Glutamate Neurotoxicity and Ischemic Neuronal Damage

  • Tadeusz Wieloch


The first observation of glutamate neurotoxicity was reported in 1957 when Lucas and Newhouse found that glutamate given intraperitoneally to newborn mice induced neurodegeneration in the retina. Later, in a similar experimental paradigm, Olney observed neuronal degeneration in the hypothalamus of infant mice brain, and found that glutamate causes extensive swelling of dendrites and while some axons are spared. Based on a series of additional observations, he formulated the excitotoxic hypothesis of cell damage, stating that glutamate causes a continuous depolarization of the plasma membrane by interacting with receptors on the vulnerable neurons. The depolarization causes energy exhaustion due to a disturbed ion homeostasis, and triggers adverse intracellular reactions causing cell damage. Two mechanisms have been proposed to explain glutamate neurotoxicity, both based on experiments performed on dissociated neurons in culture. One suggests that glutamate-induced membrane depolarization enhances sodium ion influx with accompanying chloride ions and water causing massive cellular swelling and acute osmolysis of the cells due to mechanical disruption. Chloride and sodium are essential for this acute glutamate neurotoxicity while calcium ions are not. Osmotic cytolysis was also observed when dissociated neuronal cultures were exposed to anoxia. The other mechanism favors the calcium ion as the decisive factor in glutamate-induced delayed neuronal death. Delayed neuronal necrosis of dissociated neurons in culture exposed to anoxia also requires calcium ions. However, the connection between glutamate and hypoxia dates back to the late 1950s, when van Harreveld discovered that glutamate could induce cortical spreading depression and cause dendritic swelling, similar to that observed during hypoxia. Later, in 1982 Jorgensen and coworkers proposed that the correlation between glutamate uptake sites and selective neuronal damage in the hippo-campus indicate that glutamate may be involved in selective neuronal damage to the hippocampus, and that glutamate antagonists may be cerebroprotective. Since these initial observations, a vast number of investigations on glutamate toxicity in ischemia have been published. Although many reports favor glutamate as a major pathogenetic factor in ischemia and support the notion that glutamate antagonists—notably NMDA antagonists—are cerebroprotective agents following ischemia and may be ready for clinical use, several recent investigations reached the opposite conclusion. This review discusses glutamate neurotoxicity in cerebral ischemia and its relation to the mechanisms of ischemic brain damage.


NMDA Receptor Middle Cerebral Artery Occlusion Excitatory Amino Acid Glutamate Uptake NMDA Antagonist 
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Copyright information

© Springer-Verlag Tokyo 1991

Authors and Affiliations

  • Tadeusz Wieloch
    • 1
  1. 1.Laboratory for Experimental Brain Research, Forskningsavd 4Lund University HospitalLundSweden

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