Selective inhibition of the tricarboxylic acid cycle of GABAergic neurons with 3-nitropropionic acid in vivo.
The effects of 3-nitropropionic acid (3-NPA), an inhibitor of succinate dehydrogenase, on cerebral metabolism were investigated in mice by NMR spectroscopy. 3-NPA, 180 mg/kg, caused a dramatic buildup of succinate. Succinate was labeled 5.5 times better from [1-(13)C]glucose than from [2-(13)C]acetate, showing a predominantly neuronal accumulation. [1-(13)C]Glucose labeled GABA in the C-2 position only, compatible with inhibition of the tricarboxylic acid (TCA) cycle associated with GABA formation, at the level of succinate dehydrogenase. Aspartate was not labeled by [1-(13)C]glucose in 3-NPA-intoxicated animals. In contrast, [1-(13)C]glucose labeled glutamate in the C-2, C-3, and C-4 positions showing uninhibited cycling of label in the TCA cycle associated with the large, neuronal pool of glutamate. The labeling of glutamine, and hence GABA, from [2-(13)C]acetate showed that the TCA cycle of glial cells was unaffected by 3-NPA and that transfer of glutamine from glia to neurons took place during 3-NPA intoxication. The high 13C enrichment of the C-2 position of glutamine from [1-(13)C]glucose showed that pyruvate carboxylation was active in glia during 3-NPA intoxication. These findings suggest that 3-NPA in the initial phase of intoxication fairly selectively inhibited the TCA cycle of GABAergic neurons; whereas the TCA cycle of glia remained uninhibited as did the TCA cycle associated with the large neuronal pool of glutamate, which includes glutamatergic neurons. This may help explain why the caudoputamen, which is especially rich in GABAergic neurons, selectively undergoes degeneration both in humans and animals intoxicated with 3-NPA.(ABSTRACT TRUNCATED AT 250 WORDS)
Hassel
B
B
Norwegian Defence Research Establishment, Division for Environmental Toxicology, Kjeller.
Sonnewald
U
U
D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002247:Carbon Isotopes; D002952:Citric Acid Cycle / Q000187:drug effects*; D005260:Female; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009574:Nitro Compounds; D011422:Propionates / Q000494:pharmacology*; D013385:Succinate Dehydrogenase / Q000037:antagonists & inhibitors*; D013386:Succinates / Q000378:metabolism; D019802:Succinic Acid; D005680:gamma-Aminobutyric Acid / Q000502:physiology*
D000596:Amino Acids; D002247:Carbon Isotopes; D007773:Lactates; D009574:Nitro Compounds; D011422:Propionates; D013386:Succinates; D019344:Lactic Acid; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D019802:Succinic Acid; D013385:Succinate Dehydrogenase; D005947:Glucose; C015392:3-nitropropionic acid