Influence of apoptosis on neurological outcome following traumatic cerebral contusion

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Object. Apoptosis has increasingly been implicated in the pathobiology of traumatic brain injury (TBI). The present study was undertaken to confirm the presence of apoptosis in the periischemic zone (PIZ) of traumatic cerebral contusions and to determine the role of apoptosis, if any, in neurological outcome.

Methods. Brain tissue harvested at Wentworth Hospital from the PIZ in 29 patients with traumatic supratentorial contusions was compared with brain tissue resected in patients with epilepsy. Immunohistochemical analyses were performed on the tissues to see if they contained the apoptosis-related proteins p53, bcl-2, bax, and caspase-3. The findings were then correlated to demographic, clinical, surgical, neuroimaging, and outcome data.

In the PIZ significant increases of bax (18-fold; p < 0.005) and caspase-3 (20-fold; p < 0.005) were recorded, whereas bcl-2 was upregulated in only 14 patients (48.3%; 2.9-fold increase) compared with control tissue. Patients in the bcl-2—positive group exhibited improved outcomes at the 18-month follow-up examination despite an older mean age and lower mean admission Glasgow Coma Scale score (p < 0.03). Caspase-3 immunostaining was increased in those patients who died (Glasgow Outcome Scale [GOS] Score 1, 12 patients) when compared with those who experienced a good outcome (GOS Score 4 or 5, 17 patients) (p < 0.005). Regression analysis identified bcl-2—negative status (p < 0.04, odds ratio [OR] 5.5; 95% confidence interval [CI] 1.1–28.4) and caspase-3—positive status (p < 0.01, OR 1.4, 95% CI 1.1—1.8) as independent predictors of poor outcome. No immunostaining for p53 was recorded in the TBI specimens.

Conclusions. The present findings confirm apoptosis in the PIZ of traumatic cerebral contusions and indicate that this form of cell death can influence neurological outcome following a TBI.

Article Information

Contributor Notes

Address reprint requests to: Narendra Nathoo, M.D., Ph.D., Department of Neurosurgery-S80, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195. email: nathoon@ccf.org.
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References
  • 1.

    Bullock RMaxwell WLGraham DIet al: Glial swelling following human cerebral contusion: an ultrastructural study. J Neurol Neurosurg Psychiatry 54:4274341991Bullock R Maxwell WL Graham DI et al: Glial swelling following human cerebral contusion: an ultrastructural study. J Neurol Neurosurg Psychiatry 54:427–434 1991

    • Search Google Scholar
    • Export Citation
  • 2.

    Bullock RStatham PPatterson Jet al: The time course of vasogenic oedema after focal human head injury—evidence from SPECT mapping of blood brain barrier defects. Acta Neurochir Suppl 51:2862881990Bullock R Statham P Patterson J et al: The time course of vasogenic oedema after focal human head injury—evidence from SPECT mapping of blood brain barrier defects. Acta Neurochir Suppl 51:286–288 1990

    • Search Google Scholar
    • Export Citation
  • 3.

    Cernak IChapman SMHamlin GPet al: Temporal characterisation of pro- and anti-apoptotic mechanisms following diffuse traumatic brain injury in rats. J Clin Neurosci 9:5655722002Cernak I Chapman SM Hamlin GP et al: Temporal characterisation of pro- and anti-apoptotic mechanisms following diffuse traumatic brain injury in rats. J Clin Neurosci 9:565–572 2002

    • Search Google Scholar
    • Export Citation
  • 4.

    Chen JJin KChen Met al: Early detection of DNA strand breaks in the brain after transient focal ischemia: implications for the role of DNA damage in apoptosis and neuronal cell death. J Neurochem 69:2322451997Chen J Jin K Chen M et al: Early detection of DNA strand breaks in the brain after transient focal ischemia: implications for the role of DNA damage in apoptosis and neuronal cell death. J Neurochem 69:232–245 1997

    • Search Google Scholar
    • Export Citation
  • 5.

    Clark RSKochanek PMAdelson PDet al: Increases in bcl-2 protein in cerebrospinal fluid and evidence for programmed cell death in infants and children after severe traumatic brain injury. J Pediatr 137:1972042000Clark RS Kochanek PM Adelson PD et al: Increases in bcl-2 protein in cerebrospinal fluid and evidence for programmed cell death in infants and children after severe traumatic brain injury. J Pediatr 137:197–204 2000

    • Search Google Scholar
    • Export Citation
  • 6.

    Clark RSBChen JWatkins SCet al: Apoptotic-suppressor gene bcl-2 expression after traumatic brain injury in rats. J Neurosci 17:917291821997Clark RSB Chen J Watkins SC et al: Apoptotic-suppressor gene bcl-2 expression after traumatic brain injury in rats. J Neurosci 17:9172–9182 1997

    • Search Google Scholar
    • Export Citation
  • 7.

    Clark RSBKochanek PMChen Met al: Increases in Bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury. FASEB J 13:8138211999Clark RSB Kochanek PM Chen M et al: Increases in Bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury. FASEB J 13:813–821 1999

    • Search Google Scholar
    • Export Citation
  • 8.

    Conti ACRaghupathi RTrojanowski JQet al: Experimental brain injury induces regionally distinct apoptosis during the acute and delayed post-traumatic period. J Neurosci 18:566356721998Conti AC Raghupathi R Trojanowski JQ et al: Experimental brain injury induces regionally distinct apoptosis during the acute and delayed post-traumatic period. J Neurosci 18:5663–5672 1998

    • Search Google Scholar
    • Export Citation
  • 9.

    Gold RSchmied MGiegerich Get al: Differentiation between cellular apoptosis and necrosis by the combined use of in situ tailing and nick translation techniques. Lab Invest 71:2192251997Gold R Schmied M Giegerich G et al: Differentiation between cellular apoptosis and necrosis by the combined use of in situ tailing and nick translation techniques. Lab Invest 71:219–225 1997

    • Search Google Scholar
    • Export Citation
  • 10.

    Harter LKeel MHentze Het al: Caspase-3 activity is present in cerebrospinal fluid from patients with traumatic brain injury. J Neuroimmunol 121:76782001Harter L Keel M Hentze H et al: Caspase-3 activity is present in cerebrospinal fluid from patients with traumatic brain injury. J Neuroimmunol 121:76–78 2001

    • Search Google Scholar
    • Export Citation
  • 11.

    Hengartner MOHorvitz HR: C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76:6656761994Hengartner MO Horvitz HR: C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2. Cell 76:665–676 1994

    • Search Google Scholar
    • Export Citation
  • 12.

    Hengartner MOHorvitz HR: Programmed cell death in Caenorhabditis elegans. Curr Opin Genet Develop 4:5815861994Hengartner MO Horvitz HR: Programmed cell death in Caenorhabditis elegans. Curr Opin Genet Develop 4:581–586 1994

    • Search Google Scholar
    • Export Citation
  • 13.

    Jennett BBond M: Assessment of outcome after severe brain damage. A practical scale. Lancet 1:4804841975Jennett B Bond M: Assessment of outcome after severe brain damage. A practical scale. Lancet 1:480–484 1975

    • Search Google Scholar
    • Export Citation
  • 14.

    Johnson EM JrDeckwerth TL: Molecular mechanisms of developmental neuronal death. Annu Rev Neurosci 16:31461993Johnson EM Jr Deckwerth TL: Molecular mechanisms of developmental neuronal death. Annu Rev Neurosci 16:31–46 1993

    • Search Google Scholar
    • Export Citation
  • 15.

    Johnson EM JrGreenlund LJSAkins PTet al: Neuronal apoptosis: current understanding of molecular mechanisms and potential role in ischemic brain injury. J Neurotrauma 12:8438521995Johnson EM Jr Greenlund LJS Akins PT et al: Neuronal apoptosis: current understanding of molecular mechanisms and potential role in ischemic brain injury. J Neurotrauma 12:843–852 1995

    • Search Google Scholar
    • Export Citation
  • 16.

    Kerr JFWyllie AHCurrie AR: Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:2392571972Kerr JF Wyllie AH Currie AR: Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257 1972

    • Search Google Scholar
    • Export Citation
  • 17.

    MacLennan KAEllis IORobinson G: Immunocytochemistry in diagnostic tumour pathology in Bancroft JDStevens A (eds): Theory and Practise of Histological Techniquesed 3. Edinburgh: Churchill Livingstone1990 pp 437451MacLennan KA Ellis IO Robinson G: Immunocytochemistry in diagnostic tumour pathology in Bancroft JD Stevens A (eds): Theory and Practise of Histological Techniques ed 3. Edinburgh: Churchill Livingstone 1990 pp 437–451

    • Search Google Scholar
    • Export Citation
  • 18.

    Martinou JCDubois-Dauphin MStaple JKet al: Overexpression of Bcl-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13:101710301994Martinou JC Dubois-Dauphin M Staple JK et al: Overexpression of Bcl-2 in transgenic mice protects neurons from naturally occurring cell death and experimental ischemia. Neuron 13:1017–1030 1994

    • Search Google Scholar
    • Export Citation
  • 19.

    Maxwell WLBullock RLandholt Het al: Massive astrocytic swelling in response to extracellular glutamate—a possible mechanism for post-traumatic brain swelling. Acta Neurochir Suppl 60:4654671994Maxwell WL Bullock R Landholt H et al: Massive astrocytic swelling in response to extracellular glutamate—a possible mechanism for post-traumatic brain swelling. Acta Neurochir Suppl 60:465–467 1994

    • Search Google Scholar
    • Export Citation
  • 20.

    Miyashita TReed JC: Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80:2932991995Miyashita T Reed JC: Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80:293–299 1995

    • Search Google Scholar
    • Export Citation
  • 21.

    Newcomb JKZhao XPike BRet al: Temporal profile of apoptotic-like changes in neurons and astrocytes following controlled cortical impact injury in the rat. Exp Neurol 158:76881999Newcomb JK Zhao X Pike BR et al: Temporal profile of apoptotic-like changes in neurons and astrocytes following controlled cortical impact injury in the rat. Exp Neurol 158:76–88 1999

    • Search Google Scholar
    • Export Citation
  • 22.

    Ng IYeo TTTang WYet al: Apoptosis occurs after cerebral contusions in humans. Neurosurgery 46:9499562000Ng I Yeo TT Tang WY et al: Apoptosis occurs after cerebral contusions in humans. Neurosurgery 46:949–956 2000

    • Search Google Scholar
    • Export Citation
  • 23.

    Nicholson DWAli AThornberry JPet al: Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376:37431995Nicholson DW Ali A Thornberry JP et al: Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature 376:37–43 1995

    • Search Google Scholar
    • Export Citation
  • 24.

    Oppenheim RW: Cell death during development of the nervous system. Annu Rev Neurosci 14:4535011991Oppenheim RW: Cell death during development of the nervous system. Annu Rev Neurosci 14:453–501 1991

    • Search Google Scholar
    • Export Citation
  • 25.

    Oren MMaltzman WLevine AJ: Post-translational regulation of 54K cellular tumor antigen in normal and transformed cells. Mol Cell Biol 1:1011101981Oren M Maltzman W Levine AJ: Post-translational regulation of 54K cellular tumor antigen in normal and transformed cells. Mol Cell Biol 1:101–110 1981

    • Search Google Scholar
    • Export Citation
  • 26.

    Patel TGores GJKaufmann SH: The role of proteases during apoptosis. FASEB J 10:5875971996Patel T Gores GJ Kaufmann SH: The role of proteases during apoptosis. FASEB J 10:587–597 1996

    • Search Google Scholar
    • Export Citation
  • 27.

    Raghupathi RFernandez SCMurai Het al: BCL-2 overexpression attenuates cortical cell loss after traumatic brain injury in transgenic mice. J Cereb Blood Flow Metab 18:125912691998Raghupathi R Fernandez SC Murai H et al: BCL-2 overexpression attenuates cortical cell loss after traumatic brain injury in transgenic mice. J Cereb Blood Flow Metab 18:1259–1269 1998

    • Search Google Scholar
    • Export Citation
  • 28.

    Rink AFung KMTrojanowski JQet al: Evidence of apoptotic cell death after experimental trauma brain injury in the rat. Am J Pathol 147:157515831995Rink A Fung KM Trojanowski JQ et al: Evidence of apoptotic cell death after experimental trauma brain injury in the rat. Am J Pathol 147:1575–1583 1995

    • Search Google Scholar
    • Export Citation
  • 29.

    Robinson GEllis IOMacLennan KA: Immunocytochemistry in Bancroft JDStevens A (eds): Theory and Practise of Histological Techniquesed 3. Edinburgh: Churchill Livingstone1990 pp 413436Robinson G Ellis IO MacLennan KA: Immunocytochemistry in Bancroft JD Stevens A (eds): Theory and Practise of Histological Techniques ed 3. Edinburgh: Churchill Livingstone 1990 pp 413–436

    • Search Google Scholar
    • Export Citation
  • 30.

    Sakas DEBullock MRPatterson Jet al: Focal cerebral hyperemia after focal head injury in humans: a benign phenomenon? J Neurosurg 83:2772841995Sakas DE Bullock MR Patterson J et al: Focal cerebral hyperemia after focal head injury in humans: a benign phenomenon? J Neurosurg 83:277–284 1995

    • Search Google Scholar
    • Export Citation
  • 31.

    Savitz SIRosenbaum DM: Apoptosis in neurological disease. Neurosurgery 42:5555741998Savitz SI Rosenbaum DM: Apoptosis in neurological disease. Neurosurgery 42:555–574 1998

    • Search Google Scholar
    • Export Citation
  • 32.

    Schroder MLMuizelaar JPBullock MRet al: Focal ischemia due to traumatic contusions documented by stable xenon-CT and ultrastructural studies. J Neurosurg 82:9669711995Schroder ML Muizelaar JP Bullock MR et al: Focal ischemia due to traumatic contusions documented by stable xenon-CT and ultrastructural studies. J Neurosurg 82:966–971 1995

    • Search Google Scholar
    • Export Citation
  • 33.

    Shaw KMacKinnon MARaghupathi Ret al: TUNEL-positive staining in white and grey matter after fatal head injury in man. Clin Neuropathol 20:1061122001Shaw K MacKinnon MA Raghupathi R et al: TUNEL-positive staining in white and grey matter after fatal head injury in man. Clin Neuropathol 20:106–112 2001

    • Search Google Scholar
    • Export Citation
  • 34.

    Smith FMRaghupathi RMacKinnon MAet al: TUNEL-positive staining of surface contusions after fatal head injury in man. Acta Neuropathol 100:5375452000Smith FM Raghupathi R MacKinnon MA et al: TUNEL-positive staining of surface contusions after fatal head injury in man. Acta Neuropathol 100:537–545 2000

    • Search Google Scholar
    • Export Citation
  • 35.

    Teasdale GJennett B: Assessment of coma and impaired consciousness. A practical scale. Lancet 2:81841974Teasdale G Jennett B: Assessment of coma and impaired consciousness. A practical scale. Lancet 2:81–84 1974

    • Search Google Scholar
    • Export Citation
  • 36.

    Yakovlev AGKnoblach SMFan Let al: Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. J Neurosci 17:741574241997Yakovlev AG Knoblach SM Fan L et al: Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. J Neurosci 17:7415–7424 1997

    • Search Google Scholar
    • Export Citation
  • 37.

    Zhao JSchmid-Kotsas AGross HJet al: Sensitivity and specificity of different staining methods to monitor apoptosis induced by oxidative stress in adherent cells. Chin Med J 116:192319292003Zhao J Schmid-Kotsas A Gross HJ et al: Sensitivity and specificity of different staining methods to monitor apoptosis induced by oxidative stress in adherent cells. Chin Med J 116:1923–1929 2003

    • Search Google Scholar
    • Export Citation
  • 38.

    Zipfel GJBabcock DJLee JMet al: Neuronal apoptosis after CNS injury: the roles of glutamate and calcium. J Neurotrauma 17:8578692000Zipfel GJ Babcock DJ Lee JM et al: Neuronal apoptosis after CNS injury: the roles of glutamate and calcium. J Neurotrauma 17:857–869 2000

    • Search Google Scholar
    • Export Citation
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