title: The omega-3 fatty acid eicosapentaenoic acid accelerates disease progression in a model of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a progressive fatal neurodegenerative disease characterised by loss of motor neurons that currently has no cure. Omega-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA), have many health benefits including neuroprotective and myoprotective potential. We tested the hypothesis that a high level of dietary EPA could exert beneficial effects in ALS. The dietary exposure to EPA (300 mg/kg/day) in a well-established mouse model of ALS expressing the G93A superoxide dismutase 1 (SOD1) mutation was initiated at a pre-symptomatic or symptomatic stage, and the disease progression was monitored until the end stage. Daily dietary EPA exposure initiated at the disease onset did not significantly alter disease presentation and progression. In contrast, EPA treatment initiated at the pre-symptomatic stage induced a significantly shorter lifespan. In a separate group of animals sacrificed before the end stage, the tissue analysis showed that the vacuolisation detected in G93A-SOD1 mice was significantly increased by exposure to EPA. Although EPA did not alter motor neurone loss, EPA reversed the significant increase in activated microglia and the astrocytic activation seen in G93A-SOD1 mice. The microglia in the spinal cord of G93A-SOD1 mice treated with EPA showed a significant increase in 4-hydroxy-2-hexenal, a highly toxic aldehydic oxidation product of omega-3 fatty acids. These data show that dietary EPA supplementation in ALS has the potential to worsen the condition and accelerate the disease progression. This suggests that great caution should be exerted when considering dietary omega-3 fatty acid supplements in ALS patients.
authors.affiliation: Blizard Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Ping K
authors.initials: PK
authors.lastname: Yip
authors.forename: Chiara
authors.initials: C
authors.lastname: Pizzasegola
authors.forename: Stacy
authors.initials: S
authors.lastname: Gladman
authors.forename: Maria Luigia
authors.initials: ML
authors.lastname: Biggio
authors.forename: Marianna
authors.initials: M
authors.lastname: Marino
authors.forename: Maduka
authors.initials: M
authors.lastname: Jayasinghe
authors.forename: Farhan
authors.initials: F
authors.lastname: Ullah
authors.forename: Simon C
authors.initials: SC
authors.lastname: Dyall
authors.forename: Andrea
authors.initials: A
authors.lastname: Malaspina
authors.forename: Caterina
authors.initials: C
authors.lastname: Bendotti
authors.forename: Adina
authors.initials: A
authors.lastname: Michael-Titus
mesh_terms: D000284:Administration, Oral; D000690:Amyotrophic Lateral Sclerosis / Q000097:blood / Q000473:pathology* / Q000503:physiopathology; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019587:Dietary Supplements; D004195:Disease Models, Animal; D018450:Disease Progression; D015118:Eicosapentaenoic Acid / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D005260:Female; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects; D009046:Motor Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D050505:Mutant Proteins / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D016019:Survival Analysis; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; C000606290:SOD1 protein, human; C002744:3-nitrotyrosine; D014443:Tyrosine; D015118:Eicosapentaenoic Acid; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1