The Importance of Glutamate Receptors in Brain Ischemia

  • Anker Jon Hansen
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 363)


The chapter reviews some aspects of the hypothesis that excitatory amino acids under pathological conditions stimulate neuronal glutamate receptors and cause the cells to die. A number of neurological conditions have been related to this excitotoxic hypothesis, but we limit the description to conditions in which acute and substantial changes are at hand, such as brain ischemia. Here excitatory amino acids are released from brain cells and major changes of the interstitial ion composition are observed. In the following a description of the chain of events in the central nervous system leading to cell necrosis will be given. We shall concentrate on the events in global ischemia because these are the conditions that have been most extensively described. First, some details of the glutamate transmitter system are given.


Glutamate Receptor Brain Ischemia AMPA Receptor Excitatory Amino Acid NMDA Antagonist 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Andine, P., Jacobson, I., and Hagberg, H. (1992) Enhanced calcium uptake by CA1 pyramidal cell dendrites in the postischemic phase despite subnormal evoked field potentials: Excitatory amino acid receptor dependency and relationship to neuronal damage. J. Cereb. Blood Flow Metab. 12: 773–783.PubMedCrossRefGoogle Scholar
  2. Benveniste, H., Drejer, J., Schousboe, A., and Diemer, N. (1984)Elevation of extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J. Neurochem. 43: 1369–1374.PubMedCrossRefGoogle Scholar
  3. Benveniste, H., Jogensen, M.B., Diemer, NH, and Hansen, A.J. (1988) Calcium accumulation by glutamate activation is involved in hippocampal cell damage after ischemia. Acta Neurol. Scand. 78: 529–536.PubMedCrossRefGoogle Scholar
  4. Benveniste, H., Jorgensen, M.B., Sandberg, M., Hagberg, H., and Diemer, N.H. (1989)Ischemia-induced damage in the hippocampal CA1 region depends on glutamate and intact innervation from CA3. J. Cereb. Blood Row Metab. 9: 629–639.CrossRefGoogle Scholar
  5. Buchan, A., Li, H., and Pulsinelli, W. (1991)The N-methyl-D-asparte antagonist, MK-801, fails to protect against neuronal damage caused by transient, severe forebrain ischemia in adultrats. J. Neurosci. 11(4): 1049–1056.PubMedGoogle Scholar
  6. Buchan, A., and Pulsinelli, W.A. (1990)Hypothermia but not the N-methyl-D-asparte antagonist, MK-801, attenuates neuronal damage in gerbils subjected to transient global ischemia. J. Neurosci. 10 (1): 311–316.Google Scholar
  7. Busto, R., Dietrich, W.D., Globus, M.Y.-T., and Ginsberg, M.D. (1989) Postischemic moderate hypothermia inhibits CA1 hippocampal ischemic neuronal injury. Neurosci. Lett. 101: 299–304.PubMedCrossRefGoogle Scholar
  8. Butcher, S.P., Bullock, R., Graham, D.I., and McCulloch, J. (1990) correlation between amio acid release and neuropathologic outcome in rat brain following middle cerebral artery occlusion. Stroke 21: 1727–1733.PubMedCrossRefGoogle Scholar
  9. Chiamulera, C., Albertini, P., Valerio, E., and Reggiani, A. (1992) Activation of metabotropic receptors has a neuroprotective effect in a rodent model of focal ischemia. Eur. J. Pharmacol. 216: 335–336.PubMedCrossRefGoogle Scholar
  10. Choi, D.W., Maulucci-Gedde, M.A., and Kriegstein, A.R. (1987)Glutamate neurotoxicity in cortical cell culture. J. Neurosci. 7: 357–368.PubMedGoogle Scholar
  11. Choi, D.W. (1988)Glutamate neurotoxicity and diseases of the nervous system. Neuron 1: 623–634.PubMedCrossRefGoogle Scholar
  12. Diemer, N.H., Jorgensen, M.B., Johansen, F.F., Sheardown, M.J., and Honore, T. (1992)Protection against ischemic hippocampal CA1 damage in rat with a new non-NMDA antagonist, NBQX. Acta Neuro. Scand. 86: 45–49.CrossRefGoogle Scholar
  13. Faden, A.I., Demediuk, P., Panter, S.S., and Vink, R. (1989) The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244: 798–800.PubMedCrossRefGoogle Scholar
  14. Frandsen, A.A., and Schousboe, A. (1987) Time and concentration dependency of the toxicity of excitatory amino acids on cerebral neurones in primary culture. Neurochem. Int. 10: 583–591.PubMedCrossRefGoogle Scholar
  15. Gill, R., Nordholm, L., and Lodge, D. (1992b) The neuroprotective actions of 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBOX) in a rat focal ischemia model. Brain Res. 580: 35–43.PubMedCrossRefGoogle Scholar
  16. Gill, R., Foster, A.C., and Woodruff, G.N. (1987) Systemic administration of MK-801 protects against ischemia-induced hippocampal neurodegeneration in gerbil. J. Neurosci. 7: 3343–3349.PubMedGoogle Scholar
  17. Gill, R., Andine, P., Hillered, L., Persson, L., and Hagberg, H. (1992a) The effect of MK-801 on cortical spreading depression in the penumbra zone following focal ischemia in the rat. J. Cereb. Blood Flow Metab. 12: 371–379.PubMedCrossRefGoogle Scholar
  18. Hansen, A.J. (1985) Effects of anoxia on ion distribution in the brain. Physiol. Rev. 65: 101–148.PubMedGoogle Scholar
  19. Hansen, A.J., and Zeuthen, T. (1981) Extracellular ion concentrations during spreading depression and ischemia in the rat brain cortex. Acta Physiol. Scand. 113: 437–445.PubMedCrossRefGoogle Scholar
  20. Hansen, A.J., and Nedergaard, M. (1988) Brain ion homeostasis in cerebral ischemia. Neurochem. Pathol. 9: 195–209.PubMedGoogle Scholar
  21. Hillered, L, Hallstrom, A., Segersvard, S., Persson, L., and Ungerstedt, U. (1989) Dynamics of extracellular metabolites in the striatum after middle cerebral artery occlusion in the rat monitored by intracerebral microdialysis. J. Cereb. Blood Flow Metab. 9: 607–666.PubMedCrossRefGoogle Scholar
  22. Hollmann, M., Hartley, M., and Heinemann, S. (1991) Calcium permeability of KA-AMPA-gated glutamate channels depends on subunit composition. Science 252: 851–853.PubMedCrossRefGoogle Scholar
  23. Honore, T., Davis, S.N., Drejer, J., Fretcher, E.J., Jacobson, P. Lodge, D., and Nielsen, F.E. (1988) Quinoxalinediones: Potent comparative non-NMDA glutamate receptor antagonists. Science 241: 701–703.PubMedCrossRefGoogle Scholar
  24. Hume, R.I., Dingledine, R., and Heinemann, S.F. (1991) Identification of a site in glutamate receptor subunits that controls calcium permeability. Science 253: 1028–1031.PubMedCrossRefGoogle Scholar
  25. Johansen, F.F., Jorgensen, M.B., and Diemer, N.H. (1983) Resistance of hippocampal CA1 interneurones to 20 min of transient ischemia in the rat. Acta Neuropath. 61: 135–140.CrossRefGoogle Scholar
  26. Le Peillet, E., Arvin, B., Moncada, C., and Meldrum, B. (1992) The non-NMDA antagonists, NBQX and GYKI 52466, protect against cortical and striatal cell loss following transient global ischemia in the rat. Brain Res. 571: 115–120.PubMedCrossRefGoogle Scholar
  27. Mayer, M.L., and Westbrook, G.L. (1987a) Penneation and block of N-methyl-D-aspartic acid receptor channels by divalent cations in mouse culture central neurons. J. Physiol. 394: 501–527.PubMedGoogle Scholar
  28. Mayer, M.L., and Westbrook, G.L. (1987b) The physiology of excitatory amino acids in the vertebrate central nervous system. Prog. Neurobiol. 28: 197–276.PubMedCrossRefGoogle Scholar
  29. McCulloch, J. (1992)Excitatory amino acid antagonists and their potential for the treatment of ischemia brain damage in man. Br. J. Clin. Pharac. 34: 106–114.CrossRefGoogle Scholar
  30. Nellgard, B., and Wieloch, T. (1992a)Postischemic blockade of AMPA but not NMDA receptors mitigates neuronal damage in the rat brain following tranient severe cerebral ischemia. J. Cereb. Blood Row Metab. 12: 2–11.CrossRefGoogle Scholar
  31. Nellgard, B., and Wieloch, T. (1992b) Cerebral protection by AMPA-and NMDA-receptor antagonists administration after severe insulin-induced glycemia. Exp. Brain Res. 92: 259–266.PubMedCrossRefGoogle Scholar
  32. Olney, J.W. (1989) Excitatory amino acids and neuropsychiatric disorders. Biol. Psychiatry 26: 505–525.PubMedCrossRefGoogle Scholar
  33. Olney, J.W., Ho, O.L., and Rhee, V. (1971) Cytotoxic effects of acidic and sulphur containing amino acids on the infant mouse central nervous system. Exp. Brain Res. 14: 61–76.PubMedCrossRefGoogle Scholar
  34. Ozawa, S., Iino, M., and Tsuzuki, K. (1991) Two types of kainate responses in cultured rat hippocampal neurons. J. Neurophysiol. 66: 2–11.PubMedGoogle Scholar
  35. Pellegrini-Giampietro, D.E., Zukin, R.S., Bennett, M.V.L., Cho, S., and Pulsinelli, W.A. (1992) Switch in glutamate receptor subunit gene expression in CA1 subfield of hippocampus following global ischemia in rats. Proc. Natl. Acad. Sci. 89: 10499–10503.PubMedCrossRefGoogle Scholar
  36. Pulsinelli, W., Dimagl, U, Jacewicz, M., and Buchan, A. (1992) Antagonists of excitatory amino acid neurotransmitters: A comparison of their effects on global versus focal ischemia. In: Drug Research Related to Neuroactive Amino Acids (Schousboe, A., Diemer, N., Kofok, H., eds.), Munksgaard, Copenhagen, pp. 225–238.Google Scholar
  37. Pulsinelli, W.A., Waldeman, S., Rawlinson, S., and Plum, F. (1982b) Moderate hyperglycemia augments ischemie brain damage: a neuropathological study in the rat. Neurology 32:1239.PubMedCrossRefGoogle Scholar
  38. Pulsinelli, W.A., Brierely, J.B., and Plum, F. (1982a) Temporal profile of neuronal damage in model of transient forebrain ischemia. Ann. Neurol. 11: 491.PubMedCrossRefGoogle Scholar
  39. Sacaan, A.I., and Schoepp, D.D. (1992) Activation of hippocampal metabotropic excitatory amino acid receptors leads to seizures and neuronal damage. Neurosci. Lett. 139: 77–82.PubMedCrossRefGoogle Scholar
  40. Schanne, F.A.X., Kane, A.B., Young, E.E., and Farber, J.L. (1979) Calcium dependence of toxic cell death: A final common pathway. Science 206: 700–702.PubMedCrossRefGoogle Scholar
  41. Sheardown, M.J., Hansen, A.J., Eskesen, K., Suzdak, P., Diemer, N.H., and Honore, T. (1990a)Blockade of AMPA receptors in the CA1 region of the hippocampus prevents ischemia induced cell death. In: Pharmacology of Cerebral Ischemia (Krieglstein, J., Oberpichler, H., eds), Stuttgart, Wissenschaftliche Verlagsgesellschaft mbH, pp. 245–253.Google Scholar
  42. Sheardown, M.J., Nielsen, E.O., Hansen, A.J., Jacobson, P., and Honore, T. (1990b) 2, 3-dihydroxy-6-nitro-7-sul-famoyl-benzo(F)quinoxaline: A neuroprotectant for cerebral ischemia. Science 247: 571–574.PubMedCrossRefGoogle Scholar
  43. Siesjo, B.K., and Bengtsson, F. (1989) Calcium fluxes, calcium antagonists, and calcium-related pathology in brain ischemia, hypoglycemia, and spreading depression: A unifying hypothesis. J. Cereb. Blood Flow and Metab. 9: 127–140.CrossRefGoogle Scholar
  44. Simon, R.P., Swan, J.H., Griffiths, T., and Meldrum, B.S. (1984) Blockade of N-methyl-D-aspartate receptors may protect against ischemie damage in the brain. Science 226: 850–885.PubMedCrossRefGoogle Scholar
  45. Smith, S.E., and Meldrum, B. (1992) Cerebroprotective effect of a non-N-methyl-D-aspartate antagonist, GYKI 52466, after focal ischemia in the rat. Stroke 23(6): 861–864.PubMedCrossRefGoogle Scholar
  46. Smith, M.-L., Auer, R.N., and Siesjo, B.K. (1984) The density and distribution of ischemie brain injury in the rat following two to ten minutes of forebrain ischemia. Acta Neuropathol. 64: 319.PubMedCrossRefGoogle Scholar
  47. Smith, S.E., and Meldrum, B.S. (1993) Cerebroprotective effect of anon-methyl-D-aspartate antagonist, NBQX, after focal ischemia in the rat. Functional Neurol., in press.Google Scholar
  48. Sommer, B., Kohler, M., Sprengel, R., and Seeburg, O. (1991)RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67: 11–19.PubMedCrossRefGoogle Scholar
  49. Sugiyama, H., Ito, I., and Watanabe, M. (1989) Glutamate receptor subtypes may be classfied into two major categories: a study on Xenopus oocytes injected with rat brain mRNA. Neuron 3: 129–132.PubMedCrossRefGoogle Scholar
  50. Thomsen, C., Kristensen, P., Mulvihil, E., Haldeman, Band Suzdak, P. (1992) L-2-amino-4-phosphonobutyrate(L-AP4) is an agonist at the type-iv metabotropic glutamate receptor which is negatively coupled to adenylate cyclase. Eur. J. Pharmacol. 227: 361–362.PubMedCrossRefGoogle Scholar
  51. Trombley, P.Q., and Westbrook, G.L. (1992) L-AP4 inhibits calcium currents and synaptic transmission via a G-protein-coupled glutamate receptor. J. Neurosci. 12 (6): 2043–2050.Google Scholar
  52. Urban, L., Neill, K.H., Crain, B.J., Nadler, J.V., and Somjen, G.G. (1989) Postischemic synaptic physiology in area CA1 of the gerbil hippocampus studied in vitro. J.Neurosci. 9(11): 3966–3975.PubMedGoogle Scholar
  53. Verdoorn, T.A., Burnashev, N., Monyer, H., Seeburg, P.H., and Sakmann, B. (1991)Structural determinants of ion flow through recombinant glutamate receptor channels. Science 252: 1715–1718.PubMedCrossRefGoogle Scholar
  54. Wieloch, T., Lindvall, O., Blomqvist, P. and Gage, F.H. (1984) Evidence for amelioration of ischemic neuronal damage in the hippocampal formation by lesions of the perforant path. Neurol. Res. 7: 24–26.Google Scholar

Copyright information

© Springer Science+Business Media New York 1995

Authors and Affiliations

  • Anker Jon Hansen
    • 1
  1. 1.Pharmaceuticals Division Department of NeuropharmacologyNovo Nordisk A/SMålovDenmark

Personalised recommendations