Vinyl GABA Research Articles

Effects of the inhibitor of the γ-aminobutyrate-transaminase, vinyl-γ-aminobutyrate, on development and nitrogen metabolism in Brassica napus seedlings

γ-aminobutyrate-transaminase (EC 2.6.1.19) catalyzes the first step of the catabolism of γ-aminobutyric acid (GABA), a non-protein amino acid well-known to accumulate in plant in response to environmental stimuli. Recent studies reinforce more and more the role of its metabolism in carbon and/or nitrogen metabolisms and as a signalling molecule in developmental processes. Here we investigated the effects of inhibition of γ-aminobutyrate-transaminase (GABA-T) in seedlings of Brassica napus, using vinyl-GABA (VGB) as a specific inhibitor of GABA-T to prevent enzyme activity. Root growth was reduced by 44% in VGB-treated seedlings but was less inhibited when VGB was associated with exogenous GABA and was not reduced with exogenous GABA alone. Measurements of GABA content in seedlings grown on VGB, GABA or VGB+GABA demonstrated that GABA level in root was not linked with the root length reduction, suggesting that GABA was not the sole component acting in root growth inhibition. Besides, metabolic profiling revealed that in root, VGB-treatment caused a twofold increase in content of almost all amino acids, except for alanine whose content was 19-fold higher than in control. In order to test the involvement of alanine accumulation on growth we studied the effects of exogenous alanine. High alanine content slightly reduced root growth suggesting that VGB-induced alanine accumulation was not responsible for root length reduction. We conclude that root growth inhibition in plants whose GABA catabolism was impaired could result at least partly from the disruption of the primary metabolism as a whole rather than direct effect of GABA on cellular growth process.

Safety and efficacy of ?-vinyl GABA (GVG) for the treatment of methamphetamine and/or cocaine addiction

This study examined the safety and efficacy of gamma vinyl-GABA (GVG, vigabatrin) for the treatment of methamphetamine and/or cocaine addiction. A total of 30 subjects, who met DSM-IV criteria for methamphetamine and/or cocaine dependence, were enrolled in an open label 9-week safety study. The protocol was specifically designed to include extensive visual field monitoring as well as outcome measures of therapeutic efficacy. Patients were screened twice weekly for the presence of urinary cocaine, methamphetamine, heroin, alcohol, and marijuana. In total, 18/30 subjects completed the study and 16/18 tested negative for methamphetamine and cocaine during the last 6 weeks of the trial. GVG did not produce any visual field defects or alterations in visual acuity. Furthermore, it did not produce changes in vital signs even with continued use of methamphetamine and cocaine. Thus, under conditions that appear to be appropriate for the successful treatment of methamphetamine and/or cocaine addiction, GVG is safe.

Synthesis of [5,6‐3H](.+‐.) Gamma Vinyl GABA.

Abstract An efficient synthesis of [5,6-3H] (+/−) gamma vinyl GABA 5 from 4-aminohex-5-ynoic acid 3 is described.

Synthesis of [5,6-3H](+/−) Gamma Vinyl GABA

An efficient synthesis of [5,6-3H] (+/−) gamma vinyl GABA 5 from 4-aminohex-5-ynoic acid 3 is described.

Gamma-vinyl GABA reduces paired pulse inhibition in the rat dentate gyrus in vivo and in vitro

Gamma vinyl GABA (GVG), an irreversible GABA transaminase inhibitor, has anticonvulsant effects. GVG increases GABA levels in the brain by blocking its degradation, and is presumed to enhance GABAergic inhibition, however, in some cases it exacerbates seizures. We investigated the effects of GVG in vivo and in vitro on paired pulse inhibition (PPI) recorded in the rat dentate gyrus (DG) evoked by perforant path stimulation. At 2.5 h and 24 h after administration of GVG (1 g/kg, i.p.), there was a loss of PPI at both 15- and 25-ms interpulse intervals (IPI). Activation of presynaptic GABA B autoreceptors could explain this in vivo effect. We therefore further investigated the effects of co-application of GVG with the GABA B antagonists 2-OH saclofen (saclofen) or CGP 35348 (CGP) on PPI in hippocampal slices by in vitro study. Bath application of GVG (400 and 500 μM) not only resulted in a loss of perforant path evoked PPI at a 15-ms IPI, but produced facilitation of the second population spike relative to the first. Co-application of saclofen (250 μM) with GVG (500 μM) prevented facilitation of the second response of a paired-pulse. The facilitation of the second stimulation response produced by GVG (400 μM) was converted to inhibition by bath application of CGP 35348 (400 μM). These results suggest that activation of presynaptic GABA B receptors by increased extracellular GABA may be one of the contributing factors to the apparent paradoxical effect of GVG on PPI in the DG.

Evidence that long-lasting potentiation of amygdala efferents in the right hemisphere underlies pharmacological stressor (FG-7142) induced lasting increases in anxiety-like behaviour: role of GABA tone in initiation of brain and behavioural changes.

The hypothesis that long-lasting potentiation (LLP) in amygdala efferents to the periacqueductal gray (PAG) of the right hemisphere mediates initiation of lasting increases in defensive response to rats induced by FG-7142 was supported in this study. GABA transmission was potentiated with Vigabatrin (gamma vinyl GABA, GVG), a suicide inhibitor of GABA transaminase. It was predicted that increasing GABA transmission would interfere with LLP and behavioural changes. The hypothesis was confirmed, for the most part. GVG given 1 day prior to FG-7142 prevented increased defensive response to rats as well as LLP in right amygdala efferent transmission to the PAG. It did not prevent LLP in the left amygdalo-PAG pathway, although LLP duration was shortened. Nor did it prevent LLP in the right amygdalo-ventromedial hypothalamic (VMH) pathway, and LLP in this pathway was associated with a slightly increased response to vocal threat, but not to rats. GVG given without FG-7142 had no behavioural effects, although it did potentiate transmission in the left amygdalo-PAG pathway. The effects of increasing GABA transmission are consistent with the hypothesis that FG-7142 changes behaviour by inducing a failure of GABA transmission, which in turn facilitates NMDA transmission and NMDA dependent limbic LLP. Finally, the hypothesis that altering GABA tone would change the efficacy of Flumazenil from a neutral antagonist to an inverse agonist was tested on limbic transmission. The hypothesis was confirmed in the left amygdalo-VMH pathway, but no other. It was concluded that mechanisms other than a change in GABA tone account for the drug-dependent reversal of LLP in the right amygdalo-PAG by Flumazenil. The findings of the present study suggest that response to FG-7142 may be a useful model of the effects of traumatic stressors on limbic system function in anxiety.

Afferent visual function after single dose application of -vinyl GABA

The authors studied the short term effects of a transient increase in global GABA on retinal functions. GABA is an inhibitory transmitter in the central nervous system and in the retina as well, γ-Vinyl GABA (GVG) irreversibly inhibits the GABA degrading enzyme GABA transaminase. It is known to reverse visual dysfunction induced by various conventional antiepileptic drugs. The authors performed a double-blind, placebo controlled cross-over study of visual functions on 24 healthy volunteers 24 hours after a single dose of 3 g GVG. The investigation included visual acuity, slit-lamp examination, fundoscopy, intraocular pressure, kinetic and static perimetry, spatial contrast sensitivity and color discrimination with pseu-doisochromatic plates and Farnsworth-Munsell 100 hue test. Clinical ophthalmologic examination did not show any significant abnormalities, both after placebo and GVG. Similarly, visual fields, color discrimination and contrast sensitivity were unaffected. In six subjects minor color discrim...

Vigabatrin as an Anticonvulsant Against Pentylenetetrazol Seizures

The anticonvulsant effects of gamma vinyl GABA (GVG) were investigated against pentylenetetrazol (PTZ) seizures, while sodium valproate (VP) was used as positive control. At 1000 and 1500 mg kg -1 GVG was found to decrease seizure intensity either in 4 or 24 h, as effectively as VP. At 2000 mg kg -1 GVG was found to be almost ineffective. At both doses and both time spans of drug action, seizure latency was prolonged, compared to controls and VP group.

Asymmetric synthesis of (S)-4-aminohex-5-enoic acid: a potent inhibitor of 4-aminobutyrate-2-oxoglutarate aminotransferase

The potent inhibitor of 4-aminobutyrate-2-oxoglutarate aminotransferase (GABA-T), 4-aminohex-5-enoic acid (vinyl GABA), has been synthesized with excellent enantioselectivity in six steps from L-glutamic acid in an overall yield of 33%. This is the most efficient synthesis of this important compound and illustrates the use of a novel alkenyl protecting group for pyroglutamate. This allowed the preparation and manipulation of the key (S)-2-oxopyrrolidine-5-carboxaldehyde intermediate

Gamma vinyl GABA in the treatment of levodopa-induced dyskinesias in Parkinson's disease.

Gamma vinyl GABA in the treatment of levodopa-induced dyskinesias in Parkinson's disease.

Effect of γ-vinyl γ -aminobutyric acid on the γ-aminobutyric acid receptor-coupled chloride ion channel in vesicles from the brain of the rat

The effect of γ -vinyl GABA on the γ-aminobutyric acid (GABA) receptor-coupled chloride ion (Cl −) channel was studied using membrane vesicles from cerebral cortex of the rat. γ-Vinyl GABA, an antiepileptic drug, had no effect on uptake of 36Cl −, without preincubation. However, preincubation of membrane vesicles with γ-vinyl GABA (100–1000μM) produced a concentration-dependent decrease in net uptake of 36Cl −. No alteration was observed in basal uptake of 36C1 −. This decrease in net uptake of 36C1 − was not related to desensitization induced by endogenous GABA, which might be increased by γ-vinyl GABA through selective, irreversible inhibition of GABA-transaminase (GABA-T). Concentration-response curves for GABA showed that preincubation with γ-vinyl GABA inhibited GABA-stimulated uptake of 36Cl − with no change in ED 50. These results indicate that γ-vinyl GABA may act directly at the GABA/benzodiazepine ionophore complex, as a non-competitive antagonist of GABA.

Specificity of vigabatrin for the GABAergic system in human epilepsy.

The therapeutic action of vigabatrin (gamma vinyl GABA, GVG) has been reported to be mediated by GABAergic neurotransmission. In the present study, we evaluated different neurotransmitter systems in the cerebrospinal fluid (CSF) of patients with complex partial epilepsy, before and during GVG treatment. The markers of the GABAergic system (free GABA, total GABA, homocarnosine) showed a two- to threefold elevation. There was also an increase in glycine during the 6 months of GVG treatment. In contrast, we did not find any constant CSF changes in either excitatory amino acids or in markers of the cholinergic (acetylcholinesterase), dopaminergic (homovanillic acid), serotonergic (5-hydroxyindoleacetic acid), or peptidergic (somatostatin, prolactin, beta-endorphin) systems. This finding (except an elevation in glycine) was in agreement with previous studies which suggest a specific action of GVG on the GABAergic system. The role of glycine in antiepileptic efficacy of GVG needs further evaluation.

Gamma Vinyl GABA: current role in the management of drug-resistant epilepsy.

The goal of management in epilepsy is to make patients completely seizure-free without side effects. Currently, this goal can be achieved fully in only about one-half of the 50,000,000 people in the world with epilepsy. Epilepsy is not a benign condition. Uncontrolled epilepsy produces significant morbidity and mortality. Even infrequent seizures put a patient at risk of sudden death and compromise employability and other social functions. The potential risk of a new antiepileptic drug has to be weighted against the potential risk of continuing seizures and the potential for the new drug to control those seizures. Vigabatrin (gamma vinyl GABA, GVG) is one of the promising new antiepileptic drugs now under development. In four large clinical trials half of the patients in each trial had a greater than or equal to 50% reduction in seizure frequency when GVG was added to existing antiepileptic drug. This represents a significant response rate in add-on trials, which are a severe test of a new antiepileptic drug. Although microvacuoles have been seen in the white matter of the brains of rats and dogs treated with GVG, such pathological changes have not yet been observed in humans. Evoked potential studies have failed to reveal any evidence of microvacuolization in humans. Because of the potential efficacy of GVG in controlling previously therapeutic-resistant seizures and of the absence of evidence of significant toxicity in humans, carefully monitored clinical trials of GVG in therapy-resistant patients with epilepsy should continue.

Pharmacokinetic effects of vigabatrin on cerebrospinal fluid amino acids in humans.

A study was conducted to assess the impact of single dosing and different dosing intervals of vigabatrin [gamma vinyl GABA (GVG)] in 11 patients with drug-resistant complex partial seizures. Cerebrospinal fluid (CSF) concentrations of total GABA, free GABA, homocarnosine, homovanillic acid (HVA), GVG, and 5-hydroxyindolacetic acid were measured up to seven days after a single dose. GVG levels were maximal within 24 h, suggesting that GVG acts to inhibit GABA-transaminase, and may also increase biogenic amines.

Effects of Long‐Term Vigabatrin on Somatosensory‐Evoked Potentials in Epileptic Patients

Vigabatrin (gamma vinyl GABA, GVG) has been shown to be an effective antiepileptic agent. GVG specifically and irreversibly inhibits GABA-transaminase (GABA-T). Long-term animal toxicology studies have demonstrated that GVG can induce nonprogressive, reversible intramyelinic edema in central white matter tracts. The response to GVG varies among species, with rodents being the most dramatic and monkeys showing an equivocal effect even at high doses. The response in dogs is marked and measurable. The detection of these subtle findings requires the use of sophisticated technology. Evoked potentials are becoming reliable and sensitive tools in clinical neurology. This study, involving 54 patients for 11 months, was undertaken to assess the effect and safety of GVG in humans with refractory epilepsy. No data from this investigation indicate prolongation of neuronal conduction time in CNS pathways, suggesting that this agent is safe in humans.

The neuropathology of vigabatrin.

Vigabatrin (gamma vinyl GABA, GVG), an enzyme-activated, irreversible inhibitor of GABA transaminase, was administered orally to rats, dogs, and monkeys to observe toxicologic reactions. Myelin vacuolation of the brain was observed. The vacuolation was limited to myelinated tracts and resulted from separation of the myelin sheath at the interperiod line. There was no evidence of demyelination, axonal degeneration, or damage uolation was histologically similar to that observed in association with other drugs such as triethyltin, isoniazid, or hexachlorophene. However, the distribution is limited to the brain and is reversible upon discontinuation of therapy. Two postmortem and three operative specimens from humans have revealed no evidence of vacuolation of myelin.

Long-term evaluation of vigabatrin (gamma vinyl GABA) in epilepsy.

In studies spanning more than 5 years, more than 1,100 patients with epilepsy have been treated with vigabatrin (gamma vinyl GABA, GVG). Sixty-two patients with partial seizures with secondary generalization took part in this trial: 41 patients continued in the trial after 19 months of treatment. After 36 months, the median percentage of baseline seizures was less than 20%. GVG is a very potent antiepileptic drug. It is well tolerated in humans. The side effects are few. Skin rash and other allergic reactions have rarely been seen. Tolerance to the sedative effect is in contrast to the lack of tolerance to the anti-epileptic effect.

GABA in Epilepsy: The Pharmacologic Basis

GABA transmission plays a key role in controlling seizure activity. The precise nature of its effect depends on the particular location in the brain and the pathway involved. Animal studies have helped to define specific brain regions such as the substantia nigra and area tempestas that are critical in controlling seizure activity. Antiepileptic drugs such as vigabatrin [gamma vinyl GABA (GVG)], a drug rationally developed to treat resistant epilepsy, can enhance GABA transmission in these regions and may thereby afford seizure protection.

ChemInform Abstract: Direct Regiospecific Allylic Amination via Silicon‐Induced Pericyclic Reactions. A Novel Synthesis of Gamma Vinyl GABA.

ChemInformVolume 19, Issue 45 Preparative Organic Chemistry ChemInform Abstract: Direct Regiospecific Allylic Amination via Silicon-Induced Pericyclic Reactions. A Novel Synthesis of Gamma Vinyl GABA. G. DELERIS, G. DELERIS Rech. Cardiol., INSERM, 33600 Pessac, Fr.Search for more papers by this authorJ. DUNOGUES, J. DUNOGUES Rech. Cardiol., INSERM, 33600 Pessac, Fr.Search for more papers by this authorA. GADRAS, A. GADRAS Rech. Cardiol., INSERM, 33600 Pessac, Fr.Search for more papers by this author G. DELERIS, G. DELERIS Rech. Cardiol., INSERM, 33600 Pessac, Fr.Search for more papers by this authorJ. DUNOGUES, J. DUNOGUES Rech. Cardiol., INSERM, 33600 Pessac, Fr.Search for more papers by this authorA. GADRAS, A. GADRAS Rech. Cardiol., INSERM, 33600 Pessac, Fr.Search for more papers by this author First published: November 8, 1988 https://doi.org/10.1002/chin.198845116Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat No abstract is available for this article. Volume19, Issue45November 8, 1988 RelatedInformation

Direct regiospecific allylic amination via silicon induced pericyclic reactions : A novel synthesis of gamma vinyl gaba

Silylation of the product of the ene reaction of N -sulphinylbenzene sulphonamide and an alkene induces a [2,3]sigmatropic rearrangement, leading to an allylamine derivative. The reaction is used in a synthesis of γ-vinyl GABA.