Sequential neuropathology of dogs treated with vigabatrin, a GABA- transaminase inhibitor

J. T. Yarrington, J. P. Gibson, J. E. Dillberger, G. Hurst, B. Lippert, N. M. Sussman, W. E. Heydorn, Ronald J Marler

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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 fornix, 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.

Original languageEnglish (US)
Pages (from-to)480-489
Number of pages10
JournalToxicologic Pathology
Volume21
Issue number5
StatePublished - 1993
Externally publishedYes

Fingerprint

4-Aminobutyrate Transaminase
Vigabatrin
gamma-Aminobutyric Acid
Dogs
Brain
Cerebrospinal fluid
Pharmaceutical Preparations
Cerebrospinal Fluid
Brain Fornix
Aminobutyrates
Drug and Narcotic Control
Brain Edema
Anorexia
Dietary Supplements
Thalamus
Hypothalamus
Vomiting
Rats
Epilepsy
Neuropathology

Keywords

  • γ-vinyl GABA
  • brain vacuolation
  • intramyelinic edema
  • reversibility

ASJC Scopus subject areas

  • Health, Toxicology and Mutagenesis
  • Pathology and Forensic Medicine
  • Toxicology

Cite this

Yarrington, J. T., Gibson, J. P., Dillberger, J. E., Hurst, G., Lippert, B., Sussman, N. M., ... Marler, R. J. (1993). Sequential neuropathology of dogs treated with vigabatrin, a GABA- transaminase inhibitor. Toxicologic Pathology, 21(5), 480-489.

Sequential neuropathology of dogs treated with vigabatrin, a GABA- transaminase inhibitor. / Yarrington, J. T.; Gibson, J. P.; Dillberger, J. E.; Hurst, G.; Lippert, B.; Sussman, N. M.; Heydorn, W. E.; Marler, Ronald J.

In: Toxicologic Pathology, Vol. 21, No. 5, 1993, p. 480-489.

Research output: Contribution to journalArticle

Yarrington, JT, Gibson, JP, Dillberger, JE, Hurst, G, Lippert, B, Sussman, NM, Heydorn, WE & Marler, RJ 1993, 'Sequential neuropathology of dogs treated with vigabatrin, a GABA- transaminase inhibitor', Toxicologic Pathology, vol. 21, no. 5, pp. 480-489.
Yarrington JT, Gibson JP, Dillberger JE, Hurst G, Lippert B, Sussman NM et al. Sequential neuropathology of dogs treated with vigabatrin, a GABA- transaminase inhibitor. Toxicologic Pathology. 1993;21(5):480-489.
Yarrington, J. T. ; Gibson, J. P. ; Dillberger, J. E. ; Hurst, G. ; Lippert, B. ; Sussman, N. M. ; Heydorn, W. E. ; Marler, Ronald J. / Sequential neuropathology of dogs treated with vigabatrin, a GABA- transaminase inhibitor. In: Toxicologic Pathology. 1993 ; Vol. 21, No. 5. pp. 480-489.
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