title: n-3 fatty acids effectively improve the reference memory-related learning ability associated with increased brain docosahexaenoic acid-derived docosanoids in aged rats.
abstract: We investigated whether a highly purified eicosapentaenoic acid (EPA) and a concentrated n-3 fatty acid formulation (prescription TAK-085) containing EPA and docosahexaenoic acid (DHA) ethyl ester could improve the learning ability of aged rats and whether this specific outcome had any relation with the brain levels of EPA-derived eicosanoids and DHA-derived docosanoids. The rats were tested for reference memory errors (RMEs) and working memory errors (WMEs) in an eight-arm radial maze. Fatty acid compositions were analyzed by GC, whereas brain eicosanoid/docosanoids were measured by LC-ESI-MS-MS-based analysis. The levels of lipid peroxides (LPOs) were measured by thiobarbituric acid reactive substances. The administration of TAK-085 at 300 mg·kg⁻¹day⁻¹ for 17 weeks reduced the number of RMEs in aged rats compared with that in the control rats. Both TAK-085 and EPA administration increased plasma EPA and DHA levels in aged rats, with concurrent increases in DHA and decreases in arachidonic acid in the corticohippocampal brain tissues. TAK-085 administration significantly increased the formation of EPA-derived 5-HETE and DHA-derived 7-, 10-, and 17-HDoHE, PD1, RvD1, and RvD2. ARA-derived PGE2, PGD2, and PGF2α significantly decreased in TAK-085-treated rats. DHA-derived mediators demonstrated a significantly negative correlation with the number of RMEs, whereas EPA-derived mediators did not exhibit any relationship. Furthermore, compared with the control rats, the levels of LPO in the plasma, cerebral cortex, and hippocampus were significantly reduced in TAK-085-treated rats. The findings of the present study suggest that long-term EPA+DHA administration may be a possible preventative strategy against age-related cognitive decline.
authors.affiliation: Department of Environmental Physiology, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan. Electronic address: michio1@med.shimane-u.ac.jp.
authors.forename: Michio
authors.initials: M
authors.lastname: Hashimoto
authors.affiliation: Department of Environmental Physiology, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Katakura
authors.affiliation: Department of Environmental Physiology, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tanabe
authors.affiliation: Department of Environmental Physiology, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Al Mamun
authors.affiliation: Department of Environmental Physiology, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Environmental Physiology, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan; Department of Biochemistry and Molecular Biology, Jahangirnagar University, Savar, Dhaka, Bangladesh.
authors.forename: Shahdat
authors.initials: S
authors.lastname: Hossain
authors.affiliation: Laboratory for Metabolomics, RIKEN Center for Integrative Medical Sciences (IMS), Yokohama-City, Kanagawa 230-0045, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Arita
authors.affiliation: Department of Environmental Physiology, Shimane University Faculty of Medicine, Izumo, Shimane 693-8501, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Shido
mesh_terms: D000367:Age Factors; D000375:Aging / Q000378:metabolism / Q000523:psychology*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003071:Cognition / Q000187:drug effects; D004281:Docosahexaenoic Acids / Q000097:blood / Q000494:pharmacology*; D004338:Drug Combinations; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects*; D018697:Nootropic Agents / Q000378:metabolism / Q000494:pharmacology*; D017208:Rats, Wistar; D013997:Time Factors
chemical_list: D004338:Drug Combinations; D018697:Nootropic Agents; C587319:TAK-085; D004281:Docosahexaenoic Acids; D016718:Arachidonic Acid; D015118:Eicosapentaenoic Acid
keywords: Aging; Brain; EPA and DHA; Memory; PUFA-derived mediators