UNIPROT:P80404 - FACTA Search

Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P80404 (GABA transaminase)
786 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Gamma-vinyl GABA (GVG, Vigabatrin), an irreversible inhibitor of GABA transaminase (GABA-T) that inhibits cocaine-induced place preference and self administration has been proposed as a treatment for cocaine addiction. It was therefore important to assess if there was an enhanced toxicity from the combination of GVG with cocaine. No mortality was observed with administration of GVG (60 mg/kg i.v.) alone (n=8) or in combination (n=6) with cocaine (5 mg/kg i.v.). Cocaine-induced EKG alterations were not affected by GVG pretreatment. Plasma alanine amino transferase activity was reduced by GVG treatment and this was not further modified by cocaine administration. These results suggest that acute co-administration of GVG and cocaine does not result in immediate cardiovascular or hepatic toxicity of sufficient significance, to preclude further clinical trials.
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PMID:Co-administration of gamma-vinyl GABA and cocaine: preclinical assessment of safety. 1050 33

Vigabatrin is an antiepileptic drug for the treatment of partial seizures. The anticonvulsant effect is achieved by irreversible inhibition of the enzyme GABA-transaminase which catalyses the inactivation of GABA. Vigabatrin has been associated with visual field loss and electrophysiological abnormalities. The purpose of the study was to determine any alterations in normal volunteers of the visual field and the visual electrophysiology resulting from a short exposure to vigabatrin. A three-way, double-blind study of placebo, carbamazepine and vigabatrin was undertaken at baseline and on days two, four and nine. Seven subjects completed all three cycles and 14 subjects (six females and eight males; mean age 27.3 years SD 6.7) completed at least one cycle. Static threshold automated perimetry comprised Humphrey Visual Field Analyzer Programs 30-2 and 30/60-2. Electro-oculography and electroretinograms were performed with undilated pupils using the Medelec Ganzfeld stimulator GS2000. The visual field was unaffected by placebo, carbamazepine or vigabatrin. The group mean amplitudes and latencies for the scotopic ERG, 30 Hz flicker ERG and the oscillatory potentials remained unchanged for any cycle. The group mean photopic ERG b-wave latency increased from baseline (p<0.05); no significant change occurred with carbamazepine or placebo. The group mean Arden Index for vigabatrin decreased from baseline to day 9 (p<0.01); no significant differences were present for carbamazepine or placebo. Vigabatrin has a rapid effect on both the photopic ERG and the EOG; however, the changes merely reflect alterations in retinal GABA levels secondary to concomitant blocking of GABA transaminase by existing vigabatrin therapy.
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PMID:Visual electrophysiological effect of a GABA transaminase blocker. 1076 70

Vigabatrin (VGB) is a novel antiepileptic drug effective as adjunctive therapy in patients with partial seizures. In this study, the efficacy and tolerability of VGB as adjunctive therapy were evaluated in patients with refractory epilepsy. Adult patients with a definite diagnosis of complex partial seizures and/or partial seizures secondarily generalized were recruited from 10 Canadian centres. Patients were randomized to receive either active medication or placebo in a double- blind fashion and entered a 36-week titration and maintenance phase with regularly scheduled visits. Both efficacy parameters and safety assessments were monitored. Clinical laboratory, evoked potential studies, MRI, and neuropsychological tests were also performed. Forty-eight percent of VGB-treated patients vs. 26 percent of placebo-treated patients had a 50 percent or greater reduction in the frequency of complex partial seizures and partial seizures secondarily generalized. Vigabatrin was well tolerated by the majority of patients. Minor neurological side effects were observed in a number of patients in both treatment groups. No serious systemic toxicity was observed. No changes in evoked potential studies or MRI findings were noted. Vigabatrin was found to be an effective and well-tolerated antiepileptic drug when used as adjunctive therapy in patients with difficult to control complex partial seizures and for partial seizures secondarily generalized. Vigabatrin is a selective irreversible inhibitor of the GABA- degradating enzyme GABA transaminase and has shown efficacy in a number of clinical trials in patients with difficult to control partial seizures. Vigabatrin has been found most effective against complex partial and secondarily generalized tonic-clonic seizures in both adults and children. Vigabatrin has also been shown to reduce infantile spasms secondary to various aetiologies and is most effective in spasms associated with tuberous sclerosis. The aim of this study was to further extend the clinical experience with VGB as adjunctive therapy in the treatment of adult patients with difficult to control complex partial seizures and/or partial seizures secondarily generalized. In addition to the assessments of efficacy and tolerability to VGB, neuropsychological evaluations were also carried out.
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PMID:Vigabatrin as add-on therapy for adult complex partial seizures: a double-blind, placebo-controlled multicentre study. The Canadian Vigabatrin Study Group. 1077 31

Dopaminergic activity in the mesocorticolimbic system is associated with reinforcing properties of psychostimulant drugs. We previously demonstrated that increased gamma-aminobutyric acid (GABA)-ergic activity produced by gamma-vinyl GABA [D,L-4-amino-hex-5-enoic acid (Vigabatrin(R))], an irreversible inhibitor of GABA-transaminase, attenuated cocaine, nicotine, heroin, alcohol, and methamphetamine-induced increases in extracellular nucleus accumbens dopamine as well as behaviors associated with these biochemical changes. In the present study, using in vivo microdialysis techniques, we compared three different strategies to increase GABAergic activity in order to modulate cocaine-induced increase in extracellular dopamine. Our data demonstrate that the anticonvulsant 1-(2-(((diphenylmethylene)amino)oxy)ethyl)-1,2,5, 6-tetrahydro-3-pyridinecarboxylic acid hydrochloride (NNC-711), a GABA uptake inhibitor, dose and time dependently diminished increases in extracellular dopamine following acute cocaine challenge. Furthermore, we demonstrated that cyclized analogue of vigabatrin, a competitive reversible GABA-transaminase inhibitor, is a more potent inhibitor of cocaine-induced dopamine increase than vigabatrin. Our data suggest that in addition to irreversible inhibition of GABA transaminase, inhibition of GABA uptake represent another potentially effective, indirect strategy for the treatment of cocaine abuse.
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PMID:gamma-aminobutyric acid mimetic drugs differentially inhibit the dopaminergic response to cocaine. 1079 18

Human neocortical temporal lobe tissue resected for treatment of pharmacoresistant epilepsy was investigated. In slices prepared from this tissue, epileptiform field potentials (EFP) were induced by omission of magnesium from the artificial cerebrospinal fluid (ACSF). The effects of the gamma-aminobutyric acid transaminase inhibitor vigabatrin on EFP were tested. Vigabatrin exerted a dose-dependent reduction of the repetition rate of EFP: after 3 h of administration of vigabatrin in concentrations of 100 and 200 micromol/l, the repetition rate of EFP was reduced to 35% and 18% of the initial values, respectively. This effect was not reversible. In control experiments with neocortical slices from rats, vigabatrin reduced EFP in a comparable range. The results demonstrate a strong antiepileptic effect of vigabatrin on EFP in tissues from pharmacoresistant epilepsy patients.
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PMID:Vigabatrin reduces epileptiform activity in brain slices from pharmacoresistant epilepsy patients. 1092 22

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.
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PMID: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. 1119 49

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 gamma-vinyl GABA (vigabatrin; 0.05-100 microm) resulted in a large leak current that was blocked by bicuculline (50 microm). This leak current occurred in the absence of extracellular calcium and was blocked by the GABA transporter antagonist SKF-89976a (5 microm). 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 microm vigabatrin, at which time it reached an equivalent conductance of 9.0 +/- 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(+)](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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PMID:GABA transaminase inhibition induces spontaneous and enhances depolarization-evoked GABA efflux via reversal of the GABA transporter. 1130 16

gamma-Aminobutyric acid (GABA) is considered to be the major inhibitory neurotransmitter in the brain and loss of GABA inhibition has been clearly implicated in epileptogenesis. GABA interacts with 3 types of receptor: GABAA, GABAB and GABAC. The GABAA receptor has provided an excellent target for the development of drugs with an anticonvulsant action. Some clinically useful anticonvulsants, such as the benzodiazepines and barbiturates and possibly valproic acid (sodium valproate), act at this receptor. In recent years 4 new anticonvulsants, namely vigabatrin, tiagabine, gabapentin and topiramate, with a mechanism of action considered to be primarily via an effect on GABA, have been licensed. Vigabatrin elevates brain GABA levels by inhibiting the enzyme GABA transaminase which is responsible for intracellular GABA catabolism. In contrast, tiagabine elevates synaptic GABA levels by inhibiting the GABA uptake transporter, GAT1, and preventing the uptake of GABA into neurons and glia. Gabapentin, a cyclic analogue of GABA, acts by enhancing GABA synthesis and also by decreasing neuronal calcium influx via a specific subunit of voltage-dependent calcium channels. Topiramate acts, in part, via an action on a novel site of the GABAA receptor. Although these drugs are useful in some patients, overall, they have proven to be disappointing as they have had little impact on the prognosis of patients with intractable epilepsy. Despite this, additional GABA enhancing anticonvulsants are presently under development. Ganaxolone, retigabine and pregabalin may prove to have a more advantageous therapeutic profile than the presently licensed GABA enhancing drugs. This anticipation is based on 2 characteristics. First, they act by hitherto unique mechanisms of action in enhancing GABA-induced neuronal inhibition. Secondly, they act on additional antiepileptogenic mechanisms. Finally, CGP 36742, a GABAB receptor antagonist, may prove to be particularly useful in the management of primary generalised absence seizures. The exact impact of these new GABA-enhancing drugs in the treatment of epilepsy will have to await their licensing and a period of postmarketing surveillance. As to clarification of their role in the management of epilepsy, this will have to await further clinical trials, particularly direct comparative trials with other anticonvulsants.
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PMID:The new generation of GABA enhancers. Potential in the treatment of epilepsy. 1147 40

Vigabatrin increases gamma aminobutyric acid (GABA) levels by irreversible inhibition of the GABA-catabolizing enzyme GABA-transaminase (GABA-T). Preclinical studies suggest anxiolytic effects in vigabatrin treated rats. Anxiolytic effects in patients with panic disorder (PD) could therefore be expected. To evaluate putative anxiolytic properties of vigabatrin in humans, CCK-4-induced panic symptoms were studied in healthy volunteers before and after vigabatrin treatment. After placebo-controlled administration of 50 microg CCK-4, ten healthy volunteers received vigabatrin for seven days with a daily dosage of 2 g. The treatment period was followed by a second CCK-4 challenge. Panic and anxiety were assessed using the Acute Panic Inventory (API) score and a DSM-IV derived panic-symptom-scale (PSS). ACTH and cortisol plasma levels were determined during the CCK-4 challenge. All subjects reported a marked reduction of CCK-4-induced panic symptoms and anxiety after seven days of vigabatrin treatment both in the API- and PSS-scores. Moreover, there was a significant attenuation of CCK-induced elevation of ACTH and cortisol levels following vigabatrin treatment. In conclusion, our data show that GABA-transaminase inhibitors exert anxiolytic effects in CCK-4-induced panic in healthy volunteers and suggest that GABA transaminase inhibitors might be useful in ameliorating panic symptoms also in patients with PD.
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PMID:Vigabatrin decreases cholecystokinin-tetrapeptide (CCK-4) induced panic in healthy volunteers. 1168 53

Vigabatrin (VGB) was found to be an effective anti-epileptic drug to reduce infantile spasms in about 50% of patients and it has been found most effective in infantile spasms due to tuberous sclerosis (TSC) in which up to 95% of infants had complete cessation of their spasms. VGB was synthesized to enhance inhibitory gamma-aminobutyric acidergic (GABAergic) transmission by elevating GABA levels via irreversible inhibition of GABA transaminase. The mechanism underlying the particular efficacy of VGB in TSC is still unknown. However, its efficacy suggests that epileptogenesis in TSC may be related to an impairment of GABAergic transmission. VGB should be considered as the first line monotheraphy for the treatment of infantile spasms in infants with confirmed diagnosis of TSC. The efficacy of VGB treatment can be assessed in less than 10 days, but usually a few days treatment with a dose of about 100 mg/kg/day stops infantile spasms. The cessation of the spasms is associated with a marked improvement of behaviour and mental development. Unfortunately, it has become clear that the use of VGB is associated with a late appearance of visual-field defects in up to 50% of patients. Currently the minimum duration and doses of VGB treatment that can produce side effects are unknown. The feasibility of using short treatment periods (2-3 months) should be investigated.
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PMID:Vigabatrin for tuberous sclerosis complex. 1170 Dec 71

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