Endogenous Excitotoxins as Possible Mediators of Ischemic and Hypoglycemic Brain Damage

  • T. Wieloch
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 203)


Hypoglycemia and cerebral ischemia are conditions associated with a vast number of complicated clinical situations (Marks, 1972; Graham, 1985). If severe, both hypoglycemia and cerebral ischemia inevitably lead to irreversible neuronal damage (Brierley, 1976). Similarly as in epilepsy, the damage incurred following hypoglycemia and ischemia is distributed to specific vulnerable areas of the brain. However, the distribution of the damage differs between these three conditions (Siesjö and Wieloch, 1986), suggesting that at least in some aspects different pathophysiological mechanisms prevail. Although this selective neuronal damage has been known for several decades (Spielmeyer, 1925), its pathophysiological and molecular mechanisms are largely elusive.


Cerebral Ischemia Dentate Gyrus Neuronal Damage Excitatory Amino Acid Brain Damage 
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. Auer, R.N., Wieloch, T., Olsson, Y., and Siesjö, B.K., 1984a, The distribution of hypoglycemic brain damage, Acta Neuropathol.,64:177.Google Scholar
  2. Auer, R.N., Olsson, Y., and Siesjö, B.K., 1984b, Hypoglycemic brain injury in the rat, Diabetes, 33: 1090.Google Scholar
  3. Auer, R., Kalimo, H., Olsson, Y., and Wieloch, T., 1985, The dentate gyrus in hypoglycemia: pathology implicating excitotoxin-mediated neuronal necrosis, Acta Neuropathol., 67: 279.Google Scholar
  4. 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 intracerebral microdialysis, J. Neurochem., 43:1369.Google Scholar
  5. Blomqvist, P., Lindvall, 0., and Wieloch, T., 1985, Lesions of the locus coeruleus system aggravate ischemic damage in the rat brain, Neurosci. Lett., 58: 353.Google Scholar
  6. Blomqvist, P., and Wieloch, T., 1985, Ischemic brain damage in rats following cardiac arrest using a long-term recovery model, J. Cereb. Blood Flow Metabol., 5:420.Google Scholar
  7. Bodsch, W., Takahashi, K., Barbier, A., Grosse Ophoff, B., and Hossmann, K.-A., 1985, Cerebral protein synthesis and ischemia, Prog. Brain Res., 63:197.Google Scholar
  8. Brierley, J.B., 1976, Cerebral hypoxia, in: Greenfield’s Neuropathology 3rd Edition, W. Blackwood and J.A.N. Corsellis, eds., Edward Arnold Publishers, Ltd., London, p. 43.Google Scholar
  9. Chin, J.H., Buckholz, T.M., and DeLorenzo, R.J., 1985, Calmodulin and protein phosphorylation: implications in brain ischemia, Prog. Brain Res., Vol. 63, in press.Google Scholar
  10. Deshpande, J., and Wieloch, T., 1985, Amelioration of ischemic brain damage by postischemic treatment with flunarizine, Neurol. Res., 7:27.Google Scholar
  11. Fonnum, F., 1984, Glutamate: a neurotransmitter in mammalian brain, J. Neurochem., 42: 1.PubMedCrossRefGoogle Scholar
  12. Graham, D.I., 1985, The pathology of brain ischemia and possibilities for therapeutic intervention, Br. J. Anesth., 57:3.Google Scholar
  13. Harris, R.J., Wieloch, T., Symon, L., and Siesjö, B.K., 1984, Cerebral extracellular calcium activity in severe hypoglycemia: relation to extracellular potassium and energy state, J. Cereb. Blood Flow Metabol., 4:187.Google Scholar
  14. Kirino, T., 1982, Delayed neuronal death in the gerbil hippocampus following ischemia, Brain Res., 239: 57.Google Scholar
  15. Lewis, L.D., Ljunggren, B., Ratcheson, R.A., and Siesjö, B.K., 1974, Cerebral energy state in insulin-induced hypoglycemia, related to blood glucose and to EEG, J, Neurochem., 23:673.Google Scholar
  16. Marks, V., 1972, Spontaneous hypoglycemia, Br. Med. J., 1:430.Google Scholar
  17. Monaghan, D.T., Bolets, V.R., Toy, D.W., and Cotman, C.W., 1983, Anatomical distributions of four pharmacologically distinct 3H-L-glutamate binding sites, Nature, 306: 176.Google Scholar
  18. Olney, J., 1978, Neurotoxicity of excitatory amino acids, in: Kainic Acid as a Tool in Neurobiology, E.G. McGeer, J.W. Olney, and P.L. McGeer, eds., Raven Press, New York, p. 95.Google Scholar
  19. Pulsinelli, W.A., and Brierley, J.B., 1979, A new model of bilateral hemispheric ischemia in the unanesthetized rat, Stroke 10: 267.Google Scholar
  20. Rothman, S., 1984, Synaptic release of excitatory amino acid neurotransmitter mediates anoxic neuronal death, J. Neurosci., 4:1884.Google Scholar
  21. Rothman, S.M., 1985, The neurotoxicity of excitatory amino acids is produced by passive chloride influx, J. Neurosci., 5:1483.Google Scholar
  22. Schlapfer, W.W., and Zimmerman, U.-J.P., 1985, Mechanisms underlying the neuronal response to ischemic injury. Calcium-activated proteolysis of neurofilaments, Prog. Brain Res., Vol. 63, in press.Google Scholar
  23. Siesjö, B.K., and Agardh, C.-D., 1983, Hypoglycemia, in: Handbook of Neurochemistry, 2nd Edition, Vol. 3 Metabolism in the Nervous System, A. Lajtha, ed., Plenum Press, New York, p. 353.Google Scholar
  24. Siesjö, B.K., 1985, Acid-base homeostasis in the brain: physioloby, chemistry and neurochemical pathology, Prog. Brain Res., Vol. 63, in press.Google Scholar
  25. Siesjö, B.K., and Wieloch, T., 1985a, Brain injury: neurochemical aspects,in: Central Nervous System Trauma Status Report, D.P. Becker, J.T.Povlishock, eds., William Byrd Press, Inc., Richmond, p. 513.Google Scholar
  26. Siesjö, B.K., and Wieloch, T., 1985b, Cerebral metabolism in ischemia: neurochemical basis for therapy, Br. J. Anaesth., 57:47.Google Scholar
  27. Siesjö, B.K., and Wieloch, T., 1986, Epileptic brain damage, pathophysiology and neurochemical pathology, in: Basic Mechanisms of Epilepsies A.V. Delgado-Escueta and W. Ward, eds., Raven Press, New York, in press.Google Scholar
  28. Simon, R.P., Griffith, T., Evans, M.C., Swan, J.H., and Meldrum, B.S., 1984, Calcium overload in selectively vulnerable neurons of the hippo-campus during and after ischemia: an electron microscopy study in the rat, J. Cereb. Blood Flow Metabol., 4:350.Google Scholar
  29. Sloviter, R.S., and Damiano, B.P., 1981, Sustained electrical stimulation of the perforant path duplicates kainate-induced electrophysiological effects and hippocampal damage in rats, Neurosci. Lett., 24:279.Google Scholar
  30. Sloviter, R.S., and Dempster, D.W., 1985, ’Epileptic’ brain damage is replicated qualitatively in the rat hippocampus by central injection of glutamate or aspartate but not by GABA or acetylcholine, Brain Res Bull., 15:39.Google Scholar
  31. 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., 64: 319.Google Scholar
  32. Spielmeyer, W., 1925, Zur Pathogenese örtlich elektiver Gehirnveränderungen, Z. Ges. Neurol. Psvchiatr., 99:756.Google Scholar
  33. Tossman, U., Wieloch, T., and Ungerstedt, U., 1985, GABA and taurine release in the striatum of the rat during hypoglycemic coma, studied by micro-dialysis, Neurosci. Lett., 62:231.Google Scholar
  34. Wieloch, T., Harris, R., Symon, L., and Siesjö, B.K., 1984, Influence of severe hypoglycemia on brain extracellular calcium and potassiumactivities, energy charge, and phospholipid metabolism, J. Neurochem., 43:160.Google Scholar
  35. Wieloch, T., 1985a, Neurochemical correlates to selective neuronal vulnerability, Prog. Brain Res., 63:69.Google Scholar
  36. Wieloch, T., 1985b, Hypoglycemia-induced neuronal damage prevented by an N-methyl-d-aspartate antagonist, Science 230: 681.Google Scholar
  37. Wieloch, T., Auer, R.N., Westerberg, E., Tossman, U., Ungerstedt, U.,and Engelsen, B., 1985a, Hypoglycemic brain damage is mediated by excitotoxins, in: Excitatory Amino Acids P. Roberts, J. Storm-Mathisen,and H.F. Bradford, eds., MacMillan Press, London, in press.Google Scholar
  38. Wieloch, T., Engelsen, B., Westerberg, E., and Auer, R., 1985b, Lesions of the glutamatergic cortico-striatal projections in the rat ameliorate hypoglycemic brain damage in the striatum, Neurosci. Lett., 58:25 Google Scholar
  39. Wieloch, T., Lindvall, 0., Blomqvist, P., and Gage, F.H., 1985, Evidence for amelioration of ischemic neuronal damage in the hippocampal formation by lesions of the perforant path, Neurol. Res., 7:24.Google Scholar
  40. Wilkinson, D.S., and Prockop. L.D., 1976, Hypoglycemia effects on the central nervous system, in: Handbook of Clinical Neurology. Vol. 27 Elsevier North-Holland Publishing Company, Amsterdam, p. 53.Google Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • T. Wieloch
    • 1
  1. 1.Laboratory for Experimental Brain ResearchUniversity Hospital, University of LundLundSweden

Personalised recommendations