Early and Late Neuronal Damage Following Cerebral Ischemia

  • Takaaki Kirino
  • Akira Tamura
  • Keiji Sano
Part of the Advances in Behavioral Biology book series (ABBI, volume 35)


The hippocampus is one of the most vulnerable structures in the brain to ischemia. It is been widely believed that the hippocampus is most easily subject to neuronal death and “sclerosis” following only a brief period of ischemia of merely a few minutes. However, neurophysiologists have long been using the hippocampal slice method for their experiments. They know that their in vitro slice preparation of the hippocampus obtained mainly from rodent species is surprisingly normal and remains normal for many hours (Lynch, 1980). In this procedure, hippocampal tissue is unavoidably exposed to brief ischemia during preparation until it is cut into slices. The experience of neurophysiologists may, therefore, confirm that hippocampal neurons, if any, are only on rare occasions destroyed rapidly following brief ischemia. These seemingly contradictory observations may be resolved by the recognition of delayed neuronal death in the hippocampus. Most of the hippocampal CA1 neurons die following brief ischemia, but cell disintegration takes place very slowly (Kirino, 1982; Pulsinelli et al., 1982). It takes almost days until overt morphological signs of neuronal death appear. As the brain is subjected to longer ischemia, this neuronal cell alteration develops faster following recirculation (Kirino and Sano, 1984a). This general tendency of neuronal pathology is describled by Ito et al. and called “maturation phenomenon” (Ito et al., 1975). In the rodent hippocampus, delayed neuronal death is most commonly encountered in animals which survive longer than a few days following ischemia. On the other hand, ischemia which is long enough to cause widespread acute cell change in the hippocampus is usually incompatible with animal survival.


Purkinje Cell Neuronal Death Middle Cerebral Artery Occlusion Kainic Acid Ischemic Insult 


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  1. Arai, H., Passonneau, J.V. and Lust, W.D., 1986, Energy metabolism in delayed neuronal death of CA1 neurons of the hippocampus following transient ischemia in the gerbil., Metabol. Brain Dis., 1: 263–278.CrossRefGoogle Scholar
  2. Auer, R.N., Kalimo, H., Olsson, Y. and Siesjö B.K., 1985, The temporal evolution of hypoglycemic brain damage. I. Light-and electron-microscopic findings in the rat cerebral cortex., Acta Neuropath. (Berl.), 67: 13–25.Google Scholar
  3. Benveniste, H., Drejer, J., Schousboe, A. and Diemer, N.H., 1984, Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerehral microdialysis., J. Neurochem., 43: 1369–1374.CrossRefGoogle Scholar
  4. Brierley, J.B. and Graham, D.I., 1984, Hypoxia and vascular disorders of the central nervous system. in: Adams JH, Corsellis JAN, Duchen LW (eds) Greenfield’s Neuropathology. 4th edn, Eward Arnold, London, pp 125–207.Google Scholar
  5. Brown, A.W., Levy, D.E., Kublik, M., Harrow, J. and Plum, F., 1979, Selective chromatolysis of neurons in the gerbil brain: a possible consequence of ‘epleptic’ activity produced by common carotid artery occlusion., Ann. Neurol., 5: 127–138.CrossRefGoogle Scholar
  6. Cotman, C.W., Monaghan, D.T., Ottersen, O.P. and Storm-Mathisen, J, 1987, Anatomical organization of excitatory amino acid receptors and their pathways. Trend Neurosci., 10: 273–280.CrossRefGoogle Scholar
  7. Deshpande, J.K., Siesjó, B.K. and Wieloch T., 1987, Calcium accumulation and neuronal damage in the rat hippocampus following cerebral ischemia., J. Cereb. Blood Flow Metab., 7: 89–95.CrossRefGoogle Scholar
  8. Hagberg, H., Lehmann, A., Sandberg, M., Nystrom, B., Jacobson, I. and Hamberger, A., 1985, Ischemia-induced shift of inhibitory and excitatory amino acids from intra-to extracellular compartments., J. Cereb. Blood Flow Metab., 5: 413–419.CrossRefGoogle Scholar
  9. Hallmayer, J., Hossmann, K-A. and Mies, G., 1985, Low dose of barbiturates for prevention of hippocampal lesions after brief ischemic episodes., Acta Neuropath. (Berl.), 68: 27–31.Google Scholar
  10. Ito, U., Spatz, M., Walker, J.T. and Klatzo, I., 1975, Experimental cerebral ischemia in Mongolian gerbils. I. Light microscopic observations., Acta Neuropth. (Berl.), 32: 209–223.Google Scholar
  11. Johansen, F.F., Jorgensen, M.B. and Diemer, N.H., 1983, Resistance of hippocamal CA-1 interneurons to 20 min of transient cerebral ischemia in the rat., Acta Neuropath. (Berl.), 61: 135–140.Google Scholar
  12. Johansen, F.F., Jorgensen, M.B. and Diemer, N.H., 1986, Ischemic CA-1 pyramidal cell loss in prevented by preischemic colchicine destruction of dentate gyrus granule cells., Brain Res., 377: 344–347.CrossRefGoogle Scholar
  13. Kirino, T., 1982, Delayed neuronal death in the gerbil hippocampus following ischemia., Brain Res., 239: 57–69.CrossRefGoogle Scholar
  14. Kirino, T. and Sano, K., 1984a, Selective vulnerability in the gerbil hippocampus following transient ischemia., Acta Neuropath. (Berl.), 62: 201–208.Google Scholar
  15. Kirino, T. and Sano, K., 1984b, Fine structural nature of delayed neuronal death following ischemia in the gerbil hippocampus., Acta Neuro-path. (Berl.), 62: 209–218.Google Scholar
  16. Kirin, T., Tamura, A. and Sano, K., 1986a, A reversible type of neuronal injury following ischemia in the gerbil hippocampus., Stroke, 17: 455–459.CrossRefGoogle Scholar
  17. Kirino, T., Tamura, A., Tomukai, N. and Sano, K., 1986b, Treatable ischemic neuronal damage in the gerbil hippocampus (in Japanese)., Brain Nerve, 38: 1157–1163.Google Scholar
  18. Ljunggran, B., Schutz, H. and Siesjö, B.K., 1974, Changes in energy state and acid-base parameters of the rat brain during complete compression ischemia., Brain Res., 73: 277–289.CrossRefGoogle Scholar
  19. Lynch, G., 1980, The use of in vitro brain slices for multidisciplinary studies of synaptic function., Ann. Rev. Neurosci., 3: 1–22.CrossRefGoogle Scholar
  20. Monmaur, P., Thomson, M.A. and M’Harzi, M., 1986, Temporal changes in hippocampal theta activity following twenty minutes of forebrain ischemia in the chronic rat., Brain Res., 378: 262–273.CrossRefGoogle Scholar
  21. Nadler, J.V., Perry, B.W. and Cotman, C.W., 1978, Intraventricular kainic acid preferentially destroys hippocampal pyramidal cells., Nature, 271: 676–677.CrossRefGoogle Scholar
  22. Onodera, H., Sato, G. and Kogure, K., 1986, Lesions to schaffer col-laterals prevent ischemic death of CM pyramidal cells., Neurosci. Lett., 68: 169–174.Google Scholar
  23. Petito, C.K. and Pulsinelli, W.A., 1984, Delayed neuronal recovery and neuronal death in rat hippocampus following severe cerebral ischemia: Possible relationship to abnormalities in neuronal processes., rT. Cereb. Blood Flow Metab., 4: 194–205.CrossRefGoogle Scholar
  24. Pulsinelli, W.A., Brierley, J.B. and Plum, F., 1982, Temporal profile of neuronal damage in a model of transient forebrain ischemia., Ann. Neurol., 11: 491–498.CrossRefGoogle Scholar
  25. Pulsinelli, W.A. and Duffy, T.E., 1983, Regional energy balance in rat brain after transient forebrain ischemia., J. Neurochem., 40: 1500–1503.CrossRefGoogle Scholar
  26. Pulsinelli, W.A., 1985, Deafferentation of the hippocampus protects CA1 pyramidal neurons against ischemic injury., Stroke, 16: 144.Google Scholar
  27. 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 Metab., 7: 74–81.CrossRefGoogle Scholar
  28. Siesjö B.K., 1981, Cell damage in the brain: A speculative synthesis., J. Cereb. Blood Flow Metab., 1: 155–185.CrossRefGoogle Scholar
  29. Smith, M-L., Auer, R.N. and Siesjö, B.K., 1984, The density and distribution of ischemic brain injury in the rat following 2–10 min of forebrain ischemia., Acta Neuropathol. (Berl.), 64: 319–332.Google Scholar
  30. 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 cerebral cortex and CM sector of hippocampus., Acta Neuropath. (Berl.), 60: 217–222.Google Scholar
  31. Tamura, A., Graham, D.I., McCulloch, J. and Teasdale, G.M., 1981, Focal cerebral ischaemia in the rat: 1. Description of technique and early neuropathological consequences following middle cerebral artery occlusion., J. Cereb. Blood Flow Metab., 1:53–60.CrossRefGoogle Scholar
  32. Wieloch, T., Lindvall, O., Blomqvist, P. and Gage, F.H., 1985, Evidence for amelioration of ischaemic neuronal damage in the hippocampal formation by lesions of the perforant path., Neurol. Res., 7: 24–26.Google Scholar

Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Takaaki Kirino
    • 1
  • Akira Tamura
    • 1
  • Keiji Sano
    • 1
  1. 1.Department of NeurosurgeryTeikyo University School of MedicineItabashi-Ku, Tokyo 173Japan

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