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Evaluation of apoptosis in cerebrospinal fluid of patients with severe head injury

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Summary

Objective. To determine whether sFas, caspase-3, proteins which propagate apoptosis, and bcl-2, a protein which inhibits apoptosis, would be increased in cerebrospinal fluid (CSF) in patients with severe traumatic brain injury (TBI) and to examine the correlation of sFas, caspase-3, and bcl-2 with each other and with clinical variables.

Methods. sFas, caspase-3, and bcl-2 were measured in CSF of 14 patients with severe TBI on days 1, 2, 3, 5, 7, and 10 post-trauma. The results were compared with CSF samples from control patients who had no brain and spinal pathology and had undergone spinal anesthesia for some other reason. Soluble Fas and bcl-2 were measured by ELISA while caspase-3 was measured enzymatically.

Results. No sFas, caspase-3, and bcl-2 activities were found in CSF of controls, but activities significantly increased in CSF of patients at all time points post-trauma (p < 0.01). Caspase-3 significantly correlated to intracranial pressure (p = 0.01) and cerebral perfusion pressure (p = 0.04). Soluble Fas and caspase-3 peaks coincided on day 5 post-trauma and there was significant association between sFas and caspase-3 increase (p = 0.01).

Conclusion. This study indicates a prolonged activation of pro-apoptotic (sFas, caspase-3) and anti-apoptotic (bcl-2) proteins after severe TBI in humans. The degree of activation of particularly caspase-3 may be related to the severity of the injury. Parallel increases of these three molecules may indicate a pivotal role of apoptosis in the pathophysiology of post-traumatic brain oedema, secondary cell destruction and chronic cell loss following severe TBI and may open new targets for post-traumatic therapeutic interventions.

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References

  • AK Abbas (1996) ArticleTitleDie and let live: eliminating dangerous lymphocytes Cell 84 655–657 Occurrence Handle8625402 Occurrence Handle1:CAS:528:DyaK28Xhs1Cgurs%3D Occurrence Handle10.1016/S0092-8674(00)81042-9

    Article  PubMed  CAS  Google Scholar 

  • R Beer G Franz M Schopf M Reindl B Zelger E Schmutzhard W Poewe A Kampfl (2000) ArticleTitleExpression of Fas and Fas ligand after experimental traumatic brain injury in the rat J Cereb Blood Flow Metab 20 669–677 Occurrence Handle10779011 Occurrence Handle1:CAS:528:DC%2BD3cXjtVGksL0%3D Occurrence Handle10.1097/00004647-200004000-00004

    Article  PubMed  CAS  Google Scholar 

  • I Cernak SM Chapman GP Hamlin R Vink (2002) ArticleTitleTemporal characterization of pro- and anti-apoptotic mechanisms following diffuse traumatic brain injury in rats J Clin Neurosci 9 565–572 Occurrence Handle12383417 Occurrence Handle10.1054/jocn.2002.1132

    Article  PubMed  Google Scholar 

  • RS Clark PM Kochanek PD Adelson MJ Bell JA Carcillo M Chen SR Wisniewski K Janesko MJ Whalen SH Graham (2000) ArticleTitleIncreases 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 Occurrence Handle10931412 Occurrence Handle1:CAS:528:DC%2BD3cXmslaru7c%3D Occurrence Handle10.1067/mpd.2000.107616

    Article  PubMed  CAS  Google Scholar 

  • RS Clark PM Kochanek M Chen SC Watkins DW Marion J Chen RL Hamilton JE Loeffert SH Graham (1999) ArticleTitleIncreases in bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury FASEB J 13 813–821 Occurrence Handle10224225 Occurrence Handle1:CAS:528:DyaK1MXjtFGksrY%3D

    PubMed  CAS  Google Scholar 

  • RS Clark PM Kochanek SC Watkins M Chen CE Dixon NA Seidberg J Melick E Loeffert PD Nathaniel KL Jin SH Graham (2000) ArticleTitleCaspase-3 mediated neuronal death after traumatic brain injury in rats J Neurochem 74 740–753 Occurrence Handle10646526 Occurrence Handle1:CAS:528:DC%2BD3cXntFyisA%3D%3D Occurrence Handle10.1046/j.1471-4159.2000.740740.x

    Article  PubMed  CAS  Google Scholar 

  • P Dowling G Shang S Raval J Menonna S Cook W Husar (1996) ArticleTitleInvolvement of CD95 (APO-1/Fas) receptor/ligand system in multiple sclerosis J Exp Med 184 1513–1518 Occurrence Handle8879222 Occurrence Handle1:CAS:528:DyaK28XmtlKhs7s%3D Occurrence Handle10.1084/jem.184.4.1513

    Article  PubMed  CAS  Google Scholar 

  • W Ertel M Keel R Stocker HG Imhof M Leist U Steckholzer M Tanaka O Trentz S Nagata (1997) ArticleTitleDetectable concentrations of Fas ligand in cerebrospinal fluid after severe head injury J Neuroimmunol 80 93–96 Occurrence Handle9413263 Occurrence Handle1:CAS:528:DyaK2sXnsVyiur0%3D Occurrence Handle10.1016/S0165-5728(97)00139-2

    Article  PubMed  CAS  Google Scholar 

  • LE French M Hahne I Viard G radlgruber R Zanone K Becker C Müller J Tschopp (1996) ArticleTitleFas and Fas Ligand in embros and adult mice: Ligand expression in several immune-privilegad tissues and coexpression in adult tissues characterized by apoptotic cell turnover J Cell Biol 133 335–343 Occurrence Handle8609166 Occurrence Handle1:CAS:528:DyaK28Xitlyms7g%3D Occurrence Handle10.1083/jcb.133.2.335

    Article  PubMed  CAS  Google Scholar 

  • L Harter M Keel H Hentze M Leist W Ertel (2001) ArticleTitleCaspase-3 activity is present in cerebrospinal fluid from patients with traumatic brain injury J Neuroimmunol 121 76–78 Occurrence Handle11730942 Occurrence Handle1:CAS:528:DC%2BD3MXos1Cgurc%3D Occurrence Handle10.1016/S0165-5728(01)00409-X

    Article  PubMed  CAS  Google Scholar 

  • B Jennett M Bond (1975) ArticleTitleAssessment of outcome after severe brain damage Lancet 1 480–484 Occurrence Handle46957 Occurrence Handle1:STN:280:DyaE2M7hsl2jsw%3D%3D Occurrence Handle10.1016/S0140-6736(75)92830-5

    Article  PubMed  CAS  Google Scholar 

  • K Kuida (2000) ArticleTitleCaspase-9 Int J Biochem Cell Biol 32 121–124 Occurrence Handle10687948 Occurrence Handle1:CAS:528:DyaK1MXnvFeis78%3D Occurrence Handle10.1016/S1357-2725(99)00024-2

    Article  PubMed  CAS  Google Scholar 

  • PM Lezlinger A Marx O Trentz T Kossmann MC Morganti-Kossmann (2002) ArticleTitleProlonged intrathecal release of soluble Fas following severe traumatic brain injury in humans J Neuroimmunol 122 167–174 Occurrence Handle10.1016/S0165-5728(01)00466-0

    Article  Google Scholar 

  • P Li D Nijhawan I Budihardjo SM Srinivasula M Ahmad ES Alnemri X Wang (1997) ArticleTitleCytochrome c and dATP dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade Cell 91 479–487 Occurrence Handle9390557 Occurrence Handle1:CAS:528:DyaK2sXnsFGls70%3D Occurrence Handle10.1016/S0092-8674(00)80434-1

    Article  PubMed  CAS  Google Scholar 

  • AKF Liou RS Clark DC Henshall XM Yin J Chen (2003) ArticleTitleTo die or not to die for neurons in ischemia, traumatic brain injury and epilepsy: a review on the stress-activated signaling pathways and apoptotic pathways Prog Neurobiol 69 103–142 Occurrence Handle12684068 Occurrence Handle1:CAS:528:DC%2BD3sXis1yqt74%3D Occurrence Handle10.1016/S0301-0082(03)00005-4

    Article  PubMed  CAS  Google Scholar 

  • J Lu S Moochhala C Kaur EA Ling (2000) ArticleTitleChanges in apoptosis-related protein (p53, Bax, Bcl-2 and Fos) expression with DNA fragmentation in the central nervous system in rats after closed head injury Neurosci Lett 290 89–92 Occurrence Handle10936684 Occurrence Handle1:CAS:528:DC%2BD3cXlsFCisb4%3D Occurrence Handle10.1016/S0304-3940(00)01307-0

    Article  PubMed  CAS  Google Scholar 

  • YA Lezebnik A Takahashi GG Poirier SH Kaufmann WC Earnshaw (1995) ArticleTitleCharacterization of the execution phase of apoptosis in vitro using extracts from condemmed-phase cells J Cell Sci 19 41–49

    Google Scholar 

  • LF Marshall SB Marshall MR Klauber CM van Berkum (1991) ArticleTitleA new classification of head injury based on computerized tomography J Neurosurg 75 IssueID[Suppl] S14–S20

    Google Scholar 

  • JP Medema C Scaffidi FC Kischkel A Shevchenko M Mann PH Krammar ME Peter (1997) ArticleTitleFLICE is activated by association with the CD95 death inducing signaling complex (DISC) Embo J 16 2794–2804 Occurrence Handle9184224 Occurrence Handle1:CAS:528:DyaK2sXjsF2mtL0%3D Occurrence Handle10.1093/emboj/16.10.2794

    Article  PubMed  CAS  Google Scholar 

  • M Muzio BR Stcokwell HR Stennicke GS Salvesen VM Dixit (1998) ArticleTitleAn iduced proximity model for caspase-8 activation J Biol Chem 273 2926–2930 Occurrence Handle9446604 Occurrence Handle1:CAS:528:DyaK1cXnvFSkug%3D%3D Occurrence Handle10.1074/jbc.273.5.2926

    Article  PubMed  CAS  Google Scholar 

  • S Nagata (2000) ArticleTitleApoptotic DNA fragmentation Exp Cell Res 256 12–18 Occurrence Handle10739646 Occurrence Handle1:CAS:528:DC%2BD3cXitVajs7c%3D Occurrence Handle10.1006/excr.2000.4834

    Article  PubMed  CAS  Google Scholar 

  • N Nathoo PK Narotam DK Agrawal CA Connolly JR van Dellen GH Barnett R Chetty D Phill (2004) ArticleTitleInfluence of apoptosis on neurological outcome following traumatic cerebral contusion J Neurosurg 101 233–240 Occurrence Handle15309913

    PubMed  Google Scholar 

  • I Ng TT Yeo WT Tang R Soong PY Ng DS Smith (2000) ArticleTitleApoptosis occurs after cerebral contusions in humans Neurosurgery 46 949–956 Occurrence Handle10764270 Occurrence Handle1:STN:280:DC%2BD3c3isFensg%3D%3D Occurrence Handle10.1097/00006123-200004000-00034

    Article  PubMed  CAS  Google Scholar 

  • R Raghupathi AC Conti DI Graham S Kralewski JC Reed MS Grady JQ Trojanowski TK Mcintosh (2002) ArticleTitleMild traumatic brain injury induces apoptotic cell death in the cortex that is preceded by decreases in cellular Bcl-2 immunoreactivity Neuroscience 110 605–616 Occurrence Handle11934469 Occurrence Handle1:CAS:528:DC%2BD38XisV2hsr4%3D Occurrence Handle10.1016/S0306-4522(01)00461-4

    Article  PubMed  CAS  Google Scholar 

  • R Raghupathi SC Fernandez H Murai SP Trusko RW Scott WK Nishioka TK McIntosh (1998) ArticleTitleBCL-2 overexpression attenuates cortical cell loss after traumatic injury in transgenic mice J Cereb Blood Flow Metab 18 1259–1269 Occurrence Handle9809516 Occurrence Handle1:CAS:528:DyaK1cXnsFSqsr8%3D Occurrence Handle10.1097/00004647-199811000-00013

    Article  PubMed  CAS  Google Scholar 

  • JC Reed (1994) ArticleTitleBcl-2 and the regulation of programmed cell death J Cell Biol 124 1–6 Occurrence Handle8294493 Occurrence Handle1:CAS:528:DyaK2cXntl2mtA%3D%3D Occurrence Handle10.1083/jcb.124.1.1

    Article  PubMed  CAS  Google Scholar 

  • JC Reed (1998) ArticleTitleBcl-2 family proteins Oncogene 17 3225–3236 Occurrence Handle9916985 Occurrence Handle10.1038/sj.onc.1202591

    Article  PubMed  Google Scholar 

  • GS Salvesen VM Dixit (1997) ArticleTitleCaspases: intracellular signaling by proteolysis Cell 91 443–446 Occurrence Handle9390553 Occurrence Handle1:CAS:528:DyaK2sXnsFGmtLg%3D Occurrence Handle10.1016/S0092-8674(00)80430-4

    Article  PubMed  CAS  Google Scholar 

  • TG Saul TB Ducker (1982) ArticleTitleEffect of intracranial pressure monitoring and aggressive treatment on mortality in severe head injury J neurosurg 56 498–503 Occurrence Handle6801218 Occurrence Handle1:STN:280:DyaL387ksVOrsw%3D%3D Occurrence Handle10.3171/jns.1982.56.4.0498

    Article  PubMed  CAS  Google Scholar 

  • G Teasdale B Jennett (1974) ArticleTitleAssessment of coma and impaired consciousness. A practical scale Lancet 2 81–84 Occurrence Handle4136544 Occurrence Handle1:STN:280:DyaE2c3pvVGjuw%3D%3D Occurrence Handle10.1016/S0140-6736(74)91639-0

    Article  PubMed  CAS  Google Scholar 

  • G Teasdale G Murray L Parker B Jennett (1979) ArticleTitleAdding up the Glasgow Coma Score Acta Neurochir [Suppl] 28 13–16 Occurrence Handle1:STN:280:DyaL3c%2Fhs1yqtA%3D%3D

    CAS  Google Scholar 

  • NA Thornberry (1994) ArticleTitleInterleukin-1 beta converting enzyme Methods Enzymol 244 615–631 Occurrence Handle7845238 Occurrence Handle1:CAS:528:DyaK2MXjvFWrt7k%3D Occurrence Handle10.1016/0076-6879(94)44045-X

    Article  PubMed  CAS  Google Scholar 

  • A Wennersten S Holmin T Mathiesen (2003) ArticleTitleCharacterization of Bax and Bcl-2 in apoptosis after experimental traumatic brain injury in the rat Acta Neuropathol 105 281–288 Occurrence Handle12557016 Occurrence Handle1:CAS:528:DC%2BD3sXntV2htA%3D%3D

    PubMed  CAS  Google Scholar 

  • AG Yakovlev SM Knoblach L Fan GB Fox R Goodnight AI Faden (1997) ArticleTitleActivation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury J Neurosci 17 7415–7424 Occurrence Handle9295387 Occurrence Handle1:CAS:528:DyaK2sXmtl2ltrg%3D

    PubMed  CAS  Google Scholar 

  • AG Yakovlev K Ota G Wang V Movsesyan WL Bao K Yoshihara AI Faden (2001) ArticleTitleDifferential expression of apoptotic protease-activating factor-1 and caspase-3 genes and susceptibility to apoptosis during brain development and after traumatic brain injury J Neurosci 21 7439–7446 Occurrence Handle11567033 Occurrence Handle1:CAS:528:DC%2BD3MXnsFCksrg%3D

    PubMed  CAS  Google Scholar 

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Uzan, M., Erman, H., Tanriverdi, T. et al. Evaluation of apoptosis in cerebrospinal fluid of patients with severe head injury. Acta Neurochir (Wien) 148, 1157–1164 (2006). https://doi.org/10.1007/s00701-006-0887-1

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