The development of myelin in the brain of the juvenile rat.

The development process of myelination varies between region and species. Fully myelinated fibers are required if mammalian neural circuits are to function normally. Histology samples at staggered time points throughout the study were examined at days 4, 5, 7, 8, 10, 14, 17, 24, 37, and 44. We suggest that the development of myelin in the juvenile rodent brain can be conveniently separated into 3 phases. Evaluation of myelin basic protein-stained sections of the areas of brain that contain the elements of the developing limbic system over the sensitive period from postnatal day (PND) 14 to 34 may provide an insight into possible toxicity that may lead to cognition and learning issues in adults. We will hope to develop this notion further in the future. The precise chronology of the development of the blood-brain barrier in rats has yet to be established; thus, there is potential for significant exposure of the juvenile brain to chemicals that do not cross the blood-brain barrier in the adult. Thus, it is suggested that evaluation of myelin development should probably be extended to all new chemical entities intended for pediatric use, and not just those that are intended for central nervous system use.

Vigabatrin-induced CNS changes in juvenile rats: Induction, progression and recovery of myelin-related changes.

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.