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Effect of α-Ketoisocaproate and Leucine on the in Vivo Oxidation of Glutamate and Glutamine in the Rat Brain

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Abstract

Leucine and α-ketoisocaproate (α-KIC) were perfused at increasing concentrations into rat brain hippocampus by microdialysis to mimic the conditions of maple syrup urine disease. The effects of elevated leucine or α-KIC on the oxidation of L-[U-14C]glutamate and L-[U-14C]glutamine in the brain were determined in the non-anesthetized rat. 14CO2 generated by the metabolic oxidation of [l4C]glutamate and [14C]glutamine in brain was measured following its diffusion into the eluant during the microdialysis. Leucine and α-KIC exhibited differential effects on 14CO2 generation from radioactive glutamate or glutamine. Infusion of 0.5 mM α-KIC increased [l4C]glutamate oxidation approximately 2-fold; higher concentrations of α-KIC did not further stimulate [14C]glutamate oxidation. The enhanced oxidation of [14C]glutamate may be attributed to the function of α-KIC as a nitrogen acceptor from [14C]glutamate yielding [14C]α-ketoglutarate, an intermediate of the tricarboxylic acid cycle. [14C-]glutamine oxidation was not stimulated as much as [14C-]glutamate oxidation and only increased at 10 mM α-KIC reflecting the extra metabolic step required for its oxidative metabolism. In contrast, leucine had no effect on the oxidation of either [14C]glutamate or [14C]glutamine. In maple syrup urine disease elevated α-KIC may play a significant role in altered energy metabolism in brain while leucine may contribute to clinical manifestations of this disease in other ways.

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Authors and Affiliations

  1. Department of Pediatrics, University of Maryland at Baltimore, Maryland, 21201-1559

    H. Ronald Zielke, Yinyin Huang, Peter J. Baab, Roger M. Collins Jr., Carol L. Zielke & J. Tyson Tildon

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  1. H. Ronald Zielke
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  2. Yinyin Huang
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Zielke, H.R., Huang, Y., Baab, P.J. et al. Effect of α-Ketoisocaproate and Leucine on the in Vivo Oxidation of Glutamate and Glutamine in the Rat Brain. Neurochem Res 22, 1159–1164 (1997). https://doi.org/10.1023/A:1027325620983

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