ArticleJournal of inherited metabolic disease2013
Non-physiological amino acid (NPAA) therapy targeting brain phenylalanine reduction: pilot studies in PAHENU2 mice.
Article in Journal of inherited metabolic disease, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
16 citing papers in PubMed, 1 synthesis or guideline pooled it, 21 citations in OpenAlex.
- Single amino acid supplementation in aminoacidopathies: a systematic review.Orphanet journal of rare diseases · 2014Pooled it
- The Multifaceted Role of L-Type Amino Acid Transporter 1 at the Blood-Brain Barrier: Structural Implications and Therapeutic Potential.Molecular neurobiology · 2025Review
- Genetic etiology and clinical challenges of phenylketonuria.Human genomics · 2022Review
- Metabolomic analyses of vigabatrin (VGB)-treated mice: GABA-transaminase inhibition significantly alters amino acid profiles in murine neural and non-neural tissues.Neurochemistry international · 2019Article
- Multicompartment analysis of protein-restricted phenylketonuric mice reveals amino acid imbalances in brain.Journal of inherited metabolic disease · 2017Article
- Excess cerebral TNF causing glutamate excitotoxicity rationalizes treatment of neurodegenerative diseases and neurogenic pain by anti-TNF agents.Journal of neuroinflammation · 2016Review
- DNA methylation in the pathophysiology of hyperphenylalaninemia in the PAH(enu2) mouse model of phenylketonuria.Molecular genetics and metabolism · 2016Article
- Physiological Competition of Brain Phenylalanine Accretion: Initial Pharmacokinetic Analyses of Aminoisobutyric and Methylaminoisobutyric Acids inMolecular genetics and metabolism reports · 2015Article
- Phenylalanine sensitive K562-D cells for the analysis of the biochemical impact of excess amino acid.Scientific reports · 2014Article
- New Strategies for the Treatment of Phenylketonuria (PKU).Metabolites · 2014Review
- Pharmacologic inhibition of L-tyrosine degradation ameliorates cerebral dopamine deficiency in murine phenylketonuria (PKU).Journal of inherited metabolic disease · 2014Article
- Brain-blood amino acid correlates following protein restriction in murine maple syrup urine disease.Orphanet journal of rare diseases · 2014Article
- Advances in the nutritional and pharmacological management of phenylketonuria.Current opinion in clinical nutrition and metabolic care · 2014Review
- Maternal Phenylketonuria International Collaborative Study revisited: evaluation of maternal nutritional risk factors besides phenylalanine for fetal congenital heart defects.Journal of inherited metabolic disease · 2014Article
- Characterization of 2-(methylamino)alkanoic acid capacity to restrict blood-brain phenylalanine transport in Pah enu2 mice: preliminary findings.Molecular genetics and metabolism · 2013Article
- Phenylketonuria: A new look at an old topic, advances in laboratory diagnosis, and therapeutic strategies.International journal of health sciencesReview
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Transport of large neutral amino acids (LNAA) across the blood brain barrier (BBB) is facilitated by the L-type amino acid transporter, LAT1. Peripheral accumulation of one LNAA (e.g., phenylalanine (phe) in PKU) is predicted to increase uptake of the offending amino acid to the detriment of others, resulting in disruption of brain amino acid homeostasis. We hypothesized that selected non-physiological amino acids (NPAAs) such as DL-norleucine (NL), 2-aminonorbornane (NB; 2-aminobicyclo-(2,1,1)-heptane-2-carboxylic acid), 2-aminoisobutyrate (AIB), and N-methyl-aminoisobutyrate (MAIB), acting as competitive inhibitors of various brain amino acid transporters, could reduce brain phe in Pah (enu2) mice, a relevant murine model of PKU. Oral feeding of 5 % NL, 5 % AIB, 0.5 % NB and 3 % MAIB reduced brain phe by 56 % (p < 0.01), -1 % (p = NS), 27 % (p < 0.05) and 14 % (p < 0.01), respectively, compared to untreated subjects. Significant effects on other LNAAs (tyrosine, methionine, branched chain amino acids) were also observed, however, with MAIB displaying the mildest effects. Of interest, MAIB represents an inhibitor of the system A (alanine) transporter that primarily traffics small amino acids and not LNAAs. Our studies represent the first in vivo use of these NPAAs in Pah (enu2) mice, and provide proof-of-principle for their further preclinical development, with the long-term objective of identifying NPAA combinations and concentrations that selectively restrict brain phe transport while minimally impacting other LNAAs and downstream intermediates.
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Registered trials
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