Evaluation of drugs acting at glutamate transporters in organotypic hippocampal cultures: new evidence on substrates and blockers in excitotoxicity.

Removal of L-glutamate (Glu) from the synapse is critical to maintain normal transmission and to prevent excitotoxicity, and is performed exclusively by excitatory amino acid transporters (EAATs). We investigated the effects of substrates and blockers of EAATs on extracellular Glu and cellular viability in organotypic cultures of rat hippocampus. Seven-day treatment with a range of drugs (L-trans-pyrrolidine-2,4-dicarboxylate, (2S,4R)-4-methyl-glutamate, (+/-)-threo-3-methylglutamate and DL-threo-beta-benzyloxyaspartate), in the presence of 300 microM added Glu, resulted in increased extracellular Glu and a significant correlation between Glu concentration and cellular injury (as indicated by lactate dehydrogenase release).