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

Purpose: To determine whether the neuropathologic changes produced by vigab atrin (VGB; gamma-vinyl GABA) administration in the developing rat brain ar e reversible. Methods: We injected rats daily with VGB (25-40 mg/kg/day, s.c.) from age 1 2 days for 2 weeks followed by 2 weeks of a drug-free period. Behavioral te sting, 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 hyperac tivity and a shortened latency to escape out of cool water; (b) white matte r 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 an d oligodendrocyte-associated enzymes and the decrease in myelin basic prote in on Western blots. Two weeks after stopping VGB administration: (a) MR im ages 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 rem ained abnormal. Conclusions: Long-term VGB administration to young rats causes brain injury , which recovers partially on its cessation. The observed cell death, disru pted myelination, and alterations in behavior indicate a need for further s afety assessment in infants and children.