High extracellular glutamate and neuronal death in neurological disorders. Cause, contribution or consequence?

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 excitotoxicity, 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).