Neurotransmitter Modulation of Neuronal Damage Following Cerebral Ischemia: Effects on Protein Ubiquitination

  • Kerstin Magnusson
  • Ingvar Gustafsson
  • Eva Westerberg
  • Tadeusz Wieloch
Part of the Advances in Behavioral Biology book series (ABBI, volume 35)

Summary

During recent years neurotransmitters and neuromodulators have been recognized as important extracellular modulators of ischemic and hypoglycemic brain damage. Several investigations have demonstrated protection against neuronal damage following global and focal ischemia, using antagonist against the N-methyl-d-aspartate (NMDA) receptor. However, we have not been able to demonstrate a decrease in neuronal damage in the rat following 10 min of bilateral common carotid artery occlusion combined with hypotension, when the animals were pre- or post-treated with the non-competitive NMDA antagonist MK-801. In contrast, using an alpha 2-adrenergic receptor antagonist, a significant decrease in ischemic damage was found following 10 min of ischemia. This demonstrates the importance of the noradrenergic locus coeruleus system as a protective system in the brain against ischemic neuronal damage. On the other hand, it is possible to decrease the hypoglycemic damage with MK-801 given prior to isoelectricity, corroborating our earlier findings of a glutamatergic influence on hypoglycemic brain damage.

We propose that an ischemic insult, severe enough to cause prolonged periods of membrane depolarization, induces changes in the membrane properties leading to cycling of calcium ions across the plasmamembrane, which cannot be blocked by noncompetitive NMDA receptor antagonist. This enhanced calcium entry can possibly be inhibited by stimulation of inhibitory protective systems such as the noradrenergic LC system. We envisage that the combination of glutamate and alpha-2 adrenergic antagonists could be potent therapies against neuronal damage following stroke and cardiac arrest.

An intracellular system severely affected by ischemia is the ubiquitin system, which participates in protein turnover and has been implicated as a factor that regulates turnover of cytoskeleton proteins and that participates in the mechanism of gene expression. In the hippocampus ubiquitin immunoreactivity (UIR) was found to disappear in regions of high calcium conductance early during recirculation following 15 min of ischemia. Over a subsequent 72 hour period the UIR returned to normal in areas not vulnerable to the ischemic insult. In the vulnerable areas UIR never recovered. We propose that impairment of protein ubiquitination may be an important factor in delayed neuronal death.

Keywords

Ischemia Neurol NMDA Catecholamine Hyperglycemia 

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Copyright information

© Plenum Press, New York 1988

Authors and Affiliations

  • Kerstin Magnusson
    • 1
  • Ingvar Gustafsson
    • 1
  • Eva Westerberg
    • 1
  • Tadeusz Wieloch
    • 1
  1. 1.Laboratory for Experimental Brain ResearchUniversity of Lund, Lund HospitalLundSweden

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