Excitotoxic profile of LY339434, a GluR5 agonist, in cultured murine cortical neurons

The neurotoxic profile of (2S,4R,6E)-2-amino-4-carboxy-7-(2-naphthyl)hept-6 -enoic acid (LY339434), a low-affinity kainate receptor subtype 5 (GluR5) a gonist at recombinant human glutamate receptors, was evaluated to investiga te the involvement of GluR5 in excitotoxic neuronal death. Murine cortical neurons were exposed to treatments for 24 h and assessed by a cell viabilit y assay and phase-contrast microscopy. LY339434 (1-1000 mu M) caused a conc entration-dependent decrease in cell viability (EC50 = 11.4+/-1.2 mu M) tha t was only attenuated by (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d ]cyclohepten-5, 10-imine (MK-801, 10 mu M), but not by 6-cyano-7-nitroquino xaline-2,3-dione (CNQX; 50 mu M) or 1-(4-aminophenyl)-4-methyl-7,8-methylen edioxy-5H-2,3-benzodiazepine (GYKI 52466, 20 mu M). Labeling with nucleic a cid binding dyes revealed that LY339434 induced few apoptotic-like characte ristics. These findings indicate that in cultured murine cortical neurons, LY339434 acts predominantly through N-methyl-D-aspartate (NMDA) receptors r ather than GluR5 to effect neuronal death that is rapid and involves predom inantly necrosis rather than morphological apoptosis. (C) 2000 Elsevier Sci ence B.V. All rights reserved.