An analysis of the kinetics of the inhibition of rabbit brain γ-aminobutyrate aminotransferase by sodium n-dipropylacetate and some other simple carboxylic acids

Fowler, Leslie J.; Beckford, J.; John, R.A.

doi:10.1016/0006-2952(75)90334-2

Cited by 55 publications

(9 citation statements)

References 11 publications

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“…The effect of VPA on brain GABA concentrations in rodents has been ascribed to an inhibition of GABA metabolism, probably by a preferential inhibition of succinic semialdehyde dehydrogenase (Harvey et al 1975;Van Der Laan et al, 1979). VPA is also a weak inhibitor of GABA-aminotransferase (GABA-T) in brain (Fowler et al, 1975;Loscher and Frey, 1977a) and activates the GABAsynthesizing enzyme glutamate decarboxylase (Ldscher and Frey, 1977a). Since GABA, as well as GAD and GABA-T, is also present in the nonneuronal tissues such as liver, kidneys, and pancreas in different species, including man (Zachmann et al, 1966;Okada et al, 1976;Wood et al, 1978), the peripheral increase in plasma GABA by VPA may be caused either by an activation of its synthesis and/or inhibition of its metabolism in peripheral organs.…”

Section: Discussionmentioning

confidence: 99%

Increase of Human Plasma GABA by Sodium Valproate

Löscher

Schmidt

1980

Epilepsia

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gamma-Aminobutyric acid (GABA) was measured in the plasma of volunteers during subchronic treatment with sodium valproate (VPA). After 2 days of oral treatment with 300 mg VPA, t.i.d., the GABA concentration was increased to about 30% compared to 2 control days. This response was similar to that after 2 days of treatment with 600 mg VPA, t.i.d., whereas on the fourth day of treatment with the latter dose, a plasma GABA increase of about 90% was observed.

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Section: Discussionmentioning

confidence: 99%

Increase of Human Plasma GABA by Sodium Valproate

Löscher

Schmidt

1980

Epilepsia

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“…It should be noted that any in vivo inhibition of GABA-T by DPA will not be observed in subsequent in vitro assays on account of the reversibility of the DPA-induced inhibition (Fowler et al, 1975). Thus, the lack of effect of DPA on GABA-T activity (Table 4) does not necessarily indicate that the compound failed to inhibit the enzyme in vivo.…”

Section: Drug-induced Changes In Gaba-t Activitymentioning

confidence: 99%

“…2). Subsequently, the easily reversible DPA binding to the enzyme (Fowler et al, 1975) becomes negligible leaving the irreversible AOAA binding as the sole cause of GABA-T inhibition observed 6 h postinjection. As AOAA is quickly inactivated in brain tissue, presumably by reaction with endogenous carbonyl groups, the compound is unable to make up the initial deficit in its binding to GABA-T subsequent to the disappearance of the DPA.…”

Section: Anticonvulsant and Biochemical Action Of Dpa Alonementioning

confidence: 99%

Interactions of Di‐n‐Propylacetate, Gabaculine, and Aminooxyacetic Acid: Anticonvulsant Activity and the γ‐Aminobutyrate System

Wood

Kurylo

Tsui

1981

Journal of Neurochemistry

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Di-n-propylacetate (DPA), aminooxyacetic acid (AOAA), and gabaculine were administered alone or in combination to Swiss mice. Six hours after administration of the drugs the anticonvulsant action (against isonicotinic acid hydrazide-induced seizures) of AOAA and DPA combined was less than that of AOAA alone. 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). An excellent correlation was observed between the delay in onset of seizures and the elevation of synaptosomal GABA content.

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“…The threshold dose for the prolongation of the latency was 400 mg/ kg p.o. At this dose the increase in GABA levels produced by inhibition of GABA-T or succinic semialdehyde dehydrogenase (EC 1.2.1.16), is not negligible (Anlezark et aL, 1976;Fowler et aL, 1975;Simler et aL, 1973). It is therefore more difficult than in the case of diazepam to differentiate between two hypotheses.…”

Section: Discussionmentioning

confidence: 88%

The specific protective effect of diazepam and valproate against isoniazid-induced seizures is not correlated with increased GABA levels

Bernasconi

Klein

Martin

et al. 1985

J. Neural Transmission

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Amino acid concentrations were measured in the cortex, cerebellum and hippocampus of the mouse brain before and during seizures induced by isoniazid (250 mg/kg i.p.), an inhibitor of L-glutamate-1-decarboxylase (EC 4.1.1.15: GAD). Valproate sodium and diazepam dose-dependently delay the onset of convulsive fits caused by isoniazid. However, neither diazepam nor valproate prevented the decrease in GABA concentrations produced by isoniazid alone. Also, these antiepileptic drugs did not modify the rate of GABA depletion elicited by isoniazid. These results, observed in four different brain structures, strengthen those first obtained with beta-vinyllactic acid, another inhibitor of GAD.

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An analysis of the kinetics of the inhibition of rabbit brain γ-aminobutyrate aminotransferase by sodium n-dipropylacetate and some other simple carboxylic acids

Cited by 55 publications

References 11 publications

Increase of Human Plasma GABA by Sodium Valproate

Increase of Human Plasma GABA by Sodium Valproate

Interactions of Di‐n‐Propylacetate, Gabaculine, and Aminooxyacetic Acid: Anticonvulsant Activity and the γ‐Aminobutyrate System

The specific protective effect of diazepam and valproate against isoniazid-induced seizures is not correlated with increased GABA levels

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