Protection of Brain Metabolism with Glutathione,Glutamate,γ-Aminobutyrate and Succinate ∗

Studies on protective agents in oxygen toxicity experiments led us to believe that a glutathione (GSH)-glutamate-γ-aminobutyrate (GABA)-succinate pathway may serve as a secondary support system in the maintenance of brain energy levels (adenosine triphosphate [ATP] concentration). This “shunt” is shown in Fig. 1. The glutamate-GABA-succinicsemialdehyde-succinate shunt is a well established pathway (1-8) to which no major physiological significance has been attached. The GABA-succinate shunt has been suggested as a means of metabolizing GABA (9, 10). It has also been reported to function as a means of bypassing inhibition of the alpha-ketoglutarate dehydrogenase system of the citric acid cycle by withdrawal of alpha-ketoglutarate from the cycle by transamination with GABA to yield glutamate and reentry of the carbon chain of GABA into the cycle at the succinate level (9, 10). The possible physiological importance of the shunt is seen if one recognizes that succinate markedly stimulates respiration and oxidative phosphorylation.

Krebs et al. (11) reported that succinate oxidation can monopolize the respiratory-electron transport chain which is the major source of ATP production. Sanders et al. (12, 13) observed significantly higher respiration rates with succinate in brain, liver, and kidney of rats when compared with alpha-ketoglutarate and glutamate. Data shown later indicate that succinate stimulates brain respiration and oxidative phosphorylation in the mouse, rat, guinea pig, rabbit, cat and dog.

The factor limiting the amount of succinate available for metabolism has generally been considered to be the rate at which alpha-ketoglutarate is converted to succinate by enzymes of the Krebs cycle. Roberts (8) showed that conversion of GABA to succinate by GABA transaminase is rapid, and that both glutamic acid decarboxylase and GABA transaminase have pH optima (6.5 and 8.2, respectively) such that small changes in intracellular pH—within the physiological range—could result in large changes in these enzyme activities in situ (8, 14, 15).