Oral toxicity of vigabatrin in immature rats: characterization of intramyelinic edema.

Abstract Objectives Two toxicologic studies of vigabatrin were conducted with immature Sprague Dawley rats to characterize intramyelinic edema (IME) formation and assess potential impact on behavioral measures. Study 1 was a dosage-ranging characterization of overall toxicity of vigabatrin in young, developing rats. Study 2 evaluated vacuolar brain lesions found in Study 1. Methods During Study 1, immature Sprague Dawley rats were orally administered deionized water (vehicle control), or vigabatrin at 5, 15, or 50 mg/kg/day for ≤9 weeks, beginning at postnatal day 4 (PND 4) and followed by a recovery period. Toxicologic observations were collected, including adverse clinical signs, body weight gains, food consumption, ophthalmoloscopy, electroretinograms, sexual maturation, motor activity, memory, and learning behaviors. At sacrifice, CNS tissues were examined by light microscopy for evidence of IME. In Study 2, immature Sprague Dawley rats were again orally administered vigabatrin (50 mg/kg/day for ≤9 weeks, beginning at PND 4). At sacrifice, CNS tissues were examined by both light and transmission electron microscopy for evidence of IME. Results At 5–50 mg/kg/day, dosage-related reduced food consumption, decreased body weight, and delayed sexual maturation were found. Persisting through recovery, effects were more pronounced in males. Increased degrees of vacuolation were observed on PND 67 only after a dosage of 50 mg/kg/day, and were attenuated during recovery. Vacuolar-change morphology was characteristic of IME, with no evidence of cellular or neuritic degeneration. Ultrastructural analyses revealed brain vacuoles initiated as splits of myelin sheaths along intra-period lines. These splits expanded, evolving into large membrane-rich vacuoles, and were more prominent at later stages of myelin development. Hypomyelination and gliopathy were noted from PNDs 4–15, and were likely related to vigabatrin exposure during active myelination. A lesser degree of hypomyelination was observed from PNDs 4–46 and 4–65. Vacuolation was markedly attenuated in post-recovery–period rats. Conclusions The present studies indicated toxicities in young rats at vigabatrin dosages lower than those reported for toxicities in older rats. Dosages