Amino acid and biogenic amine studies in experimental hyperphenylalaninemia.
Item
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Title
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Amino acid and biogenic amine studies in experimental hyperphenylalaninemia.
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Identifier
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AAI8914778
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identifier
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8914778
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Creator
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McChesney, Ruth Elizabeth.
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Contributor
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Adviser: O. Greengard
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Date
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1988
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Language
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English
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Publisher
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City University of New York.
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Subject
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Health Sciences, Human Development
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Abstract
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The developmental profile of phenylalanine uptake into the brain was defined and its implications for amino acid levels and biogenic amine metabolism in experimental animal models of phenylketonuria (PKU) was investigated.;The technique of rapid intracarotid injection used to study cerebral amino acid influx at physiological blood level was rendered applicable to neonatal rats. The brain uptake index of phenylalanine, thus measured for the first time during the suckling period, was found to be significantly higher at the age of 4 than at 7 or 24 days, with no further decrease occurring after weaning. This developmental change in the blood brain barrier appears to be a factor in the age dependence of cerebral amino acid uptake from pathological blood levels. At the same sustained elevation of plasma phenylalanine concentration, the cerebral accumulation of phenylalanine was found to be greater during the first week of life than at any subsequent age.;Chronic experimental hyperphenylalaninemia during gestation or infancy was associated with elevations of the glycine concentration of the maturing brain, which correlated quantitatively to increases in the activity of the serine biosynthetic enzyme phosphoserine phosphatase. Analysis of cerebral biogenic amines and metabolites showed that hyperphenylalaninemia maintained by administration of {dollar}\alpha{dollar}-methylphenylalanine plus phenylalanine decreased the concentration of cerebral serotonin, 5-hydroxyindoleacetic acid, dopamine, homovanillic acid and norepinephrine. The increase of tryptophan found in the gastric contents (accompanied by elevated phenylalanine) with unchanged levels in peripheral tissues indicates that inhibition of gastrointestinal absorption may contribute to the diminished plasma tryptophan levels. However, inhibition by excess phenylalanine of the cerebral influx of tryptophan (rather than the low plasma levels) was responsible for the diminished brain concentration of tryptophan. This diminution underlies the indoleamine depletion of the brain, whereas the cerebral catecholamine depletion resulting from the action of phenylalanine on biosynthetic enzymes, can arise even at normal tyrosine levels. The methods found for the selective depletion and restoration of the biogenic amine deficits, the identification of a new suppressor of phenylalanine hydroxylase ({dollar}\beta{dollar}-methylphenylalanine), and study of the consequences of gestational and postnatal hyperphenylalaninemia in two different rat strains, provide additional experimental systems for study of the pathogenesis of cerebral maldevelopment in PKU.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
