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Nutritional Neurosciences

Chronic Administration of Docosahexaenoic Acid Ameliorates the Impairment of Spatial Cognition Learning Ability in Amyloid ß–Infused Rats

Michio Hashimoto^*,1, Yoko Tanabe^*,, Yoshimi Fujii^*, Toshihiko Kikuta^**, Hitoshi Shibata^** and Osamu Shido^*

^* Department of Environmental Physiology, Center for Integrated Research in Science, Shimane University Faculty of Medicine, Izumo 693-8501, Japan and ^** Department of Life Science and Biotechnology, Shimane University of Faculty of Life and Environmental Science, Matsue 690-8504, Japan

¹To whom correspondence should be addressed. E-mail: michio1{at}med.shimane-u.ac.jp.

We investigated whether administration of docosahexaenoic acid (DHA), a major (n-3) fatty acid of the brain, ameliorates the impairment of learning ability in an animal model of Alzheimer’s disease (AD), rats infused with amyloid-ß (Aß) peptide (1–40) into the cerebral ventricle. Inbred 3rd generation male rats (20 wk old) fed a fish oil–deficient diet were randomly divided into 4 groups: a vehicle group, an Aß peptide-infused group (Aß group), a DHA group, and an Aß + DHA group. A mini-osmotic pump filled with Aß peptide or vehicle was implanted in the rats, and they were tested for learning ability–related reference and working memory in an 8-arm radial maze. The rats were then orally fed DHA dissolved in 5% gum Arabic solution at 300 mg/(kg · d) (DHA and Aß + DHA groups) or vehicle alone (vehicle and Aß groups) and tested again for learning ability. DHA administered for 12 wk significantly reduced the increase in the number of reference and working memory errors in the Aß-infused rats, and increased both the cortico-hippocampal level of DHA and the molar ratio of DHA/arachidonic acid, suggesting an amelioration of the impaired spatial cognition learning ability. Furthermore, DHA suppressed the increases in the levels of lipid peroxide and reactive oxygen species in the cerebral cortex and the hippocampus of Aß-infused rats, suggesting that DHA increases antioxidative defenses. DHA is thus a possible therapeutic agent for ameliorating learning deficiencies due to Alzheimer’s disease.

KEY WORDS: • docosahexaenoic acid • therapeutic agent • spatial working memory • antioxidative defense • Alzheimer’s disease

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