Alteration in Composition of Deoxyribonucleic Acid, Ribonucleic Acid, Proteins, and Amino Acids in Brain of Rats Fed High and Low Phenylalanine Diets

Castells, Salvador; Zischka, Rosemarie; Addo, Nicholas

doi:10.1203/00006450-197107000-00005

Cited by 8 publications

(2 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Glycine levels were not increased in spinal cord or liver of hyperphenylalanemic rats [19]. Significant increases in brain glycine content are also evoked in 6-week-old rats fed a high Phe diet for 2 weeks [46] and a 2-day-old monkey fed a high Phe diet for 20 weeks [47]. Notably, elevated brain glycine levels are reported in 10-day-old and 4-week-old Phe hydroxylase-deficient mice in conjunction with abnormal levels of other amino acids at 4 weeks, including reduced levels of glutamate, aspartate, and glutamine but no change in GABA [48, 49].…”

Section: Discussionmentioning

confidence: 99%

Biochemical, Metabolic, and Behavioral Characteristics of Immature Chronic Hyperphenylalanemic Rats

Dienel

Cruz

2015

Neurochem Res

View full text Add to dashboard Cite

Phenylketonuria and hyperphenylalanemia are inborn errors in metabolism of phenylalanine arising from defects in steps to convert phenylalanine to tyrosine. Phe accumulation causes severe mental retardation that can be prevented by timely identification of affected individuals and their placement on a Phe-restricted diet. In spite of many studies in patients and animal models, the basis for acquisition of mental retardation during the critical period of brain development is not adequately understood. All animal models for human disease have advantages and limitations, and characteristics common to different models are most likely to correspond to the disorder. This study established similar levels of Phe exposure in developing rats between 3 and 16 days of age using three models to produce chronic hyperphenylalanemia, and identified changes in brain amino acid levels common to all models that persist for ~16h of each day. In a representative model, local rates of glucose utilization (CMRglc) were determined at 25–27 days of age, and only selective changes that appeared to depend on Phe exposure were observed. CMRglc was reduced in frontal cortex and thalamus and increased in hippocampus and globus pallidus. Behavioral testing to evaluate neuromuscular competence revealed poor performance in chronically-hyperphenylalanemic rats that persisted for at least three weeks after cessation of Phe injections and did not occur with mild or acute hyperphenylalanemia. Thus, the abnormal amino acid environment, including hyperglycinemia, in developing rat brain is associated with selective regional changes in glucose utilization and behavioral abnormalities that are not readily reversed after they are acquired.

show abstract

Section: Discussionmentioning

confidence: 99%

Biochemical, Metabolic, and Behavioral Characteristics of Immature Chronic Hyperphenylalanemic Rats

Dienel

Cruz

2015

Neurochem Res

View full text Add to dashboard Cite

show abstract

“…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

Phenylketonuria: Biochemical Mechanisms

Kaufman

1977

Advances in Neurochemistry

View full text Add to dashboard Cite

Alteration in Composition of Deoxyribonucleic Acid, Ribonucleic Acid, Proteins, and Amino Acids in Brain of Rats Fed High and Low Phenylalanine Diets

Cited by 8 publications

References 17 publications

Biochemical, Metabolic, and Behavioral Characteristics of Immature Chronic Hyperphenylalanemic Rats

Biochemical, Metabolic, and Behavioral Characteristics of Immature Chronic Hyperphenylalanemic Rats

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

Phenylketonuria: Biochemical Mechanisms

Contact Info

Product

Resources

About