Effect of phenylalanine on protein synthesis in the developing rat brain

Agrawal, Harish C.; Bone, A. H.; Davison, Alan

doi:10.1042/bj1170325

Cited by 101 publications

(42 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A theory supported by a substantial amount of experimental evidence is that overloading of a common carrier system for large neutral amino acids by excess phenylalanine interferes with transport of other essential amino acids into brain (5,20,21,27). The decreased availability of amino acids leads to depressed protein and lipoprotein synthesis both in vivo and in vitro (1,5,14,19,22,25,26). The actual inhibition of protein synthesis by excess phenylalanine is about 20% (17).…”

Section: Discussionmentioning

confidence: 99%

Reduction of Cerebrospinal Fluid Phenylalanine after Oral Administration of Valine, Isoleucine, and Leucine

et al. 1982

View full text Add to dashboard Cite

SummaryA supplement of the branched chain amino acids, valine, isoleucine, and leucine (VIL) was administered orally to patients with phenylketonuria, either together with unrestricted diet of natural protein or with a low phenylalanine diet. The VIL supplement brought about a significant reduction of the cerebrospinal fluidserum ratio of phenylalanine from a mean value of 0.254 without VIL to 0.204 with VIL. The reduction varied from 15-40% (mean 21%). Concentrations of glycine, lysine, methionine, threonine, tryptophan, and tyrosine were within normal limits in serum and cerebrospinal fluid of infants with phenylketonuria. No amino acid imbalance was created by the supplement and no adverse effects from VIL were observed. SpeculationThe branched chain amino acids and phenylalanine share a common transport system. High levels of phenylalanine in brain of children with phenylketonuria may be reduced by administration of a supplement of valine, isoleucine and leucine (VIL). Supplementation of the low-phenylalanine diet with VIL during the first 2 years of life may add a measure of protection to the developing brain beyond that which can be achieved by diet alone. In older children, VIL supplementation may permit liberalization of the diet without unfavorable behavioral consequences.Treatment for phenylketonuria (PKU) by means of a lowphenylalanine diet has become common practice since its first use in affected newborn infants (3). The treatment partially corrects the abnormal amino acid pattern, including the high concentration of phenylalanine and its metabolites, and allows relatively normal intellectual and physical development if the treatment is begun early enough (10). Initially it was assumed that treatment would be terminated when major phases of brain growth were completed. Evidence has accumulated which suggests that termination of treatment for the patient with classic PKU, at least during the school years, is unwise (13,15,16) and it may be prudent to continue the diet into adult years for women with PKU in order to avoid the teratogenic effects of phenylalanine (6).An animal model developed in this laboratory was used to demonstrate the effects of experimental hyperphenylalaninemia (PKU) (12). Methods to inhibit the deleterious effects of phenylalanine on the central nervous system were studied in the model. Administration of branched chain amino acids, valine, isoleucine, and leucine (VIL), to pregnant rats with experimentally induced PKU prevented the decrease in fetal brain weight characteristic of PKU animals (7). A striking finding was that phenylalanine levels in brain of PKU fetuses whose mothers received VIL supplement were lower than in PKU fetuses not exposed to VIL, although fetal blood phenylalanine levels were similar. Subsequent studies suggested that isoleucine was more effective than other amino acids in exerting a beneficial effect on fetal rat brain growth (1 1).Human trials followed. VIL was first used as a supplement to the low-phenylalanine diet of several older PKU children in w...

show abstract

Section: Discussionmentioning

confidence: 99%

Reduction of Cerebrospinal Fluid Phenylalanine after Oral Administration of Valine, Isoleucine, and Leucine

et al. 1982

View full text Add to dashboard Cite

show abstract

“…The L- [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]leucine method is based on a compartmental model for the behavior of leucine in brain that includes bidirectional carrier-mediated transport of leucine at the bloodbrain barrier, an extracellular and multiple intracellular compartments in brain, and the possibility that unlabeled leucine from the breakdown of tissue protein can be reincorporated into tissue protein. The application of the model together with an appropriate experimental design, i.e., a pulse injection of a tracer dose of L-[1-14 C]leucine followed by a 60-min interval for clearance of the tracer from the blood and the brain, gives rise to Eq.…”

Section: Discussionmentioning

confidence: 99%

“…The radiolabeled tracer is [1][2][3][4][5][6][7][8][9][10][11][12][13][14] C]leucine, which is used in conjunction with quantitative autoradiography to achieve spatial localization of the labeled protein in the brain for the determination of rates of protein synthesis in discrete brain regions (17). The operational equation of the method is:…”

Section: Methodsmentioning

confidence: 99%

“…Despite extensive biochemical characterization of PKU, the mechanism by which hyperphenylalaninemia results in mental retardation is not understood. It has been hypothesized that an elevated plasma Phe concentration impedes entry of other neutral amino acids via the L-amino acid carrier at the bloodbrain barrier, and that reduced influx may limit their availability for incorporation into tissue protein (2). There is ample evidence for the effective competitive inhibition of the transport system in hyperphenylalaninemic patients with PKU (3)(4)(5).…”

mentioning

confidence: 99%

“…Before the recent development of a genetic model of PKU in mice (8), hyperphenylalaninemia was produced by systemic administration to rodents of large doses of Phe (2,9) in conjunction with an inhibitor of PAH (10,11) to prevent an increase in Tyr concentration. Animals were studied after acute or chronic treatment in adulthood and during maturation.…”

mentioning

confidence: 99%

See 2 more Smart Citations