THE INHIBITION OF GLUTAMINE-SYNTHETASE IN RAT CORPUS STRIATUM INVITRO 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-mu-M), or N-methyl-D-aspartate (500-mu-M). 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-mu-M 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.