TY - JOUR
T1 - The influx of neutral amino acids into the porcine brain during development
T2 - A positron emission tomography study
AU - Brust, Peter
AU - Vorwieger, Gerd
AU - Walter, Bernd
AU - Füchtner, Frank
AU - Stark, Holger
AU - Kuwabara, Hiroto
AU - Herzau, Michael
AU - Opfermann, Thomas
AU - Steinbach, Jörg
AU - Ganapathy, Vadivel
AU - Bauer, Reinhard
N1 - Funding Information:
The study was supported in part by the Thuringian State Ministry of Science, Research, and Arts, Grant 3/95-13 and the Saxon Ministry of Science and Art, Grant 7541.82-FZR/309.
PY - 2004/9/17
Y1 - 2004/9/17
N2 - 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 (K 1) and the rate constant for the brain-blood transfer (k 2) of [ 18F]FDOPA and [ 18F]OMFD after i.v. injection. A 40-70% decrease of K 1 OMFD, K 1 FDOPA and k 2 OMFD from newborns to juvenile pigs was found whereas k 2 FDOPA did not change. Generally, K 1 OMFD and k 2 OMFD are lower than K 1 FDOPA and k 2 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.
AB - 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 (K 1) and the rate constant for the brain-blood transfer (k 2) of [ 18F]FDOPA and [ 18F]OMFD after i.v. injection. A 40-70% decrease of K 1 OMFD, K 1 FDOPA and k 2 OMFD from newborns to juvenile pigs was found whereas k 2 FDOPA did not change. Generally, K 1 OMFD and k 2 OMFD are lower than K 1 FDOPA and k 2 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.
KW - Blood-brain barrier
KW - FDOPA
KW - Kinetic modeling
KW - LAT1
KW - Large neutral amino acids
KW - Pig
KW - Positron emission tomography
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U2 - 10.1016/j.devbrainres.2004.07.002
DO - 10.1016/j.devbrainres.2004.07.002
M3 - Article
C2 - 15351512
AN - SCOPUS:4444243335
SN - 0165-3806
VL - 152
SP - 241
EP - 253
JO - Developmental Brain Research
JF - Developmental Brain Research
IS - 2
ER -