Inhibition of peroxisomal beta-oxidation and brain development in rats

Thioridazine, an inhibitor of peroxisomal beta-oxidation, was administered orally to nursing rats during the period of maximal myelination in the pups (8-21 days postnatally). Under the experimental conditions, thioridazine causes accumulation of C24 and C26 fatty acids in pup brain lipids, an effect we consider to be a typical consequence of inhibited peroxisomal beta-oxidation. In the corpus callosum of treated pups, the relationship between axon diameter and myelin sheath thickness is altered compared with matched controls. Thioridazine also induces undernourishment effects in 21 day-old rats. Body and brain weight are severely reduced. Liver peroxisomes show a starvation-type metabolism. Undernourishment is known to influence myelination in developing rat brain. However, known consequences of undernourishment, such as decreased myelin concentration in whole brain, decreased percentage of myelinated fibers, and decreased granule-to-Purkinje cell ratio are not present.