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The effects of acetoacetate and 3-hydroxybutyrate on glial amino acid metabolism were studied in primary cultures of astrocytes. The exchange of nitrogen among amino acids was measured with 15N as a metabolic probe and gas chromatography-mass spectrometry as a tool with which to quantify isotope abundance. Addition of either acetoacetate or 3-hydroxybutyrate (5 mM) to the incubation medium did not alter the initial rate of appearance of 15Nglutamate in the glia, but it did inhibit transamination of glutamate to 15Naspartate. Addition of acetoacetate also inhibited formation of 2-(15)Nglutamine, but 3-hydroxybutyrate had a stimulatory effect. The presence in the medium of sodium acetate (5 mM) was also associated with diminished production of 15Naspartate and 2-(15)Nglutamine with 15Nglutamate as precursor. Studies with 2-(15)Nglutamine as precursor indicated that treatment of the astrocytes with ketone bodies did not alter flux through the glutaminase pathway. Nor did the presence of the ketone bodies reduce significantly the flux of nitrogen from 15NGABA to 2-(15)Nglutamine when the former species served as a metabolic tracer. The concentration of internal citrate increased in the presence of acetoacetate, 3-hydroxybutyrate, and acetate. Studies with purified sheep brain glutamine synthetase showed that citrate inhibited this enzyme. These findings are considered in terms of the known anticonvulsant effect of a ketogenic diet.
Yudkoff et al. (Fri,) studied this question.