Inhibition of peroxisomal beta‐oxidation and brain development in rats

Abstract

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.

Modulation of peroxisome proliferator‐activated receptor‐α activity by N‐acetyl cysteine attenuates inhibition of oligodendrocyte development in lipopolysaccharide stimulated mixed glial cultures

“…So far, peroxisomal dysfunction has been shown to be associated with several inherited metabolic diseases because of the deficiency of one or more peroxisomal proteins, and these defects are responsible for about 18 different fatal neurological disorders (Moser 1996, 1999). In addition, animal studies revealed that inhibition of VLCFAs β‐oxidation by thioridazine affects the rate of myelination in the developing brain (Van den Branden et al. 1989, 1990).…”

Lipopolysaccharide-induced peroxisomal dysfunction exacerbates cerebral white matter injury: Attenuation by N-acetyl cysteine

“…Peroxisomal dysfunctions manifested in inherited metabolic diseases due to one or more peroxisomal proteins deficiencies are thought to be responsible for ~ 18 unique fatal neurological disorders (Moser, 1996;Moser, 1999). Biochemical inhibition of VLC-fatty acid β-oxidation by thioridazine causing peroxisomal dysfunction has been shown to affect the rate of myelination in the developing brain (Van den Branden et al, 1989;Van den Branden et al, 1990). Moreover, neuroinflammation has been shown to cause peroxisomal dysfunction in the CNS of an animal model of multiple sclerosis .…”

Alterations in eighteen‐carbon saturated, monounsaturated and polyunsaturated fatty acid peroxisomal oxidation in mouse brain during development and aging

“…Moreover, a number of peroxisomal diseases in humans affect the fatty acid profile in the brain (1), and fatty acid analysis is the basis for diagnosis of peroxisomal disorders with neurological involvement (2). Only very limited information is available on eighteen-carbon atom However, it has been reported that stearic and lignoceric acids are oxidized in brain peroxisomes (3) and inhibition in vivo of peroxisomal oxidation induces alterations in rat brain development and changes in the brain fatty acid profile (4,5). Moreover, peroxisome proliferator-activated receptors are localized in the brain (6).…”