Journal of Inherited Metabolic Disease

, Volume 36, Issue 3, pp 513–523

Non-physiological amino acid (NPAA) therapy targeting brain phenylalanine reduction: pilot studies in PAHENU2 mice

  • Kara R. Vogel
  • Erland Arning
  • Brandi L. Wasek
  • Teodoro Bottiglieri
  • K. Michael Gibson
Original Article

DOI: 10.1007/s10545-012-9524-8

Cite this article as:
Vogel, K.R., Arning, E., Wasek, B.L. et al. J Inherit Metab Dis (2013) 36: 513. doi:10.1007/s10545-012-9524-8

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 Pahenu2 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 Pahenu2 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.

Abbreviations

3-MT

3-methoxytyramine

5-HIAA

5-hydroxyindoleacetic acid

5-HT

Serotonin

5-HTP

5-hydroxytryptophan

AIB

Aminoisobutyric acid

BBB

Blood brain barrier

DA

Dopamine

DOPAC

3,4-dihydroxyphenylacetic acid

HVA

Homovanillic acid

Ile; I

Isoleucine

L-DOPA

L-dihydroxyphenylalanine

LAT1

L-type amino acid transporter

Leu; L

Leucine

LNAA

Large neutral amino acid

NL

DL-norleucine

MAIB

Methyl-aminoisobutyric acid

Met; M

Methionine

NB

2-aminobicyclo(2,2,1)heptane-2-carboxylic acid (2-aminonorbornane)

NPAA

Non-physiological amino acid

PAH

Phenylalanine hydroxylase

Phe; F

Phenylalanine

PKU

Phenylketonuria

SAH

S-adenosylhomocysteine

SAMe

S-adenosylmethionine

Trp; W

Tryptophan

Tyr; Y

Tyrosine

Val; V

Valine

Copyright information

© SSIEM and Springer 2012

Authors and Affiliations

  • Kara R. Vogel
    • 1
  • Erland Arning
    • 2
  • Brandi L. Wasek
    • 2
  • Teodoro Bottiglieri
    • 2
  • K. Michael Gibson
    • 1
  1. 1.Section of Clinical Pharmacology, College of PharmacyWashington State UniversityPullmanUSA
  2. 2.Institute of Metabolic Disease, Baylor Research InstituteBaylor University Medical CenterDallasUSA