title: Vigabatrin-induced CNS changes in juvenile rats: Induction, progression and recovery of myelin-related changes.
abstract: The purpose of this study was to expand on the knowledge previously published on the central nervous system effects of Vigabatrin in juvenile animals. By employing extended sectioning of the brain and by using four different tissue staining techniques it is demonstrated that oral administration of Vigabatrin to juvenile rats (treatment periods of post-natal day (PND) 4-7, 7-14 or 14-30) will cause histological CNS changes at dose levels of 15 and 50mg/kg/day, but not at a dose level of 5mg/kg/day. No evidence of neuronal degeneration or gliosis was seen at any stage of treatment. Consistent with previous reports microvacuolation, as well as effects on myelination and on oligodendrocytes were recorded. The present study expands on these findings and demonstrates that the variation in the location of the vigabatrin-induced lesions in the juvenile rat brain (both neuropil vacuolation and reduction of myelin) appears to be consistent with the process of myelination: In the youngest animals (PND 4-7) myelination occurs mainly in the hind brain (medulla oblongata and pons) where neuropil vacuolations is recorded. In animals dosed during PNDs 7-14 or during PNDs 14-30, the first changes were found in the thalamus. It seems likely that the earlier stages of myelination are more vulnerable to treatment related effects and the swollen oligodendrocytes seen as the initial change in the thalamus in animals treated during PNDs 4-7 and 7-14 represents an early stage in the development of the myelin lesion which is seen later as neuropil vacuolation.
authors.affiliation: Department of Regulatory Toxicology & Safety Assessment, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark. Electronic address: adar@lundbeck.com.
authors.forename: Allan D
authors.initials: AD
authors.lastname: Rasmussen
authors.affiliation: Sequani Limited, Bromyard Road, Ledbury, Herefordshire HR8 1LH, UK.
authors.forename: Emily
authors.initials: E
authors.lastname: Richmond
authors.affiliation: Department of Regulatory Toxicology & Safety Assessment, H. Lundbeck A/S, Ottiliavej 9, DK-2500 Valby, Denmark.
authors.forename: Karen Malene
authors.initials: KM
authors.lastname: Wegener
authors.affiliation: Sequani Limited, Bromyard Road, Ledbury, Herefordshire HR8 1LH, UK.
authors.forename: Noel
authors.initials: N
authors.lastname: Downes
authors.affiliation: Sequani Limited, Bromyard Road, Ledbury, Herefordshire HR8 1LH, UK.
authors.forename: Pamela
authors.initials: P
authors.lastname: Mullins
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology*; D002490:Central Nervous System / Q000187:drug effects*; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D005911:Gliosis / Q000139:chemically induced*; D008297:Male; D009186:Myelin Sheath / Q000378:metabolism*; D019581:Neuropil / Q000187:drug effects; D051381:Rats; D012737:Sex Factors; D020888:Vigabatrin / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D020888:Vigabatrin
keywords: AED; Anti-epileptic drugs; Demyelination; Intra-myelinic edema; Microvacuolation