Excitotoxic Damage in Traumatic Brain Injury

  • Óscar L. Alves
  • Ross Bullock
Part of the Molecular and Cellular Biology of Critical Care Medicine book series (MCCM, volume 2)


Traumatic brain injury (TBI) is one of the most prevalent causes of morbidity and mortality all over the world. More than 350,000 individuals are admitted each year as a result of TBI in the USA alone (Kraus et al., 1996). This disease affects mainly young adults in their productive stage of life, producing long lasting disabilities in 25% of cases. This represents an enormous social and economical cost estimated to be around 38 billion dollars per year in the USA (Max et al. 1990). However, at the present there is no available treatment to reduce the extent of cerebral damage following brain injury, other than supportive intensive care.


Traumatic Brain Injury NMDA Receptor Glutamate Receptor Glutamate Release Excitatory Amino Acid 
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  1. 1.
    Al-Chalabi A and Leigh PN (2000). Recent advances in amyotrophic lateral sclerosis. Curr Opin Neurol 13:397–405.PubMedGoogle Scholar
  2. 2.
    Alessandri B, Doppenberg E, Bullock R, et al. (1999). Glucose and lactate metabolism after severe human head injury: influence of excitatory neurotransmitters and injury type. Acta Neurochir Suppl 75:21–24.PubMedGoogle Scholar
  3. 3.
    Alessandri B, Landolt H, Langemann H, et al. (1996). Application of glutamate in the cortex of rats: a microdialysis study. Acta Neurochir Suppl 67:6–12.PubMedGoogle Scholar
  4. 4.
    Arvin B, Lekieffre D, Graham JL, et al. (1994). Effect of the non-NMDA receptor antagonist GYKI 52466 on the microdialysate and tissue concentrations of amino acids following transient forebrain ischaemia. J Neurochem 62:1458–1467.PubMedGoogle Scholar
  5. 5.
    Baker AJ, Moulton RJ, MacMillan VH, et al. (1993). Excitatory amino acids in cerebrospinal fluid following traumatic brain injury in humans. J Neurosurg 79:369–372.PubMedGoogle Scholar
  6. 6.
    Basarsky TA, Feighan D and MacVicar BA (1999). Glutamate release through volume-activated channels during spreading depression. J Neurosci 19:6439–6445.PubMedGoogle Scholar
  7. 7.
    Benveniste H (1991). The excitotoxin hypothesis in relation to cerebral ischemia. Cerebrovasc Brain Metab Rev 3:213–245.PubMedGoogle Scholar
  8. 8.
    Bergsneider M, Hovda DA, Shalmon E, et al. (1997). Cerebral hyperglycolysis following severe traumatic brain injury in humans: a positron emission tomography study. J Neurosurg 86:241–251.PubMedGoogle Scholar
  9. 9.
    Blumbers PC (1997). Pathology. In: Reilly, P., and Bullock, R. (eds) Pathophysiology and management of severe close head injury, Chapman & Hall Medical, London.Google Scholar
  10. 10.
    Bowman CL, Ding JP, Sachs F, et al. (1992). Mechanotransducing ion channels in astrocytes. Brain Res 584:272–286.PubMedGoogle Scholar
  11. 11.
    Brown JI, Baker AJ, Konasiewicz SJ, et al. (1998). Clinical significance of CSF glutamate concentrations following severe traumatic brain injury in humans. J Neurotrauma 15:253–263.PubMedGoogle Scholar
  12. 12.
    Bullock R, Butcher SP, Chen MH, et al. (1991a). Correlation of the extracellular glutamate concentration with extent of blood flow reduction after subdural hematoma in the rat. J Neurosurg 74:794–802.PubMedGoogle Scholar
  13. 13.
    Bullock R and Di X (1997). Synergistic effect of glutamate on secondary brain damage following fluid percussion brain injury in rats. J Neurotrauma 14:765.Google Scholar
  14. 14.
    Bullock R and Fujisawa H (1992). The role of glutamate antagonists for the treatment of CNS injury. J Neurotrauma 9 Suppl 2:S443–462.Google Scholar
  15. 15.
    Bullock R, Inglis FM, Kuroda Y, et al. (1991b). Transient hippocampal hypermetabolism associated with glutamate release after acute subdural hematoma in the rat:A potentially neurotoxic mechanism. J Cereb Blood Flow Metab 11:S109.Google Scholar
  16. 16.
    Bullock R, McCulloch J, Graham DI, et al. (1990). Focal ischemic damage is reduced by CPP-ene studies in two animal models. Stroke 21:III32–36.PubMedGoogle Scholar
  17. 17.
    Bullock R, Zauner A, Myseros JS, et al. (1995a). Evidence for prolonged release of excitatory amino acids in severe human head trauma. Relationship to clinical events. Ann N Y Acad Sci 765:290–297; discussion 298.Google Scholar
  18. 18.
    Bullock R, Zauner A, Tsuji O, et al. (1994). Excitatory amino acid release after severe human head trauma:effect of intracranial pressure and cerebral perfusion pressure changes. In: Nagal, H., et al (eds): Intracranial Pressure IX. Tokyo: Springer.: 264–267.Google Scholar
  19. 19.
    Bullock R, Zauner A, Tsuji O, et al. (1995b). Paterns of excitatory amino acid release and ionic flux after severe head trauma. In: Tsubokawa, T., Marmarous, A., Robertson, C., et al. (eds): Neurochemical Monitoring in the Intensive Care Unit. Tokyo:Springer.: 64–67.Google Scholar
  20. 20.
    Bullock R, Zauner A, Woodward JJ, et al. (1998). Factors affecting excitatory amino acid release following severe human head injury. J Neurosurg 89:507–518.PubMedGoogle Scholar
  21. 21.
    Butcher SP, Bullock R, Graham DI, et al. (1990). Correlation between amino acid release and neuropathologic outcome in rat brain following middle cerebral artery occlusion. Stroke 21:1727–1733.PubMedGoogle Scholar
  22. 22.
    Carbonell WS and Grady MS (1999). Evidence disputing the importance of excitotoxicity in hippocampal neuron death after experimental traumatic brain injury. Ann N Y Acad Sci 890:287–298.PubMedGoogle Scholar
  23. 23.
    Choi DW (1985). Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci Lett 58:293–297.PubMedGoogle Scholar
  24. 24.
    Choi DW (1987). Ionic dependence of glutamate neurotoxicity. J Neurosci 7:369–379.PubMedGoogle Scholar
  25. 25.
    Choi DW (1991). Excitotoxicity. In: Meldrum, B (ed) Excitatory Amino Acid Antagonists. London: Blackwell Scientific.:216–237.Google Scholar
  26. 26.
    Choi DW, Maulucci-Gedde M and Kriegstein AR (1987). Glutamate neurotoxicity in cortical cell culture. J Neurosci 7:357–368.PubMedGoogle Scholar
  27. 27.
    Collingridge GL and Lester RA (1989). Excitatory amino acid receptors in the vertebrate central nervous system. Pharmacol Rev 41:143–210.PubMedGoogle Scholar
  28. 28.
    Cotman C, Monghan D, Otterson O, et al. (1987). Anatomical organization of excitatory amino acids receptors and their pathways. TINS 10:273–280.Google Scholar
  29. 29.
    Coyle JT (1996). The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry 3:241–253.PubMedGoogle Scholar
  30. 30.
    DeCoster MA, Schabelman E, Tombran-Tink J, et al. (1999). Neuroprotection by pigment epithelial-derived factor against glutamate toxicity in developing primary hippocampal neurons. J Neurosci Res 56:604–610.PubMedGoogle Scholar
  31. 31.
    Di X and Bullock R (1996a). Effect of the novel high-affinity glycine-site N-methyl-D-aspartate antagonist ACEA 1021 on the 1251-MK-801 binding after subdural hematorma in the rat:an invivo autoradiographic study. J Neurosurg 85:655–661.PubMedGoogle Scholar
  32. 32.
    Di X, Gordon J and Bullock R (2000). Fluid percussion brain injury exacerbates glutamate-induced focal damage in rats. J Neurortrauma 16:195–201.Google Scholar
  33. 33.
    Di X, Harpold T, Watson JC, et al. (1996b). Excitotoxic damage in neurotrauma:fact or fiction? Restor Neurol Neurosci 9:231–241.PubMedGoogle Scholar
  34. 34.
    Dixon CE, Lyeth BG, Povlishock JT, et al. (1987). A fluid percussion model of experimental brain injury in the rat. J Neurosurg 67:110–119.PubMedGoogle Scholar
  35. 35.
    Doble A (1999). The role of excitotoxicity in neurodegenerative disease:implications for therapy. Pharmacol Ther 81:163–221.PubMedGoogle Scholar
  36. 36.
    Doppenberg E and Bullock R (1997). Clinical neuro-protection trials in severe traumatic brain injury:lessons from previous studies. J Neurotrauma 14:71–80.PubMedGoogle Scholar
  37. 37.
    Doppenberg E, Zauner A, Bullock R, et al. (1996). Evidence of glutamate-mediated anaerobic glycolysis after human head injury? A microdialysis study. J Neurotrauma 13:597.Google Scholar
  38. 38.
    Espey MG, Kustova Y, Sei Y, et al. (1998). Extracellular glutamate levels are chronically elevated in the brains of LP-BM5-infected mice:a mechanism of retrovirus-induced encephalopathy. J Neurochem 71:2079–2087.PubMedGoogle Scholar
  39. 39.
    Faden AI (1993). Comparison of single and combination drug treatment strategies in experimental brain trauma. J Neurotrauma 10:91–100.PubMedGoogle Scholar
  40. 40.
    Faden AI, Demediuk P, Panter SS, et al. (1989). The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244:798–800.PubMedGoogle Scholar
  41. 41.
    Figiel I and Kaczmarek L (1997). Cellular and molecular correlates of glutamate-evoked neuronal programmed cell death in the in vitro cultures of rat hippocampal dentate gyrus. Neurochem Int 31:229–240.PubMedGoogle Scholar
  42. 42.
    Fujisawa H, Dawson D, Browne SE, et al. (1993). Pharmacological modification of glutamate neurotoxicity in vivo. Brain Res 629:73–78.PubMedGoogle Scholar
  43. 43.
    Fujisawa H, Landolt H and Bullock R (1996). Patterns of increased glucose use following extracellular infusion of glutamate:an autoradiographic study. J Neurotrauma 13:245–254.PubMedGoogle Scholar
  44. 44.
    Fujisawa H, Maxwell WL, Graham DI, et al. (1994). Focal microvascular occlusion after acute subdural haematoma in the rat:a mechanism for ischaemic damage and brain swelling? Acta Neurochir Suppl 60:193–196.Google Scholar
  45. 45.
    Furukawa K and Mattson MP (1995). Taxol stabilizes [Ca2+]i and protects hippocampal neurons against excitotoxicity. Brain Res 689:141–146.PubMedGoogle Scholar
  46. 46.
    Garthwaite G and Garthwaite J (1989). Quisqualate neurotoxicity:a delayed, CNQX-sensitive process triggered by a CNQX-insensitive mechanism in young rat hippocampal slices. Neurosci Lett 99:113–118.PubMedGoogle Scholar
  47. 47.
    Goldberg MP, Weiss JH, Pham PC, et al. (1987). N-methyl-D-aspartate receptors mediate hypoxic neuronal injury in cortical culture. J Pharmacol Exp Ther 243:784–791.PubMedGoogle Scholar
  48. 48.
    Gong QZ, Phillips LL and Lyeth BG (1999). Metabotropic glutamate receptor protein alterations after traumatic brain injury in rats. J Neurotrauma 16:893–902.PubMedGoogle Scholar
  49. 49.
    Graham DI (1985). The pathology of brain ischaemia and possibilities for therapeutic intervention. Br J Anaesth 57:3–17.PubMedGoogle Scholar
  50. 50.
    Graham DI, Adams JH and Doyle D (1968). Ischemic brain damage in fatale non-missile head injury. J Neurol Sci 39:213–234.Google Scholar
  51. 51.
    Grilli M, Diodato E, Lozza G, et al. (2000). Presenilin-1 regulates the neuronal threshold to excitotoxicity both physiologically and pathologically. Proc Natl Acad Sci U S A 97:12822–12827.PubMedGoogle Scholar
  52. 52.
    Hamm RJ, Dixon CE, Gbadebo DM, et al. (1992). Cognitive deficits following traumatic brain injury produced by controlled cortical impact. J Neurotrauma 9:11–20.PubMedGoogle Scholar
  53. 53.
    Hayes RL, Jenkins LW, Lyeth BG, et al. (1988). Pretreatment with phencyclidine, an N-methyl-D-aspartate antagonist, attenuates long-term behavioral deficits in the rat produced by traumatic brain injury. J Neurotrauma 5:259–274.PubMedGoogle Scholar
  54. 54.
    Higgins DS, Hoyt KR, Baie C, et al. (1999). Metabolic and glutamatergic disturbances in the Huntington’s disease transgenic mouse. Ann NY Acad Sci 893:298–300.PubMedGoogle Scholar
  55. 55.
    Hossmann KA (1994). Glutamate-mediated injury in focal cerebral ischemia:the excitotoxin hypothesis revised. Brain Pathol 4:23–36.PubMedGoogle Scholar
  56. 56.
    Hovda DA, Yoshino A, Kawamata T, et al. (1990). The increase in local cerebral glucose utilization following fluid percussion brain injury is prevented with kynurenic acid and is associated with an increase in calcium. Acta Neurochir Suppl 51:331–333.Google Scholar
  57. 57.
    Hylton C, Perri BR and Voddi MD (1995). Non-NMDA antagonist GYKI-52466 enhances spatial memory after experimental brain injuryl. J Neurotrauma 12:124.Google Scholar
  58. 58.
    Inglis F, Kuroda Y and Bullock R (1992). Glucose hypermetabolism after acute subdural hematoma is ameliorated by a competitive NMDA antagonist. J Neurotrauma 9:75–84.PubMedGoogle Scholar
  59. 59.
    Katayama Y, Becker DP, Tamura T, et al. (1990). Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J Neurosurg 73:889–900.PubMedGoogle Scholar
  60. 60.
    Kawamata T, Katayama Y, Hovda DA, et al. (1992). Administration of excitatory amino acid antagonists via microdialysis attenuates the increase in glucose utilization seen following concussive brain injury. J Cereb Blood Flow Metab 12:12–24.PubMedGoogle Scholar
  61. 61.
    Kharlamov A, Uz T, Joo JY, et al. (1996). Pharmacological characterization of apoptotic cell death in a model of photothrombotic brain injury in rats. Brain Res 734:1–9.PubMedGoogle Scholar
  62. 62.
    Khaspekov LG, Stastny F, Viktorov IV, et al. (1990). Cytotoxic effect of glutamate and its agonists on mouse hippocampal neurons. J Hirnforsch 31:635–643.PubMedGoogle Scholar
  63. 63.
    Kimura M, Sawada K, Miyagawa T, et al. (1998). Role of glutamate receptors and voltage-dependent calcium and sodium channels in the extracellular glutamate/aspartate accumulation and subsequent neuronal injury induced by oxygen/glucose deprivation in cultured hippocampal neurons. J Pharmacol Exp Ther 285:178–185.PubMedGoogle Scholar
  64. 64.
    Kohmura E, Yamada K, Hayakawa T, et al. (1990). Hippocampal neurons become more vulnerable to glutamate after subcritical hypoxia:an in vitro study. J Cereb Blood Flow Metab 10:877–884.PubMedGoogle Scholar
  65. 65.
    Kotapka MJ, Graham DI, Adams JH, et al. (1992). Hippocampal pathology in fatal non-missile human head injury. Acta Neuropathol 83:530–534.PubMedGoogle Scholar
  66. 66.
    Kraus JF and McArthur DL (1996). Epidemiology of violent injury in the workplace. Occup Med 11:201–217.PubMedGoogle Scholar
  67. 67.
    Kuroda Y, Inglis FM, Miller JD, et al. (1992). Transient glucose hypermetabolism after acute subdural hematoma in the rat. J Neurosurg 76:471–477.PubMedGoogle Scholar
  68. 68.
    Landolt H, Fujisawa H, Graham D, et al. (1998). Reproducible peracute glutamate-induced focal lesions of the normal rat brain using microdialysis. J Clin Neurosci 5:194–202.Google Scholar
  69. 69.
    Maeda T, Katayama Y, Kawamata T, et al. (1998). Mechanisms of excitatory amino acid release in contused brain tissue:effects of hypothermia and in situ administration of Co2+ on extracellular levels of glutamate. J Neurotrauma 15:655–664.PubMedGoogle Scholar
  70. 70.
    Marmarou A, Foda MA, van den Brink W, et al. (1994). A new model of diffuse brain injury in rats. Part I:Pathophysiology and biomechanics. J Neurosurg 80:291–300.PubMedGoogle Scholar
  71. 71.
    Marshall LF (2000). Head injury:recent past, present, and future. Neurosurgery 47:546–561.PubMedGoogle Scholar
  72. 72.
    Matsushita Y, Shima K, Nawashiro H, et al. (2000). Real-time monitoring of glutamate following fluid percussion brain injury with hypoxia in the rat. J Neurotrauma 17:143–153.PubMedGoogle Scholar
  73. 73.
    Max W, Rice DP and MacKenzie EJ (1990). The lifetime cost of injury. Inquiry 27:332–343.PubMedGoogle Scholar
  74. 74.
    Maxwell WL, Bullock R, Landholt H, et al. (1994). Massive astrocytic swelling in response to extracellular glutamate—a possible mechanism for post-traumatic brain swelling? Acta Neurochir Suppl 60:465–467.Google Scholar
  75. 75.
    McIntosh TK, Faden AI, Yamakami I, et al. (1988). Magnesium deficiency exacerbates and pretreatment improves outcome following traumatic brain injury in rats:31P magnetic resonance spectroscopy and behavioral studies. J Neurotrauma 5:17–31.PubMedGoogle Scholar
  76. 76.
    Meldrum BS (1993). Excitotoxicity and selective neuronal loss in epilepsy. Brain Pathol 3:405–412.PubMedGoogle Scholar
  77. 77.
    Miller LP, Lyeth BG, Jenkins LW, et al. (1990). Excitatory amino acid receptor subtype binding following traumatic brain injury. Brain Res 526:103–107.PubMedGoogle Scholar
  78. 78.
    Minervini M, Atlante A, Gagliardi S, et al. (1997). Glutamate stimulates 2-deoxyglucose uptake in rat cerebellar granule cells. Brain Res 768:57–62.PubMedGoogle Scholar
  79. 79.
    Mitchell HL, Frisella WA, Brooker RW, et al. (1995). Attenuation of traumatic cell death by an adenosine A1 agonist in rat hippocampal cells. Neurosurgery 36:1003–1007; discussion 1007–1008.PubMedGoogle Scholar
  80. 80.
    Mukhin A, Fan L and Faden AI (1996). Activation of metabotropic glutamate receptor subtype mGluR1 contributes to post-traumatic neuronal injury. J Neurosci 16:6012–6020.PubMedGoogle Scholar
  81. 81.
    Nichols D and Attwell M (1990). The release and uptake of excitatory amino acids. Trends Pharmacol Sci 12:462–468.Google Scholar
  82. 82.
    Nilsson P, Hillered L, Olsson Y, et al. (1993). Regional changes in interstitial K+ and Ca2+ levels following cortical compression contusion trauma in rats. J Cereb Blood Flow Metab 13:183–192.PubMedGoogle Scholar
  83. 83.
    Nilsson P, Hillered L, Ponten U, et al. (1990). Changes in cortical extracellular levels of energy-related metabolites and amino acids following concussive brain injury in rats. J Cereb Blood Flow Metab 10:631–637.PubMedGoogle Scholar
  84. 84.
    Novelli A, Reilly JA, Lysko PG, et al. (1988). Glutamate becomes neurotoxic via the N-methyl-D-aspartate receptor when intracellular energy levels are reduced. Brain Res 451:205–212.PubMedGoogle Scholar
  85. 85.
    Obrenovitch TP (1999). High extracellular glutamate and neuronal death in neurological disorders. Cause, contribution or consequence? Ann N Y Acad Sci 890:273–286.PubMedGoogle Scholar
  86. 86.
    Obrenovitch TP and Urenjak J (1997). Is high extracellular glutamate the key to excitotoxicity in traumatic brain injury? J Neurotrauma 14:677–698.PubMedGoogle Scholar
  87. 87.
    Obrenovitch TP, Zilkha E and Urenjak J (1996). Evidence against high extracellular glutamate promoting the elicitation of spreading depression by potassium. J Cereb Blood Flow Metab 16:923–931.PubMedGoogle Scholar
  88. 88.
    Obrenovitch TP (1996). Origins of glutamate release in ischaemia. Acta Neurochir Suppl 66:50–55.PubMedGoogle Scholar
  89. 89.
    Okiyama K, Smith DH, Gennarelli TA, et al. (1995). The sodium channel blocker and glutamate release inhibitor BW1003C87 and magnesium attenuate regional cerebral edema following experimental brain injury in the rat. J Neurochem 64:802–809.PubMedGoogle Scholar
  90. 90.
    Palmer AM, Marion DW, Botscheller ML, et al. (1993). Traumatic brain injury-induced excitotoxicity assessed in a controlled cortical impact model. J Neurochem 61:2015–2024.PubMedGoogle Scholar
  91. 91.
    Panter SS and Faden AI (1992). Pretreatment with NMDA antagonists limits release of excitatory amino acids following traumatic brain injury. Neurosci Lett 136:165–168.PubMedGoogle Scholar
  92. 92.
    Pellerin L and Magistretti PJ (1994). Glutamate uptake into astrocytes stimulates aerobic glycolysis:a mechanism coupling neuronal activity to glucose utilization. Proc Natl Acad Sci U S A 91:10625–10629.PubMedGoogle Scholar
  93. 93.
    Pellerin L and Magistretti PJ (1996). Excitatory amino acids stimulate aerobic glycolysis in astrocytes via an activation of the Na+/K+ ATPase. Dev Neurosci 18:336–342.PubMedGoogle Scholar
  94. 94.
    Peterson C, Neal JH and Cotman CW (1989). Development of N-methyl-D-aspartate excitotoxicity in cultured hippocampal neurons. Brain Res Dev Brain Res 48:187–195.PubMedGoogle Scholar
  95. 95.
    Povlishock JT (1992). Traumatically induced axonal injury:pathogenesis and pathobiological implications. Brain Pathol 2:1–12.PubMedGoogle Scholar
  96. 96.
    Prehn JH (1998). Mitochondrial transmembrane potential and free radical production in excitotoxic neurodegeneration. Naunyn Schmiedebergs Arch Pharmacol 357:316–322.PubMedGoogle Scholar
  97. 97.
    Reeves TM, Zhu J, Povlishock JT, et al. (1997). The effect of combined fluid percussion and entorhinal cortical lesions on long-term potentiation. Neuroscience 77:431–444.PubMedGoogle Scholar
  98. 98.
    Regan RF (1996). The vulnerability of spinal cord neurons to excitotoxic injury:comparison with cortical neurons. Neurosci Lett 213:9–12.PubMedGoogle Scholar
  99. 99.
    Regan RF and Guo YP (1999). Potentiation of excitotoxic injury by high concentrations of extracellular reduced glutathione. Neuroscience 91:463–470.PubMedGoogle Scholar
  100. 100.
    Reinert M, Khaldi A, Zauner A, et al. (2000). High level of extracellular potassium and its correlates after severe head injury:relationship to high intracranial pressure. J Neurosurg 93:800–807.PubMedGoogle Scholar
  101. 101.
    Rosenberg PA and Aizenman E (1989). Hundred-fold increase in neuronal vulnerability to glutamate toxicity in astrocyte-poor cultures of rat cerebral cortex. Neurosci Lett 103:162–168.PubMedGoogle Scholar
  102. 102.
    Rosenberg PA, Amin S and Leitner M (1992). Glutamate uptake disguises neurotoxic potency of glutamate agonists in cerebral cortex in dissociated cell culture. J Neurosci 12:56–61.PubMedGoogle Scholar
  103. 103.
    Rothman SM and Olney JW (1986). Glutamate and the pathophysiology of hypoxic—ischemic brain damage. Ann Neurol 19:105–111.PubMedGoogle Scholar
  104. 104.
    Schauwecker PE and Steward O (1997). Genetic determinants of susceptibility to excitotoxic cell death:implications for gene targeting approaches. Proc Natl Acad Sci U S A 94:4103–4108.PubMedGoogle Scholar
  105. 105.
    Schoepp D, Bockaert J and Sladeczek F (1990). Pharmacological and functional characteristics of metabotropic excitatory amino acid receptors. Trends Pharmacol Sci 11:508–515.PubMedGoogle Scholar
  106. 106.
    Schroder ML, Muizelaar JP and Kuta A J (1994). Documented reversal of global ischemia immediately after removal of an acute subdural hematoma. Report of two cases. J Neurosurg 80:324–327.PubMedGoogle Scholar
  107. 107.
    Schurr A, Payne RS, Heine MF, et al. (1995). Hypoxia, excitotoxicity, and neuroprotection in the hippocampal slice preparation. J Neurosci Methods 59:129–138.PubMedGoogle Scholar
  108. 108.
    Shapira Y, Yadid G, Cotev S, et al. (1990). Protective effect of MK801 in experimental brain injury. J Neurotrauma 7:131–139.PubMedGoogle Scholar
  109. 109.
    Shimada N, Graf R, Rosner G, et al. (1989). Ischemic flow threshold for extracellular glutamate increase in cat cortex. J Cereb Blood Flow Metab 9:603–606.PubMedGoogle Scholar
  110. 110.
    Shohami E, Novikov M and Bass R (1995). Long-term effect of HU-211, a novel non-competitive NMDA antagonist, on motor and memory functions after closed head injury in the rat. Brain Res 674:55–62.PubMedGoogle Scholar
  111. 111.
    Siegel GJ, Agranoff BW, Albers RW, et al. (1989). Basic Neurochemistry:Molecular, cellular and medical aspects. Sixth Edition. New York, Raven Press.Google Scholar
  112. 112.
    Siesjo BK (1992). Pathophysiology and treatment of focal cerebral ischemia. Part II:Mechanisms of damage and treatment. J Neurosurg 77:337–354.PubMedGoogle Scholar
  113. 113.
    Smith DH, Okiyama K, Thomas MJ, et al. (1993). Effects of the excitatory amino acid receptor antagonists kynurenate and indole-2-carboxylic acid on behavioral and neurochemical outcome following experimental brain injury. J Neurosci 13:5383–5392.PubMedGoogle Scholar
  114. 114.
    Szatkowski M and Attwell D (1994). Triggering and execution of neuronal death in brain ischaemia:two phases of glutamate release by different mechanisms. Trends Neurosci 17:359–365.PubMedGoogle Scholar
  115. 115.
    Sze C, Bi H, Kleinschmidt-DeMasters BK, et al. (2001). N-Methyl-D-aspartate receptor subunit proteins and their phosphorylation status are altered selectively in Alzheimer’s disease. J Neurol Sci 182:151–159.PubMedGoogle Scholar
  116. 116.
    Tamminga CA (1998). Schizophrenia and glutamatergic transmission. Crit Rev Neurobiol 12:21–36.PubMedGoogle Scholar
  117. 117.
    Tanaka K (2000). Functions of glutamate transporters in the brain. Neurosci Res 37:15–19.PubMedGoogle Scholar
  118. 118.
    Tanaka K, Watase K, Manabe T, et al. (1997). Epilepsy and exacerbation of brain injury in mice lacking the glutamate transporter GLT-1. Science 276:1699–1702.PubMedGoogle Scholar
  119. 119.
    Tavalin SJ, Ellis EF and Satin LS (1995). Mechanical perturbation of cultured cortical neurons reveals a stretch-induced delayed depolarization. J Neurophysiol 74:2767–2773.PubMedGoogle Scholar
  120. 120.
    Temple MD and Hamm RJ (1996). Chronic, post-injury administration of D-cycloserine, an NMDA partial agonist, enhances cognitive performance following experimental brain injury. Brain Res 741:246–251.PubMedGoogle Scholar
  121. 121.
    Tenneti L, D’Emilia DM, Troy CM, et al. (1998). Role of caspases in N-methyl-D-aspartate-induced apoptosis in cerebrocortical neurons. J Neurochem 71:946–959.PubMedGoogle Scholar
  122. 122.
    Torp R, Lekieffre D, Levy LM, et al. (1995). Reduced postischemic expression of a glial glutamate transporter, GLT1, in the rat hippocampus. Exp Brain Res 103:51–58.PubMedGoogle Scholar
  123. 123.
    Toulmond S, Serrano A, Benavides J, et al. (1993). Prevention by eliprodil (SL 82.0715) of traumatic brain damage in the rat. Existence of a large (18 h) therapeutic window. Brain Res 620:32–41.PubMedGoogle Scholar
  124. 124.
    Tsuchida E and Bullock R (1995). The effect of the glycine site-specific N-methyl-D-aspartate antagonist ACEA1021 on ischemic brain damage caused by acute subdural hematoma in the rat. J Neurotrauma 12:279–288.PubMedGoogle Scholar
  125. 125.
    Tsuchida E, Harms JF, Woodward JJ, et al. (1996). A use-dependent sodium channel antagonist, 619C89, in reduction of ischemic brain damage and glutamate release after acute subdural hematoma in the rat. J Neurosurg 85:104–111.PubMedGoogle Scholar
  126. 126.
    Van Harreveld A and Fifkova E (1971). Light- and electron-microscopic changes in central nervous tissue after electrophoretic injection of glutamate. Exp Mol Pathol 15:61–81.PubMedGoogle Scholar
  127. 127.
    Velasco I, Tapia R and Massieu L (1996). Inhibition of glutamate uptake induces progressive accumulation of extracellular glutamate and neuronal damage in rat cortical cultures. J Neurosci Res 44:551–561.PubMedGoogle Scholar
  128. 128.
    Vespa P, Prins M, Ronne-Engstrom E., et al. (1998). Increase in extracellular glutamate caused by reduced cerebral perfusion pressure and seizures after human traumatic brain injury:a microdialysis study. J Neurosurg 89:971–982.PubMedGoogle Scholar
  129. 129.
    Vink R, McIntosh TK, Demediuk P, et al. (1988). Decline in intracellular free Mg2+ is associated with irreversible tissue injury after brain trauma. J Biol Chem 263:757–761.PubMedGoogle Scholar
  130. 130.
    Werth JL, Park TS, Silbergeld DL, et al. (1998). Excitotoxic swelling occurs in oxygen and glucose deprived human cortical slices. Brain Res 782:248–254.PubMedGoogle Scholar
  131. 131.
    Westergren I and Johansson BB (1992). NBQX, an AMPA antagonist, reduces glutamate-mediated brain edema. Brain Res 573:324–326.PubMedGoogle Scholar
  132. 132.
    Xiong Y, Gu Q, Peterson PL, et al. (1997). Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. J Neurotrauma 14:23–34.PubMedGoogle Scholar
  133. 133.
    Yamamoto T, Rossi S, Stiefel M, et al. (1999). CSF and ECF glutamate concentrations in head injured patients. Acta Neurochir Suppl 75:17–19.PubMedGoogle Scholar
  134. 134.
    Yang CS, Tsai PJ, Lin NN, et al. (1998). Elevated extracellular glutamate concentrations increased malondialdehyde production in anesthetized rat brain cortex. Neurosci Lett 243:33–36.PubMedGoogle Scholar
  135. 135.
    Ye ZC and Sontheimer H (1999). Glioma cells release excitotoxic concentrations of glutamate. Cancer Res 59:4383–4391.PubMedGoogle Scholar
  136. 136.
    Yu Z, Zhou D, Bruce-Keller AJ, et al. (1999). Lack of the p50 subunit of nuclear factor-kappaB increases the vulnerability of hippocampal neurons to excitotoxic injury. J Neurosci 19:8856–8865.PubMedGoogle Scholar
  137. 137.
    Zauner A, Bullock R, Kuta AJ, et al. (1996). Glutamate release and cerebral blood flow after severe human head injury. Acta Neurochir Suppl 67:40–44.PubMedGoogle Scholar
  138. 138.
    Zhang L, Rzigalinski BA, Ellis EF, et al. (1996). Reduction of voltage-dependent Mg2+ blockade of NMDA current in mechanically injured neurons. Science 274:1921–1923.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • Óscar L. Alves
    • 1
    • 2
  • Ross Bullock
    • 1
  1. 1.Department of NeurosurgeryMedical College of VirginiaUSA
  2. 2.Faculdade de Medicina da Universidade do PortoPortugal

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