Metabolism of brain amino acids following pentylenetetrazole treatment.
We studied the effects of pentylenetetrazole (PTZ) on brain amino acid metabolism in mice. Administration of this convulsant did not change forebrain concentrations of amino acids, but when treated animals also received an injection of [15N]leucine, which served as a tracer of brain nitrogen metabolism, total (14N+15N) forebrain [leucine] exceeded control and [glutamate] and [aspartate] were less than control, as were forebrain concentrations of [15N]glutamate and [2-15N]glutamine. These data suggest greater uptake of [15N]leucine but diminished transamination of leucine to glutamate in experimental mice. In contrast to the [15N]leucine studies, which were associated with increased brain [leucine], the administration of [15N]alanine did not alter levels of alanine, glutamate or glutamine. However, label appeared in [2-15N]glutamine much more readily with [15N]alanine than with [15N]leucine as precursor and the ratio of enrichment in [2-15N]glutamine/[15N]alanine was much higher than that in [2-15N]glutamine/[15N]leucine, a finding that is compatible with preferential metabolism of alanine in astrocytes, which are the primary site of brain glutamine synthetase. We conclude that PTZ treatment favors the uptake of selected amino acids such as leucine but also diminishes transamination of leucine to yield glutamate via branched-chain amino acid transaminase. PTZ treatment may favor the "reverse" transamination of 2-keto-isocaproate (KIC), the ketoacid of leucine, to form leucine and to consume glutamate. A net result of these processes may be to enable the brain more readily to dispose of the glutamate that is released from neurons during convulsive activity.
Yudkoff
Marc
M
Department of Pediatrics, Division of Child Development, School of Medicine, Children's Hospital of Philadelphia, University of Pennsylvania, 34th Street and Civic Center Blvd, Philadelphia, PA, USA. yudkoff@email.chop.edu
Daikhin
Yevgeny
Y
Nissim
Ilana
I
Horyn
Oksana
O
Lazarow
Adam
A
Nissim
Itzhak
I
D000409:Alanine / Q000378:metabolism; D000596:Amino Acids / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects*; D003292:Convulsants / Q000494:pharmacology*; D008401:Gas Chromatography-Mass Spectrometry; D005947:Glucose / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D008297:Male; D051379:Mice; D009584:Nitrogen / Q000378:metabolism; D010433:Pentylenetetrazole / Q000494:pharmacology*; D016548:Prosencephalon / Q000187:drug effects / Q000378:metabolism; D012640:Seizures / Q000378:metabolism
D000596:Amino Acids; D003292:Convulsants; D007930:Leucine; D005947:Glucose; D009584:Nitrogen; D000409:Alanine; D010433:Pentylenetetrazole