Masanori Kontani

Arachidonic acid drives postnatal neurogenesis and elicits a beneficial effect on prepulse inhibition, a biological trait of psychiatric illnesses.

Prepulse inhibition (PPI) is a compelling endophenotype (biological markers) for mental disorders including schizophrenia. In a previous study, we identified Fabp7, a fatty acid binding protein 7 as one of the genes controlling PPI in mice and showed that this gene was associated with schizophrenia. We also demonstrated that disrupting Fabp7 dampened hippocampal neurogenesis. In this study, we examined a link between neurogenesis and PPI using different animal models and exploring the possibility of postnatal manipulation of neurogenesis affecting PPI, since gene-deficient mice show biological disturbances from prenatal stages. In parallel, we tested the potential for dietary polyunsaturated fatty acids (PUFAs), arachidonic acid (ARA) and/or docosahexaenoic acid (DHA), to promote neurogenesis and improve PPI. PUFAs are ligands for Fabp members and are abundantly expressed in neural stem/progenitor cells in the hippocampus. Our results are: (1) an independent model animal, Pax6 (+/−) rats, exhibited PPI deficits along with impaired postnatal neurogenesis; (2) methylazoxymethanol acetate (an anti-proliferative drug) elicited decreased neurogenesis even in postnatal period, and PPI defects in young adult rats (10 weeks) when the drug was given at the juvenile stage (4–5 weeks); (3) administering ARA for 4 weeks after birth promoted neurogenesis in wild type rats; (4) raising Pax6 (+/−) pups on an ARA-containing diet enhanced neurogenesis and partially improved PPI in adult animals. These results suggest the potential benefit of ARA in ameliorating PPI deficits relevant to psychiatric disorders and suggest that the effect may be correlated with augmented postnatal neurogenesis.

Supplementation of arachidonic acid-enriched oil increases arachidonic acid contents in plasma phospholipids, but does not increase their metabolites and clinical parameters in Japanese healthy elderly individuals: a randomized controlled study

BackgroundThe importance of arachidonic acid (ARA) among the elderly has recently gained increased attention. The effects of ARA supplementation in the elderly are not fully understood, although ARA is considered to be associated with various diseases. We investigate whether ARA supplementation to Japanese elderly subjects affects clinical parameters involved in cardiovascular, inflammatory, and allergic diseases. We also examine the levels of ARA metabolites such as prostanoids during intervention.MethodsWe conducted a randomized, double-blind and placebo-controlled parallel group intervention trial. ARA-enriched oil (240 or 720 mg ARA per day) or placebo was administered to Japanese healthy men and women aged 55-70 years for 4 weeks followed by a 4-week washout period. The fatty acid contents of plasma phospholipids, clinical parameters, and ARA metabolites were determined at baseline, 2, 4, and 8 weeks.ResultsThe ARA content in plasma phospholipids in the ARA-administrated groups increased dose-dependently and was almost the same at 2 weeks and at 4 weeks. The elevated ARA content decreased to nearly baseline during a 4-week washout period. During the supplementation and washout periods, no changes were observed in eicosapentaenoic acid and docosahexaenoic acid contents. There were no changes in clinical blood parameters related to cardiovascular, inflammatory and allergic diseases. ARA supplementation did not alter the level of ARA metabolites such as urinary 11-dehydro thromboxane B2, 2,3-dinor-6-keto prostaglandin (PG) F1α and 9,15-dioxo-11α-hydroxy-13,14-dihydro-2,3,4,5-tetranor-prostan-1,20-dioic acid (tetranor-PGEM), and plasma PGE2 and lipoxin A4. ARA in plasma phospholipids was not correlated with ARA metabolite levels in the blood or urine.ConclusionThese results indicate that ARA supplementation, even at a relatively high dose, does not increase ARA metabolites, and suggest that it does not induce cardiovascular, inflammatory or allergic diseases in Japanese elderly individuals.

Arachidonic Acid Supplementation Decreases P300 Latency and Increases P300 Amplitude of Event-Related Potentials in Healthy Elderly Men

In the present study, we examined the effects of arachidonic acid (ARA) on age-related event-related potential (ERP) changes in 25 healthy elderly men. This study was performed using a double-blind crossover design. The subjects were administered 600 mg/day of ARA-enriched triglyceride (SUNTGA40S; containing 240 mg ARA) in capsules or the same amount of olive oil in capsules as an inactive placebo for 1 month. ERPs were measured before capsule administration and after 1 month of administration, and P300 latency and amplitude were also measured. In subjects administered 240 mg/day ARA, P300 latency was significantly shorter, and P300 amplitude was significantly higher than in those administered olive oil capsules, and they exhibited a significant increase in ARA content in serum phospholipids. These findings suggest that supplementation of ARA can improve cognitive function in healthy elderly men.

Differential effect of arachidonic acid and docosahexaenoic acid on age-related decreases in hippocampal neurogenesis.

Hippocampal neurogenesis affects learning and memory. We evaluated in rats effects of ingestion of arachidonic acid (ARA) and/or docosahexaenoic acid (DHA) on age-related decreases in proliferating neural stem/progenitor cells (NSPCs) or newborn neurons (NNs). Rats were fed with ARA- and/or DHA-containing diet from 2 to 18 months old and then sacrificed 1 day or 4 weeks after 5-bromo-2-deoxyuridine (BrdU) injections at 2, 6 and 18 months. The numbers of NSPCs (SOX2+/BrdU+) and NNs (NeuN+/BrdU+) were determined immunohistochemically. The number of BrdU+ cells 1 day after BrdU injections decreased with age, but increased 65% after ARA ingestion compared to the control at 18 months. The SOX2+/BrdU+ cell ratio was unchanged by aging or ingestion of ARA or DHA. The number of NeuN+/BrdU+ cells 4 weeks after BrdU injections decreased with age, but increased 34% (yet not statistically significant) after DHA ingestion compared to the control at 18 months. These results indicate that ARA ingestion can ameliorate the age-related decrease in the number of NSPCs in rats. The functions of ARA and DHA in hippocampal neurogenesis appear to be different in aged rats; ARA may maintain an NSPC pool, whereas DHA may support NN production and/or survival.

Arachidonic or Docosahexaenoic Acid Diet Prevents Memory Impairment in Tg2576 Mice

It is believed that the amyloid β-protein (Aβ) plays a causative role in the development of Alzheimers disease (AD). The amyloid-β protein precursor (AβPP), a substrate of Aβ, and β-secretase and γ-secretase complex proteins, which process AβPP to generate Aβ, are all membrane proteins. Thus, it is reasonable to assume that alterations in brain lipid metabolism modulate AβPP and/or Aβ metabolism. However, the role of cellular polyunsaturated fatty acids in AβPP processing has not been completely understood yet. We report here that 4 months of treatment of Tg2576 mice with an arachidonic acid (ARA)- or a docosahexaenoic acid (DHA)-containing (ARA+ or DHA+) diet prevented memory impairment at 13 months of age. Although, AβPP processing to generate soluble AβPP and induce Aβ synthesis was enhanced, Aβ(1- 42)/Aβ(1- 40) ratio decreased in 14-month-old Tg2576 mice fed with the ARA+ or DHA+ diet. The ARA+ or DHA+ diet did not alter the AβPP levels and the expression levels of Aβ-degrading enzymes. In cortical primary neuron cultures, ARA or DHA treatment also increased soluble AβPP and Aβ(1- 40) levels, and decreased Aβ(1- 42)/Aβ(1- 40) ratio, which are similar to what were observed in Tg2576 mice fed with ARA+ or DHA+ diet. These findings suggest that not only the DHA+ diet, but also the ARA+ diet could prevent cognitive dysfunction in Tg2576 mice through the alteration of AβPP processing.

Arachidonic acid diet attenuates brain Aβ deposition in Tg2576 mice.

The amyloid β-protein (Aβ) is believed to play a causative role in the development of Alzheimers disease (AD). Because the amyloid precursor protein (APP), a substrate of Aβ, and β-secretase and γ-secretase complex proteins, which process APP to generate Aβ, are all membrane proteins, it is possible to assume that alterations in brain lipid metabolism modulate APP and/or Aβ metabolism. However, the role of polyunsaturated fatty acids in Aβ metabolism remains unknown. We report here that 9 months-treatment of Tg2576 mice with arachidonic acid (ARA)-containing (ARA+) diet prevented brain Aβ deposition in 17-month-old Tg2576 mice. APP processing to generate soluble APPα, CTF-β, and Aβ synthesis was attenuated in Tg2576 mice fed with the ARA+ diet. These findings suggest that ARA+ diet could prevent Aβ deposition through the alteration of APP processing in Tg2576 mice.

Low Doses of Long-chain Polyunsaturated Fatty Acids Affect Cognitive Function in Elderly Japanese Men: A Randomized Controlled Trial.

Several studies have reported that the supplementation of long-chain polyunsaturated fatty acids (LCPUFA), such as docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (ARA) improve cognitive function in the elderly. However, the doses used in these studies were higher than general dietary LCPUFA intake levels. This randomized, double-blind, placebo-controlled trial evaluated the effects of low doses of LCPUFA supplementation corresponding to general dietary intake on cognitive function in non-demented elderly Japanese participants. Japanese men aged 55-64 years were enrolled and randomly allocated to the placebo or LCPUFA group. Participants received 4 weeks of supplementation with LCPUFA-containing oil (DHA, 300 mg/day; EPA, 100 mg/day; and ARA, 120 mg/day) or purified olive oil as placebo. Event-related potential P300, reflecting cognitive processes, was measured before and after supplementation. A total of 113 participants completed the supplementation period, and the per-protocol analysis included 69 participants. Changes in P300 latency were significantly different between the placebo group (+13.6 msec) and the LCPUFA group (-1.8 msec) after supplementation. Significant increases in DHA (+0.9%) and ARA (+0.6%) contents in plasma phospholipids were observed in the LCPUFA group; no changes were observed in the placebo group. Dietary DHA, EPA, and ARA intake were in the normal range for Japan participants and remained unchanged during the study. These results suggest that low doses of LCPUFA supplementation have the potential to improve cognitive function in elderly Japanese men.

Arachidonic acid enhances intracellular calcium levels in dentate gyrus, but not CA1, in aged rat.

The effect of dietary supplementation with polyunsaturated fatty acids (PUFAs) on long-term potentiation (LTP) and calcium mobilization in hippocampal slices from aged rats was assessed. LTP magnitude was significantly greater in PUFA-supplemented animals compared to age-matched controls (OCs). LTP did not differ among PUFA-supplemented groups. Calcium mobilization was estimated following membrane depolarization and selective activation of NMDA receptors. The resting level of [Ca2+](i) was slightly elevated in aged preparations compared to young controls (YCs). The transient increase in [Ca2+](i) in CA1 was significantly smaller in aged rats than in YC. The maximum increase in [Ca2+](i) in the CA1 and dentate gyrus (DG) did not differ among aged groups. The maximum increase in [Ca2+](i) and the calcium buffering ability were significantly greater in YC than in the aged rats. Selective activation of NMDA receptors induced regional differences in Ca2+ elevation. In the DG, Ca2+ elevation in OA was comparable to that in YC, and significantly higher than that in OC, suggesting that long-term arachidonic acid supplementation rescues the reduced neurogenesis in the DG. The decay in the depolarization and NMDA-induced increase in [Ca2+](i) was prolonged in aged CA1 and DG.