Excitotoxic mechanisms, and age-related susceptibility to brain damage in ischemia, hypoglycemia and toxic mussel poisoning.
Initial research by Olney, investigating the toxicity of glutamate as a food additive, demonstrated that irreversible (necrotic) changes could be produced in the CNS by glutamate. Subsequently, it became clear that the release of excitatory amino acids into the extracellular space of nervous tissue may play a role in CNS ischemia, and, later hypoglycemia. Experiments utilizing excitatory amino acid antagonists at the N-methyl-d-aspartate and other subtypes of excitatory receptor have shown neuronal protection, in both ischemia and hypoglycemia. The protection is robust enough to produce a detectable improvement in neurologic deficit on neurobehavioral testing, in addition to significantly reducing the number of necrotic cells in the brain. A third condition where excitotoxicity plays a role is toxic mussel poisoning. In contrast to ischemia and hypoglycemia, an excitotoxin which is exogenous to the brain plays a role. Domoic acid is contained in mussels which have filter-fed large quantities of domoate-rich phytoplankton, and when contaminated mussels are ingested in large quantities, serious and irreversible CNS effects, accompanied by necrosis, may result. In contrast to ischemia and hypoglycemia, however, damage is mediated at a different excitatory CNS receptor, namely the kainate receptor. In all three conditions, a constant aspect of the excitotoxic pathology is an increased susceptibility to excitotoxic damage with increasing age. This may be due to the dendritic location of excitatory receptors, and the richer branching of neuronal dendritic trees in aged animals, leading to enhanced susceptibility of the neuron to excitotoxic necrosis with age.
Department of Pathology, University of Calgary, Faculty of Medicine, Alberta.
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D000375:Aging / Q000502:physiology*; D000818:Animals; D049872:Bivalvia; D001925:Brain Damage, Chronic / Q000139:chemically induced*; D002545:Brain Ischemia / Q000139:chemically induced*; D004198:Disease Susceptibility; D005517:Foodborne Diseases / Q000503:physiopathology*; D005971:Glutamates / Q000506:poisoning / Q000633:toxicity*; D018698:Glutamic Acid; D007003:Hypoglycemia / Q000139:chemically induced; D009474:Neurons / Q000187:drug effects
D005971:Glutamates; D018698:Glutamic Acid