Interrelationships between ornithine, glutamate and GABA—I. Feed-back inhibition of ornithine aminotransferase by elevated brain GABA levels

Ornithine Aminotransferase, an Important Glutamate-Metabolizing Enzyme at the Crossroads of Multiple Metabolic Pathways

“…However, other experiments suggest that GABA is not derived from Orn [42,170]. GABA itself has an inhibitory effect on OAT that could be due to substrate competition with Orn (see above) [42]. This was observed in vivo by peritoneal administration of vigabatrin, leading to an increase in GABA levels and Orn levels, and confirms the Orn → GSA/Glu function of OAT in the brain.…”

“…This last idea is supported by the high amount of OAT found in nerve endings [174], and by a decrease in OAT activity in brain anoxia models, in tissues where GABAergic neuron degradation occurs. However, other experiments suggest that GABA is not derived from Orn [42,170]. GABA itself has an inhibitory effect on OAT that could be due to substrate competition with Orn (see above) [42].…”

5-Fluoromethylornithine, an irreversible and specific inhibitor of l-ornithine:2-oxo-acid aminotransferase

“…Treatment of mice with vigabatrin (4-aminohex-5-enoic acid), a specific inactivator of GABA-T (Jung et al, 1977), has previously been shown to increase brain putrescine beyond the time of elevated ODC activity (Seiler et al, 1979). Since we know now that elevated brain 4-aminobutyrate concentrations are accompanied by elevated Orn concentrations (Seiler et al, 1987), it is likely that in both cases the same mechanism underlies the elevation of brain putrescine concentrations.…”

“…column. Separation was achieved by ion-pair formation with SDS and gradient elution, as described in detail previously (Seiler & Knodgen, 1985b Selective determination of ornithine Orn was determined as described previously (Seiler et al, 1987) by treating HC104 tissue extracts with o-phthalaldehyde/2-mercaptoethanol, and separation and electrochemical detection of the isoindoles that are formed by this reaction by h.p.l.c.…”

Experimental studies of the influence of vigabatrin on the GABA system.

“…Currently no information is available regarding GVG brain concentrations in man. Consequently, in our release investigation, we had to extrapolate from information on blood levels obtained in patients, being in the range of 50-150 FLM (Gram et al, 1983;Rimmer & Richens, 1984), and recent information of GVG brain levels in mice, demonstrating a range of 30-50 FM (Seiler et al, 1987), following chronic treatment with anticonvulsant doses of the drug. Comparing these levels with the obtained result, that a GVG concentration as low as 25 FM caused a more than 100% increase in the amount of released GABA, it must be assumed that sufficient concentrations of GVG are obtained in the brains of patients to augment GABA release.…”