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High Extracellular Glutamate and Neuronal Death in Neurological Disorders: Cause, Contribution or Consequence?
Author(s) -
OBRENOVITCH TIHOMIR P.
Publication year - 1999
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.1999.tb08004.x
Subject(s) - excitotoxicity , glutamate receptor , neurotoxicity , extracellular , neuroscience , nmda receptor , endogeny , biology , neuroprotection , depolarization , chemistry , pharmacology , microbiology and biotechnology , receptor , biochemistry , biophysics , toxicity , organic chemistry
In models of neurological disorders, increased extracellular glutamate and beneficial effects produced by glutamate‐receptor antagonists are consistently taken as supporting evidence of excitotoxicity. This systematic interpretation is over‐simplified and potentially misleading. High extracellular glutamate is not a reliable indicator of endogenous excitotoxixity, i.e., the intrinsic, potential neurotoxicity of endogenous glutamate whenever it accumulates extracellularly. Firstly, because the extracellular levels of glutamate necessary to produce depolarization and death in vivo , are far above those measured in models of neurological disorders. Secondly, because changes in the concentration of glutamate in the synaptic cleft (i.e., the relevant compartment for endogenous excitotoxicity) are not reflected extracellularly. Protection by glutamate‐receptor antagonists does not necessarily imply inhibition of excitotoxic abnormalities. Indeed, neuronal death initiated by insults such as ischemia results from multifactorial processes that may be interrelated. Therefore, beneficial effects resulting from an interaction with glutamate‐mediated transmission may actually render the cell more resistant to other deleterious mechanisms (e.g., mitochondrial injury, oxidative stress).