Glutamate‐Mediated Injury in Focal Cerebral Ischemia: The Excitotoxin Hypothesis Revised

Glutamate‐Mediated Injury in Focal Cerebral Ischemia: The Excitotoxin Hypothesis Revised Neuronal injury following focal cerebral ischemia is widely attributed to the excitotoxic effects of gluta‐mate. However, critical analysis of published data on glutamate toxicity in vitro and the comparison of these data with in vivo release of glutamate and the therapeutic effect of glutamate antagonists raises doubts about a neurtoxic mechamism. An alternative explanation for glutamate‐mediated injury is hypoxia due to peri‐infarct spreading depression‐like depolarizations. These depolarizations are triggered in the core of the ischemic infarct and spread at irregular intervals into the peri‐infarct surrounding. In ischemically uncompromised tissue, the metabolic workload associated with spreading depression is coupled to an increase in blood flow and oxygen supply, assuring maintenance of oxidative respiration. In the penumbra region of focal ischemia, the hemodynamic constraints of collateral blood circulation prevail the adequate adjustment of oxygen delivery, leading to transient episodes of relative tissue hypoxia. The hypoxic episodes cause a suppression of protein synthesis, a gradual deterioration of energy metabolism and a progression of irreversibly damaged tissue into the penumbra zone. The generation of peri‐infarct spreading depressions and the associated metabolic workload can be suppressed by NMDA and non‐NMDA antagonists. As a result, the penumbral inhibition of protein synthesis and the progressing energy failure is also prevented, and the volume of ischemic infarct decreases. Interventions to improve ischemic resistance should therefore aim at improving the oxygen supply or reducing the metabolic workload in the penumbra region. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Brain Pathology Wiley

Glutamate‐Mediated Injury in Focal Cerebral Ischemia: The Excitotoxin Hypothesis Revised

Brain Pathology, Volume 4 (1) – Jan 1, 1994

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Publisher
Wiley
Copyright
Copyright © 1994 Wiley Subscription Services, Inc., A Wiley Company
ISSN
1015-6305
eISSN
1750-3639
D.O.I.
10.1111/j.1750-3639.1994.tb00808.x
Publisher site
See Article on Publisher Site

Abstract

Neuronal injury following focal cerebral ischemia is widely attributed to the excitotoxic effects of gluta‐mate. However, critical analysis of published data on glutamate toxicity in vitro and the comparison of these data with in vivo release of glutamate and the therapeutic effect of glutamate antagonists raises doubts about a neurtoxic mechamism. An alternative explanation for glutamate‐mediated injury is hypoxia due to peri‐infarct spreading depression‐like depolarizations. These depolarizations are triggered in the core of the ischemic infarct and spread at irregular intervals into the peri‐infarct surrounding. In ischemically uncompromised tissue, the metabolic workload associated with spreading depression is coupled to an increase in blood flow and oxygen supply, assuring maintenance of oxidative respiration. In the penumbra region of focal ischemia, the hemodynamic constraints of collateral blood circulation prevail the adequate adjustment of oxygen delivery, leading to transient episodes of relative tissue hypoxia. The hypoxic episodes cause a suppression of protein synthesis, a gradual deterioration of energy metabolism and a progression of irreversibly damaged tissue into the penumbra zone. The generation of peri‐infarct spreading depressions and the associated metabolic workload can be suppressed by NMDA and non‐NMDA antagonists. As a result, the penumbral inhibition of protein synthesis and the progressing energy failure is also prevented, and the volume of ischemic infarct decreases. Interventions to improve ischemic resistance should therefore aim at improving the oxygen supply or reducing the metabolic workload in the penumbra region.

Journal

Brain PathologyWiley

Published: Jan 1, 1994

References

  • Excitotoxic cell death
    Choi, Choi
  • Excitatory amino acid antagonists and their potential for the treatment of ischaemic brain damage in man
    McCulloch, McCulloch
  • Glutamate and the pathophysiology of hypoxic‐ischemic brain damage
    Rothman, Rothman; Olney, Olney
  • The glutamate antagonist MK‐801 reduces focal ischemic brain damage in the rat
    Park, Park; Nehls, Nehls; Graham, Graham; Teasdale, Teasdale; McCulloch, McCulloch
  • The neuroprotective action of dizocilpine (MK‐801) in the rat middle cerebral artery occlusion model of focal ischaemia
    Gill, Gill; Brazell, Brazell; Woodruff, Woodruff; Kemp, Kemp
  • Kynurenate inhibition of cell excitation decreases stroke size and deficits
    Germano, Germano; Bartowsky, Bartowsky; Cassel, Cassel; Pitts, Pitts
  • Evaluation of a competitive NMDA antagonist (D‐CPPene) in feline focal cerebral ischemia
    Chen, Chen; Bullock, Bullock; Graham, Graham; Frey, Frey; Lowe, Lowe; McCulloch, McCulloch

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