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Detectable Levels of Cytochrome c and Activated Caspase-9 in Cerebrospinal Fluid after Human Traumatic Brain Injury

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Abstract

Background

The intrinsic pathway of apoptosis has been proposed as one mechanism of cell death after traumatic brain injury (TBI). This study tested the hypothesis that cytochrome c and activated caspase-9 are released into the cerebrospinal fluid (CSF) after severe TBI and that their presence correlates with mitochondrial injury and severity of neurologic outcome.

Methods

Nine adult patients with severe TBI (GCS ≤ 8) underwent placement of intraventricular catheters for monitoring and management of intracranial pressure. CSF was sampled at catheter insertion (2–26 h after injury) and at intervals of 24, 48, and 72 h thereafter. Control samples were obtained from patients undergoing spinal anesthesia (ASA1). CSF levels of cytochrome c and activated caspase-9 were measured using ELISA.

Results

Cytochrome c was detected in 18 (51.4%) samples, in the range of 0.08–5 ng/ml; mean value for cytochrome c was 0.44 ng/ml (SD ± 0.632). Activated caspase-9 was detected in 10 samples (28.6%); mean value was 0.28 ng/ml (SD ± 0.39). R s between cytochrome c and Glasgow outcome score (GOS) was −0.25 (P = 0.14), and between GOS and activated caspase-9 was −0.35 (P = 0.04). R calculated based on linear regression of activated caspase-9 and cytochrome c concentrations was 0.18. Control CSF samples had no detectable levels of either marker (detection level for cytochrome c was 0.08 ng/ml and 0.20 for activated caspase-9).

Conclusions

We concluded that activated caspase-9 and cytochrome c are present in the CSF of patients with severe TBI. Activated caspase-9 shows weak correlation with poor neurologic outcome.

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References

  1. Langlois JA, Rutland-Brown W, Wald M. The epidemiology and impact of traumatic brain injury. J Head Trauma Rehab. 2006;21:375–8.

    Article  Google Scholar 

  2. Wright KM, Vaughn AE, Deshmukh M. Apoptosome dependent caspase-3 activation pathway is non-redundant and necessary for apoptosis in sympathetic neurons. Cell Death Differ. 2007;14:625–33.

    Article  CAS  PubMed  Google Scholar 

  3. Clark RSB, Kochanek PM, Watkins S. Caspase mediated neuronal death after traumatic brain injury in rats. J Neurochem. 2000;74:740–53.

    Article  CAS  PubMed  Google Scholar 

  4. Yakovlev A, Knoblach S, Fan L. Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. J Neurosci. 1997;17:7415–24.

    CAS  PubMed  Google Scholar 

  5. Knoblach SM, Nikolaeva M, Huang X. Multiple caspases are activated after traumatic brain injury: evidence for involvement in functional outcome. J Neurotrauma. 2002;19:1155–70.

    Article  PubMed  Google Scholar 

  6. Qiu J, Whalen MJ, Lowenstein P, et al. Upregulation of the Fas receptor death-inducing signaling complex after traumatic brain injury in mice and humans. J Neurosci. 2002;22:3504–11.

    CAS  PubMed  Google Scholar 

  7. Lenzlinger PM, Marx A, Trentz O, Kossmann T, Morganti-Kossmann MC. Prolonged intrathecal release of soluble Fas following severe traumatic brain injury in humans. J Neuroimmunol. 2002;122:167–74.

    Article  CAS  PubMed  Google Scholar 

  8. Ertel W, Keel M, Stocker R, et al. Detectable concentrations of Fas ligand in cerebrospinal fluid after severe head injury. J Neuroimmunol. 1997;80:93–6.

    Article  CAS  PubMed  Google Scholar 

  9. Uzan M, Erman H, Tanriverdi T, Sanus GC, Kafadar A, Uzun H. Evaluation of apoptosis in cerebrospinal fluid of patients with severe head injury. Acta Neurochir (Wien). 2006;148:1157–64.

    Article  CAS  Google Scholar 

  10. Kirchhoff C, Buhmann S, Bogner V, et al. Cerebrospinal IL-10 concentration is elevated in non-survivors as compared to survivors after severe traumatic brain injury. Eur J Med Res. 2008;13:464–8.

    CAS  PubMed  Google Scholar 

  11. Chiaretti A, Antonelli A, Mastrangelo A, et al. Interleukin-6 and nerve growth factor upregulation correlates with improved outcome in children with severe traumatic brain injury. J Neurotrauma. 2008;25:225–34.

    Article  PubMed  Google Scholar 

  12. Darwish R, Amiridze N, Aarabi B. Nitrotyrosine as an oxidative stress marker: evidence for involvement in neurologic outcome in human traumatic brain injury. J Trauma. 2007;63:439–42.

    Article  PubMed  Google Scholar 

  13. Bayir H, Kochanek PM, Liu SX, et al. Increased S-nitrosothiols and S-nitrosoalbumin in cerebrospinal fluid after severe traumatic brain injury in infants and children: indirect association with intracranial pressure. J Cereb Blood Flow Metab. 2003;23:51–61.

    Article  CAS  PubMed  Google Scholar 

  14. Darwish, R, Ahn E, FiskumG. Activated caspase 3 immunoreactivity in specimens of cerebral cortex obtained after human traumatic brain injury. Presented at the annual meeting of the American Association of Neurological Surgeons, Orlando, FL; May 2004.

  15. Härter L, Keel M, Hentze H, Leist M, Ertel W. Caspase-3 activity is present in cerebrospinal fluid from patients with traumatic brain injury. J Neuroimmunol. 2001;121:76–8.

    Article  PubMed  Google Scholar 

  16. Satchell MA, Lai Y, Kochanek PM. Cytochrome c, a biomarker of apoptosis, is increased in cerebrospinal fluid from infants with inflicted brain injury from child abuse. J Cereb Blood Flow Metab. 2005;25:919–27.

    Article  CAS  PubMed  Google Scholar 

  17. Li YZ, Li CJ, Pinto AV, Pardee AB. Release of mitochondrial cytochrome C in both apoptosis and necrosis induced by beta-lapachone in human carcinoma cells. Mol Med. 1999;5:232–9.

    PubMed  Google Scholar 

  18. Du C, Fang M, Li Y, Wang X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell. 2000;102:33–42.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Anesthesiology, Critical Care Medicine Division, University of Maryland Medical Center, 22 S. Greene Street, Baltimore, MD, 21201-1595, USA

    Ribal S. Darwish

  2. Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland School of Medicine, 22 S. Greene Street, Baltimore, MD, 21201-1595, USA

    Nana S. Amiridze

Authors
  1. Ribal S. Darwish
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  2. Nana S. Amiridze
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Correspondence to Ribal S. Darwish.

Additional information

This project was conducted at the University of Maryland School of Medicine.

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Darwish, R.S., Amiridze, N.S. Detectable Levels of Cytochrome c and Activated Caspase-9 in Cerebrospinal Fluid after Human Traumatic Brain Injury. Neurocrit Care 12, 337–341 (2010). https://doi.org/10.1007/s12028-009-9328-3

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