Effects of ?-methylphenylalanine plus phenylalanine treatment during development on myelin in rat brain

Johnson, Ronald C.; Shah, Saleh

doi:10.1007/bf00964709

Cited by 25 publications

(7 citation statements)

References 20 publications

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“…The mechanisms for producing this permanent structural damage remain unclear, but several hypotheses have developed. Decreased or abnormal myelin formation and/or impaired oligodendroglial migration during the first 6 mo of postpartum brain development are the most probable mechanisms (3)(4)(5)(6)(7).…”

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confidence: 99%

Biochemical and neuropsychological effects of elevated plasma phenylalanine in patients with treated phenylketonuria. A model for the study of phenylalanine and brain function in man.

Krause¹,

Halminski²,

McDonald³

et al. 1985

J. Clin. Invest.

190

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Phenylketonuria provides a human model for the study of the effect of phenylalanine on brain function. Although irreversible mental retardation is preventable through newborn diagnosis and dietary phenylalanine restriction, controversy exists regarding the effects of increased concentrations of phenylalanine in older patients. We have studied ten older, treated, phenylketonuric patients using a triple-blind, multiple trials, crossover design. Each patient was tested at the end of each of three 1-wk periods of high or low phenylalanine intakes. Tests included a repeatable battery of neuropsychological tests, analysis of plasma amino acids, and measurement of urine amino acids, phenyl organic acids, dopamine, and serotonin. In all 10 patients, plasma phenylalanine rose (9004,000 AM). In 9 of 10 patients there was an inverse relationship between plasma phenylalanine and urine dopamine excretion. When blood phenylalanine was elevated, these patients had prolonged performance times on neuropsychological tests of higher but not lower integrative function. Urinary serotonin fell during phenylalanine loading in six patients. The concentration of phenylacids in the urine was not proportional to the plasma phenylalanine at concentrations below 1.5 mM. In one patient, neither performance time nor dopamine excretion varied as blood phenylalanine rose or fell. We interpret these data as follows: blood phenylalanine above 13 mM impairs performance on neuropsychological tests of higher integrative function, this effect is reversible, and one mechanism may involve impaired biogenic amine synthesis.

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confidence: 99%

Biochemical and neuropsychological effects of elevated plasma phenylalanine in patients with treated phenylketonuria. A model for the study of phenylalanine and brain function in man.

Krause¹,

Halminski²,

McDonald³

et al. 1985

J. Clin. Invest.

190

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“…Johnson et al (1977) reported that myelin from the brains of patients with PKU contained reduced proportions of unsaturated fatty acids. Johnson and Shah (1980) also reported that unsaturated fatty acid levels in myelin from hyperphenylalaninemic rat brains were reduced. These findings suggest that exposure to hyperphenylalaninemia during the prenatal or postnatal period interferes with either the uptake of unsaturated fatty acids from the blood and/ or inhibits the fatty acids desaturation in the brain.…”

Section: Discussionmentioning

confidence: 92%

Effects of Maternal Hyperphenylalaninemia on Postnatal Myelination in Mice

Sasahara

Ohya

Shimada

1987

Congenital Anomalies

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The effects of maternal hyperphenylalaninemia induced by phenylalanine and p-chlorophenylalanine loading diets on brain growth and myelination were studied in mice. The wet weights, protein contents and activities of 2', 3'-cyclic nucleotide 3'-phosphodiesterase (CNP) of the cerebrum, brain stem and cerebellum were estimated on 7, 14, 21, 28 and 56 days after the birth. Protein and lipid contents in the myelin fraction of the whole brain were also examined on days 28 and 56. In the experimental groups, the activities of CNP, a marker enzyme of myelin, were lower than those in the control in each part of the brain. The protein contents in the light myelin subfraction, which is regarded as a mature type of myelin, were also decreased in the experimental group after 28 days of age, while those in the heavy myelin subfraction, which is regarded as an immature type of myelin, showed no significant reduction even after 28 days of age. These results suggest that maternal hyperphenylalaninemia has a potential effect on postnatal myelination of the brain, and also that impaired myelination may play some role in the pathogenesis of mental retardation of maternal phenylketonuria. The proportions of unsaturated to saturated fatty acids in phosphatidylethanolamine and sphingomyelin were decreased significantly on day 56 in the heavy myelin subfraction in compariscin to the controls. These changes may have some correlation with interference in the formation of matured myelin.

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“…As few as five daily injections of a-methylphenylalanine and phenylalanine in newborn mice result in permanent learning disabilities (Luttges & Gerren, 1980). Prolonged hyperphenylalaninaemia also results in myelin deficits (Shah & Johnson, 1978;Johnson & Shah, 1980), with the primary defect involving myelin basic proteins (Figlewicz & Druse, 1980). Maintaining normal brain protein synthesis during chronic hyperphenylalaninaemia wyith the amino acid mixture will provide a means of determining the contribution of decreased proteinsynthesis activity to the overall impairment of brain development associated with hyperphenylalaninaemia.…”

Section: Discussionmentioning

confidence: 99%

“…brain protein synthesis remained inhibited for as long as 18 h of each day. The consequences of chronic hyperphenylalaninaemia, when maintained throughout postnatal growth, are decreased myelination in the mature central nervous system (Johnson & Shah. 1980: Figlewicz & Druse, 1980) and a permanent learning impairment (Greengard et al, 1979;Luttges & Gerren, 1980).…”

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confidence: 99%

The effects of chronic hyperphenylalaninaemia on mouse brain protein synthesis can be prevented by other amino acids

Binek-Singer¹,

Johnson²

1982

Biochemical Journal

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A prolonged elevation in the concentrations of circulating phenylalanine was maintained in newborn mice by daily injections of phenylalanine and a phenylalanine hydroxylase inhibitor, alpha-methylphenylalanine. The result of this chronic hyperphenylalaninaemia was an accumulation of vacant or inactive monoribosomes that persisted for 18 h of each day. An elongation assay in vitro with brain postmitochondrial supernatants demonstrated that, in addition, there was an equally prolonged decrease in the rates of polypeptide-chain elongation by the remaining brain polyribosomes. Analyses of the free amino acid composition in the brains of hyperphenylalaninaemic mice showed a loss of several amino acids from the brain, particularly the large, neutral amino acids, which are co- or counter-transported across plasma membranes with phenylalanine. When a mixture of these amino acids (leucine, isoleucine, valine, threonine, tryptophan, tyrosine, methionine) was injected into hyperphenylalaninaemic mice, there was an immediate cessation of monoribosome accumulation in the brain and there was no inhibition of the rates of polypeptide-chain elongation. Although the concentrations of the large, neutral amino acids in the brain were partially preserved by treatment of hyperphenylalaninaemic mice with the amino acid mixture, the elevated concentrations of phenylalanine remained unaltered. The amino acid mixture had no detectable effect on brain protein synthesis in the absence of the hyperphenylalaninaemic condition.

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Effects of ?-methylphenylalanine plus phenylalanine treatment during development on myelin in rat brain

Cited by 25 publications

References 20 publications

Biochemical and neuropsychological effects of elevated plasma phenylalanine in patients with treated phenylketonuria. A model for the study of phenylalanine and brain function in man.

Biochemical and neuropsychological effects of elevated plasma phenylalanine in patients with treated phenylketonuria. A model for the study of phenylalanine and brain function in man.

Effects of Maternal Hyperphenylalaninemia on Postnatal Myelination in Mice

The effects of chronic hyperphenylalaninaemia on mouse brain protein synthesis can be prevented by other amino acids

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