Excitatory Amino Acid and Purinergic Transmitter Involvement in Ischemia-Induced Selective Neuronal Death

  • G. A. Block
  • W. A. Pulsinelli
Part of the Advances in Behavioral Biology book series (ABBI, volume 35)


We have examined the effects of noncompetitive N-methyl-D-aspartate receptor antagonists (MK-801; LY154045), kainate/quisqualate receptor antagonists (glutamyltaurine; γ-aminomethylsulphonic acid), and adenosine A1 receptor agonists on selective nerve cell death in an unanesthetized rat model of transient forebrain ischemia. The N-methyl-D-aspartate, kainate, and quisqualate receptor antagonists, either singly or in combination, failed to attenuate striatal or hippocampal damage. In contrast, the adenosine A1 receptor agonist, R-phenylisopropyladenosine, and the A1 and A2 receptor agonist, N-ethylcarboxamidoadenosine, significantly (p< 0.01) reduced CA1 pyramidal cell death in hippocampus. Excitatory amino acid neurotransmitter-mediated excitation appears not to play a major role in the pathogenesis of selective neuronal damage in this rat model. The ability of adenosine receptor agonists to attenuate hippocampal neuronal damage must be mediated via mechanisms other than inhibition of excitatory amino acid release. These results indicate that abnormalities of adenosinergic transmission are an important factor in ischemic injury to CA1 hippocampal pyramidal neurons.


Excitatory Amino Acid Ischemic Damage Transient Forebrain Ischemia Adenosine Receptor Agonist Vulnerable Neuron 
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. Benveniste, H., Drejer, J., Schousboe, A., and Diemer, N.H., 1984, Elevation of extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis, J. Neurochem., 43: 1369.CrossRefGoogle Scholar
  2. Block, G.A., and Pulsinelli, W.A., 1987, N-methyl-D-aspartate antagonists: Failure to prevent ischemia-induced selective nerve cell death, in: “Cerebrovascular Diseases,” M.E. Raichle and W.J. Powers, eds., Raven Press, New York.Google Scholar
  3. Braas, K.M., Newby, A.C., Wilson, V.C., and Snyder, S.H., 1986, Adenosine-containing neurons in the brain localized by immunocytochemistry, J. Neurosci., 6: 1952.Google Scholar
  4. Cooper, D.M.F., Londos, C., and Rodbell, M., 1980, Adenosine receptor-mediated inhibition of rat cerebral cortical adenylate cyclase by a GTP dependent process, Mol. Pharmacol., 19: 598.Google Scholar
  5. Coyle, J.T., 1983, Neurotoxic action of kainic acid, J. Neurochem., 41: 1.CrossRefGoogle Scholar
  6. Francis, A., and Pulsinelli, W.A., 1982, Response of GABAergic and cholinergic neurons to transient forebrain ischemia, Brain Res., 243: 271.CrossRefGoogle Scholar
  7. Hagberg, H., Andersson, J., Lacarewicz, I., Butcher, S., and Sandberg, M. 1987, Extracellular adenosine, inosine, hypoxanthine, and xanthine in relation to tissue nucleotides and purines in rat striatum during transient ischemia, J. Neurochem., 9: 227.CrossRefGoogle Scholar
  8. Harms, H.H., Nardeh, G., and Mulder, A.H., 1979, Effects of adenosine on depolarization-induced release of various radiolabelled neurotransmitters from slices of rat corpus striatum, Neuropharm., 18: 577.CrossRefGoogle Scholar
  9. Harreveld, A.V., and Fifkova, E., 1971, Light-and electron microscopic changes in central nervous tissue after electrophoretic injection of glutamate, Exp. Mol. Pathol., 15: 61.CrossRefGoogle Scholar
  10. Jorgensen, M.B., and Diemer, N.H., 1982, Selective neuron loss after cerebral ischemia in the rat: possible role of transmitter glutamate, J. Neurochem., 66: 536.Google Scholar
  11. Kemp, J.A., Priestley, T., Gill, R., and Foster, A.C., 1986, MK-801 is a potent and selective N-methyl-D-aspartate (NMDA) antagonist which following peripheral administration, prevents NMDA-induced neuronal degeneration, in: “Pharmacology of Cerebral Ischemia,” J. Krielstein, ed., Elsevier, Amsterdam.Google Scholar
  12. Kirino, T., 1982, Delayed neuronal death in the gerbil hippocampus following ischemia, Brain Res., 237: 57.CrossRefGoogle Scholar
  13. Leander, J.D., Ornstein, P.L., and Zimmerman, D.M., 1987, Antagonism of NMDAinduced lethality and behavioral effects of phencyclidine-like drugs, in: “Excitatory Amino Acid Transmission,” T.P. Hicks, D. Lodge, and H. McLennan, eds., Alan R. Liss, New York.Google Scholar
  14. Lee, K.S., Schubert, P., Reddington, M., and Kreutzberg, G.W., 1986a, The distribution of adenosine Al receptors and 5’-nucleotidase in the hippocampal formation of several mammalian species, J. Comp. Neurol., 246: 427.CrossRefGoogle Scholar
  15. Lee, K.S., Tetzlaff, W., and Kreutzberg, G.W., 1986b, Rapid down regulation of hippocampal adenosine receptors following brief anoxia, Brain Res., 380: 155.CrossRefGoogle Scholar
  16. 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., Pitman, London.Google Scholar
  17. Murphy, K.M., and Snyder, S., 1982, Heterogeneity of adenosine Al receptor binding in brain tissue, Mol. Pharmacol., 22: 250.Google Scholar
  18. Onodera, H., Iijima, K., and Kogure, K., 1986, Mononucleotide metabolism in the rat brain after transient ischemia, J. Neurochem., 46: 1704.CrossRefGoogle Scholar
  19. Pulsinelli, W.A., Brierley, J.B., and Plum, F., 1982a, Temporal profile of neuronal damage in a model of transient forebrain ischemia, Ann. Neurol., 11: 491.CrossRefGoogle Scholar
  20. Pulsinelli, W.A., Levy, D., and Duffy, T.E., 1982b, Regional cerebral blood flow and glucose metabolism following transient forebrain ischemia, Ann. Neurol., 11: 499.CrossRefGoogle Scholar
  21. Rudolphi, K.A., Keil, M., and Hinze, H.-J., 1987, Effect of theophylline on ischemically induced hippocampal damage in Mongolian gerbils: A behavioral and histopathological study, J. Cereb. Blood Flow Metal., 7: 74.CrossRefGoogle Scholar
  22. Simon, R.P., Swan, J.H., Griffiths, T., and Meldrum, B.S., 1984, Blockade of Nmethyl-D-aspartate receptors may protect against ischemic damage in the brain, Science, 226: 850.CrossRefGoogle Scholar
  23. Snell, L.D., and Johnson, K.M., 1986, Characterization of the inhibition of excitatory amino acid-induced neurotransmitter release in the rat striatum by phencyclidine-like drugs, J. Pharm. Exp. Ther., 238: 938.Google Scholar
  24. Snyder, S.H., Katims, J.J., Annau, Z., Bruns, R.F. and Daly, J.W., 1981. Adenosine receptors and behavioral actions of methylxanthines, Proc. Natl. Acad. Sci. USA, 78: 3260.CrossRefGoogle Scholar
  25. Spielmeyer, W., 1922, “Histopathologie des Nervensystems,” Springer, Berlin.Google Scholar
  26. Suzuki, R., Yamaguchi, T., Li, C.-L., and Klatzo, I., 1983, The effects of 5 minute ischemia in Mongolian gerbils. II. Changes of spontaneous neuronal activity in the cerebral cortex and CAl sector of the hippocampus, Acta Neuropathol., 60: 217.CrossRefGoogle Scholar
  27. Wieloch, T., Koide, T., and Westerberg, E., 1986, Inhibitory neurotransmitters and neuromodulators as protective agents against ischemic brain damage, in: “Pharmacology of Cerebral Ischemia,” J. Krielstein, ed., Elsevier, Amsterdam.Google Scholar
  28. Wojcik, W.J., and Neff, N.H., 1983, Differential location of adenosine Al and A2 receptors in striatum, Neurosci. Letts., 41: 55.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • G. A. Block
    • 1
  • W. A. Pulsinelli
    • 1
  1. 1.Department of NeurologyCornell University Medical CollegeNew YorkUSA

Personalised recommendations