No abstract

Docosahexaenoic acid (C22:6, n-3), a major n-3 fatty acid of the brain, has been implicated in restoration and enhancement of memory-related functions. Because Alzheimer's disease impairs memory, and infusion of amyloid-b (Ab) peptide (1-40) into the rat cerebral ventricle reduces learning ability, we investigated the effect of dietary pre-administration of docosahexaenoic acid on avoidance learning ability in Ab peptide-produced Alzheimer's disease model rats. After a mini-osmotic pump filled with Ab peptide or vehicle was implanted in docosahexaenoic acid-fed and control rats, they were subjected to an active avoidance task in a shuttle avoidance system apparatus. Pre-administration of docosahexaenoic acid had a profoundly beneficial effect on the decline in avoidance learning ability in the Alzheimer's disease model rats, associated with an increase in the cortico-hippocampal docosahexaenoic acid/arachidonic acid molar ratio, and a decrease in neuronal apoptotic products. Docosahexaenoic acid pre-administration furthermore increased cortico-hippocampal reduced glutathione levels and glutathione reductase activity, and suppressed the increase in lipid peroxide and reactive oxygen species levels in the cerebral cortex and hippocampus of the Alzheimer's disease model rats, suggesting an increase in antioxidative defence. Docosahexaenoic acid is thus a possible prophylactic means for preventing the learning deficiencies of Alzheimer's disease.

Insulin resistance is a major cause of type 2 diabetes mellitus (T2DM). Resistin, an adipocyte-secreted hormone, antagonizes insulin. Transgenic mice that overexpress the resistin gene (Retn) in adipose tissue are insulin-resistant, whereas Retn (-/-) mice show lower fasting blood glucose, suggesting that the altered Retn promoter function could cause diabetes. To determine the role of RETN in human T2DM, we analyzed polymorphisms in its 5' flanking region. We found that the -420G/G genotype was associated with T2DM (397 cases and 406 controls) (P=.008; adjusted odds ratio = 1.97 [by logistic regression analysis]) and could accelerate the onset of disease by 4.9 years (P=.006 [by multiple regression analysis]). Meta-analysis of 1,888 cases and 1,648 controls confirmed this association (P=.013). Linkage disequilibrium analysis revealed that the -420G/G genotype itself was a primary variant determining T2DM susceptibility. Functionally, Sp1 and Sp3 transcription factors bound specifically to the susceptible DNA element that included -420G. Overexpression of Sp1 or Sp3 enhanced RETN promoter activity with -420G in Drosophila Schneider line 2 cells that lacked endogenous Sp family members. Consistent with these findings, fasting serum resistin levels were higher in subjects with T2DM who carried the -420G/G genotype. Therefore, the specific recognition of -420G by Sp1/3 increases RETN promoter activity, leading to enhanced serum resistin levels, thereby inducing human T2DM.

N-(6-Aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) and its derivatives are putative calmodulin antagonists that bind to calmodulin and inhibit Ca2+/calmodulin-regulated enzyme activities. Autoradiographic studies using tritiated W-7 showed that this compound penetrates the cell membrane, is distributed mainly in the cytoplasm, and inhibits proliferation of Chinese hamster ovary K1 (CHO-K1) cells. Cytoplasmic [3H]W-7 was excluded completely within 6 hr after removal of [3H]W-7 from the culture medium. N-(6-aminohexyl)-1-naphthalenesulfonamide, an analogue of W-7 that interacts only weakly with calmodulin, proved to be a much weaker inhibitor of cell proliferation. CHO-K1 cells were synchronized by shaking during mitosis and then released into the cell cycle in the presence of 25 microM W-7 or 2.5 mM thymidine for 12 hr. Cell division was observed approximately 6 hr later. The results suggest that the effect of W-7 on cell proliferation might be through selective inhibition of the G1/S boundary phase, which is similar to the effect of excess thymidine. This pharmacological demonstration that cytoplasmic calmodulin is involved in cell proliferation is significant; W-7 and its derivatives may be useful tools for research on calmodulin and cell biology-related studies.

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-beta (Abeta) 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 Abeta peptide-infused group (Abeta group), a DHA group, and an Abeta + DHA group. A mini-osmotic pump filled with Abeta 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 Abeta + DHA groups) or vehicle alone (vehicle and Abeta 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 Abeta-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 Abeta-infused rats, suggesting that DHA increases antioxidative defenses. DHA is thus a possible therapeutic agent for ameliorating learning deficiencies due to Alzheimer's disease.