van Vliet Danique, Bruinenberg Vibeke M, Mazzola Priscila N, van Faassen Martijn H J R, de Blaauw Pim, Kema Ido P, Heiner-Fokkema M Rebecca, van Anholt Rogier D, van der Zee Eddy A, van Spronsen Francjan J
University of Groningen, University Medical Center Groningen, Beatrix Children's Hospital, Groningen, The Netherlands.
University of Groningen, Center of Behavior and Neurosciences, Department of Molecular Neurobiology, Groningen, The Netherlands.
PLoS One. 2015 Dec 1;10(12):e0143833. doi: 10.1371/journal.pone.0143833. eCollection 2015.
Phenylketonuria (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.
As 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.
C57Bl/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.
In 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).
This 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.
苯丙酮尿症（PKU）是第一种可通过饮食治疗预防严重神经认知功能障碍的疾病。然而，尽管有此效果，PKU患者的神经心理结局仍不尽人意，且苯丙氨酸限制饮食要求苛刻。为改善PKU患者的神经心理结局并减轻饮食限制，建议补充大中性氨基酸（LNAA）作为替代治疗策略，该策略可能纠正高血苯丙氨酸引起的所有脑生化紊乱，从而改善神经认知功能。
作为原理验证，本研究旨在探究PKU小鼠补充LNAA的所有假设生化治疗目标（使脑苯丙氨酸、非苯丙氨酸LNAA和单胺能神经递质浓度正常化）。
C57Bl/6 Pah-enu2（PKU）小鼠和野生型小鼠接受补充LNAA的饮食、等氮/等热量高蛋白对照饮食或正常食物。经过六周饮食治疗后，评估血液和脑氨基酸及单胺能神经递质浓度。
与正常食物相比，在PKU小鼠中，所研究的补充LNAA方案分别使血液和脑苯丙氨酸浓度显著降低33%和26%（p<0.01），同时缓解了部分但非全部补充的LNAA的脑缺乏情况。此外，PKU小鼠补充LNAA分别使脑血清素和去甲肾上腺素浓度显著提高至野生型浓度的35%至71%和57%至86%（p<0.01），但未提高脑多巴胺浓度（p = 0.307）。
本研究表明，在PKU小鼠中不限制饮食苯丙氨酸补充LNAA可通过所有三种假设的生化机制改善脑生化。因此，这些数据为补充LNAA作为PKU中有价值的替代饮食治疗策略提供了概念验证。基于这些结果，应进一步优化LNAA治疗在临床应用中的LNAA补充剂组成和剂量，同时考虑LNAA治疗的所有三种作用机制。
