The influx of neutral amino acids into the porcine brain during development: a positron emission tomography study.
Pigs of three different age groups (newborns, 1 week old, 6 weeks old) were used to study the transport of the large neutral amino acids 6-[18F]fluoro-L-DOPA ([18F]FDOPA) and 3-O-methyl-6-[18F]fluoro-L-DOPA ([18F]OMFD) across the blood-brain barrier (BBB) with positron emission tomography (PET). Compartmental modeling of PET data was used to calculate the blood-brain clearance (K1) and the rate constant for the brain-blood transfer (k2) of [18F]FDOPA and [18F]OMFD after i.v. injection. A 40-70% decrease of K1(OMFD), K1(FDOPA) and k2(OMFD) from newborns to juvenile pigs was found whereas k2(FDOPA) did not change. Generally, K1(OMFD) and k2(OMFD) are lower than K1(FDOPA) and k2(FDOPA) in all regions and age groups. The changes cannot be explained by differences in brain perfusion because the measured regional cerebral blood flow did not show major changes during the first 6 weeks after birth. In addition, alterations in plasma amino acids cannot account for the described transport changes. In newborn and juvenile pigs, HPLC measurements were performed. Despite significant changes of single amino acids (decrease: Met, Val, Leu; increase: Tyr), the sum of large neutral amino acids transported by LAT1 remained unchanged. Furthermore, treatment with a selective inhibitor of the LAT1 transporter (BCH) reduced the blood-brain transport of [18F]FDOPA and [18F]OMFD by 35% and 32%, respectively. Additional in-vitro studies using human LAT1 reveal a much lower affinity of FDOPA compared to OMFD or L-DOPA. The data indicate that the transport system(s) for neutral amino acids underlie(s) developmental changes after birth causing a decrease of the blood-brain barrier permeability for those amino acids during brain development. It is suggested that there is no tight coupling between brain amino acid supply and the demands of protein synthesis in the brain tissue.
Brust
Peter
P
Institute of Interdisciplinary Isotope Research Leipzig, Permoserstrasse 15, D-04318 Leipzig, Germany. brust@iif-leipzig.de
Vorwieger
Gerd
G
Walter
Bernd
B
Füchtner
Frank
F
Stark
Holger
H
Kuwabara
Hiroto
H
Herzau
Michael
M
Opfermann
Thomas
T
Steinbach
Jörg
J
Ganapathy
Vadivel
V
Bauer
Reinhard
R
D000375:Aging / Q000378:metabolism; D021542:Amino Acids, Neutral / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D000831:Animals, Newborn; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000254:growth & development* / Q000378:metabolism*; D001921:Brain / Q000000981:diagnostic imaging / Q000254:growth & development* / Q000378:metabolism*; D001923:Brain Chemistry / Q000502:physiology*; D004295:Dihydroxyphenylalanine / Q000031:analogs & derivatives / Q000378:metabolism / Q000493:pharmacokinetics; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007700:Kinetics; D027283:Large Neutral Amino Acid-Transporter 1 / Q000187:drug effects / Q000378:metabolism; D008657:Metabolic Clearance Rate / Q000502:physiology; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D049268:Positron-Emission Tomography; D034421:Sus scrofa
D021542:Amino Acids, Neutral; D004791:Enzyme Inhibitors; D027283:Large Neutral Amino Acid-Transporter 1; D009419:Nerve Tissue Proteins; C055151:3-O-methyl-6-fluoro-dopa; C043437:fluorodopa F 18; D004295:Dihydroxyphenylalanine