1. Dietary Supplementation with n-3 Polyunsaturated Fatty Acids Delays the Phenotypic Manifestation of Krabbe Disease and Partially Restores Lipid Mediator Production in the Brain-Study in a Mouse Model of the Disease.
- Author
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Signorini C, Pannuzzo G, Graziano ACE, Moretti E, Collodel G, and Cardile V
- Subjects
- Animals, Mice, Phenotype, Docosahexaenoic Acids pharmacology, Docosahexaenoic Acids metabolism, Lipid Metabolism drug effects, Dinoprost analogs & derivatives, Dinoprost metabolism, Male, Dietary Supplements, Fatty Acids, Omega-3 metabolism, Fatty Acids, Omega-3 pharmacology, Fatty Acids, Omega-3 administration & dosage, Disease Models, Animal, Brain metabolism, Brain drug effects, Leukodystrophy, Globoid Cell diet therapy, Leukodystrophy, Globoid Cell metabolism, Leukodystrophy, Globoid Cell drug therapy, Leukodystrophy, Globoid Cell genetics
- Abstract
Lipid mediators from fatty acid oxidation have been shown to be associated with the severity of Krabbe disease (KD), a disorder linked to mutations in the galactosylceramidase ( GALC ) gene. This study aims to investigate the effects of n-3 polyunsaturated fatty acid (PUFA) supplementation on KD traits and fatty acid metabolism using Twitcher (Tw) animals as a natural model for KD. Wild-type (Wt), heterozygous (Ht), and affected Tw animals were treated orally with 36 mg n-3 PUFAs/kg body weight/day from 10 to 35 days of life. The end product of PUFA peroxidation (8-isoprostane), the lipid mediator involved in the resolution of inflammatory exudates (resolvin D1), and the total amount of n-3 PUFAs were analyzed in the brains of mice. In Tw mice, supplementation with n-3 PUFAs delayed the manifestation of disease symptoms ( p < 0.0001), and in the bran, decreased 8-isoprostane amounts ( p < 0.0001), increased resolvin D1 levels ( p < 0.005) and increased quantity of total n-3 PUFAs ( p < 0.05). Furthermore, total brain n-3 PUFA levels were associated with disease severity (r = -0.562, p = 0.0001), resolvin D1 (r = 0.712, p < 0.0001), and 8-isoprostane brain levels (r = -0.690, p < 0.0001). For the first time in a natural model of KD, brain levels of n-3 PUFAs are shown to determine disease severity and to be involved in the peroxidation of brain PUFAs as well as in the production of pro-resolving lipid mediators. It is also shown that dietary supplementation with n-3 PUFAs leads to a slowing of the phenotypic presentation of the disease and restoration of lipid mediator production.
- Published
- 2024
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