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1. In the present study, we investigated the effect of docosahexaenoic acid (DHA) on spatial memory related learning ability in aged (100 weeks) male Wistar rats. 2. Rats were fed a fish oil-deficient diet through three generations and were then randomly divided into two groups. Over 10 weeks, one group was per orally administered 300 mg/kg per day DHA dissolved in 5% gum Arabic solution and the other group was administered the vehicle alone. Five weeks after the start of the administration, rats were tested with the partially baited eight-arm radial maze to estimate two types of spatial memory related learning ability displayed by reference memory error and working memory error. 3. Chronic administration of DHA significantly decreased the number of reference memory errors and working memory errors. 4. The level of lipid peroxide (LPO) in the hippocampus tended to decrease with chronic DHA administration and demonstrated a positive correlation with the number of reference memory errors. 5. These results suggest that the accumulation of hippocampal LPO reduces spatial memory related learning ability in aged rats. Moreover, chronic administration of DHA was effective in decreasing the level of hippocampal LPO, then improving learning ability.

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Fish oils have been shown to lower blood pressure in hypertensive subjects. To determine the mechanism of this hypotensive effect, we examined the effects of docosahexaenoic acid (DHA), one of the (n-3) polyunsaturated fatty acids in fish oil, on blood pressure and on the release of adenyl purines, such as ATP, ADP, AMP and adenosine, from the caudal arteries of aged rats. Aged female Wistar rats (100 wk) were fed a high cholesterol diet and were administered intragastrically ethyl all-cis-4,7,10,13,16,19-docosahexaenoate [300 mg/(kg.d)] for 12 wk (DHA group) or vehicle alone (control group). Compared with the controls, rats supplemented with DHA had significantly greater (10.1%) DHA concentrations in the caudal arteries. This was associated with more total (n-3) arterial fatty acids, a greater unsaturation index of arterial fatty acids, 43.9% lower plasma noradrenaline levels and the repression of the elevation in blood pressure observed with advancing age. The amount of purines released, both spontaneously and in response to noradrenaline, from arterial segments of DHA-supplemented rats was significantly higher than that released from tissues of control rats. Regression analysis revealed significant negative relationships between the total amount of purines released from the artery and the systolic (SBP) and diastolic (DBP) blood pressures. These results suggest that in aged rats, supplementation with DHA alters the membrane fatty acid composition as well as the amount of ATP released from vascular endothelial cells and decreases plasma noradrenaline, and that these factors may ameliorate the rise in blood pressure normally associated with advancing age.

We have previously reported that dietary docosahexaenoic acid (DHA) improves and/or protects against impairment of cognition ability in amyloid beta1‐40 (Aβ1‐40)‐infused Alzheimer’s disease (AD)‐model rats. Here, after the administration of DHA to AD model rats for 12 weeks, the levels of Aβ1‐40, cholesterol and the composition of fatty acids were investigated in the Triton X100‐insoluble membrane fractions of their cerebral cortex. The effects of DHA on the in vitro formation and kinetics of fibrillation of Aβ1‐40 were also investigated by thioflavin T fluorescence spectroscopy, transmission electron microscopy and fluorescence microscopy. Dietary DHA significantly decreased the levels of Aβ1‐40, cholesterol and saturated fatty acids in the detergent insoluble membrane fractions of AD rats. The formation of Aβ fibrils was also attenuated by their incubation with DHA, as demonstrated by the decreased intensity of thioflavin T‐derived fluorescence and by electron micrography. DHA treatment also decreased the intensity of thioflavin fluorescence in preformed‐fibril Aβ peptides, demonstrating the anti‐amyloidogenic effects of DHA. We then investigated the effects of DHA on the levels of oligomeric amyloid that is generated during its in vitro transformation from monomers to fibrils, by an anti‐oligomer‐specific antibody and non‐reducing Tris‐Glycine gradient (4–20%) gel electrophoresis. DHA concentration‐dependently reduced the levels of oligomeric amyloid species, suggesting that dietary DHA‐induced suppression of in vivo Aβ1‐40 aggregation occurs through the inhibitory effect of DHA on oligomeric amyloid species.

Female Wistar rats (100 weeks old) were divided into two groups; one group was fed a high-cholesterol diet (HC) and the other a high-cholesterol diet plus docosahexaenoic acid (HC-fed DHA rats). Fatty acid concentrations in brain tissues were analyzed by gas chromatography. In the HC-fed DHA rats, brain catalase (CAT), GSH, and glutathione peroxidase (GPx) increased in the cerebrum but not in the brainstem or cerebellum. The rate of increase was 23.0% for CAT, 24.5% for GSH, and 26.3% for GPx compared with that in the HC animals ( p Ͻ 0.05). In the cerebrum of the HC-fed DHA rats, CAT and GPx increased, with an increase in the ratio of DHA to arachidonic acid. The cerebrum, unlike the other areas of the brain, seems to be more sensitive to DHA in stimulating CAT and GPx. We suggest that DHA plays an important role in inducing an antioxidative defense against active oxygen by enhancing the cerebral activities of CAT, GPx, and GSH. Key Words: Docosahexaenoic acid-Arachidonic acid-Lipid peroxide-Reactive oxygen species-Antioxidative enzymes-Rat brain.

To characterize the functional differentiation of neural stem cells into smooth muscle cells, multipotent stem cells in the central nervous system (CNS) were isolated from rat embryonic day 14 (E14) cortex and cultured by neurosphere formation in serum‐free medium in the presence of 10 ng ml−1 of basic fibroblast growth factor. Differentiation was induced by the addition of 10 % fetal bovine serum to low‐density cultures (2.5 × 103 cells cm−2). Immunological analyses and reverse transcriptase‐polymerase chain reaction indicated that the differentiated cells expressed smooth‐muscle‐specific marker proteins such as SM‐1, SM‐2, and SMemb myosin heavy chains, SM‐22, basic calponin and α‐smooth‐muscle actin, but not the astrocyte marker glial fibrillary acidic protein. To examine whether smooth‐muscle‐like cells that are differentiated from CNS stem cells possess the characteristics of contractile smooth muscle, we prepared reconstituted collagen gel fibres and measured their contractile tension. The reconstituted fibres were prepared by thermal gelation of collagen and the differentiated cells. The fibres contracted in response to treatment with KCl (80 mm), ACh (100 μm), endothelin‐1 (10 nm), endothelin‐2 (10 nm), and prostaglandin F2α (100 μm). ACh‐induced contraction was partially inhibited by the L‐type voltage‐dependent Ca2+ channel inhibitor nifedipine and by the intracellular Ca2+ chelator 1,2‐bis (2‐aminophenoxy) ethane‐N,N,N’,N'‐tetraacetic acid acetoxymethyl ester, the myosin light chain kinase inhibitor ML‐9, the Rho kinase inhibitor Y‐27632, dibutyryl cAMP and 8‐bromo‐cGMP. These results suggest that CNS stem cells give rise to smooth muscle cells in vitro that have an identical contractile function to smooth muscle in vivo.

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