A Study of the Effects of Vigabatrin on the Central Nervous System and Retina of Sprague Dawley and Lister-Hooded Rats

Abstract

Vigabatrin (gamma-vinyl GABA), an enzyme-activated, irreversible inhibitor of GABA transaminase, was administered orally to albino Sprague Dawley and pigmented Lister-Hooded rats. A dose-dependent retinal lesion characterized histologically by disruption of the outer nuclear layer was observed in the Sprague Dawley rat but not in Lister-Hooded rats, indicating that this alteration is related to the absence of pigment. The lesion is similar to that induced in albino rats by light and certain drugs. In addition, myelin vacuolation of the brain was observed in both rat strains, consistent with the findings of other toxicity studies with vigabatrin. In all cases, the vacuolation was limited to myelinated tracts and resulted from separation of the myelin sheath at the intraperiod line. There was no evidence of demyelination, axonal degeneration or damage to contiguous structures in the affected areas. The vacuolation is histologically similar to that induced in rats by certain other compounds such as isoniazid, hexachlorophene, and triethyltin, but differs in that it is focal in distribution, it is limited to the brain, and is reversible upon cessation of treatment.

Acute Vigabatrin Retinotoxicity in Albino Rats Depends on Light But Not GABA

“…Our results extend the findings of Butler et al (27), who reported that systemic administration of VGB to Sprague-Dawley rats for 90 days produces retinotoxicity. Butler et al posited that light exposure might play a role in this subacute toxicity, but they did not investigate this possibility.…”

“…The damage to the outer retina we observed with brief systemic administration of VGB is similar to that observed with repeated systemic administration over a 90-day period (27). Although both brief and subacute systemic administration of VGB caused less damage than directly applying VGB to an isolated retina, the damage occurred in the outer retina in all cases.…”

“…We investigated whether VGB produces acute retinotoxicity because retinal VGB and GABA levels increase 2 to 4 h after intraperitoneal injections of VGB in Sprague-Dawley rats (25,26). We examined the role of light because oral administration of VGB for 90 days produced disorganization of the outer nuclear layer of the retinas in Sprague-Dawley (albino) but not in Lister-Hooded (pigmented) rats (27). Although another study found no retinal lesions after administering VGB orally for 1 year to CD[SD]BR (albino) rats, this study also hypothesized that light has a critical role in VGB retinotoxicity (28).…”

Neuropathology of vigabatrin.

“…In addition to routine assessment of paraffin-embedded sections, selected rats have been perfused for study by electron microscopy. These studies (Yarrington et al, 1985;Butler et al, 1987) show that the myelin vacuolation has resulted from separation of myelin lamellae at the intraperiod line, i.e., the membrane formed from fusion of the surface membranes of encircling oligodentrocyte cytoplasm. While identical intramyelinic oedema follows exposure to hexachlorophene (Towfighi et al, 1973), triethyltin (Aleu et al, 1963), and isoniazid (Carlton & Kreutzberg, 1966) (Butler et al, 1987 …”

Effects of vigabatrin on evoked potentials in dogs.

“…Vigabatrin (y-vinyl GABA) is an enzyme-activated, irreversible, GABA-T inhibitor that has shown considerable promise in single and double-blind studies for the treatment seizure disorders in man (Gram et al, 1983;Rimmer & Richens, 1984;Browne et al, 1987). However, the clinical utility of this compound is potentially limited by the observation of microvacuolation within select CNS fibre tracts at high dose levels in the mouse, rat and dog (Yarrington et al, 1985; Butler et al, 1987).…”