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.