title: Detection of Mild and Reversible Neurohistopathological Changes in the Brain of Juvenile (Preweaned) Beagle Dogs Treated with Vigabatrin for up to 91 Days.
abstract: Neurohistopathological changes in the brain were assessed in juvenile beagle dogs given vigabatrin at 30 or 100 mg/kg/day by oral gavage from postnatal day 22 (PND22) until 16 weeks of age (PND112), when brain myelination is considered to reach the adult stage in dogs. Separate subgroups were treated from PND22 to PND35 or PND36 to PND49 to assess early effects. In addition to extensive brain histopathology, there were assessments of toxicokinetics, clinical condition, body weight, organ weights, and macroscopic pathology. In animals treated for 14 days from PND22, minimal or slight vacuolation was seen in the neuropil of the septal nuclei, hippocampus, hypothalamus, thalamus, cerebellum, and globus pallidus at 100 mg/kg/day and minimal vacuolation in the thalamus, globus pallidus, and cerebellum at 30 mg/kg/day. In animals given 100 mg/kg/day for 91 days from PND22, minimal or slight vacuolation was observed only in the hippocampus, hypothalamus, and thalamus. No vigabatrin-related brain vacuolation was observed in animals given 30 or 100 mg/kg/day for 14 days from PND36. Clear evidence of recovery was observed after 14-day and 6-week off-dose periods that followed treatment from PND22 to PND35 or PND22 to PND112, respectively.
authors.affiliation: Huntingdon Life Sciences, Huntingdon, Cambridgeshire, UK.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Bottomley
authors.affiliation: Huntingdon Life Sciences, Eye, Suffolk, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Rowles
authors.affiliation: Huntingdon Life Sciences, Eye, Suffolk, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mitchell
authors.affiliation: H. Lundbeck A/S, Valby, Denmark adar@lundbeck.com.
authors.forename: Allan D
authors.initials: AD
authors.lastname: Rasmussen
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D001921:Brain / Q000187:drug effects* / Q000473:pathology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D020888:Vigabatrin / Q000633:toxicity*
chemical_list: D000927:Anticonvulsants; D020888:Vigabatrin
keywords: brain; dogs; juvenile; neuropil; recovery; vacuolation