Excitatory Amino Acid Neurotransmission and Protection Against Ischaemic Brain Damage

  • Brian Meldrum
  • Mary Evans
  • Jeanette Swan
Part of the Advances in Behavioral Biology book series (ABBI, volume 35)


Studies of the early cytological changes and the pattern of intracellular accumulation of calcium have suggested that the selective neuronal loss seen in the hippocampus after a transient period of cerebral ischaemia depends in part on excessive excitation occurring during the reperfusion period. In the rat occlusion of the common carotid artery for 10 min combined with arterial hypotension is followed by loss of the majority of CA1 pyramidal cells assessed after 7 days. The focal or systemic injection of 2-amino-7-phosphono-heptanoate, a selective antagonist at the N-methyl-D-aspartate receptor, prior to and at 4 and 10 h after the ischaemia gives partial protection against this cell loss. Non-competitive antagonists acting on the NMDA receptor (such as ketamine and MK 801) also prevent delayed cell loss. The adenosine agonist, 2-chloroadenosine, protects against cell loss when focally injected in the hippocampus.These data provide strong evidence that excitatory transmission at the NMDA receptor during the first 24 h of reperfusion contributes significantly to selective neuronal loss after ischaemia. A novel therapeutic approach to cerebral ischaemia is indicated.


NMDA Receptor Status Epilepticus Middle Cerebral Artery Occlusion Excitatory Amino Acid Burst Firing 
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. Boast, C. A., Gerhardt, S. C., and Janak, P., 1987, Systemic AP7 reduces ischaemic brain damage, in: “Excitatory Amino Acid Transmission,” T.P. Hicks, D. Lodge, & H. McLennan, ed., Alan R. Liss Inc., New York, pp. 245–248.Google Scholar
  2. Boast, C. A., Gerhardt, S. C., Pastor, G., Lehmann, J., Etienne, P. E., and Liebmann, J. M., 1988, The N-methyl-D-aspartate antagonists, CGS 19755, or CPP, reduce ischaemic brain damage in gerbils. Brain Res., (in press).Google Scholar
  3. Brierley, J. B., Brown, A. W., Excell, B. J., and Meldrum, B. S., 1969, Brain damage in the rhesus monkey resulting from profound arterial hypotension. I. Its nature, distribution and general physiological correlates, Brain Res., 13: 68–100CrossRefGoogle Scholar
  4. Brierley J. B., and Graham, D., 1984, Hypoxia and vascular disorders of the central nervous system, in: “Greenfield’s Neuropathology” 5th Edition, Edward Arnold, London, pp. 125–207.Google Scholar
  5. Choi, D. W., 1987, Ionic dependence of glutamate neurotoxicity, J. Neurosci. 7: 369–379Google Scholar
  6. Dolphin, A. C., and Archer E. R., 1983, An adenosine agonist inhibits and a cyclic AMP analogue enhances the release of glutamate but not GABA from slices of rat dentate gyrus, Neurosci. Lett. 43: 49–54.CrossRefGoogle Scholar
  7. Duverger, D., Benavides, J., Cudennec, A., MacKenzie, E. T., Scatton, B., Seylaz, J., and Verrechia, C., 1987, A glutamate antagonist reduces infarction size following cerebral ischaemia independently of vascular and metabolic changes. J. Cereb. Blood Flow Metab. 7: S144CrossRefGoogle Scholar
  8. Evans, M. C., Griffiths, T., and Meldrum, B. S., 1984, Kainic acid seizures and the reversibility of calcium loading in vulnerable neurons in the hippocampus, Neuropath Appl Neurobiol., 10: 285–302.CrossRefGoogle Scholar
  9. Evans, M. C., Swan J. H., and Meldrum, B. S., 1987, An adenosine analogue, 2-chloroadenosine, protects against long-term development of ischaemic cell loss in the rat hippocampus, Neurosci. Lett.Google Scholar
  10. Evans, M. C., Swan J. H., and Meldrum, B. S. 1988. Ischaemic brain damage in the rat. H. Mechanism of action of 2-amino-7- phosphonoheptanoic acid: effect on regional cerebral blood flow and the extent of diffusion focal injection. J. Cereb. Blood Flow Metab., submitted.Google Scholar
  11. Germano I. M., Pitts, L. H., Meldrum, B. S., Bartkowski, H. M., and Simon, R. P., 1987, Kynurenate inhibition of cell excitation decrease stroke size and deficits, Ann. Neurol., in press.Google Scholar
  12. Gill, R., Foster, A. C., and Woodruff, G. N., 1987, Systemic administration of MK801 protects against ischaemia-induced hippocampal damage in the gerbil, J. Neurosci., (in press).Google Scholar
  13. Griffiths, T., Evans, M. C., and Meldrum, B.S., 1983, Intracellular calcium accumulation in rat hipoocampus during seizures induced by bicuculline or L-allylglycine, Neuroscience, 10: 385–395.CrossRefGoogle Scholar
  14. Griffiths, T., Evans, M. C., and Meldrum, B.S., 1984, Status epilepticus: the reversibility of calcium loading and acute neuronal pathological changes in the rat hippocampus, Neuroscience, 12: 557–567.CrossRefGoogle Scholar
  15. Heinemann, U., Lux, H. D., and Gutnick, M., 1977, Extracellular free calcium and potassium during paroxysmal activity in the cerebral cortex of the cat. Exp. Brain Res., 27: 237–243.CrossRefGoogle Scholar
  16. Johansen, F. F., Jorgensen, M. B., and Diemer, N.H., 1986, Ischaemic CA1 pyramidal cell loss is prevented by preischaemic colchicine destruction of dentate gyrus granule cells, Brain Res., 377: 344–347.CrossRefGoogle Scholar
  17. Johansen, F. F., Jorgensen, M. B., and Diemer, N.H., 1987, Ischaemia induced delayed neuronal death in the CA-1 hippocampus is dependent on intact glutamatergic innervation, in: “Excitatory Amino Acid Transmission,” T. P. Hicks, D. Lodge, and H. McLennan, ed., Alan R. Liss Inc, New York, pp. 245–248.Google Scholar
  18. Jorgensen M. B., Johansen, F. F., and Diemer N. H., 1987, Removal of the entorhinal cortex protects hippocampal CA-1 neurons from ischaemic damage, Acta Neuropathol (Berl) 73: 189–194.CrossRefGoogle Scholar
  19. Kagstrom, E., Smith, M-L., and Siesjo, B. K., 1983, Recirculation in the brain following incomplete ischaemia in the rat, J. Cereb. Blood Flow Metab. 3: 183–192.CrossRefGoogle Scholar
  20. Lee, K. S., Schubert, P., and Heinemann, U., 1984, The anticonvulsive action of adenosine: a post-synaptic, dendritic action by a possible endogenous anticonvulsant, Brain Res., 321: 160–164.CrossRefGoogle Scholar
  21. Meldrum, B. S., 1981, Metabolic effects of prolonged epileptic seizures and the causation of epileptic brain damage, in: “Metabolic Disorders of the Nervous System,” F. C. Rose, ed., London, Pitman Medical, pp. 175–187.Google Scholar
  22. Meldrum, B. S., 1983, Metabolic factors during prolonged seizures and their relation to nerve cell death, in: “Advances in Neurology. Status Epilepticus: Mechanisms of Brain Damage and Treatment,” A.V. Delgado-Escueta, C.G. Wasterlain, D.M. Treiman, & R.J. Porter, ed., New York, Raven Press, Vol. 34, pp. 261–276.Google Scholar
  23. Meldrum, B., 1985, Possible therapeutic applications of antagonists of excitatory amino acid neurotransmitters, Clin. Sci., 68: 113–122.Google Scholar
  24. Meldrum, B.S. and Brierley, J. B., 1973, Prolonged epileptic seizures in primates: ischaemic cell change and its relation to ictal physiological events, Arch. Neurol., 28, 10–17.CrossRefGoogle Scholar
  25. Meldrum, B., Evans, M., Swan, J., and Simon, R. P., 1987, Protection against hypoxic/ischaemic brain damage with excitatory amino acid antagonists, Medical Biology, in press.Google Scholar
  26. Oyzurt, E., Graham, D.I., McCulloch, J., and Woodruff, G.N., 1987, The NMDA receptor antagonist MK-801 reduces focal ischaemic brain damage in the cat, J Cereb. Blood Flow Metab., 7: S146.Google Scholar
  27. Peet, M.J., Curry, K., Magnuson D.S.K.,and McLennan, H., 1987, Conformational requirements for activation of burst firing of rat CA1 hippocampal pyramidal neurones, in: “Excitatory Amino Acid Transmission,” T.P. Hicks, D. Lodge, & H. McLennan, ed., New York, Alan R.Liss Inc., pp. 35–42.Google Scholar
  28. Rothman, S. M., 1985, The neurotoxicity of excitatory amino acids is produced by passive chloride influx, J. Neurosci., 5: 1483–1489.Google Scholar
  29. Simon, R. P., Griffiths T., Evans, M. C., Swan, J. H.,and Meldrum, B. S., 1984, Calcium overload in the selectively vulnerable neurones of the hippocampus during and after ischaemia: an EM study in the rat, J. Cereb. Blood Flow Metab., 4: 350–361.CrossRefGoogle Scholar
  30. Suzuki, R., Yamaguchi, T., Li, C-H., Klatzo, I., 1983, The effects of 5 minute ischemia in mongolian gerbils: II Changes of spontaneous neuronal activity in cerebral cortex and CA1 sector hippocampus, Acta Neuropathol (Berl) 60: 217–222.CrossRefGoogle Scholar
  31. Swan, J. H., Evans, M. C., and Meldrum, B. S., 1988, Ischaemic brain damage in the rat. I. Long term development of selective neuronal loss in the rat hippocampus and protection by 2-amino-7phosphonoheptanoic acid, J. Cereb. Blood Flow Metab., submitted.Google Scholar
  32. Wieloch, T., Lindvall, O., Blomqvist, P., and Gage F. 1985, Evidence for amelioration of ischemic neuronal damage in the hippocampal formation by lesions of th perforant path. Neurol. Res., 7: 24–26.Google Scholar
  33. Wong, E. H. F., Kemp, J. A., Priestley, T., Knight, A. R., Woodruff, G. N., and Iversen, L.L., 1986, The anticonvulsant MK-801 is a potent N-methyl-D-aspartate antagonist, Proc. Natl. Acad. Sci., 83: 7104–7108.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Brian Meldrum
    • 1
  • Mary Evans
    • 1
  • Jeanette Swan
    • 1
  1. 1.Department of NeurologyInstitute of PsychiatryLondonUK

Personalised recommendations