Inhibition of the glutamate transporter and glial enzymes in rat striatum by the gliotoxin, alpha aminoadipate.

G J McBean

Index: Br. J. Pharmacol. 113 , 536-540, (1994)

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Abstract

1. The effect of the gliotoxic analogue of glutamate, alpha aminoadipate, on the high affinity transport of D-[3H]-aspartate into a crude striatal P2 preparation, and on the activity of two enzymes of which glutamate is the substrate has been examined. 2. The L-isomer of alpha aminoadipate competitively inhibited the transport protein, with a Ki value of 192 microM, whereas the D-isomer of alpha aminoadipate was ineffective. The potent convulsant, L-methionine-S-sulphoximine, was also without effect on the activity of the glutamate transport protein. 3. L-alpha Aminoadipate was a competitive inhibitor of both glutamine synthetase, and gamma-glutamylcysteine synthetase, with Ki values of 209 microM and 7 mM respectively. Once again, the D-isomer of alpha aminoadipate was a far weaker inhibitor of either enzyme. 4. The results are discussed in terms of the mechanism of action of alpha aminoadipate in causing toxicity of glial cells.