme catabolism and iron production, its role in intracerebral hemorrhage (ICH) is controversial. The study was to investigate correlations between brain oxidative injury and HO-1 after experimental ICH.

Method

Sprague–Dawley rats received intra-striatal infusions of 100 μl autologous whole blood as ICH models. HO-1 were examined by immunohistochemical and reverse transcription polymerase chain reaction (RT-PCR) analysis. Brain oxidative stress was quantitated by malondialdehyde (MDA); antioxidation were measured by copper–zinc superoxide dismutase (Cu/Zn-SOD) activity using RT-PCR assay.

Results

The expression of the HO-1 upregulated and reached its peak at days 3 and 7 after ICH (P < 0.01). There was a significant increase of MDA and a top at 3-day post-ICH (P < 0.01); Cu/Zn-SOD was upregulated post-ICH and reached the top at day 7 (P < 0.001); HO-1 was correlated significantly with brain MDA content at days 7 and 14 following ICH (r = 0.435–0.501, P < 0.001) but there is no definite correlation between them on 1 to 3 days (P > 0.05); conversely, HO-1 was correlated significantly with Cu/Zn-SOD on 1 to 3 days after ICH (r = 0.433–0.621, P < 0.001) but there is no definite correlation between them at days 7 and 14 (P > 0.05).

Conclusions

HO-1 has both antioxidant and prooxidant properties in ICH. The early upregulation of HO-1 possibly fit with the events and be protective against oxidative stress, whereas its overexpression in the late stages may result in its dysfunction and be toxic. So it should be prudent to intervene ICH with the inhibitor/activator of HO-1.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

DAB:

Diaminobenzidine

ICH:

Intracerebral hemorrhage

MDA:

Malondialdehyde

Cu/Zn-SOD:

Copper–zinc superoxide dismutase

HO-1:

Heme oxygenase-1

RT-PCR:

Reverse transcription polymerase chain reaction

References

  1. Bostanci MO, Bağirici F (2008) Nitric oxide synthesis inhibition attenuates iron-induced neurotoxicity: a stereological study. Neurotoxicology 29:130–135

    Article  CAS  PubMed  Google Scholar 

  2. Chen-Roetling J, Regan RF (2006) Effect of heme oxygenase-1 on the vulnerability of astrocytes and neurons to hemoglobin. Biochem Biophys Res Commun 350:233–237

    Article  CAS  PubMed  Google Scholar 

  3. Davis AS, Zhao H, Sun GH, Sapolsky RM, Steinberg GK (2007) Gene therapy using SOD1 protects striatal neurons from experimental stroke. Neurosci Lett 411:32–36

    Article  CAS  PubMed  Google Scholar 

  4. Dennis MS (2003) Outcome after brain haemorrhage. Cerebrovasc Dis 16:9–13

    Article  PubMed  Google Scholar 

  5. Dohi K, Mochizuki Y, Satoh K, Jimbo H, Hayashi M, Toyoda I, Ikeda Y, Abe T, Aruga T (2003) Transient elevation of serum bilirubin (a heme oxygenase-1 metabolite) level in hemorrhagic stroke: bilirubin is a marker of oxidant stress. Acta Neurochir Suppl 86:247–249

    CAS  PubMed  Google Scholar 

  6. Ferris CD, Jaffrey SR, Sawa A, Takahashi M, Brady SD, Barrow RK, Tysoe SA, Wolosker H, Barañano DE, Doré S, Poss KD, Snyder SH (1999) Haem oxygenase-1 prevents cell death by regulating cellular iron. Nat Cell Biol 1:152–157

    Article  CAS  PubMed  Google Scholar 

  7. He Y, Hua Y, Song S, Liu W, Keep RF, Xi G (2008) Induction of autophagy in rat hippocampus and cultured neurons by iron. Acta Neurochir Suppl 105:29–32

    Article  CAS  PubMed  Google Scholar 

  8. Hua Y, Keep RF, Hoff JT, Xi G (2008) Deferoxamine therapy for intracerebral hemorrhage. Acta Neurochir Suppl 105:3–6

    Article  CAS  PubMed  Google Scholar 

  9. Hua Y, Keep RF, Hoff JT, Xi G (2003) Thrombin preconditioning attenuates brain edema induced by erythrocytes and iron. J Cereb Blood Flow Metab 23:1448–1454

    Article  CAS  PubMed  Google Scholar 

  10. Kanno H, Ozawa H, Dohi Y, Sekiguchi A, Igarashi K, Itoi E (2009) Genetic ablation of transcription repressor Bach1 reduces neural tissue damage and improves locomotor function after spinal cord injury in mice. J Neurotrauma 26:31–39

    Article  PubMed  Google Scholar 

  11. Katsu M, Niizuma K, Yoshioka H, Okami N, Sakata H, Chan PH (2010) Hemoglobin-induced oxidative stress contributes to matrix metalloproteinase activation and blood-brain barrier dysfunction in vivo. J Cereb Blood Flow Metab (in press)

  12. Koeppen AH, Dickson AC, Smith J (2004) Heme oxygenase in experimental intracerebral hemorrhage: the benefit of tin-mesoporphyrin. J Neuropathol Exp Neurol 63:587–597

    CAS  PubMed  Google Scholar 

  13. Nakamura T, Keep RF, Hua Y, Nagao S, Hoff JT, Xi G (2006) Iron-induced oxidative brain injury after experimental intracerebral hemorrhage. Acta Neurochir Suppl 96:194–198

    Article  CAS  PubMed  Google Scholar 

  14. Nishio S, Yunoki M, Noguchi Y, Kawauchi M, Asari S, Ohmoto T (1997) Detection of lipid peroxidation and hydroxyl radicals in brain contusion of rats. Acta Neurochir Suppl 70:84–86

    CAS  PubMed  Google Scholar 

  15. Peluffo H, Acarin L, Arís A, González P, Villaverde A, Castellano B, González B (2006) Neuroprotection from NMDA excitotoxic lesion by Cu/Zn superoxide dismutase gene delivery to the postnatal rat brain by a modular protein vector. BMC Neurosci 7:35

    Article  PubMed  Google Scholar 

  16. Peluffo H, Acarin L, Faiz M, Castellano B, Gonzalez B (2005) Cu/Zn superoxide dismutase expression in the postnatal rat brain following an excitotoxic injury. J Neuroinflammation 2:12

    Article  PubMed  Google Scholar 

  17. Pyne-Geithman GJ, Morgan CJ, Wagner K, Dulaney EM, Carrozzella J, Kanter DS, Zuccarello M, Clark JF (2005) Bilirubin production and oxidation in CSF of patients with cerebral vasospasm after subarachnoid hemorrhage. J Cereb Blood Flow Metab 25(8):1070–1077

    Article  CAS  PubMed  Google Scholar 

  18. Qing WG, Dong YQ, Ping TQ, Lai LG, Fang LD, Min HW, Xia L, Heng PY (2009) Brain edema after intracerebral hemorrhage in rats: the role of iron overload and AQP4. J Neurosurg 110:462–468

    Article  PubMed  Google Scholar 

  19. Regan RF, Kumar N, Gao F, Guo Y (2002) Ferritin induction protects cortical astrocytes from heme-mediated oxidative injury. Neuroscience 113:985–994

    Article  CAS  PubMed  Google Scholar 

  20. Ryter WW, Tyrrell RM (2000) The heme synthesis and degradation pathways: role in oxidant sensitivity. Heme oxygenase has both pro- and antioxidant properties. Free Radic Biol Med 28:289–309

    Article  CAS  PubMed  Google Scholar 

  21. Salvador GA (2010) Iron in neuronal function and dysfunction. Biofactors 36(2):103–110

    Article  CAS  PubMed  Google Scholar 

  22. Shimada Y, Tsunoda H, Zang L, Hirano M, Oka T, Tanaka T (2009) Synergistic induction of heme oxygenase-1 by nicaraven after subarachnoid hemorrhage to prevent delayed cerebral vasospasm. Eur J Pharmacol 620(1–3):16–20

    Article  CAS  PubMed  Google Scholar 

  23. Song S, Hua Y, Keep RF, He Y, Wang J, Wu J, Xi G (2008) Deferoxamine reduces brain swelling in a rat model of hippocampal intracerebral hemorrhage. Acta Neurochir Suppl 105:13–18

    Article  CAS  PubMed  Google Scholar 

  24. Suttner DM, Dennery PA (1999) Reversal of HO-1 related cytoprotection with increased expression is due to reactive iron. FASEB J 13:1800–1809

    CAS  PubMed  Google Scholar 

  25. Tang Y, Lu A, Aronow BJ, Wagner KR, Sharp FR (2002) Genomic responses of the brain to ischemic stroke, intracerebral haemorrhage, kainate seizures, hypoglycemia, and hypoxia. Eur J Neurosci 15:1937–1952

    Article  PubMed  Google Scholar 

  26. True AL, Olive M, Boehm M, San H, Westrick RJ, Raghavachari N, Xu X, Lynn EG, Sack MN, Munson PJ, Gladwin MT, Nabel EG (2007) Heme oxygenase-1 deficiency accelerates formation of arterial thrombosis through oxidative damage to the endothelium, which is rescued by inhaled carbon monoxide. Circ Res 101:893–901

    Article  CAS  PubMed  Google Scholar 

  27. Turner CP, Bergeron M, Matz P, Zegna A, Noble LJ, Panter SS, Sharp FR (1998) Heme oxygenase-1 is induced in glia throughout brain by subarachnoid hemoglobin. J Cereb Blood Flow Metab 18:257–273

    Article  CAS  PubMed  Google Scholar 

  28. Wagner KR, Sharp FR, Ardizzone TD, Lu A, Clark JF (2003) Heme and iron metabolism: role in cerebral hemorrhage. J Cereb Blood Flow Metab 23:629–652

    Article  CAS  PubMed  Google Scholar 

  29. Wang J, Doré S (2007) Heme oxygenase-1 exacerbates early brain injury after intracerebral haemorrhage. Brain 130:1643–1652

    Article  PubMed  Google Scholar 

  30. Welch KD, Davis TZ, Van Eden ME, Aust SD (2002) Deleterious Iron-mediated oxidation of bio-molecules. Free Radic Biol Med 32:577–583

    Article  CAS  PubMed  Google Scholar 

  31. 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 34:2964–2969

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

Download references

Conflicts of interest

None.

Author information

Authors and Affiliations

  1. Department of Neurology, Xiangya Hospital, Central-South University, ChangSha, Hu Nan, China

    Gaiqing Wang & Qidong Yang

  2. Department of Neurology, The Second Hospital, Shanxi Medical University, 382 WuYi avenue, Tai Yuan, 030001, Shan Xi, China

    Gaiqing Wang, Guanglai Li, Li Wang, Weimin Hu, Dongfang Li & Zhitang Sun

  3. Department of Convalescence, Hu Nan Province Brain faculty Hospital, Changsha, Hu Nan, China

    Qingping Tang

Authors
  1. Gaiqing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qidong Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Guanglai Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Li Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Weimin Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qingping Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dongfang Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhitang Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gaiqing Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, G., Yang, Q., Li, G. et al. Time course of heme oxygenase-1 and oxidative stress after experimental intracerebral hemorrhage. Acta Neurochir 153, 319–325 (2011). https://doi.org/10.1007/s00701-010-0750-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00701-010-0750-2

Keywords

Search

Navigation