The inhibition of glutamine synthetase in rat corpus striatum in vitro by methionine sulfoximine increases the neurotoxic effects of kainate and N-methyl-D-aspartate.
Coronal slices of rat brain were incubated in Krebs bicarbonate medium containing kainate (300 microM), or N-methyl-D-aspartate (500 microM). Degeneration of striatal neurons by both these toxins was apparent after 40 min incubation, and was accompanied by a 33% (kainate) and 21% (N-methyl-D-aspartate) reduction in striatal glutamine synthetase activity. Pre-incubation of the slices with 500 microM L-methionine sulfoximine, an inhibitor of glutamine synthetase, for 20 min prior to the exposure to either kainate or N-methyl-D-aspartate, again showed extensive degeneration of striatal neurons, and a supra-additive reduction in glutamine synthetase activity in the tissue. The activity of the neuronal marker enzyme, neuron-specific enolase, was also reduced by pre-incubation of the slices with L-methionine sulfoximine before the addition of kainate or N-methyl-D-aspartate, but to a much lesser extent than glutamine synthetase. The results are discussed in terms of a possible mechanism of interaction between either kainate or N-methyl-D-aspartate, and glial cell metabolism.
Department of Biochemistry, Trinity College, Dublin, Ireland.
H
H
Kollegger
G J
GJ
McBean
K F
KF
Tipton
D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000201:enzymology; D003342:Corpus Striatum / Q000201:enzymology* / Q000473:pathology; D004357:Drug Synergism; D005260:Female; D005974:Glutamate-Ammonia Ligase / Q000037:antagonists & inhibitors*; D007608:Kainic Acid / Q000633:toxicity*; D008717:Methionine Sulfoximine / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000633:toxicity*; D009410:Nerve Degeneration / Q000187:drug effects; D009422:Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains
D008717:Methionine Sulfoximine; D016202:N-Methylaspartate; D010751:Phosphopyruvate Hydratase; D005974:Glutamate-Ammonia Ligase; D007608:Kainic Acid