Neurotoxicity of excitatory amino acid receptor agonists in young rat hippocampal slices.
Hippocampal slices from young (8-day-old) rats were evaluated as a model for investigating the mechanisms underlying the neurotoxic action of excitatory amino acid receptor agonists. The slices were exposed to the agonists for up to 30 min and were then postincubated for 90 min in order to allow irreversibly damaged cells to become visibly necrotic. Under control conditions (greater than or equal to 3 h incubation) all regions of the hippocampus and dentate gyrus displayed good preservation. Exposure of the slices to N-methyl-D-aspartate (NMDA) resulted in widespread, oedematous necrosis of all neuronal types (except undifferentiated granule cells) which was maximal after 20 min exposure to a concentration of 100 microM. With 30 min exposure, the EC50 for NMDA was 30 microM; 10 min exposure to NMDA at a concentration of 100 microM was sufficient to destroy 50% of the neurones. Quisqualate produced a degeneration of most (98%) of the CA3 neurones, a proportion (65%) of CA1 neurons and some (25%) of the dentate granule cells. The occurrence of "dark cell degeneration" was prevalent. Half maximal effects on CA3 neurones were estimated to be produced by a concentration of 15 microM (with 30 min exposure) or by 8 min exposure (at 100 microM concentration). Incubation of the slices with kainate (100 microM for 30 min) did not cause widespread damage but led to the necrosis of a small population of cells scattered in all regions of the hippocampus and dentate gyrus. The patterns of toxicity of the different agonists resemble closely those found after their administration in vivo. It is suggested that the hippocampal slices provide a valuable new model system for studying excitatory amino acid toxicity.
Garthwaite
G
G
Department of Physiology, University of Liverpool, U.K.
Garthwaite
J
J
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D005260:Female; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007608:Kainic Acid / Q000633:toxicity*; D008297:Male; D016202:N-Methylaspartate; D009498:Neurotoxins / Q000494:pharmacology*; D010069:Oxadiazoles / Q000633:toxicity*; D016318:Quisqualic Acid; D051381:Rats; D011919:Rats, Inbred Strains; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface / Q000187:drug effects*; D013997:Time Factors
D009498:Neurotoxins; D010069:Oxadiazoles; D017459:Receptors, Amino Acid; D011956:Receptors, Cell Surface; D001224:Aspartic Acid; D016202:N-Methylaspartate; D016318:Quisqualic Acid; D007608:Kainic Acid