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) agonist at recombinant human glutamate receptors, was evaluated to investigate the involvement of GluR5 in excitotoxic neuronal death. Murine cortical neurons were exposed to treatments for 24 h and assessed by a cell viability assay and phase-contrast microscopy. LY339434 (1-1000 microM) caused a concentration-dependent decrease in cell viability (EC(50)=11.4+/-1.2 microM) that was only attenuated by (5R, 10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5, 10-imine (MK-801, 10 microM), but not by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX; 50 microM) or 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine (GYKI 52466, 20 microM). Labeling with nucleic acid binding dyes revealed that LY339434 induced few apoptotic-like characteristics. These findings indicate that in cultured murine cortical neurons, LY339434 acts predominantly through N-methyl-D-aspartate (NMDA) receptors rather than GluR5 to effect neuronal death that is rapid and involves predominantly necrosis rather than morphological apoptosis.
Moldrich
R X
RX
Department of Pharmacology, Monash University, Clayton, Australia.
Cheung
N S
NS
Pascoe
C J
CJ
Baker
S R
SR
Pedregal
C
C
Beart
P M
PM
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000596:Amino Acids / Q000633:toxicity*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001569:Benzodiazepines; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005971:Glutamates; D005977:Glutarates / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000737:chemistry / Q000166:cytology / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity; D018092:Kainic Acid Receptors / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D000596:Amino Acids; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; D016291:Dizocilpine Maleate; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D005971:Glutamates; D005977:Glutarates; D009498:Neurotoxins; D018092:Kainic Acid Receptors; D016194:Receptors, N-Methyl-D-Aspartate; C117450:2-amino-4-carboxy-7-(2-naphthyl)hept-6-enoic acid; C061950:GYKI 52466