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. 2006 Apr 5;14(2):215–222. doi: 10.1111/j.1750-3639.2004.tb00056.x

Cell Death Mechanisms Following Traumatic Brain Injury

Ramesh Raghupathi 1,✉
PMCID: PMC8096005  PMID: 15193035

Abstract

Neuronal and glial cell death and traumatic axonal injury contribute to the overall pathology of traumatic brain injury (TBI) in both humans and animals. In both head‐injured humans and following experimental brain injury, dying neural cells exhibit either an apoptotic or a necrotic morphology. Apoptotic and necrotic neurons have been identified within contusions in the acute post‐traumatic period, and in regions remote from the site of impact in the days and weeks after trauma, while degenerating oligodendrocytes and astrocytes have been observed within injured white matter tracts. We review and compare the regional and temporal patterns of apoptotic and necrotic cell death following TBI and the possible mechanisms underlying trauma‐induced cell death. While excitatory amino acids, increases in intracellular calcium and free radicals can all cause cells to undergo apoptosis, in vitro studies have determined that neural cells can undergo apoptosis via many other pathways. It is generally accepted that a shift in the balance between pro‐ and anti‐apoptotic protein factors towards the expression of proteins that promote death may be one mechanism underlying apoptotic cell death. The effect of TBI on cellular expression of survival promoting‐proteins such as Bcl‐2, Bcl‐xL, and extracellular signal‐regulated kinases, and death‐inducing proteins such as Bax, c‐Jun N‐terminal kinase, tumor‐suppressor gene, p53, and the calpain and caspase families of proteases are reviewed. In light of pharmacologic strategies that have been devised to reduce the extent of apoptotic cell death in animal models of TBI, our review also considers whether apoptosis may serve a protective role in the injured brain. Together, these observations suggest that cell death mechanisms may be representative of a continuum between apoptotic and necrotic pathways.

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REFERENCES

  • 1. Adams JH, Doyle D, Graham DI, Lawrence AE, McLellan DR, Gennarelli TA, Pastuszko M, Sakamoto T (1985) The contusion index: A reappraisal in human and experimental non‐missile injury. Neuropathol Appl Neurobiol 11:299–308. [DOI] [PubMed] [Google Scholar]
  • 2. Alessandrini A, Namura S, Moskowitz MA, Bonventre JV (1999) MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. Proc Natl Acad Sci U S A 96:12866–12869. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3. Artuso M, Esteve A, Bresil H, Vuillaume M, Hall J (1995) The role of the Ataxia telangiectasia gene in the p53, WAF1/CIP1 (p21)‐ and GADD45‐mediated response to DNA damage produced by ionizing radiation. Oncogene 11:1427–1435. [PubMed] [Google Scholar]
  • 4. Bareyre FM, Raghupathi R, Saatman KE, McIntosh TK (2001) DNase I disinhibition is predominantly associated with actin hyperpolymerization after traumatic brain injury. J Neurochem 77:173–181. [DOI] [PubMed] [Google Scholar]
  • 5. Beattie MS, Shuman SL, Bresnahan JC (1998) Apoptosis and spinal cord injury. Neuroscientist 4:163–171. [Google Scholar]
  • 6. Beer R, Franz G, Krajewski S, Pike BR, Hayes RL, Reed JC, Wang KKW, Klimmer C, Schmutzhard E, Poewe W, Kampfl A (2001) Temporal and spatial profile of caspase 8 expression and proteolysis after experimental traumatic brain injury. J Neurochem 78:862–873. [DOI] [PubMed] [Google Scholar]
  • 7. Beer R, Franz G, Srinivasan A, Hayes RL, Pike BR, Newcomb JK, Zhao X, Schmutzhard E, Poewe W, Kampfl A (2000) Temporal profile and cell subtype distribution of activated caspase‐3 following experimental traumatic brain injury. J Neurochem 75:1264–1273. [DOI] [PubMed] [Google Scholar]
  • 8. Bramlett HM, Dietrich WD, Green EJ, Busto R (1997) Chronic histopathological consequences of fluid‐percussion brain injury in rats: effects of posttraumatic hypothermia. Acta Neuropathol 93:190–199. [DOI] [PubMed] [Google Scholar]
  • 9. Bredesen DE (1995) Neural apoptosis. Ann Neurol 38:839–851. [DOI] [PubMed] [Google Scholar]
  • 10. Buki A, Okonkwo DO, Povlishock JT (1999) Postinjury cyclosprin A administration limits axonal damage and disconnection in traumatic brain injury. J Neurotrauma 16:511–521. [DOI] [PubMed] [Google Scholar]
  • 11. Buki A, Okonkwo DO, Wang KKW, Povlishock JT (2000) Cytochrome c release and caspase activation in traumatic axonal injury. J Neurosci 20:2825–2834. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Cervos‐Navarro J, Lafuente JV (1991) Traumatic brain injuries: structural changes. J Neurol Sci 103:s3–s14. [DOI] [PubMed] [Google Scholar]
  • 13. Charriaut‐Marlangue C, Aggoun‐Zouaoui D, Represa A, Ben‐Ari Y (1996) Apoptotic features of selective neuronal death in ischemia, epilepsy and gp 120 Toxicity. Trends Neurosci 19:109–114. [DOI] [PubMed] [Google Scholar]
  • 14. Chen J, Graham SH, Chan PH, Lan P, Zhou RL, Simon RP (1995) Bcl‐2 is expressed in neurons that survive focal ischemia in the rat. NeuroReport 6:394–398. [DOI] [PubMed] [Google Scholar]
  • 15. Chopp M, Li Y, Jiang N (1999) Increase in apoptosis and concomitant reduction of ischemic lesion volume and evidence for syntaptogenesis after transient focal ischemia in rat treated with staurosporine. Brain Res 828:197–201. [DOI] [PubMed] [Google Scholar]
  • 16. Chopp M, Li Y, Zhang ZG, Freytag SO (1992) p53 expression in brain after middle cerebral artery occlusion in the rat. Biochem Biophys Res Commun 482:1201–1207. [DOI] [PubMed] [Google Scholar]
  • 17. Clark RSB, 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18. Clark RSB, Kochanek PM, Chen M, Watkins SC, Marion DW, Chen J, Hamilton RL, Loeffert JE, Graham SH (1999) Increases in Bcl‐2 and cleavage of caspase‐1 and caspase‐3 in human brain after head injury. FASEB J 13:813–821. [DOI] [PubMed] [Google Scholar]
  • 19. Clark RSB, Kochanek PM, Watkins SC, Chen M, Dixon CE, Seidberg NA, Melick J, Loeffert JE, Nathaniel PD, Jin KL, Graham SH (2000) Caspase‐3 mediated neuronal death after traumatic brain injury in rats. J Neurochem 74:740–753. [DOI] [PubMed] [Google Scholar]
  • 20. Colicos MA, Dash PK (1996) Apoptotic morphology of dentate gyrus granule cells following experimental cortical impact injury in rats: possible role in spatial memory deficits. Brain Res 739:120–131. [DOI] [PubMed] [Google Scholar]
  • 21. Colicos MA, Dixon CE, Dash PK (1996) Delayed, selective neuronal death following experimental cortical impact injury in rats: possible role in memory deficits. Brain Res 739:111–119. [DOI] [PubMed] [Google Scholar]
  • 22. 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Crowe MJ, Bresnahan JC, Shuman SL, Masters JN, Beattie MS (1997) Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nature Med 3:73–76. [DOI] [PubMed] [Google Scholar]
  • 24. Dash PK, Mach SA, Moore AN (2002) The role of extracellular signal‐regulated kinase in cognitive and motor deficits following experimental traumatic brain injury. Neuroscience 114:755–767. [DOI] [PubMed] [Google Scholar]
  • 25. Dietrich WD, Alonso O, Halley M (1994) Early Microvascular and neuronal consequences of traumatic brain injury: a light and electron microscopic study in rats. J Neurotrauma 11:289–301. [DOI] [PubMed] [Google Scholar]
  • 26. Du C, Hu R, Cseransky CA, Hsu CY, Choi DW (1996) Very delayed infarction after mild focal cerebral ischemia: a role for apoptosis. J Cereb Blood Flow Metab 16:195–201. [DOI] [PubMed] [Google Scholar]
  • 27. Eliasson MJL, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, Pieper A, Wang Z‐Q, Dawson TM, Snyder SH, Dawson VL (1997) Poly(ADP‐ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nature Med 3:1089–1095. [DOI] [PubMed] [Google Scholar]
  • 28. Emery E, Aldana P, Bunge MB, Puckett W, Srinivasan A, Keane RW, Bethea J, Levi ADO (1998) Apoptosis after traumatic human spinal cord injury. J Neurosurg 89:911–920. [DOI] [PubMed] [Google Scholar]
  • 29. Endres M, Namura S, Shimizu‐Sasamata M, Waeber C, Zhang L, Gomez‐Isla T, Hyman BT, Moskowitz MA (1998) Attenuation of delayed neuronal death afer mild focal ischemia in mice by inhibition of caspase family. J Cereb Blood Flow Metab 18:238–247. [DOI] [PubMed] [Google Scholar]
  • 30. Endres M, Wang Z‐Q, Namura S, Waeber C, Moskowitz MA (1997) Ischemic brain injury is mediated by the activation of poly(ADP‐ribose) polymerase. J Cereb Blood Flow Metab 17:143–151. [DOI] [PubMed] [Google Scholar]
  • 31. Evan G, Littlewood TD (1998) A matter of life and death. Science 281:1317–1322. [DOI] [PubMed] [Google Scholar]
  • 32. Fineman I, Hovda DA, Smith M, Yoshino A, Becker DP (1993) Concussive brain injury is associated with a prolonged accumulation of calcium: a 45Ca autoradiographic study. Brain Res 624:94–102. [DOI] [PubMed] [Google Scholar]
  • 33. Fox GB, Fan L, Levasseur RA, Faden AI (1998) Sustained sensory/motor and cognitive deficits with neuronal apoptosis following controlled cortical impact brain injury in the mouse. J Neurotrauma 15:599–613. [DOI] [PubMed] [Google Scholar]
  • 34. Franz G, Beer R, Intemann D, Krajewski S, Reed JC, Engelhardt K, Pike BR, Hayes RL, Wang KKW, Schmutzhard E, Kampfl A (2002) Temporal and spatial profile of Bid cleavage after experimental traumatic brain injury. J Cereb Blood Flow Metab 22:951–958. [DOI] [PubMed] [Google Scholar]
  • 35. Friedlander RM, Gagliardini V, Hara H, Fink KB, Li W, MacDonald G, Fishman MC, Greenberg AH, Moskowitz MA, Yuan J (1997) Expression of dominant negative mutant of interleukin‐1b converting enzyme in transgenic mice prevents neuronal cell death induced by trophic factor withdrawal and ischemic brain injury. J Exp Med 185:933–940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Gavrieli Y, Sherman Y, Ben‐Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37. Gehrmann J, Banati RB (1995) Microglial turnover in the injured CNS: activated microglia undergo delayed DNA fragmentation following peripehral nerve injury. J Neuropathol Exp Neurol 54:680–688. [DOI] [PubMed] [Google Scholar]
  • 38. Gennarelli TA (1994) Animate models of human head injury. J Neurotrauma 11:357–368. [DOI] [PubMed] [Google Scholar]
  • 39. Gennarelli TA, Thibault LE, Graham DI (1998) Diffuse axonal injury: an important form of traumatic brain damage. Neuroscientist 4:202–215. [Google Scholar]
  • 40. Gillardon F, Lenz C, Waschke KF, Krajewski S, Reed JC, Zimmermann M, Kuschinsky W (1996) Altered Expression of Bcl‐2, Bcl‐X, Bax, and c‐Fos colocalizes with DNA fragmentation and ischemic cell damage following middle cerebral artery occlusion in rats. Mol Brain Res 40:254–260. [DOI] [PubMed] [Google Scholar]
  • 41. Gillardon F, Wickert H, Zimmermann M (1995) Up‐regulation of bax and down‐regulation of bcl‐2 is associated with kainate‐induced apoptosis in mouse brain. Neurosci Lett 192:85–88. [DOI] [PubMed] [Google Scholar]
  • 42. Green DR, Reed JC (1998) Mitochondria and apoptosis. Science 281:1309–1312. [DOI] [PubMed] [Google Scholar]
  • 43. Gu C, Casaccia‐Bonnefil P, Srinivasan A, Chao MV (1999) Oligodendrocyte apoptosis mediated by caspase activation. J Neurosci 19:3043–3049. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Gwag BJ, Canzoniero LMT, Sensi SL, Demaro JA, Koh J‐Y, Goldberg MP, Jacquin M, Choi DW (1999) Calcium ionophores can induce either apoptosis or necrosis in culture neurons. Neuroscience 90:1339–1348. [DOI] [PubMed] [Google Scholar]
  • 45. Hicks RR, Soares HD, Smith DH, McIntosh TK (1996) Temporal and spatial characterization of neuronal injury following lateral fluid‐percussion brain injury in the rat. Acta Neuropathol 91:236–246. [DOI] [PubMed] [Google Scholar]
  • 46. Holmin S, Mathiesen T, Shetye J, Biberfeld P (1995) Intracerebral inflammatory response to experimental brain contusion. Acta Neurochir (suppl) 132:110–119. [DOI] [PubMed] [Google Scholar]
  • 47. Holmin S, Soderlund J, Biberfeld P, Mathiesen T (1998) Intracerebral inflammation after human brain contusions. Neurosurgery 42:291–299. [DOI] [PubMed] [Google Scholar]
  • 48. Hughes PE, Alexi T, Yoshida T, Schreiber SS, Knusel B (1996) Excitotoxic lesion of rat brain with quinolinic acid induces expression of p53 mRNA and protein and p53‐inducible genes Bax and Gadd45 in brain areas showing DNA fragmentation. Neuroscience 74:1143–1160. [DOI] [PubMed] [Google Scholar]
  • 49. Kampfl A, Posmantur RM, Nixon R, Grynspan F, Zhao X, Liu JS, Newcomb JK, Clifton GL, Hayes RL (1996) m‐Calpain activation and calpain‐mediated cytoskeletal proteolysis following traumatic brain injury. J Neurochem 67:1575–1583. [DOI] [PubMed] [Google Scholar]
  • 50. Kampfl A, Posmantur RM, Zhao X, Schmutzhard E, Clifton GL, Hayes RL (1997) Mechanisms of calpain proteolysis following traumatic brain injury: implications for pathology and therapy: areview and update. J Neurotrauma 14:121–134. [DOI] [PubMed] [Google Scholar]
  • 51. Kawase M, Fujimura M, Morita‐Fujimura Y, Chan PH (1999) Reduction of apurinic/apyrimidinic endonuclease expression after transient global cerebral ischemia in rats: implication of the failure of DNA repair in neuronal apoptosis. Stroke 30:441–448. [DOI] [PubMed] [Google Scholar]
  • 52. 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. [DOI] [PubMed] [Google Scholar]
  • 53. Keane RW, Kraydieh S, Lotocki G, Alonso O, Aldana P, Dietrich WD (2001) Apoptotic and antiapoptotic mechanisms after traumatic brain injury. J Cereb Blood Flow Metab 21:1189–1198. [DOI] [PubMed] [Google Scholar]
  • 54. Kotapka MJ, Graham DI, Adams JH, Gennarelli TA (1992) Hippocampal pathology in fatal non‐missile human head injury. Acta Neuropathol 83:530–534. [DOI] [PubMed] [Google Scholar]
  • 55. Krajewski S, Krajewska M, Ellerby LM, Welsh K, Xie Z, Deveraux QL, Salvesen GS, Bredesen DE, Rosenthal RE, Fiskum G, Reed JC (1999) Release of caspase‐9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc Natl Acad Sci U S A 96:5752–5757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56. LaPlaca MC, Raghupathi R, Verma A, Pieper A, Saatman KE, Snyder SH, McIntosh TK (1999) Temporal patterns of poly(ADP‐ribose) polymerase activation in the cortex following experimental brain injury in the rat. J Neurochem 73:205–213. [DOI] [PubMed] [Google Scholar]
  • 57. LaPlaca MC, Zhang J, Raghupathi R, Li J‐H, Smith F, Bareyre F, Snyder SH, Graham DI, McIntosh TK (2001) Pharmacologic inhibition of poly(ADP‐ribose) polymerase is neuroprotective following traumatic brain injury in rats. J Neurotrauma 18:369–376. [DOI] [PubMed] [Google Scholar]
  • 58. LeBlanc A (1998) Detection of actin cleavage in Alzheimer's disease. Am J Pathol 152:329–332. [PMC free article] [PubMed] [Google Scholar]
  • 59. Li X, Zou H, Slaughter C, Wang X (1997) DFF, a heterodimeric protein that functions downstream of caspase‐3 to trigger DNA fragmentation during apoptosis. Cell 89:175–184. [DOI] [PubMed] [Google Scholar]
  • 60. Lifshitz J, Raghupathi R, Welsh FA, McIntosh TK (1999) Mitochondrial respiratory function and ATP concentration deficits in cortical and hippocampal regions following lateral fluid‐percussion brain injury in the rat. J Neurotrauma 16:990. [Google Scholar]
  • 61. Liu X, Li P, Widlak P, Zou H, Luo X, Garrard WT, Wang X (1998) The 40‐kDa subunit of DNA fragmentation factor induces DNA fragmentation and chromatin condensation during apoptosis. Proc Natl Acad Sci U S A 95:8461–8466. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62. Love S, Barber R, Wilcock GK (1998) Apoptosis and expression of DNA repair proteins in ischemic brain injury in man. NeuroReport 9:955–959. [DOI] [PubMed] [Google Scholar]
  • 63. McCracken E, Hunter AJ, Patel S, Graham DI, Dewar D (1999) Calpain activation and cytoskeletal protein breakdown in the corpus callosum of head‐injured patients. J Neurotrauma 16:749–761. [DOI] [PubMed] [Google Scholar]
  • 64. Meaney DF, Smith DH, Shreiber DI, Bain AC, Miller RT, Ross DT, Gennarelli TA (1995) Biomechanical analysis of experimental diffuse axonal injury. J Neurotrauma 12:689–694. [DOI] [PubMed] [Google Scholar]
  • 65. Merry DE, Korsmeyer SJ (1997) Bcl‐2 gene family in the nervous system. Annu Rev Neurosci 20:245–267. [DOI] [PubMed] [Google Scholar]
  • 66. Mielke K, Brecht S, Dorst A, Herdegen T (1999) Activity and expression of JNK1, p38 and ERK kinases, c‐Jun N‐terminal phosphorylation, and c‐jun promoter binding in the adult rat brain following kainate‐induced seizures. Neuroscience 91:471–483. [DOI] [PubMed] [Google Scholar]
  • 67. Miyashita M, Reed JC (1995) Tumor suppressor, p53 is a direct transcriptional activator of the human bax gene. Cell 80:293–299. [DOI] [PubMed] [Google Scholar]
  • 68. Mori T, Wang X, Jung J‐C, Sumii T, Singhal AB, Fini ME, Dixon CE, Alessandrini A, Lo EH (2002) Mitogen‐activated protein kinase inhibition in traumatic brain injury: in vitro and in vivo effects. J Cereb Blood Flow Metab 22:444–452. [DOI] [PubMed] [Google Scholar]
  • 69. Morrison RS, Wenzel HJ, Kinoshita Y, Robbins CA, Donehower LA, Schwartzkroin PA (1996) Loss of the p53 tumor suppressor gene protects neurons from kainate‐induced cell death. J Neurosci 16:1337–1345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70. Nakahara S, Yone K, Sakou T, Wada S, Nagamine T, Niiyama T, Ichijo H (1999) Induction of apoptosis signal regulating kinase 1 (ASK1) after spinal cord injury in rats: possible involvement of ASK1‐JNK and ‐p38 pathways in neuronal apoptosis. J Neuropathol Exp Neurol 58:442–450. [DOI] [PubMed] [Google Scholar]
  • 71. Nakamura M, Raghupathi R, Merry DE, Scherbel U, Saatman KE, McIntosh TK (1999) Overexpression of Bcl‐2 is neuroprotective following experimental brain injury in transgenic mice. J Comp Neurol 412:681–692. [DOI] [PubMed] [Google Scholar]
  • 72. Namura S, Zhu J, Fink K, Endres M, Srinivasan A, Tomaselli KJ, Yuan J, Moskowitz MA (1998) Activation and cleavage of caspase‐3 in apoptosis induced by experimental cerebral ischemia. J Neurosci 18:3659–3668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73. Napieralski JA, Raghupathi R, McIntosh TK (1999) The tumor‐suppressor gene, p53, is induced in injured brain regions following experimental traumatic brain injury. Mol Brain Res 71:78–86. [DOI] [PubMed] [Google Scholar]
  • 74. Nath R, Probert A, Jr. , McGinnis KM, Wang KKW (1998) Evidence for activation of caspase‐3‐like protease in excitotoxin‐ and hypoxia/ hypoglycemia‐injured neurons. J Neurochem 71:186–195. [DOI] [PubMed] [Google Scholar]
  • 75. Newcomb JK, Kampfl A, Posmantur RM, Zhao X, Pike BR, Liu S‐J, Clifton GL, Hayes RL (1997) Immunohistochemical study of calpain‐mediated breakdown products to a‐spectrin following controlled cortical impact injury in the rat. J Neurotrauma 14:369–383. [DOI] [PubMed] [Google Scholar]
  • 76. Newcomb JK, Zhao X, Pike BR, Hayes RL (1999) Temporal profile of apoptotic‐like changes in neurons and astrocytes following controlled cortical impact injury in the rat. Exp Neurol 158:76–88. [DOI] [PubMed] [Google Scholar]
  • 77. Nicotera P, Leist M, Manzo L (1999) Neuronal cell death: a demise with different shapes. Trends Pharmacol Sci 20:46–51. [DOI] [PubMed] [Google Scholar]
  • 78. Nilsson P, Laursen H, Hillered L, Hansen AJ (1996) Calcium movements in traumatic brain injury: the role of glutamate receptor‐operated ion channels. J Cereb Blood Flow Metab 16:262–270. [DOI] [PubMed] [Google Scholar]
  • 79. Okonkwo DO, Povlishock JT (1999) An intrathecal bolus of cyclosporin A before injury preserves mitochondrial integrity and attenuates axonal disruption in traumatic brain injury. J Cereb Blood Flow Metab 19:443–451. [DOI] [PubMed] [Google Scholar]
  • 80. Oppenheim RW (1991) Cell death during development of the nervous system. Annu Rev Neurosci 14:453–501. [DOI] [PubMed] [Google Scholar]
  • 81. Otani N, Nawashiro H, Fukui S, Nomura N, Yano A, Miyazawa T, Shima K (2002) Differential activation of mitogen‐activated protein kinase pathways after traumatic brain injury in the rat hippocampus. J Cereb Blood Flow Metab 22:327–334. [DOI] [PubMed] [Google Scholar]
  • 82. Ozawa H, Shioda S, Dohi K, Matsumoto H, Mizushima H, Zhou CJ, Funahashi H, Nakai Y, Nakajo S, Matsumoto K (1999) Delayed neuronal cell death in the rat hippocampus is mediated by the mitogen‐activated protein kinase signal transduction pathway. Neurosci Lett 262:57–60. [DOI] [PubMed] [Google Scholar]
  • 83. Park DS, Morris EJ, Stefanis L, Troy CM, Shelanski ML, Geller HM, Greene LA (1998) Multiple pathways of neuronal death induced by DNA‐damaging agents, NGF deprivation, and oxidative stress. J Neurosci 18:830–840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 84. Pike BR, Zhao X, Newcomb JK, Posmantur RM, Wang KKW, Hayes RL (1998) Regional calpain and caspase‐3 proteolysis of a‐spectrin after traumatic brain injury. NeuroReport 9:2437–2442. [DOI] [PubMed] [Google Scholar]
  • 85. Portera‐Cailliau C, Price DL, Martin LJ (1997) Non‐NMDA and NMDA receptor‐mediated excitotoxic neuronal deaths in adult brain are morphologically distinct: further evidence for an apoptosis‐necrosis continuum. J Comp Neurol 378:88–104. [PubMed] [Google Scholar]
  • 86. Povlishock JT, Erb DE, Astruc J (1992) Axonal response to TBI: Reactive axonal change, deafferentation, and neuroplasticity. J Neurotrauma 9 (suppl 1):S189–S200. [PubMed] [Google Scholar]
  • 87. Povlishock JT, Hayes RL, Michel ME, McIntosh TK (1994) Workshop on animal models of TBI. J Neurotrauma 11:723–732. [DOI] [PubMed] [Google Scholar]
  • 88. Raghupathi R, Conti AC, Graham DI, Krajewski S, Reed JC, Grady MS, McIntosh TK (2002) Mild traumatic brain injury induces apoptotic cell death in the cortex that is preceded by decreases in Bcl‐2 immunoreactivity. Neuroscience 110:605–616. [DOI] [PubMed] [Google Scholar]
  • 89. Raghupathi R, Fernandez SC, Murai H, Trusko SP, Scott RW, Nishioka WK, McIntosh TK (1998) Bcl‐2 overexpression attenuates cortical cell loss after traumatic brain injury in transgenic mice. J Cereb Blood Flow Metab 18:1259–1269. [DOI] [PubMed] [Google Scholar]
  • 90. Raghupathi R, Zhang C, Strauss KI, Krajewski S, Reed JC, McIntosh TK (2003) Temporal alterations in cellular Bcl‐2:Bax ratios following traumatic brain injury in the rat. J Neurotrauma 20:421–435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 91. Rink AD, Fung KM, Trojanowski JQ, Lee VM‐Y, Neugebauer E, McIntosh TK (1995) Evidence of apoptotic cell death after experimental traumatic brain injury in the rat. Am J Pathol 147:1575–1583. [PMC free article] [PubMed] [Google Scholar]
  • 92. Ross DT, Graham DI, Adams JH (1993) Selective loss of neurons from the thalamic reticular nucleus following severe human head injury. J Neurotrauma 10:151–165. [DOI] [PubMed] [Google Scholar]
  • 93. Roy M, Sapolsky RM (1999) Neuronal apoptosis in acute necrotic insults: why is this subject such a mess. Trends Neurosci 22:419–422. [DOI] [PubMed] [Google Scholar]
  • 94. Saatman KE, Bozyczko‐Coyne D, Marcy VR, Siman R, McIntosh TK (1996) Prolonged calpain‐mediated spectrin breakdown occurs regionally following experimental brain injury in the rat. J Neuropathol Exp Neurol 55:850–860. [DOI] [PubMed] [Google Scholar]
  • 95. Sakhi S, Bruce A, Sun N, Tocco G, Baudry M, Schreiber SS (1994) p53 induction is asociated with neuronal damage in the CNS. Proc Natl Acad Sci U S A 91:7525–7529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 96. Saporito MS, Brown EM, Miller MS, Carswell S (1999) CEP‐1347/KT‐7515, an inhibitor of c‐jun N‐terminal kinase activation, attenuates the 1‐methyl‐4‐phenyl tetrahydropyridine‐mediated loss of nigrostriatal dopaminergic neurons in vivo. J Pharmacol Exp Ther 288:421–427. [PubMed] [Google Scholar]
  • 97. Scheff SW, Sullivan PG (1999) Cyclosporin A significantly ameliorates cortical damage following experimental traumatic brain injury in rodents. J Neurotrauma 16:783–792. [DOI] [PubMed] [Google Scholar]
  • 98. Shaikh AY, Ezekiel UR, Liu PK, Hsu CY (1998) Ischemic neuronal apoptosis: a view based on free radical‐induced DNA damage and repair. Neuroscientist 4:88–95. [Google Scholar]
  • 99. Shamloo M, Rytter A, Wieloch T (1999) Activation of the extracellular signal‐regulated protein kinase cascade in the hippocampal CA1 region in a rat model of global cerebral ischemic preconditioning. Neuroscience 93:81–88. [DOI] [PubMed] [Google Scholar]
  • 100. Shapira Y, Yadid G, Cotev S, Shohami E (1989) Accumulation of calcium in the brain following head trauma. Neurol Res 11:169–172. [DOI] [PubMed] [Google Scholar]
  • 101. Shaw K, Mackinnon M‐A, Raghupathi R, Saatman KE, McIntosh TK, Graham DI (2001) TUNEL‐positive staining in white and gray matter after fatal head injury in man. Clin Neuropathol 20:106–112. [PubMed] [Google Scholar]
  • 102. Shuman SL, Bresnahan JC, Beattie MS (1997) Apoptosis of microglia and oligodendrocytes after spinal cord contusion in rats. J Neurosci Res 50:798–808. [DOI] [PubMed] [Google Scholar]
  • 103. Smith F, Raghupathi R, Mackinnon M‐A, 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. [DOI] [PubMed] [Google Scholar]
  • 104. Soares HD, Hicks RR, Smith DH, McIntosh TK (1995) Inflammatory leukocytic recruitment and diffuse neuronal degenerationare separate pathological processes resulting from traumatic brain injury. J Neurosci 15:8223–8233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 105. Springer JE, Azbill RD, Knapp PE (1999) Activation of the caspase‐3 apoptotic cascade in traumatic spinal cord injury. Nature Med 5:943–946. [DOI] [PubMed] [Google Scholar]
  • 106. Squier MKT, Miller ACK, Malkinson AM, Cohen JJ (1994) Calpain activation in apoptosis. J Cell Phys 159:229–237. [DOI] [PubMed] [Google Scholar]
  • 107. Stone JR, Okonkwo DO, Singleton RH, Mutlu LK, Helm GA, Povlishock JT (2002) Caspase‐3‐mediated cleavage of amyloid precursor protein and formation of amyloid b peptide in traumatic axonal injury. J Neurotrauma 19:601–614. [DOI] [PubMed] [Google Scholar]
  • 108. Sullivan PG, Keller JN, Bussen WL, Scheff SW (2002) Cytochrome c release and caspase activation after traumatic brain injury. Brain Res 949:88–96. [DOI] [PubMed] [Google Scholar]
  • 109. Sullivan PG, Keller JN, Mattson MP, Scheff SW (1998) Traumatic brain injury alters synaptic homeostasis: implications for impaired mitochondrial and transport function. J Neurotrauma 15:789–798. [DOI] [PubMed] [Google Scholar]
  • 110. Sutton RL, Lescaudron L, Stein DG (1993) Unilateral cortical contusion injury in the rat: Vascular disruption and temporal development of cortical necrosis. J Neurotrauma 10:135–149. [DOI] [PubMed] [Google Scholar]
  • 111. Thornberry NA, Lazebnik YA (1998) Caspases: enemies within. Science 281:1312–1316. [DOI] [PubMed] [Google Scholar]
  • 112. Tsujimoto Y (1997) Apoptosis and necrosis: intracellular ATP levels as a determinant of cell death modes. Cell Death Differen 4:429–434. [DOI] [PubMed] [Google Scholar]
  • 113. Umehara F, Nakamura A, Izumo S, Kubota R, Ijichi S, Kashio N, Hashimoto K, Usuku K, Sato E, Osame M (1994) Apoptosis of T lymphocytes in the spinal cord lesions in HTLV‐I‐associated myelopathy: a possible mechanism to control viral infection in the central nervous system. J Neuropathol Exp Neurol 53:617–624. [DOI] [PubMed] [Google Scholar]
  • 114. Vamvakas S, Vock EH, Lutz WK (1997) On the role of DNA double‐strand breaks in toxicity and carcinogenesis. Crit Rev Toxicol 27:155–174. [DOI] [PubMed] [Google Scholar]
  • 115. Verwij BH, Muizelaar JP, Vinas FC, Peterson PL, Xiong Y, Lee CP (1997) Mitochondrial dysfunction after experimental and human brain injury and its possible reversal with a selective N‐type calcium channel antagonist (SNX‐111). Neurol Res 19:334–339. [DOI] [PubMed] [Google Scholar]
  • 116. Wang KKW (2000) Calpain and caspase: can you tell the difference. Trends Neurosci 23:20–26. [DOI] [PubMed] [Google Scholar]
  • 117. Whalen MJ, Clark RSB, Dixon CE, Robichaud P, Marion DW, Vagni V, Graham SH, Virag L, Hasko G, Stachlewitz R, Szabo C, Kochanek PM (1999) Reduction of cognitive and motor deficits after traumatic brain injury in mice deficient in poly (ADP‐ribose) polymerase. J Cereb Blood Flow Metab 19:835–842. [DOI] [PubMed] [Google Scholar]
  • 118. Williams S, Raghupathi R, Mackinnon M‐A, McIntosh TK, Saatman KE, Graham DI (2001) In situ DNA fragmentation occurs in white matter up to 12 months after head injury in man. Acta Neuropathol 102:581–590. [DOI] [PubMed] [Google Scholar]
  • 119. Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME (1995) Opposing effects of ERK and JNK‐p38 MAP kinases on apoptosis. Science 270:1326–1331. [DOI] [PubMed] [Google Scholar]
  • 120. Xiong Y, Gu Q, Peterson PL, Muizelaar JP, Lee CP (1997) Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. J Neurotrauma 14:23–34. [DOI] [PubMed] [Google Scholar]
  • 121. Yakovlev AG, Knoblach SM, Fan L, Fox GB, Goodnight R, Faden AI (1997) Activation of CPP32‐like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. J Neurosci 17:7415–7424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 122. Yakovlev AG, Ota K, Wang G, Movsesyan V, Bao W‐L, Yoshihara K, Faden AI (2001) Differential 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. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 123. Yang DD, Kuan C‐Y, Whitmarsh AJ, Rincon M, Zheng TS, Davis RJ, Pakic P, Flavell RA (1997) Absence of excitotoxicity‐induced apoptosis in the hippocampus of mice lacking the JNK3 gene. Nature 389:865–870. [DOI] [PubMed] [Google Scholar]
  • 124. Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng T‐I, Jones DP, Wang X (1997) Prevention of apoptosis by Bcl‐2 release of cytochrome c from mitochondria blocked. Science 275:1129–1132. [DOI] [PubMed] [Google Scholar]
  • 125. Young W (1992) Role of calcium in central nervous system injuries. J Neurotrauma 9:s9–s25. [PubMed] [Google Scholar]
  • 126. Zhan Q, Chen IT, Antinore MJ, Fornace AJ (1998) Tumor suppressor p53 can participate in transcriptional induction of the GADD45 promoter in the absence of direct DNA binding. Mol Cell Biol 18:2768–2778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 127. Zhang C, Raghupathi R, LaPlaca MC, Saatman KE, McIntosh TK (1999) Regional and temporal alterations in DNA fragmentation factor (DFF)‐like proteins following experimental brain trauma in the rat. J Neurochem 73:1650–1659. [DOI] [PubMed] [Google Scholar]

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