(S)-5-fluorowillardiine-mediated neurotoxicity in cultured murine cortical neurones occurs via AMPA and kainate receptors.
We have examined the neurotoxic effects of kainate, (S)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) and the novel AMPA-receptor preferring agonist (S)-5-fluorowillardiine in murine cultured cortical neurones. Kainate induced > 90% cell death (EC50 65 microM) and (S)-AMPA only about 50% cell death (EC50 3.1 microM), both in a monophasic dose-dependent manner. (S)-5-Fluorowillardiine also killed > 90% of neurones, however, in a biphasic dose-dependent manner (EC50 0.70 and 170 microM). Additionally, the neurotoxic effects of (S)-AMPA and (S)-5-fluorowillardiine (high-affinity component) were attenuated by the AMPA receptor antagonists LY293558 ((3,S,4aR, 6R,8aR)-6[2h91 H-tetrazol-5-yl)ethyl]-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinol ine- 3-carboxylic acid). A component of kainate and (S)-5-fluorowillardiine (low-affinity component) neurotoxicity was blocked by the low-affinity kainate receptor antagonist NS-102 (5-nitro-6,7,8,9-tetrahydrobenzo[g]indole-2,3-dione-3-oxime). We have shown that both kainate and (S)-AMPA can effect substantial cell death in cortical neurones and that the novel agonist (S)-5-fluorowillardiine exerts its excitotoxicity through both AMPA- and kainate-preferring receptors.
Larm
J A
JA
Department of Pharmacology, Monash University, Clayton, Australia.
Cheung
N S
NS
Beart
P M
PM
D000409:Alanine / Q000031:analogs & derivatives* / Q000633:toxicity; D000818:Animals; D002478:Cells, Cultured; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity*; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D011743:Pyrimidines / Q000633:toxicity*; D018092:Kainic Acid Receptors / Q000187:drug effects*; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity*
D000409:Alanine; D018690:Excitatory Amino Acid Agonists; D011743:Pyrimidines; D018092:Kainic Acid Receptors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; C095178:5-fluorowillardiine