4‐Amino‐hex‐5‐enoic Acid, a Selective Catalytic Inhibitor of 4‐Aminobutyric‐Acid Aminotransferase in Mammalian Brain

Lippert, Bruce; Metcalf, Brian W.; Jung, Michael J.; Casara, Patrick

doi:10.1111/j.1432-1033.1977.tb11410.x

Cited by 368 publications

(129 citation statements)

References 19 publications

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“…Vigabatrin (y-vinyl GABA or GVG) is a selective, enzyme-activated, irreversible inhibitor of GABAtransaminase (15,18), the enzyme primarily responsible for the catabolism of y-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian central nervous system. 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

119

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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 The intramyelinic edemia disappeared within a few weeks after treatment was withdrawn.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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Section: Introductionmentioning

confidence: 99%

Chronic Toxicity Studies with Vigabatrin, A GABA-Transaminase Inhibitor

Gibson¹,

Yarrington²,

Loudy³

et al. 1990

Toxicol Pathol

119

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“…A superficial section (less than 0.2 g) of the left temporal lobe of the cerebrum was removed within 3-4 min after exsanguination of anesthetized dogs and quickly frozen in liquid nitrogen. These samples were stored frozen at -80°C until assayed for GABA, GABA-T, and GAD (glutamate decarboxylase) according to methods previously used for brains of mice, rats, and monkeys (18)(19)(20)(21). GAD is the enzyme responsible for the synthesis of GABA in GABAergic neurons (12,20 (34), which included effects of sex and week of sacrifice.…”

Section: Introductionmentioning

confidence: 99%

Sequential Neuropathology of Dogs Treated with Vigabatrin, a GABA-Transaminase Inhibitor

Yarrington¹,

Gibson²,

Dillberger³

et al. 1993

Toxicol Pathol

Self Cite

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Vigabatrin (Sabril®) is a γ-aminobutyric acid-transaminase (GABA-T) inhibitor that is effective in the treatment of certain types of drug-resistant or uncontrolled epilepsy but is known to cause microscopic vacuolation (intramyelinic edema) in the brains of treated rats, mice, and dogs. The effects of high oral doses (300 mg/kg/day) of vigabatrin administered orally to Beagle dogs were studied during treatment weeks 1-12 and recovery weeks 13, 14, 16, 20, 24, and 28. Emesis, loose stools, and anorexia and 3 drug-related deaths were observed during the first 4 wk of treatment but were virtually nonexistent thereafter because of adaptation to the drug aided by food supplementation. In more sensitive areas of the brain (columns of the fomix, thalamus, and hypothalamus), microscopic quantitative differences between background vacuolation in controls and drug-related vacuolation in treated dogs could be delineated after 4 wk, generally reached highest levels of severity between 8 and 12 wk, and were reversible upon cessation of dosing. Inhibition of brain GABA-T and elevation of brain GABA were noted after 1 wk of treatment. During the course of treatment vigabatrin ranged between 4-17 nmol/ml (plasma) and 42-1,570 nmol/ml [cerebrospinal fluid (CSF)] while CSF GABA concentrations were 4-32 nmol/ml (treated dogs) and 0.1-0.6 nmol/ml (control dogs). Although the cause of vigabatrin-induced microvacuolation is unknown, the results of the study demonstrated that GABA-T inhibition with subsequent GABA elevation occurred within the first week of treatment and was followed by the onset of detectable microvacuolation several weeks later.

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“…As GABA-AT is a key enzyme involved in the GABA metabolic pathways and GABA shunt, the inhibitors of this enzyme can increase the level of GABA, and have a potency to cure some diseases derived from the decrease of GABA. After vigabatrin was used as an irreversible GABA-AT inhibitor to cure epilepsy in clinic [18] , many other GABA analogs were synthesized for the inhibitory evaluation of GABA-AT [16,[19][20][21][22][23][24][25][26][27] . Moreover, gabaculine, a naturally occurring neurotoxin produced by the bacteria Streptomyces toyocaensis No.…”

Section: Discussionmentioning

confidence: 99%

A New Inhibitor of γ-aminobutric Acid Aminotransferase from Streptomyces sp. ZZ035 Isolated from a Folk Medicinal Soil in China

Xu¹,

Wu²,

Yuan³

et al. 2017

ijSciences

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Strain ZZ035 was isolated from a folk medicinal soil in China. Polyphasic taxonomy procedure indicated that this strain belonged to the genus Streptomyces and was closest to S. cinnamonensis with high similarities (99.2%) of 16S rDNA sequence. 1 was isolated from the broth of this strain and identified as 5-amonimethyl-2-iminoimidazolidine-4-carboxylic acid. Its chemical structure was established by its spectroscopic data, and 1 H and 13 C signals were assigned by its 1 H, 13C, Dept and HSQC spectra. Considering that 1 was a γ-aminobutric acid (GABA) derivative, its inhibitory activity against GABA-aminotransferase (GABA-AT) was assayed, and the result showed that 1 can inhibit GABA-AT activity with the 50% inhibitory concentration of approximately 60 μM. As 1 was a 2,3-disubstituted GABA derivative not published before, the approximate GABA-AT inhibitory activity of 1 compared to positive control vigabatrin showed that 1 were worthy of further research and developing.

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4‐Amino‐hex‐5‐enoic Acid, a Selective Catalytic Inhibitor of 4‐Aminobutyric‐Acid Aminotransferase in Mammalian Brain

Cited by 368 publications

References 19 publications

Chronic Toxicity Studies with Vigabatrin, A GABA-Transaminase Inhibitor

Chronic Toxicity Studies with Vigabatrin, A GABA-Transaminase Inhibitor

Sequential Neuropathology of Dogs Treated with Vigabatrin, a GABA-Transaminase Inhibitor

A New Inhibitor of γ-aminobutric Acid Aminotransferase from Streptomyces sp. ZZ035 Isolated from a Folk Medicinal Soil in China

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