γ‐Aminobutyric Acid Release from Synaptosomes Prepared from Rats Treated with Isonicotinic Acid Hydrazide and Gabaculine

Wood, J. D.; Kurylo, E.; Lane, Richard W.

doi:10.1111/j.1471-4159.1988.tb02486.x

Cited by 19 publications

(12 citation statements)

References 21 publications

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“…It has been shown previously that GABA can be released from neurons by reversal of the transporter (Schwartz, 1987;Wood et al, 1988;Taylor and Gordon-Weeks, 1991), but carrier-mediated GABA release also has been demonstrated from glia (Gallo et al, 1991). Although GABA levels are probably low in glia under normal conditions, this may not be the case after blockade of GABA transaminase.…”

Section: Discussionmentioning

confidence: 94%

“…However, exactly how this occurs is unclear. Blockade of GABA transaminase increases [GABA] within the cytoplasmic pool (Wood et al, 1988) but does not necessarily affect GABA content within synaptic vesicles or the probability of vesicular GABA release. This may explain why it has been difficult to obtain direct electrophysiological evidence for the enhancement of GABAergic IPSPs Jung and Palfreyman, 1995;Engel et al, 2000).…”

Section: Abstract: Seizure; Epilepsy; Vigabatrin; Synapse; Nonvesicumentioning

confidence: 99%

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GABA Transaminase Inhibition Induces Spontaneous and Enhances Depolarization-Evoked GABA Efflux via Reversal of the GABA Transporter

2001

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The GABA transporter can reverse with depolarization, causing nonvesicular GABA release. However, this is thought to occur only under pathological conditions. Patch-clamp recordings were made from rat hippocampal neurons in primary cell cultures. Inhibition of GABA transaminase with the anticonvulsant ␥-vinyl GABA (vigabatrin; 0.05-100 M) resulted in a large leak current that was blocked by bicuculline (50 M). This leak current occurred in the absence of extracellular calcium and was blocked by the GABA transporter antagonist SKF-89976a (5 M). These results indicate that vigabatrin induces spontaneous GABA efflux from neighboring cells via reversal of GABA transporters, subsequently leading to the stimulation of GABA A receptors on the recorded neuron. The leak current increased slowly over 4 d of treatment with 100 M vigabatrin, at which time it reached an equivalent conductance of 9.0 Ϯ 4.9 nS. Blockade of glutamic acid decarboxylase with semicarbazide (2 mM) decreased the leak current that was induced by vigabatrin by 47%. In untreated cells, carrier-mediated GABA efflux did not occur spontaneously but was induced by an increase in [K ϩ ] o from 3 to as little as 6 mM. Vigabatrin enhanced this depolarization-evoked nonvesicular GABA release and also enhanced the heteroexchange release of GABA induced by nipecotate. Thus, the GABA transporter normally operates near its equilibrium and can be easily induced to reverse by an increase in cytosolic [GABA] or mild depolarization. We propose that this transporter-mediated nonvesicular GABA release plays an important role in neuronal inhibition under both physiological and pathophysiological conditions and is the target of some anticonvulsants.

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Section: Discussionmentioning

confidence: 94%

Section: Abstract: Seizure; Epilepsy; Vigabatrin; Synapse; Nonvesicumentioning

confidence: 99%

GABA Transaminase Inhibition Induces Spontaneous and Enhances Depolarization-Evoked GABA Efflux via Reversal of the GABA Transporter

2001

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“…According to Biggs et al [172], INH administered at a dose of 250 mg/kg causes convulsions and diminishes cerebral concentrations of GABA. In vitro, INH reduces synaptosomal release of GABA [169] and has no effect on the release of glutamine or taurine stimulated by K + -mediated depolarization, but it increases the release of the excitatory amino acids, aspartate and glutamate [169,170,173]. The HZ derived from INH has convulsant effects.…”

Section: The Role Of Hz and Ammoniamentioning

confidence: 99%

Isoniazid: Metabolic Aspects and Toxicological Correlates

Preziosi

2007

CDM

131

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For over half a century, pyridine-4-carboxy hydrazide (isonicotinyl hydrazide; isoniazid - INH) has been a front-line weapon in the battle against tuberculosis. Its metabolism has been the subject of important research, much of which has focused on the pharmacodynamic and toxicological aspects of certain INH metabolites. Since 1952, when the drug was first introduced, multiple INH metabolites have been identified, including hydrazine (HZ), isonicotinic acid (INA), ammonia, the acetylated derivative N(1)-acetyl-N(2)-isonicotinylhydrazide (AcINH), hydrazones with pyruvic and ketoglutaric acids (INH-PA and INH-KA, respectively), monoacetylhydrazine (AcHZ), diacetylhydrazine (DiAcHZ), and oxidizing free radicals. Their formation is the result of hydrolysis (INA, HZ), cytochrome P450 (CYP)-dependent oxidation (HZ, NH(3), oxidizing free radicals), and N-acetyltransferase (NAT) activity (AcINH, AcHZ, DiAcHZ). Doubts remain about isonicotinamide (INAAM) as an INH metabolite in mammals. Quantitatively speaking, one of the major metabolites is AcINH, which is produced by the enzyme NAT. It has virtually no antitubercular activity and is far less toxic than INH. Its formation and elimination are genetically controlled, and its elimination profile is trimodal (rapid, intermediate, and slow acetylation). Slow acetylation, which is transmitted as an autosomal recessive trait, increases the risk for peripheral neurotoxicity and hepatotoxicity in INH users. Thus far, there is no conclusive pharmacogenetic evidence that the formation of HZ and oxidizing radicals are linked to CYP polymorphisms. This article examines INH, HZ and its mono- and diacetylated metabolites, and ammonia (which in vitro and in vivo studies indicate as another derivative of HZ) in terms of their potential to cause neurotoxic and hepatotoxic effects (the two major forms of INH toxicity observed in animals and humans). INH hepatotoxicity seems to be related mainly to HZ, AcHZ, and other HZ metabolites that are capable of generating free radicals. The pathological aspects of slow INH acetylation will be discussed in relation to the drug's hepato- and neurotoxic effects. The mechanism underlying INH neurotoxicity has yet to be fully defined. The metabolite(s) involved in this phenomenon remain obscure although a major role is clearly played by HZ (and possibly also by the ammonia it releases). There is some evidence of the involvement of gamma-glutamyl HZ and of a chemical analogue of a Schiff base formed by INH and pyridoxal-phosphate. Recent findings have also revealed important interactions between INH and the various isoforms of CYP, and these may play a role in clinically relevant interactions between INH and several other drugs. All of these aspects of INH will be covered in the review.

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“…6, 1994 tributed throughout the brain, with GAD B (the PLPrequiring form) being particularly enriched in hippocampus (reviewed by Ebadi et al, 1990) . Significantly, INH has been found to decrease the content and release of GABA from synaptosomes (Wood et al ., 1988) . The present in vivo data are in agreement with the in vitro observations of Wood et al (1988), and support the view that decreased GABA release plays a crucial role in INH-induced convulsions .…”

Section: Discussionmentioning

confidence: 99%

Effect of Isonicotinic Acid Hydrazide on Extracellular Amino Acids and Convulsions in the Rat: Reversal of Neurochemical and Behavioural Deficits by Sodium Valproate

Biggs

Pearce

Fowler

et al. 1994

Journal of Neurochemistry

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We have studied the effect of isonicotinic acid hydrazide (INH), a convulsant agent, on the extracellular levels of amino acids in the hippocampus, and the effect of sodium valproate (VPA) administration in INH-treated rats . INH (250 mg/kg) caused a rapid and sustained decrease in basal levels of GABA, and during this period convulsions of increasing severity were observed . Basal levels of glutamine, taurine, aspartate, and glutamate were unchanged by INH . When VPA was coadministered with INK basal GABA levels were increased and no convulsions were observed . When transmitter release was evoked using 100 mM K', the increase in dialysate GABA observed in INH-treated animals was less than that seen in controls and convulsions increased in frequency. K'evoked release of glutamate and aspartate tended to be higher following INH treatment, and in the case of aspartate, this increase was significant . VPA reversed the changes in evoked release of glutamate and aspartate, and release of GABA was considerably greater than that seen in control or INH-treated rats . No drug effect on evoked changes in taurine or glutamine level was seen . These are the first data to show decreased extracellular GABA in conjunction with convulsions in freely moving animals in vivo . Key Words: In vivo microdialysis-GABA-Sodium valproate-Isonicotinic acid hydrazide.

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γ‐Aminobutyric Acid Release from Synaptosomes Prepared from Rats Treated with Isonicotinic Acid Hydrazide and Gabaculine

Cited by 19 publications

References 21 publications

GABA Transaminase Inhibition Induces Spontaneous and Enhances Depolarization-Evoked GABA Efflux via Reversal of the GABA Transporter

GABA Transaminase Inhibition Induces Spontaneous and Enhances Depolarization-Evoked GABA Efflux via Reversal of the GABA Transporter

Isoniazid: Metabolic Aspects and Toxicological Correlates

Effect of Isonicotinic Acid Hydrazide on Extracellular Amino Acids and Convulsions in the Rat: Reversal of Neurochemical and Behavioural Deficits by Sodium Valproate

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