Disease relevance of Abat

• The principle of the procedure is based on the action of GABASE (GABA-aminotransferase plus succinic semialdehyde dehydrogenase), coupled to the detection of succinic semialdehyde and NADH, using Photobacterium luciferase [1].
• The results indicate the potential use of GABA-T inhibitors in the therapy of PCP intoxications and perhaps also in the treatment of certain forms of endogenous psychoses [2].
• Vigabatrin (Sabril) is a gamma-aminobutyric acid-transaminase (GABA-T) inhibitor that is effective in the treatment of certain types of drug-resistant or uncontrolled epilepsy but is known to cause microscopic vacuolation (intramyelinic edema) in the brains of treated rats, mice, and dogs [3].
• In chronic ammonia toxicity GABA-T showed a rise in all the three regions of brain [4].

Psychiatry related information on Abat

• Furthermore, we investigated the effect of GABA receptor agonists, muscimol and baclofen, or a GABA transaminase inhibitor, aminooxyacetic acid (AOAA), on these amnesia models [5].
• Vigabatrin and (S)-4-allenylGABA (MDL 72483), two anticonvulsant GABA-T inhibitors, partially antagonize phencyclidine (PCP)-induced hyperactivity in mice at doses that do not affect spontaneous motor activity [2].
• This process could be completely blocked if GABA accumulation was induced by pretreatment with the GABA transaminase inhibitor, aminooxyacetic acid (AOAA), or by emotional stress induced by 40 min of restraint [6].

High impact information on Abat

• Raising the concentration of extracellular GABA by bathing slices in the GABA transaminase inhibitor vigabatrin and blocking uptake with tiagabine reduced the power of gamma oscillations more in WT slices than alpha5-/- slices (43%versus 15%) [7].
• The activity of glutamate decarboxylase in the brains of PLP-treated mice was lowered, whereas the activity of GABA-transaminase was enhanced [8].
• Different types of responses in the activities of the polyamine-synthesizing enzymes, ornithine decarboxylase and adenosylmethionine decarboxylase, were observed after increasing the cerebral GABA concentration of mice with varying doses of two GABA transaminase inhibitors, gabaculine and ethanolamine-O-sulphate [9].
• The anticonvulsant action of the GABA-T inhibitor and the GABA uptake inhibitor together was little different from that of the GABA-T inhibitor alone [10].
• The intramuscular administration of a gamma-aminobutyrate-alpha-oxoglutarate aminotransferase (GABA-T) inhibitor, gabaculine, to mice resulted in significant increases in GABA content and decreases in the content of aspartate, glutamate, and glutamine in the nerve endings (synaptosomes) [10].

Biological context of Abat

• Our data suggest that the anticonvulsant efficacy of long term treatment with GABA-T inhibitors is limited by the development of compensatory mechanisms, such as reduction of GAD activity, which in turn reduce the amount of GABA available for synaptic transmission, though overall GABA concentrations in the brain are highly elevated [11].
• 2-Methyl-2-ethyl caproic acid, ethanolamine O-sulphate and isoniazid were less effective inhibitors of the GABA-T activity (IC50 greater than 1 mM) [12].
• Furthermore, inhalation inhibited the activity of GABA transaminase as the inhalation period was lengthened [13].

Anatomical context of Abat

• The cause of this phenomenon appeared to be an interaction between DPA and AOAA with respect to inhibition of GABA-T activity, resulting in a long-term diminished inhibition by AOAA, which in turn led to a lessening of the AOAA-induced elevation in the GABA content of nerve endings (synaptosomes) [14].
• Sodium valproate significantly enhanced the activity of GAD in the medulla and pons, cerebellum and midbrain regions of rats, and partially relieved the suppression of GAD activity caused by chronic GABA-transaminase inhibition in whole mouse brain [15].
• Development of homospecific activity of GABA-transaminase in the mouse cerebral cortex and cerebellum and in neurons cultured from these brain areas [16].
• The effects of dopamine D1 and D2 receptor agonists and antagonists on the rate of GABA synthesis in four regions of mouse brain (corpus striatum, cerebellum, cortex and hippocampus) were examined after irreversible inhibition of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19; GABA-T) by gabaculine [17].
• Kinetic characterization of GABA-transaminase from cultured neurons and astrocytes [18].

Associations of Abat with chemical compounds

• Effect of inhibitors of GABA aminotransferase on the metabolism of GABA in brain tissue and synaptosomal fractions [19].
• A major cause of these effects was the gabaculine-induced inhibition of GABA-T activity and the lessening of this inhibition by ketamine [10].
• The use of inhibitors of GABA-transaminase for the determination of GABA turnover in mouse brain regions: an evaluation of aminooxyacetic acid and gabaculine [20].
• The results suggest that activation of GAD is an important factor in the mechanism by which several inhibitors of GABA-T and also valproate increase GABA concentrations in nerve terminals, at least in the relatively non-toxic doses as used in this study [19].
• omega-Monofluoromethyl and omega-difluoromethyl analogues of the known substrates of GABA-T, beta-alanine, gamma-aminobutyric acid, and 5-aminopentanoic acid, are time-dependent inhibitors of purified 4-aminobutyrate: 2-oxoglutarate aminotransferase (GABA-T) [21].

Other interactions of Abat

• The majority of neurons contained GABA, glutamic acid decarboxylase, and GABA-transaminase [22].
• In contrast, AcAl showed remarkable reductions of neuroactive amino acids content, and of CAT and AChE activities, but induced no alteration in the activities of GAD and GABA-T [23].
• On both conventional and ethological indices, results confirmed the anxiolytic profile of diazepam under present test conditions, and revealed substantially similar effects for the GABA-T inhibitor, valproic acid (100-400 mg/kg), and the GABAA receptor agonist, muscimol (2 mg/kg) [24].
• Vigabatrin, an inhibitor of GABA breakdown by GABA transaminase and of GABA transporter isoform 1 (GAT1), and tiagabine, a highly specific inhibitor of GAT1, have successfully been applied in the treatment of epilepsy [25].
• No significant difference was demonstrated in the activities of GABA transaminase, glutamate dehydrogenase, lactate dehydrogenase, succinate dehydrogenase and NAD-malate dehydrogenase in any of the regions studied [26].

Analytical, diagnostic and therapeutic context of Abat

• Induction of analgesia and morphine potentiation by irreversible inhibitors of GABA-transaminase [proceedings] [27].
• Following chronic oral administration via drinking water containing the drugs, immobility was significantly reduced at days 5 and 10 in all of the GABA-T inhibitors examined [28].
• When the aminotransferases were tested with the antibody against the purified 4-aminobutyrate aminotransferase from brain, no difference could be detected among brain, spinal cord, and kidney preparations as judged from the results of immunodiffusion, inhibition of enzyme activity by antibody, and microcomplement fixation [29].
• Inhibition of GABA-T produced a significant increase of polyamine turnover in brain, in agreement with the known induction of ornithine decarboxylase activity after treatment with inhibitors of GABA-T [30].
• The elicited syndrome can be antagonized dose-dependently by GABA-agonists, by GABA-transaminase inhibitors, by GABA neuronal uptake inhibitors, and by benzodiazepines stereospecifically after appropriate premedication times and routes [31].

References