BackgroundPhenylketonuria (PKU) was the first disorder in which severe neurocognitive dysfunction could be prevented by dietary treatment. However, despite this effect, neuropsychological outcome in PKU still remains suboptimal and the phenylalanine-restricted diet is very demanding. To improve neuropsychological outcome and relieve the dietary restrictions for PKU patients, supplementation of large neutral amino acids (LNAA) is suggested as alternative treatment strategy that might correct all brain biochemical disturbances caused by high blood phenylalanine, and thereby improve neurocognitive functioning.ObjectiveAs a proof-of-principle, this study aimed to investigate all hypothesized biochemical treatment objectives of LNAA supplementation (normalizing brain phenylalanine, non-phenylalanine LNAA, and monoaminergic neurotransmitter concentrations) in PKU mice.MethodsC57Bl/6 Pah-enu2 (PKU) mice and wild-type mice received a LNAA supplemented diet, an isonitrogenic/isocaloric high-protein control diet, or normal chow. After six weeks of dietary treatment, blood and brain amino acid and monoaminergic neurotransmitter concentrations were assessed.ResultsIn PKU mice, the investigated LNAA supplementation regimen significantly reduced blood and brain phenylalanine concentrations by 33% and 26%, respectively, compared to normal chow (p<0.01), while alleviating brain deficiencies of some but not all supplemented LNAA. Moreover, LNAA supplementation in PKU mice significantly increased brain serotonin and norepinephrine concentrations from 35% to 71% and from 57% to 86% of wild-type concentrations (p<0.01), respectively, but not brain dopamine concentrations (p = 0.307).ConclusionsThis study shows that LNAA supplementation without dietary phenylalanine restriction in PKU mice improves brain biochemistry through all three hypothesized biochemical mechanisms. Thereby, these data provide proof-of-concept for LNAA supplementation as a valuable alternative dietary treatment strategy in PKU. Based on these results, LNAA treatment should be further optimized for clinical application with regard to the composition and dose of the LNAA supplement, taking into account all three working mechanisms of LNAA treatment.

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In this study the influence of the dietary level of the fatty acid arachidonic acid (ArA, 20:4n-6) was determined on the acute stress response and osmoregulation of adult gilthead seabream Sparus aurata L. Seabream were fed a diet containing either 0.9% or 2.4% of total fatty acids as ArA for 18 days before being subjected to a 5·min period of net confinement. Prior to this stressor, a subgroup of fish from both dietary treatment groups was treated with acetylsalicylic acid (ASA), an irreversible blocker of cyclooxygenase (COX). This would indicate whether any effects were caused by an enhanced synthesis of prostaglandins derived from ArA. The highest ArA levels were found in the kidneys, and these were further enhanced by dietary ArA-supplementation. In gill tissues, there were significant changes in all selected fatty acid classes 24 h after confinement, except for the docosahexaenoic acid (DHA, 22:6n-3) : eicosapentaenoic acid (EPA, 20:5n-3) ratio. ArA feeding strongly reduced the cortisol response to confinement, which was partially counteracted by ASA treatment. ArA also attenuated the stress-associated increase in plasma osmolality and, in combination with ASA, enhanced the osmolality and plasma chloride levels, but reduced plasma sodium levels after confinement. Furthermore, ArA enhanced the branchial Na + , K + -ATPase activity both before and after confinement, whereas feeding ASA diminished this effect. It appeared that the effects of ArA-supplementation could not always be ascribed to an increase in prostaglandin synthesis. It is advisable to determine the long-term effects of replacing fish oils in commercial diets with vegetable oils that contain no long-chain fatty acids, particularly in carnivorous/marine species with low fatty acid elongation and desaturation activities. The effects of a low dietary intake of ArA (and other polyunsaturated fatty acids) should be studied over a longer term, taking into account any consequences for the health of the fish.

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