Ischemia as an Excitotoxic Lesion: Protection Against Hippocampal Nerve Cell Loss by Denervation

  • N. H. Diemer
  • F. F. Johansen
  • H. Benveniste
  • T. Bruhn
  • M. Berg
  • E. Valente
  • M. B. Jørgensen
Part of the Acta Neurochirurgica book series (NEUROCHIRURGICA, volume 57)


There are several indications for an involvement of neuroexcitatory mechanisms in ischemic neuron damage. Since we forwarded the hypothesis in 1982 that the transmitter glutamate is playing a key role, several lines of evidence have substantiated this: there is a pronounced transmitter release induced by ischemia and there is uptake of Ca++ via NMDA-operated calcium channels. Under certain circumstances postischemic neuron death can be impaired by administration of either NMDA-antagonists or calcium blockers.

Further proof for the induction of harmful excitatory mechanisms by ischemia has been obtained by preischemic denervation of the vulnerable nerve cells. After transient cerebral ischemia in rats or gerbils, there are signs of irreversible damage (eosinophilia) of neurons in the dentate hilus (somatostatin-positive cells) after 2–3 hours and of hippocampal pyramidal neurons after 2–3 days (delayed neuron death). In the first case, removal of the (main) input to hilus cells by degranulation (colchicine selectively eliminates granule cells) protects these. In the case of pyramidal neurons removal of Schaffer collaterals/commisurals or input from the entorhinal cortex have a protective effect.

Recently, we have measured glutamate and calcium in CA1 of denervated rats during 10 min of ischemia, and it turns out that there is almost no extracellular glutamate release or lowering of calcium in contrast to ischemic animals with intact innervation.

Also in the postischemic period there are indications of a continuation of the damaging processes induced by ischemia. Besides the well known postischemic hypoperfusion, a prolonged release of glutamate has been reported, as well as burst firing in some models. If an immediately postischemic denervation of CA1 neurons is performed, there is a partly protection of these cells.

The GABA-ergic interneurons, which are lying among the pyramidal neurons in CA1 are always resistant to ischemia; receptor autoradiography indicates that they have glutamate receptors of the kainate/quisqualate type but no (or few) of the NMDA-type.


Ischemic neuronal damage excitotoxicity denervation NMDA-receptor 


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Copyright information

© Springer-Verlag 1993

Authors and Affiliations

  • N. H. Diemer
    • 1
  • F. F. Johansen
    • 1
  • H. Benveniste
    • 1
  • T. Bruhn
    • 1
  • M. Berg
    • 1
  • E. Valente
    • 1
  • M. B. Jørgensen
    • 1
  1. 1.Cerebral Ischemia Research Group and Pharmabiotec Research Center, Institute of NeuropathologyUniversity of CopenhagenDenmark

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