N-3 fatty acids effectively improve the reference memory-related learning ability associated with increased brain docosahexaenoic acid-derived docosanoids in aged rats

Michio Hashimoto, Masanori Katakura, Yoko Tanabe, Abdullah Al Mamun, Takayuki Inoue, Shahdat Hossain, Makoto Arita, Osamu Shido

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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- 1 day- 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 PGF 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.

Original languageEnglish
Pages (from-to)203-209
Number of pages7
JournalBiochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
Issue number2
Publication statusPublished - 2015
Externally publishedYes



  • Aging
  • Brain
  • EPA and DHA
  • Memory
  • PUFA-derived mediators

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Medicine(all)

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