The rate of turnover of cortical GABA from [1-13C]glucose is reduced in rats treated with the GABA-transaminase inhibitor vigabatrin (γ-vinyl GABA) |
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Authors: | Dr D Manor D L Rothman G F Mason F Hyder O A C Petroff K L Behar |
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Institution: | (1) Department of Neurology, Yale University School of Medicine, 06520-8043 New Haven, Connecticut;(2) Department of Internal Medicine, Yale University School of Medicine, 06520-8043 New Haven, Connecticut;(3) Department of IMolecular Biophysics and Biochemistry, Yale University School of Medicine, 06520-8043 New Haven, Connecticut;(4) Center for NMR Research and Development, University of Alabama, 35294 Birmingham, Alabama;(5) Magnetic Resonance Center, Yale University School of Medicine, P.O. Box 208043, 06520-8043 New Haven, Connecticut |
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Abstract: | Brain GABA levels rise and plateau following prolonged administration of the irreversible GABA-transaminase inhibitor vigabatrin
(γ-vinylGABA). Recently it has been shown that increased GABA levels reduces GAD67 protein, one of two major isoforms of glutamic acid decarboxylase (GAD). The effects of GABA elevation on GABA synthesis
were assessed in vivo using1H and13C-edited NMR spectroscopy. Rates of turnover of cortical glutamate and GABA from intravenously administered 1-13C]glucose were measured in α-chloralose anesthetized rats 24 hours after receiving vigabatrin (500 mg/kg, i.p.) and in non-treated
controls. GABA concentration was increased 2-fold at 24 hours (from 1.3±0.4 to 2.7±0.9 μmol/g) and GABA-T activity was inhibited
by 60%. Tricarboxylic acid cycle flux was not affected by vigabatrin treatment compared to non-treated rats (0.47±0.19 versus
0.52±0.18 μmol/g, respectively). GABA-C2 fractional enrichment (FE) measured in acid extracts rose more slowly in vigabatrin-treated
compared to nontreated rats, reaching >90% of the glutamate FE after 3 hours. In contrast, GABA FE≥glutamate FE in non-treated
rats. A metabolic model consisting of a single glutamate pool failed to account for the rapid labeling of GABA from glutamate.
Metabolic modelling analysis based on two (non-communicating) glutamate pools revealed a ∼70% decrease in the rate of GABA
synthesis following vigabatrin-treatment, from 0.14 (non-treated) to 0.04 μmol/g/min (vigabatrin-treated). These findings,
in conjunction with the previously reported differential effects of elevated GABA on the GAD isoforms, suggests that GAD67 may account for a major fraction of cortical GABA synthesis in the α-chloralose anesthetized rat brain in vivo.
Special issue dedicated to Dr. Herman Bachelard. |
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Keywords: | GABA gamma-aminobutyric acid glutamic acid compartmentation in vivo NMR spectroscopy glutamic acid decarboxylase GABA transaminase |
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