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Effect of Long‐Term Vigabatrin Administration on the Immature Rat Brain
Author(s) -
Qiao M.,
Malisza K. L.,
Bigio M. R.,
Kozlowski P.,
Seshia S. S.,
Tuor U. I.
Publication year - 2000
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1157.2000.tb00225.x
Subject(s) - vigabatrin , white matter , corpus callosum , myelin , endocrinology , oligodendrocyte , myelin basic protein , medicine , magnetic resonance imaging , neuroscience , psychology , pathology , central nervous system , epilepsy , anticonvulsant , radiology
Summary:Purpose : To determine whether the neuropathologic changes produced by vigabatrin (VGB; γ‐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 4–15% 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 (d) 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.