Metabolic Precursors and Compartmentation of Cerebral GABA in Vigabatrin-Treated Rats
2002
The metabolic precursors and cerebral compartmentation of the augmented GABA pool induced by vigabatrin, an irreversible inhibitor of GABA transaminase, have been investigated by 13 C NMR. Adult rats receiving rat chow ad libitum were given either drinking water only or drinking water containing 2.5 g/L vigabatrin for 7 days. Both groups of animals were infused either with [1,2- 13 C 2 ] acetate (15 μmol/min/100 g body weight), an exclusive precursor of GABA formation through the glial glutamine pathway, or with [1,2- 13 C 2 ]glucose (15 μmol/min/100 g body weight), a substrate that can produce GABA through the glial glutamine pathway or by direct metabolism in the neurons. The brains were frozen in situ, extracted with perchloric acid, and analyzed by 13 C NMR. In vigabatrin-treated animals [ 13 C]glutamine, a common intermediate for [ 13 C]GABA synthesis from glucose or acetate, was accumulated to similar amounts during infusions with [1,2- 13 C 2 ] glucose or [1,2- 13 C 2 ]acetate. However, [ 13 C]GABA accumulation was sevenfold higher during [1,2- 13 C 2 ]glucose infusions or twofold higher during [1,2- 13 C 2 ]acetate infusions. These results show that the direct pathway of GABA formation by neuronal metabolism of glucose predominates over the alternative pathway through glial glutamine. Near-equilibrium relationships of the aminotransferases of GABA and aspartate imply that the observed [ 13 C] GABA accumulation occurs initially in the neuronal compartment.
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