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Glutamate: A Role in Both Cerebral Ischaemia and Dementia of the Alzheimer Type

  • D. Dewar
  • R. Bullock
  • D. T. Chalmers
  • D. I. Graham
  • J. McCulloch
Conference paper

Abstract

Glutamate has two major roles in the CNS under normal circumstances. As well as being involved in intermediary metabolism, this amino acid is the major excitatory neurotransmitter in the cerebral cortex, mediating both corticocortical and corticofugal transmission. In addition to these physiological roles for glutamate in the normal brain, its neurotoxic actions have been known for many years. Glutamate neurotoxicity has been implicated in the pathophysiology of a variety of neurodegenerative conditions, including cerebral ischaemia, dementia of the Alzheimer type (DAT), Huntington’s chorea and epilepsy. The evidence supporting glutamate-induced neuronal death in the last three conditions is at present somewhat circumstantial. However, there is convincing experimental evidence for glutamate neurotoxicity in cerebral ischaemia. Extracellular concentrations of glutamate are markedly elevated in cerebral ischaemia [2,5,14, 16], and specific glutamate antagonists have neuroprotective effects [34,35,38].

Keywords

NMDA Receptor Cerebral Ischaemia Middle Cerebral Artery Occlusion Focal Cerebral Ischaemia Cereb Blood Flow 
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.

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References

  1. 1.
    Aebischer B, Frey P, Haerter H-P, Herding PL, Mueller W (1989) 115 Synthesis and NMDA antagonist properties of the enantiomers of 4-(3-phosphonopropyl)piperazine-2-carboxylic acid (CPP) and of the unsaturated analogue (E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (CPP-ene). Helv Chim Acta 72:1043–1051CrossRefGoogle Scholar
  2. 2.
    Benveniste H, Drejer J, Schousboe A, Diemer NH (1984) Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43:1369–1374PubMedCrossRefGoogle Scholar
  3. 3.
    Bose B, Osterholm JL, Triolo A (1985) Focal cerebral ischemia: reduction in size of infarcts by ventriculo-subarachnoid perfusion with fluorocarbon emulsion. Brain Res 328:223–231PubMedCrossRefGoogle Scholar
  4. 4.
    Bullock R, Graham DI, Chen M-H, Lowe D, McCulloch J (1990) Focal cerebral ischemia in the cat: pretreatment with a competitive NMDA receptor antagonist, D-CPP-ene. J Cereb Blood Flow Metab 10:668–674PubMedCrossRefGoogle Scholar
  5. 5.
    Butcher SP, Bullock R, Graham DI, McCulloch J (1990) Release of neuroexcitatory amino acids from rat brain following middle cerebral artery occlusion. Br J Pharmacol 99:277PGoogle Scholar
  6. 6.
    Carter C, Rivy JP, Scatton B (1989) Ifenprodil and SL820715 are antagonists at the polyamine site of the N-Methyl-D-aspartate (NMDA) receptor. Eur J Pharmacol 164:611–612PubMedCrossRefGoogle Scholar
  7. 7.
    Chalmers DT, Dewar D, Graham DI, Brooks DN, McCulloch J (1990) Differential alterations of cortical glutamatergic binding sites in senile dementia of the Alzheimer type. Proc Natl Acad Sci USA 87:1352–1356PubMedCrossRefGoogle Scholar
  8. 8.
    Choi DW (1987) Ionic dependence of glutamate neurotoxicity. J Neurosci 7:369–379PubMedGoogle Scholar
  9. 9.
    Choi DW (1990) Methods for antagonizing glutamate neurotoxicity. Cerebro Brain Metab Rev 2:105–147Google Scholar
  10. 10.
    Dewar D, Wallace MC, Kurumaji A, McCulloch J. (1989) Alterations in the N-methyl-D-aspartate receptor complex following focal cerebral ischemia. J Cereb Blood Flow Metab 9:709–712PubMedCrossRefGoogle Scholar
  11. 11.
    Fonnum F, Soreide A, Kvale I, Walker J, Walaas I (1981) Glutamate in corticofugal fibres, In: Di Chiara G, Gessa GL (eds) Glutamate as a neurotransmitter. Advances in biochemical psychopharmacology, vol 27. Raven, New York, pp 29–41Google Scholar
  12. 12.
    Foster AC, Fagg GE (1987) Taking apart NMDA receptors. Nature 329:395–396PubMedCrossRefGoogle Scholar
  13. 13.
    France CP, Woods JH, Ornstein P (1989) The competitive N-methyl-D-aspartate (NMDA) antagonist CGS 19755 attenuated the rate-decreasing effects of NMDA in rhesus monkeys without producing ketamine-like discriminative stimulus effects. Eur J Pharmacol 159:113–139CrossRefGoogle Scholar
  14. 14.
    Globus MY-T, Busto R, Dietrich WD, Martinez E, Valdés I, Ginsberg MD (1988) Effect of ischemia on the in vivo release of striatal dopamine, glutamate and y-aminobutyric acid studied by intracerebral microdialysis. J Neurochem 51:1455–1464PubMedCrossRefGoogle Scholar
  15. 15.
    Gotoh F, Fukuuchi Y, Amaon T, Tanaka K, Kawamura J, Yamawaki T, Obara K, Ito N, Muramatsu K, Takahashi K (1989) Effects of tissue plasminogen activator on microcirculation and size of infarction following MCA occlusion in cat. J Cereb Blood Flow Metab 9:9Google Scholar
  16. 16.
    Graham SG, Shiraishi K, Panter SS, Simon RP, Faden AI (1990) Changes in extracellular amino acid neurotransmitters produced by focal cerebral ischemia. Neurosci Lett 110:124–130PubMedCrossRefGoogle Scholar
  17. 17.
    Greenamyre JT, Maragos WF, Albin RL, Penney JB, Young AB (1987) Glutamate transmission and toxicity in Alzheimer’s disease. Prog Neuro-psychopharmacol Biol Psychiat 12:421–430CrossRefGoogle Scholar
  18. 18.
    Greenamyre JT, Young AB, Penney JB (1984) Quantitative autoradiographic distribution of L-[3H]-glutamate-binding sites in rat central nervous system. J Neurosci 4:2133–2144PubMedGoogle Scholar
  19. 19.
    Horwitz B, Grady CL, Schlageter NL, Duara R, Rapoport SI (1987) Intercorrelations of regional cerebral glucose metabolic rates in Alzheimer’s disease. Brain Res 407:294–306PubMedCrossRefGoogle Scholar
  20. 20.
    Kemp JA, Foster AC, Wong EHF (1987) Non-competitive antagonists of excitatory amino acid receptors. TINS 10:294–298Google Scholar
  21. 21.
    Kemp JA, Foster AC, Leeson PD, Priestly T, Tridgett R, Iversen LL (1988) 7-Chlorokynurenic acid is a selective antagonist at the glycine modulatory site of the N-methyl-D-aspartate receptor complex. Proc Natl Acad Sci USA 85:6547–6550PubMedCrossRefGoogle Scholar
  22. 22.
    Koek W, Woods JH, Winger GD (1988) MK-801, a proposed noncompetitive antagonist of excitatory amino acid neurotransmission, produces phencyclidine-like behavioral effects in pigeons, rats and rhesus monkeys. J Pharmacol Exp Ther 245:969–974PubMedGoogle Scholar
  23. 23.
    Kurumaji A, McCulloch J (1989) Effects of MK-801 upon local cerebral glucose utilization in conscious rats and in rats anaesthetised with halothane. J Cereb Blood Flow Metab 9:786–794PubMedCrossRefGoogle Scholar
  24. 24.
    Lehmann J, Hutchison AJ, McPherson SE, Mondadori C, Schmutz M, Sinton CM, Tsai C, Murphy DE, Steel DJ, Williams M, Cheney DL, Wood PL (1988) CGS 19755, a selective and competitive N-methyl-D-aspartate-type excitatory amino acid receptor antagonist. J Pharmacol Exp Ther 246:65–75PubMedGoogle Scholar
  25. 25.
    MacDermott AB, Mayer ML, Westbrook GL, Smith SJ, Barker JL (1986) NMDA-receptor activation increases cytoplasmic calcium concentration in cultural spinal cord neurons. Nature 321:519–522PubMedCrossRefGoogle Scholar
  26. 26.
    MacKenzie ET, Gotti B, Nowicki J-P and Young AR (1984) Adrenergic blockers as cerebral antiischaemic agents, In: MacKenzie ET, Seylaz J, Bès A (eds) Neurotransmitters and the cerebral circulation, vol 2. Raven, New York, pp 219–243Google Scholar
  27. 27.
    Mann DMA (1988) Neuropathological and Neurochemical Aspects of Alzheimer’s disease, In: LL Iversen, SD Iversen, Snyder SH (eds) Handbook of psychopharmacology. Plenum, New York, pp 1–48CrossRefGoogle Scholar
  28. 28.
    Mattson MP (1990) Antigenic changes similar to those seen in neurofibrillary tangles are elicited by glutamate and Ca2+ influx in cultured hippocampal neurons. Neuron 2:105–117CrossRefGoogle Scholar
  29. 29.
    Meldrum B (1985) Possible therapeutic applications of antagonists of excitatory amino acid neurotransmitters. Clin Sci 68:113–122PubMedGoogle Scholar
  30. 30.
    Meldrum B (1990) Protection against ischaemic neuronal damage by drugs acting on excitatory neurotransmission. Cerebro Brain Metab Rev 2:27–57Google Scholar
  31. 31.
    Michaels RL, Rothman SM (1990) Glutamate neurotoxicity in vitro: antagonist pharmacology and intracellular calcium concentrations. J Neurosci 10:283–292PubMedGoogle Scholar
  32. 32.
    Morris RGM, Anderson E, Lynch G, Baudry M (1986) Selective impairment of learning and blockade of long term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5. Nature 319:774–776PubMedCrossRefGoogle Scholar
  33. 33.
    Nehls DG, Park CK, MacCormack AG, McCulloch J (1990) The effects of N-methyl-D-aspartate receptor blockade with MK-801 upon the relationship between cerebral blood flow and glucose utilisation. Brain Res 511:271–279PubMedCrossRefGoogle Scholar
  34. 34.
    Ozyurt E, Graham DI, Woodruff GN, McCulloch J (1988) Protective effect of the glutamate antagonist, MK-801 in focal cerebral ischemia in the cat. J Cereb Blood Flow Metab 8:138–143PubMedCrossRefGoogle Scholar
  35. 35.
    Park CK, Nehls DG, Graham DI, Teasdale GM, McCulloch J (1988) Focal cerebral ischaemia in the cat: treatment with the glutamate antagonist MK-801 after induction of ischaemia. J Cereb Blood Flow Metab 8:757–762PubMedCrossRefGoogle Scholar
  36. 36.
    Rothman SM, Olney JW (1986) Glutamate and the pathophysiology of hypoxic-ischemic brain damage. Ann Neurol 19:105–111PubMedCrossRefGoogle Scholar
  37. 37.
    Shank RP, Campbell G (1983) Glutamate, In: Lajtha A (ed) Handbook of neurochemistry, vol 3. Plenum, New York, pp 381–404Google Scholar
  38. 38.
    Simon RP, Swan JH, Griffiths T, Meldrum BS (1984) Blockade of N-Methyl-D-aspartate receptors may protect against ischaemic damage in the brain. Science 226:850–852PubMedCrossRefGoogle Scholar
  39. 39.
    Sugiyama H, Ito H, Hirono C (1987) A new type of glutamate receptor linked to inositol phospholipid metabolism. Nature 15:597–617Google Scholar
  40. 40.
    Watkins JC, Olverman HJ (1987) Agonists and antagonists for excitatory amino acid receptors. TINS 10:265–272Google Scholar
  41. 41.
    Weissman AD, Dam M, London ED (1987) Alterations in local cerebral glucose utilization induced by phencyclidine. Brain Res 435:29–40PubMedCrossRefGoogle Scholar
  42. 42.
    Wong EHF, Kemp JA, Priestly T, Knight AR, Woodruff GN, Iversen LL (1986) The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist. Proc Natl Acad Sci USA 83:7104–7108PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1991

Authors and Affiliations

  • D. Dewar
    • 1
  • R. Bullock
    • 1
  • D. T. Chalmers
    • 1
  • D. I. Graham
    • 1
  • J. McCulloch
    • 1
  1. 1.Wellcome Surgical Institute and Hugh Fraser Neuroscience LaboratoriesUniversity of GlasgowGlasgowUK

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