Abstract: The present invention describes impaired glutamate uptake in glioma cells, and further shows that instead of removing glutamate from the extracellular fluid, glioma cells release large amounts of glutamate. The high levels of extracellular glutamate result in elevated [Ca2+]i followed by widespread neuronal death, which could be prevented by treating neurons with the NMDA receptor antagonists, MK-801 or D-AP5, or by depletion of glutamate from the medium. Significantly, several phenylglycine derivatives, including the metabotropic glutamate receptor agonist/antagonist (S)-4-carboxyphenylglycine (S-4CPG), potently and selectively inhibited glutamate release from glioma cells and thereby prevented neurotoxicity.

Abstract: Astrocytes protect neurons from excitotoxic injury by maintaining low extra-cellular glutamate concentrations ([Glu].sub.o). Compromised astrocytic glutamate uptake has been implicated in acute and chronic neurological conditions, including Parkinson's disease. This invention provides evidence that [Glu].sub.o is modulated in a feed-back manner through activation of metabotropic glutamate receptors (mGluRs), particularly group II mGluRs. Furthermore, ACPD effects were mimicked by glutamate, suggesting that astrocytic glutamate transport is dynamically regulated with mGluRs acting as sensors for changes in [Glu]. Consequently, agonists of mGluR receptors are potent drugs to modulate extracellular glutamate levels in ways that are neuroprotective.