Low-dose vigabatrin (gamma-vinyl GABA)-induced damage in the immature rat brain.
The antiepileptic drug, vigabatrin, inhibits GABA transaminase, thus elevating GABA levels in the brain. In adult animal experiments, high-dose (200 mg/kg/day) chronic vigabatrin administration is associated with potentially reversible myelin vacuolation, a phenomenon not documented in humans. We hypothesized that vigabatrin might adversely affect myelination in the developing brain. Rats were given vigabatrin in doses comparable to those used clinically (15-50 mg/kg/day), from age 12 to 16 days. The rats were killed at age 19-20 days. We observed decreased myelin staining in the external capsule, axonal degeneration in white matter, evidence of glial cell death in the white matter, and reactive astrogliosis in the frontal cortex. We did not detect myelin vacuolation. These findings indicate that vigabatrin can have adverse and potentially irreversible effects on the developing rat brain. The mechanism of damage could be direct toxicity of vigabatrin or an indirect effect mediated through elevated GABA levels. Vigabatrin has been recommended as a treatment for some forms of childhood epilepsy; therefore, further studies are needed to assess the risks in children.
Sidhu
R S
RS
Institute for Biodiagnostics, National Research Council of Canada, Winnipeg, Canada.
Del Bigio
M R
MR
Tuor
U I
UI
Seshia
S S
SS
D000612:4-Aminobutyrate Transaminase / Q000037:antagonists & inhibitors*; D000818:Animals; D000927:Anticonvulsants / Q000008:administration & dosage / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000473:pathology; D001925:Brain Damage, Chronic / Q000139:chemically induced* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000633:toxicity*; D005911:Gliosis / Q000139:chemically induced / Q000473:pathology; D009186:Myelin Sheath / Q000187:drug effects / Q000473:pathology; D009410:Nerve Degeneration / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D010865:Pilot Projects; D051381:Rats; D017208:Rats, Wistar; D014617:Vacuoles; D020888:Vigabatrin; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000502:physiology / Q000633:toxicity
D000927:Anticonvulsants; D004791:Enzyme Inhibitors; D009419:Nerve Tissue Proteins; D005680:gamma-Aminobutyric Acid; D000612:4-Aminobutyrate Transaminase; D020888:Vigabatrin