Neurotoxin domoic acid produces cytotoxicity via kainate- and AMPA-sensitive receptors in cultured cortical neurones.
Domoic acid, a naturally occurring kainoid, has been responsible for several outbreaks of fatal poisoning after shellfish ingestion, and we examined its neurotoxic mechanism in cultured murine cortical neurones. Using observations of neuronal viability and morphology, exposure to domoic acid for 24 h was found to induce substantial concentration-dependent neuronal cell death. Domoic acid-mediated neuronal death was attenuated by the non-N-methyl-D-aspartate receptor antagonist 6-cyano-7-nitro-quinoxaline-2,3-dione and the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor-selective antagonist LY293558 ((3S,4aR,6R,8aR)-6-[2-(1H-tetrazol-5-yl)-ethyl]-1,2,3, 4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid), but unaffected by NS-102 (5-nitro-6,7,8,9-tetrahydrobenzo[g]indole-2, 3-dione-3-oxime)--a low-affinity kainate receptor antagonist. Domoic acid was equipotent with (S)-AMPA (EC50 values 3.8 and 3.4 microM respectively); however, (S)-AMPA induced only 50% cell death compared to > 80% cell death induced by domoic acid. Kainate also killed > 80% of cortical neurones; however, domoic acid was about 19 times more potent than kainate (EC50 75 microM). We show the potent neurotoxicity of domoic acid for the first time in a pure neuronal model and indicate that domoic acid acts via high-affinity AMPA- and kainate-sensitive glutamate receptors to produce excitotoxic cell death.
Larm
J A
JA
Department of Pharmacology, Monash University, Clayton, Australia.
Beart
P M
PM
Cheung
N S
NS
D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005333:Fetus; D005625:Frontal Lobe / Q000166:cytology / Q000187:drug effects*; D007608:Kainic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D008387:Marine Toxins / Q000633:toxicity; D051379:Mice; D019579:Neocortex / Q000166:cytology / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D009498:Neurotoxins / Q000633:toxicity*; D018091:Receptors, AMPA / Q000187:drug effects*; D018092:Kainic Acid Receptors / Q000187:drug effects*; D013778:Tetrazolium Salts; D013844:Thiazoles
D007608:Kainic Acid; D008387:Marine Toxins; D009498:Neurotoxins; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue; C012301:domoic acid