Therapeutic brain modulation with targeted large neutral amino acid supplements in the Pah-enu2 phenylketonuria mouse model
| Autor: | M. Rebecca Heiner-Fokkema, Francjan J. van Spronsen, Vibeke M. Bruinenberg, Eddy A. van der Zee, Ido P. Kema, Tiziana Pascucci, Pim de Blaauw, Stefano Puglisi-Allegra, Danique van Vliet, Priscila Nicolao Mazzola, Martijn van Faassen |
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| Přispěvatelé: | Van der Zee lab, Guided Treatment in Optimal Selected Cancer Patients (GUTS), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM) |
| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Phenylketonurias Dopamine Medicine (miscellaneous) Phenylalanine Mice chemistry.chemical_compound 0302 clinical medicine Monoaminergic brain biochemistry Neurotransmitter pathophysiology Mice Knockout PHENYLALANINE RESTRICTION Neurotransmitter Agents Nutrition and Dietetics treatment ISOLEUCINE VALINE Brain Amino Acids Neutral PKU Female Leucine medicine.drug Serotonin medicine.medical_specialty inborn error of metabolism large neutral amino acids mouse model neurotransmitters phenylketonuria medicine (miscellaneous) nutrition and dietetics LEUCINE Biology 03 medical and health sciences Norepinephrine CEREBROSPINAL-FLUID Valine Internal medicine medicine Animals BARRIER TRANSPORT DYSFUNCTION Diet Disease Models Animal 030104 developmental biology Endocrinology chemistry TYROSINE SUPPLEMENTATION Dietary Supplements 030217 neurology & neurosurgery |
| Zdroj: | American Journal of Clinical Nutrition, 104(5), 1292-1300. Oxford University Press |
| ISSN: | 0002-9165 |
| DOI: | 10.3945/ajcn.116.135996 |
| Popis: | BACKGROUND: Phenylketonuria treatment consists mainly of a Phe-restricted diet, which leads to suboptimal neurocognitive and psychosocial outcomes. Supplementation of large neutral amino acids (LNAAs) has been suggested as an alternative dietary treatment strategy to optimize neurocognitive outcome in phenylketonuria and has been shown to influence 3 brain pathobiochemical mechanisms in phenylketonuria, but its optimal composition has not been established.OBJECTIVE: In order to provide additional pathobiochemical insight and develop optimal LNAA treatment, several targeted LNAA supplements were investigated with respect to all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria.DESIGN: Pah-enu2 (PKU) mice received 1 of 5 different LNAA-supplemented diets beginning at postnatal day 45. Control groups included phenylketonuria mice receiving an isonitrogenic and isocaloric high-protein diet or the AIN-93M diet, and wild-type mice receiving the AIN-93M diet. After 6 wk, brain and plasma amino acid profiles and brain monoaminergic neurotransmitter concentrations were measured.RESULTS: Brain Phe concentrations were most effectively reduced by supplementation of LNAAs, such as Leu and Ile, with a strong affinity for the LNAA transporter type 1. Brain non-Phe LNAAs could be restored on supplementation, but unbalanced LNAA supplementation further reduced brain concentrations of those LNAAs that were not (sufficiently) included in the LNAA supplement. To optimally ameliorate brain monoaminergic neurotransmitter concentrations, LNAA supplementation should include Tyr and Trp together with LNAAs that effectively reduce brain Phe concentrations. The requirement for Tyr supplementation is higher than it is for Trp, and the relative effect of brain Phe reduction is higher for serotonin than it is for dopamine and norepinephrine.CONCLUSION: The study shows that all 3 biochemical disturbances underlying brain dysfunction in phenylketonuria can be targeted by specific LNAA supplements. The study thus provides essential information for the development of optimal LNAA supplementation as an alternative dietary treatment strategy to optimize neurocognitive outcome in patients with phenylketonuria. |
| Databáze: | OpenAIRE |
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