Effect of long-term vigabatrin administration on the immature rat brain

Purpose: To determine whether the neuropathologic changes produced by vigabatrin (VGB; gamma-vinyl GABA) administration in the developing rat brain are reversible. Methods: We injected rats daily with VGB (25-40 mg/kg/day, s.c.) from age 12 days for 2 weeks followed by 2 weeks of a drug-free period. Behavioral testing, magnetic resonance (MR) imaging, biochemical assays, and histologic technique were used to assess the adverse effect of VGB in developing brain and its reversibility. Results: At the end of 2 weeks' VGB administration: (a) there was a hyperactivity and a shortened latency to escape out of cool water; (b) white matter appeared hyperintense in T-2 and diffusion-weighted MR images with LC 15% increases in T-2; (c) microvacuolation, TUNEL-positive nuclei, and swollen axons were observed in the corpus callosum; (d) myelin staining indicated a reduction in myelination, as did the reduction in activities of myelin and oligodendrocyte-associated enzymes and the decrease in myelin basic protein on Western blots. Two weeks after stopping VGB administration: (a) MR images were normal, and microvacuolation was no longer in the white matter; (b) reduction in myelination reversed partially; (c) the T-2 relaxation time remained elevated in the hypothalamus; and id) the behavioral response remained abnormal. Conclusions: Long-term VGB administration to young rats causes brain injury, which recovers partially on its cessation. The observed cell death, disrupted myelination, and alterations in behavior indicate a need for further safety assessment in infants and children.