Inhibitors of the alpha-ketoglutarate dehydrogenase complex alter [1-13C]glucose and [U-13C]glutamate metabolism in cerebellar granule neurons.

Abstract

Diminished activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), an important component of the tricarboxylic acid (TCA) cycle, occurs in several neurological diseases. The effect of specific KGDHC inhibitors [phosphonoethyl ester of succinyl phosphonate (PESP) and the carboxy ethyl ester of succinyl phosphonate (CESP)] on [1-13C]glucose and [U-13C]glutamate metabolism in intact cerebellar granule neurons was investigated. Both inhibitors decreased formation of [4-13C]glutamate from [1-13C]glucose, a reduction in label in glutamate derived from [1-13C]glucose/[U-13C]glutamate through a second turn of the TCA cycle and a decline in the amounts of gamma-aminobutyric acid (GABA), aspartate, and alanine. PESP decreased formation of [U-13C]aspartate and total glutathione, whereas CESP decreased concentrations of valine and leucine. The findings are consistent with decreased KGDHC activity; increased alpha-ketoglutarate formation; increased transamination of alpha-ketoglutarate with valine, leucine, and GABA; and new equilibrium position of the aspartate aminotransferase reaction. Overall, the findings also suggest that some carbon derived from alpha-ketoglutarate may bypass the block in the TCA cycle at KGDHC by means of the GABA shunt and/or conversion of valine to succinate. The results suggest the potential of succinyl phosphonate esters for modeling the biochemical and pathophysiological consequences of reduced KGDHC activity in brain diseases.

• Authors: Sónia Sá Santos, Gary E Gibson, Arthur J L Cooper, Travis T Denton, Charles M Thompson, Victoria I Bunik, Paula M Alves, Ursula Sonnewald
• Journal: Journal of neuroscience research (J Neurosci Res) Vol. 83 Issue 3 Pg. 450-8 (Feb 15 2006) ISSN: 0360-4012 [Print] United States
• PMID: 16416424 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Carbon Isotopes
• Glutamic Acid
• Ketoglutarate Dehydrogenase Complex
• Glucose

Topics

• Animals
• Animals, Newborn
• Carbon Isotopes (metabolism)
• Cells, Cultured
• Cerebellum (cytology)
• Chromatography, High Pressure Liquid (methods)
• Glucose (metabolism)
• Glutamic Acid (metabolism)
• Ketoglutarate Dehydrogenase Complex (metabolism)
• Magnetic Resonance Spectroscopy (methods)
• Mice
• Models, Statistical
• Neural Inhibition (physiology)
• Neurons (metabolism)