Effect of long-term vigabatrin administration on the immature rat brain.
OBJECTIVE
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 T2 and diffusion-weighted MR images with 4-15% increases in T2; (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 T2 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.
Qiao
M
M
Institute for Biodiagnostics, National Research Council of Canada, and Departments of Pathology, University of Manitoba, Winnipeg, Manitoba, Canada.
Malisza
K L
KL
Del Bigio
M R
MR
Kozlowski
P
P
Seshia
S S
SS
Tuor
U I
UI
D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000254:growth & development* / Q000473:pathology; D001927:Brain Diseases / Q000139:chemically induced / Q000473:pathology; D016923:Cell Death / Q000187:drug effects; D008279:Magnetic Resonance Imaging / Q000706:statistics & numerical data; D009186:Myelin Sheath / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020888:Vigabatrin / Q000009:adverse effects / Q000494:pharmacology*
D000927:Anticonvulsants; D020888:Vigabatrin