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Inhibition of peroxisomal beta-oxidation and brain development in rats
C Van den Branden1, G Dacremont, R Hooghe
1Menselijke Anatomie, Vrije Universiteit Brussel, Belgium.
Insights
Thioridazine inhibits peroxisomal beta-oxidation, altering brain fatty acid composition and myelin sheath thickness in developing rats. Despite causing undernourishment, it did not affect myelination markers typically seen in starvation.
Area of Science:
- Neuroscience
- Biochemistry
- Toxicology
Background:
- Peroxisomal beta-oxidation is crucial for fatty acid metabolism.
- Myelination is a critical developmental process in the central nervous system.
- Drug-induced metabolic alterations can impact neurodevelopment.
Purpose of the Study:
- To investigate the effects of thioridazine, a peroxisomal beta-oxidation inhibitor, on brain lipid metabolism and myelination in developing rats.
- To determine if thioridazine-induced changes mimic or differ from known effects of undernourishment on myelination.
Main Methods:
- Oral administration of thioridazine to nursing rats during peak pup myelination (postnatal days 8-21).
- Analysis of pup brain lipids for fatty acid accumulation.
- Histological examination of the corpus callosum for axon diameter and myelin sheath thickness.
- Assessment of body weight, brain weight, and liver peroxisome metabolism.
Main Results:
- Thioridazine administration led to the accumulation of C24 and C26 fatty acids in pup brain lipids, consistent with inhibited peroxisomal beta-oxidation.
- An altered relationship between axon diameter and myelin sheath thickness was observed in the corpus callosum of treated pups.
- Thioridazine induced severe reductions in body and brain weight, with liver peroxisomes exhibiting starvation-type metabolism.
- Key indicators of undernourishment-related myelination deficits, such as decreased myelin concentration and myelinated fiber percentage, were absent.
Conclusions:
- Thioridazine effectively inhibits peroxisomal beta-oxidation in the developing rat brain, leading to specific fatty acid accumulation and altered myelination.
- While thioridazine causes undernourishment, its impact on myelination differs from typical starvation effects, suggesting a direct drug-specific mechanism.
- These findings highlight the complex interplay between metabolic inhibition, drug-induced toxicity, and neurodevelopmental processes like myelination.
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.