The role of gaba metabolism in the convulsant and anticonvulsant actions of aminooxyacetic acid
TL;DR: The state of excitability of the brain following the administration of AOAA was related, within the limits of the present study, to changes in GAD activity and GABA levels, but additional data are required before the relationship can be properly evaluated.
Abstract: — At high dosage levels AOAA acted as a convulsant agent in mice and rats but in lower amounts it was an effective anticonvulsant agent against INH-induced seizures, by tripling the time to the onset of the convulsions. AOAA elevated brain GABA levels as a result of a preferential inhibition of the GABA-T enzyme system but, contrary to previous reports, the activity of the GAD enzyme system was also inhibited, even by relatively low dosage levels of AOAA. The state of excitability of the brain following the administration of AOAA was related, within the limits of the present study, to changes in GAD activity and GABA levels, but additional data are required before the relationship can be properly evaluated.
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203 citations
TL;DR: It is proposed that GABAA and GABAB receptors differ not only at the cellular level, but that they also have different functions in the mammalian central nervous system.
183 citations
168 citations
TL;DR: The experiments suggest that diazepam may act in the CNS either by altering the disposition of endogenous GABA or by mimicking the action of GABA at specific synaptic receptors.
Abstract: Subcutaneous injections of isoniazid or picrotoxin increase the cerebellar content of 3′,5′-cyclic guanosine monophosphate (cGMP) without changing the 3′,5′-cyclic adenosine monophosphate cAMP. This increase was dose dependent and the threshold for the cGMP increase was lower than that for convulsions. In cerebellum the increase of cGMP content elicited by isoniazid but not that caused by picrotoxin was paralleled by a decrease of GABA content. Diazepam doses starting from 1.74 μmol/kg intraperitoneally produced a dose dependent decrease of cerebellar cGMP concentration without changing cAMP or GABA content. Smaller doses of diazepam (0.5 μmol/kg i.p.) failed to decrease the basal cerebellar content of cGMP. However, this dose of diazepam antagonized the increase of cGMP produced by isoniazid but not that produced by picrotoxin. Higher doses of diazepam were necessary to block the increase of cerebellar cGMP elicited by picrotoxin. Low doses of diazepam (0.14 μmol/kg) antagonized the convulsions in 50% of the rats injected with 3.3 mmol/kg of isoniazid. The doses of diazepam required to block picrotoxin, pentylenetetrazol or strychnine convulsions were 7, 25 and 40 times higher than those required to block isoniazid convulsions, respectively. Desmethyldiazepam, chloridiazepoxide, oxazepam were also several times more potent in antagonizing isoniazid than picrotoxin, pentylenetetrazol, or strychnine convulsions. In contrast, barbiturates were equipotent against all the convulsants studied. These experiments suggest that diazepam may act in the CNS either by altering the disposition of endogenous GABA or by mimicking the action of GABA at specific synaptic receptors.
139 citations
TL;DR: An equation on an empirical basis is developed which provides an excellent relationship between the excitable state of the brain and a function of GABA metabolism which incorporates both changes in GABA level and changes in GAD activity.
138 citations
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TL;DR: The function of this group of amino acids seems to be related to the complex structure of the CNS and the existence of numerous compartments and metabolic pools.
Abstract: RECENT studies have stressed the important physiological role of certain amino acids in the brain. Analytical determinations revealed high concentrations of glutamic and aspartic acids as well as of glutamine and N-acetylaspartate. y-Aminobutyric acid (GABA), is especially interesting, not only because of its high concentration, but also because of its exclusive presence in the CNS, particularly in grey matter. Numerous biochemical studies have been dedicated to the metabolic interrelationships existing among this group of amino acids and the glycolytic and tricarboxylic cycles, as well as with the mechanism of ammonia removal in brain. Some of these amino acids may serve as anions, making up for part of the inorganic anion deficit, or as important substrates in intermediary metabolism. Experimental observations have shown that these amino acids may have different physiological actions. Both glutamic and aspartic acids have a powerful excitatory action. On the contrary, GABA has a general depressant action on different neuronal responses while glutamine and N-acetylaspartic acid have no effect. It has been suggested that some of these amino acids are important in maintaining the normal excitability of neuronal membranes acting in a rather unspecific way, while others have suggested a synaptic role for them (see CURTIS, PHILLIS and WATKINS, 1959, 1960; CURTIS and WATKINS, 1960; FLOREY, 1964). The function of this group of amino acids seems to be related to the complex structure of the CNS and the existence of numerous compartments and metabolic pools. With radioisotope experiments it has been found that only a small fraction of the total glutamate is rapidly interchanged, while the rest remains rather inactive (BERL, TAKACAKI and PURPURA, 1961b). Similarly, only a small fraction of GABA appears to be active (BERL, LAJTHA and WAELSCH, 1961~). Furthermore some of these amino acids apparently can exchange across cell membranes, and this exchange is accelerated by stimulation of nerve cells (LUXORO, 1960).
501 citations
TL;DR: Experiments with hydroxylamine and α-hydrazinophenylacetic acid showed that the rate of loss of enzymic activity during preincubation of the brain homogenate with these agents was less than in absence of inhibitor, a finding consistent with the interpretation that the major mode of inhibition by carbonyltrapping agents is by combination with the holoenzyme.
328 citations
TL;DR: Amino-oxyacetic acid has been found to be a potent inhibitor of the enzyme γ-aminobutyric acid-α-ketoglutaric acid transaminase derived both from E. coli and mammalian brain.
267 citations
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