Skip to main content
SpringerLink
Log in

Evaluation of the apoptosis-related proteins of the BCL-2 family In the traumatic penumbra area of the rat model of cerebral contusion, treated by hyperbaric oxygen therapy: a quantitative immunohistochemical study

  • Regular Paper
  • Published:
Acta Neuropathologica Aims and scope Submit manuscript

Abstract

The growth and progression of traumatic brain injury (TBI) lesions depend significantly on developments in the traumatic penumbra area, perilesional region, where delayed neuronal death occurs. Recent data supports the important role of apoptosis in delayed cell death in TBI. Previously we demonstrated a significant reduction of apoptosis in traumatic penumbra in animals treated by hyperbaric oxygen (HBO).In this study we evaluate the expression of apoptosis-related proteins of the Bcl-2 family (Bcl-2, Bax and Bcl-xL) in the traumatic penumbra area in correlation with the extent of apoptosis in the rat model of focal cerebral contusion, treated by HBO. Sprague-Dawley rats underwent cortical dynamic deformation, some with subsequent hypoxemia. A group of both hypoxemic and non-hypoxemic animals was treated by HBO. The pathological study was based on immunohistochemical staining of the brain sections for Bcl-2, Bax and Bcl-xL with quantitative evaluation of staining by image analysis. The expression of Bcl-2 in hypoxemic animals was lower than in non-hypoxemic animals, but a significant increase in Bcl-2 expression was seen in both groups after HBO treatment. Bcl-xL also demonstrated an increase after HBO treatment but less significant. Staining for Bax protein did not demonstrate significant change after treatment. These data correlate well with the reduction of TUNEL-positive cells in traumatic penumbra after HBO treatment. We concluded that the apoptotic mechanisms are important in delayed cell death in TBI and that post-traumatic hypoxemia increases the intensity of apoptosis, probably through a decrease in Bcl-2 and Bcl-xL expression which normally repress apoptosis. The beneficial effect of HBO treatment in our model of brain contusion correlates well with the increased expression of anti-apoptotic proteins (Bcl-2 and Bcl-xL) following treatment and the appropriate decrease in the extent of apoptosis. In light of these results, the usage of HBO is justified as neuroprotective treament in TBI.

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

Similar content being viewed by others

References

  1. Barth M, Schilling L, Schmiedek P (2000) Time course of apoptotic cell death after experimental neurotrauma. Acta Neurochir (Wien) Suppl 76:121–124

    Google Scholar 

  2. Chen L (2000) Study on histology and the expression of Bax and Bcl-2 after cerebral contusion in rats. Fa Yi Xue Za Zhi 16:211–213

    CAS  PubMed  Google Scholar 

  3. Clark RS, Chen J, Watkins SC, Kochanek PM, Chen M, Stetler RA, Loeffert JE, Graham SH (1997) Apoptosis-suppressor gene bcl-2 expression after traumatic brain injury in rats. J Neurosci 17:9172–9182

    CAS  PubMed  Google Scholar 

  4. Conti AC, Raghupathi R, Trojanowski JQ, McIntosh TK (1998) Experimental brain injury induces regionally distinct apoptosis during the acute and delayed post-traumatic period. J Neurosci 18:5663–5672

    CAS  PubMed  Google Scholar 

  5. Cregan SP, MacLaurin JG, Craig CG, Robertson GS, Nicholson DW, Park DS, Slack RS (1999) Bax-dependent caspase-3 activation is a key determinant in p53-induced apoptosis in neurons. J Neurosci 19:7860–7869

    CAS  PubMed  Google Scholar 

  6. Felderhoff-Mueser U, Sifringer M, Pesditschek S, Kuckuck H, Moysich A, Bittigau P, Ikonomidou C (2002) Pathways leading to apoptotic neurodegeneration following trauma to the developing rat brain. Neurobiol Dis 11:231–245

    CAS  PubMed  Google Scholar 

  7. Ferrer I, Planas AM (2003) Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. J Neuropathol Exp Neurol 62:329–339

    PubMed  Google Scholar 

  8. Kaya SS, Mahmood A, Li Y, Yavuz E, Goksel M, Chopp M (1999) Apoptosis and expression of p53 response proteins and cyclin D1 after cortical impact in rat brain. Brain Res 818:23-33

    CAS  PubMed  Google Scholar 

  9. Keane RW, Kraydieh S, Lotocki G, Alonso OF, Aldana P, Dietrich WD (2001) Apoptotic and antiapoptotic mechanisms after traumatic brain injury. J Cereb Blood Flow Metab 21:1189–1198

    CAS  PubMed  Google Scholar 

  10. Konda A, Baba S, Iwaki T, Harai H, Koga H, Kimura T, Takamatsu J (1996) Hyperbaric oxygenation prevents delayed neuronal death following transient ischaemia in the gerbil hippocampus. Neuropathol Appl Neurobiol 22:350–360

    CAS  PubMed  Google Scholar 

  11. Leker RR, Shohami I (2002) Cerebral ischemia and trauma-different etiologies yet similar mechanisms: neuroprotective opportunities. Brain Res 39:55–73

    Article  Google Scholar 

  12. Luo C, Lu Y, Jiang J, Zhu C (2002) Changes of bcl-x(L) and bax mRNA expression following traumatic brain injury in rats. Chin J Traumatol 5:299–302

    CAS  PubMed  Google Scholar 

  13. Martin LJ, Kaiser A, Yu JW, Natale JE, Al-Abdulla NA (2001) Injury-induced apoptosis of neurons in adult brain is mediated by p53-dependent and p53-independent pathways and requires Bax. J Comp Neurol 433:299–311

    CAS  PubMed  Google Scholar 

  14. McIntosh TK, Saatman KE, Raghupathi R, Graham DI, Smith DH, Lee VM, Trojanowski JQ (1998) The molecular and cellular sequelae of experimental traumatic brain injury: pathogenetic mechanisms. Neuropathol Appl Neurobiol 24:251–267

    CAS  PubMed  Google Scholar 

  15. Palzur E, Vlodavsky E, Mulla H, Arieli R, Feinsod M, Soustiel JF (2004) Hyperbaric oxygen therapy for reduction of secondary brain damage in head injury: an animal model of brain contusion. J Neurotrauma 21:41–48

    PubMed  Google Scholar 

  16. Raghupathi R, Conti AC, Graham DI, Krajewski S, Reed JC, Grady MS, Trojanowsky JQ, McIntosh TK (2002). Mild brain traumatic injury induces apoptotic cell death in the cortex that is preceded by decreases in cellular Bcl-2 immunoreactivity. Neuroscience 110:605–616

    CAS  PubMed  Google Scholar 

  17. Rosenthal RE, Silbergleit R, Hof PR, Haywood Y, Fiskum G (2003) Hyperbaric oxygen reduces neuronal death and improves neurologic outcomes after canine cardiac arrest. Stroke 34:1311–1316

    PubMed  Google Scholar 

  18. Royo NC, Schouten JW, Fulp CT, Shimizu S, Marklund N, Graham DI, McIntosh TK (2003) From cell death to neuronal regeneration: building a new brain after traumatic brain injury. J Neuropathol Exp Neurol 62:801–811

    CAS  PubMed  Google Scholar 

  19. Sahuquillo J, Poca MA, Amoros S (2001) Current aspects of pathophysiology and cell dysfunction after severe head injury. Curr Pharm Des 7:1475–1503

    CAS  PubMed  Google Scholar 

  20. Shreiber DI, Bain AC, Ross DT, Smith DH, Gennarelli TA, McIntosh TK, Meaney DF (1999) Experimental investigation of cerebral contusion: histopathological and immunohistochemical evaluation of dynamic cortical deformation. J Neuropathol Exp Neurol 58:153–164

    CAS  PubMed  Google Scholar 

  21. Smith FM, Raghupathi R, MacKinnon MA, McIntosh TK, Saatman KE, Meaney DF, Graham DI (2000) TUNEL-positive staining of surface contusions after fatal head injury in man. Acta Neuropathol 100:537–545

    CAS  PubMed  Google Scholar 

  22. Springer JE, Nottingham SA, McEwen ML, Azbill RD, Jin Y (2001) Caspase-3 apoptotic signaling following injury to the central nervous system. Clin Chem Lab Med 39:299–307

    CAS  PubMed  Google Scholar 

  23. Wada K, Miyazawa T, Nomura N, Yano A, Tsuzuki N, Nawashiro H, Shima K (2000) MnSOD and Bcl-2 expression after repeated hyperbaric oxygenation. Acta Neurochir (Wien) Suppl 76:285–290

    Google Scholar 

  24. Wennersten A, Holmin S, Mathiesen T (2003) Characterization of Bax and Bcl-2 in apoptosis after experimental brain injury in rat. Acta Neuropathol 105:281–288

    CAS  PubMed  Google Scholar 

  25. Yin D, Zhou C, Kusaka I, Calvert JW, Parent AD, Nanda A, Zhang JH (2003) Inhibition of apoptosis by hyperbaric oxygen in a rat focal cerebral ischemic model. J Cereb Blood Flow Metab 23:855-864

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the expert technical assistance of Shoshana Ben-Eliezer, Irina Minkov and Inna Grinberg with histological and immunohistochemical methods. The authors also thank Myrna Perlmutter for her help in the preparation of this paper.

Author information

Authors and Affiliations

  1. Institute of Pathology, Rambam Medical Center and Faculty of Medicine, Technion-Israel Institute of Technology, POB 9602, 31096, Haifa, Israel

    Eugene Vlodavsky

  2. Department of Neurosurgery and Acute Brain Research Laboratory, Rambam Medical Center and Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

    Eilam Palzur, Moshe Feinsod & Jean F. Soustiel

Authors
  1. Eugene Vlodavsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eilam Palzur
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Moshe Feinsod
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jean F. Soustiel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eugene Vlodavsky.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Vlodavsky, E., Palzur, E., Feinsod, M. et al. Evaluation of the apoptosis-related proteins of the BCL-2 family In the traumatic penumbra area of the rat model of cerebral contusion, treated by hyperbaric oxygen therapy: a quantitative immunohistochemical study. Acta Neuropathol 110, 120–126 (2005). https://doi.org/10.1007/s00401-004-0946-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00401-004-0946-8

Keywords

Search

Navigation