Cell culture studies of the role of elevated extracellular glutamate and K+ in neuronal cell death during and after anoxia/ischemia.

During vascular insults in the brain (stroke) the extracellular concentrations of glutamate and K+ increase. It is well acknowledged that the increase in glutamate contributes to the death of neuronal cells at an earlier time than they would have succumbed to energy deprivation as such, but the origin of the released glutamate is not known and cannot easily be studied in the brain in vivo. We have therefore resorted to cell culture studies which have shown that the neuronal rate of formation of glutamate from glutamine is substantially increased during anoxia, especially in glutamatergic neurons. This increase is further enhanced in the presence of excess K+. Phenylsuccinate, a compound that decreases formation of glutamate from glutamine in glutamatergic neurons, counteracts the increase in glutamate formation and, by doing so, improves cell survival. Astrocytes (glial cells) in neuronal-astrocytic co-cultures to some extent protect against anoxic neuronal damage by accumulating glutamate and thus keeping the extracellular glutamate concentration lower than in isolated neuronal cultures.