The pharmacology of GABA-transaminase inhibitors

Palfreyman, Michael G.; Schechter, Paul J.; Buckett, W. R.; Tell, G.; Koch‐Weser, Jan

doi:10.1016/s0006-2952(81)80001-9

Cited by 115 publications

(24 citation statements)

References 76 publications

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“…To potentiate whole-brain GABAergic transmission, g-vinyl GABA (GVG, a specific suicide inhibitor of GABA amino-transferase, GABA-T; Jung et al, 1977) was administered 2.5 h prior to PCP administration. The inhibition of GABA-T has been shown to elevate GABA concentrations significantly in the human CNS, maximally between 2 and 4 h following parenteral administration (Palfreyman et al, 1981).…”

Section: Pharmacologic Treatment Strategymentioning

confidence: 99%

Positron Emission Tomography Studies of Potential Mechanisms Underlying Phencyclidine-Induced Alterations in Striatal Dopamine

Schiffer

Logan

Dewey

2003

Neuropsychopharmacol

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Positron emission tomography (PET), in combination with 11 C-raclopride, was used to examine the effects of phencyclidine (PCP) on dopamine (DA) in the primate striatum. In addition, we explored the hypotheses that GABAergic pathways as well as molecular targets beyond the N-methyl-D-aspartate (NMDA) receptor complex (ie dopamine transporter proteins, DAT) contribute to PCP's effects. In the first series of experiments, 11 C-raclopride was administered at baseline and 30 min following intravenous PCP administration. In the second series of studies, g-vinyl GABA (GVG) was used to assess whether enhanced GABAergic tone altered NMDA antagonistinduced changes in DA. Animals received an initial PET scan followed by pretreatment with GVG (300 mg/kg), then PCP 30 min prior to a second scan. Finally, we explored the possible contributions of DAT blockade to PCP-induced increases in DA. By examining 11 Ccocaine binding a paradigm in which PCP was coadministered with the radiotracer, we assessed the direct competition between these two compounds for the DAT. At 0.1, 0.5, and 1.0 mg/kg, PCP decreased 11 C-raclopride binding by 2.1, 14.9 7 2.2 and 8.18 7 1.1%, respectively. These effects were completely attenuated by GVG (3.38 7 3.1% decrease in 11 C-raclopride binding). Finally, PCP (0.5 mg/ kg) decreased 11 C-cocaine binding by 25.5 7 4.3%, while at 1.0 mg/kg this decrease was 13.5%, consistent with a competitive interaction at the DAT. These results suggest that PCP may be exerting some direct effects through the DAT and that GABA partially modulates NMDA-antagonist-induced increases in striatal DA.

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Section: Pharmacologic Treatment Strategymentioning

confidence: 99%

Positron Emission Tomography Studies of Potential Mechanisms Underlying Phencyclidine-Induced Alterations in Striatal Dopamine

Schiffer

Logan

Dewey

2003

Neuropsychopharmacol

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“…At one time it was proposed that the anticonvulsant activity of valproate could be attributed to inhibition of GABA-T, but this enzymic action is not now thought to be a significant effect of valproate in vivo (Chapman et al, 1982). It was the introduction of the irreversible or catalytic inhibitors of GABA-T that finally established the relationship between GABA-T inhibition and anticonvulsant action (Fowler & John, 1972;Anlezark et al, 1976;Palfreyman et al, 1981). The structures of some of these compounds are shown in Figure 1.…”

Section: Gaba-transaminase Inhibitorsmentioning

confidence: 99%

GABAergic mechanisms in the pathogenesis and treatment of epilepsy.

1989

Brit J Clinical Pharma

153

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1. Evidence relating to the role of GABA in the pathogenesis of epilepsy is reviewed. 2. Impaired GABAergic function appears to contribute to seizure susceptibility in a variety of genetically‐ determined syndromes in animals, e.g. genetically epilepsy prone rats showing sound‐induced seizures, gerbils with genetically determined epilepsy, and baboons, Papio papio, with photosensitive epilepsy. 3. In epilepsy secondary to a cerebral insult there is some morphological and biochemical evidence for impaired GABAergic function in experimental situations, but little definitive evidence in man. 4. Pharmacological approaches to enhancing GABAergic inhibition include the use of GABA agonists (or prodrugs), GABA‐transaminase inhibition, GABA uptake inhibition, and action at the GABA/benzodiazepine allosteric site. 5. Experimental data suggest that the best prospect for potent anticonvulsant action with fewest side effects (myoclonus, sedation, ataxia) is at present offered by GABA‐transaminase inhibitors or novel agents acting on the benzodiazepine receptor site.

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“…Animal studies have shown that elevation of brain GABA by this mechanism can prevent experimental seizures (2 1- 23,29), and clinical trials have shown vigabatrin to have beneficial eKects in 'certain types of drug re-sistant or uncontrolled epilepsy (4,8,20,26,31,32).…”

Section: Introductionmentioning

confidence: 99%

Chronic Toxicity Studies with Vigabatrin, A GABA-Transaminase Inhibitor

Gibson¹,

Yarrington²,

Loudy³

et al. 1990

Toxicol Pathol

118

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The GABA-transaminase inhibitor, vigabatrin, has been shown to have a rather low degree ofacute toxicity in several animal species. Oral administration ofthe drug at 1,000 mg/kg/day for 2 4 weeks caused decreased food consumption and weight loss with resultant prostration and death in both rats and dogs. Dosages of 200 mg/kg/day were tolerated for a year without clinical signs in dogs, although rats suffered reduced weight gains and convulsions after 3-4 months when given the drug in the diet. The convulsions continued to occur frequently throughout the one-yr study, but abated 3 4 months after cessation of treatment. The only consistent histopathologic evidence of toxicity in rats and dogs has been the finding of intramyelinic edema (microvacuolation) in the brain, most notably in certain areas ofwhite matter (cerebellum, reticular formation and optic tract in rats and columns of fornix and optic tract in dogs). No lesions were found in the spinal cord or peripheral nervous system. It took several weeks for the microvacuolation to develop, even at high dosages, but it did not continue to progress thereafter, even though a slight effect was noted at dosages as low as 30-50 mg/kg/day after one yr of treatment. The intramyelinic edemia disappeared within a few weeks after treatment was withdrawn. No residual effects were observed in dogs, whereas rats exhibited swollen axons and microscopic mineralized bodies in the cerebellum. Monkeys exhibited no adverse clinical effects except for occasional loose stools at 300 mg/kg/day. After 16 months of oral treatment at 300 m&g/day any suggestion of intramyelinic edema was considered to be equivocal, and there was no evidence of any erect in the 50 or 100 mg/kg/day monkeys after 6 yr of treatment. Higher doses caused chronic diarrhea, thus limiting the dosage in this species. Vigabatrin was shown to be well absorbed in rat, dog and man, whereas dose-limited absorption occurred in the monkey. Metabolism is practically nil in all 4 species and the primary elimination pathway is by glomerular filtration. Because vigabatrin is an irreversible inhibitor of GABA-transaminase and the enzyme has a slow turnover rate, plasma levels of the drug are not indicative of its pharmacologic activity. For this reason cerebrospinal fluid levels ofGABA and vigabatrin were evaluated, with considerable species differences being noted. The significance of these differences in relation to the differences in toxic response is discussed.

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The pharmacology of GABA-transaminase inhibitors

Cited by 115 publications

References 76 publications

Positron Emission Tomography Studies of Potential Mechanisms Underlying Phencyclidine-Induced Alterations in Striatal Dopamine

Positron Emission Tomography Studies of Potential Mechanisms Underlying Phencyclidine-Induced Alterations in Striatal Dopamine

GABAergic mechanisms in the pathogenesis and treatment of epilepsy.

Chronic Toxicity Studies with Vigabatrin, A GABA-Transaminase Inhibitor

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