Regional differences in glutamine synthetase inhibition by L-methionine sulfoximine: a microdialysis study in the rabbit brain.

Elevated levels of glutamate, an endogenous excitatory amino acid, contribute to the development of neuronal injury in various cerebral diseases. Using a microdialysis approach, the response of extracellular levels of amino acids and metabolic parameters to glutamine synthetase inhibition by l-methionine sulfoximine was monitored simultaneously in the hippocampal formation and in the frontal cortex of the rabbit brain. In the hippocampal formation the decrease of glutamine levels during l-methionine sulfoximine treatment was more pronounced than in the frontal cortex, and was accompanied by a delayed decline of extracellular glutamate concentrations. Furthermore, l-methionine sulfoximine diminished the increase of lactate and pyruvate concentrations in the hippocampal formation, but not in the frontal cortex. Neither l-methionine sulfoximine treatment nor microdialysis probe insertion caused neuronal apoptosis, as measured by in situ tailing. An impaired function of hippocampal astrocyte glutamate uptake mechanisms or a higher functional capacity of the cortical glutamine synthetase may be possible explanations for the differences demonstrated. The present data are in accordance with regional differences in glutamine synthetase activation during bacterial meningitis and may explain, in part, the higher susceptibility of certain areas of the hippocampal formation (i.e., the dentate gyrus) to neuronal injury.