A Biochemical Explanation of Phenyl Acetate Neurotoxicity in Experimental Phenylketonuria

Loo, Y. H.; Potempska, Anna; Wisniewski, H. M.

doi:10.1111/j.1471-4159.1985.tb07232.x

Cited by 8 publications

(2 citation statements)

References 37 publications

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“…The high percentage of radioac tivity incorporated into lipids within 4 h shows that NAA is not metabolically inert as stated by McIntosh and Cooper [7], These results are even more impressive when compared to those of other precursors such as [U-I4C]-glucose of [3-14C]3-hydroxybutyrate (3-OHB). Only 30% of the radioactivity following intracerebral injec tions of 3-OHB, which is metabolized into acetoacetate and then to acetyl-CoA, is recovered in the brain lipid fraction 4 h after the injections [36], In a different exper imental procedure, when [U-l4C]-glucose is injected in tramuscularly, only 20% of the radioactivity recovered in the brain is found in the lipid fraction 2 h after the injections [37], Our experiments did not show the same difference between NAA and AcA as found by d'Adamo and Yatsu [13]. In their experiments about 3 times more radioactivity was incorporated into fatty acids from NAA than from AcA.…”

Section: Discussionmentioning

confidence: 99%

N-Acetyl-<i>L</i>-Aspartate is a Major Source of Acetyl Groups for Lipid Synthesis during Rat Brain Development

1991

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The function of N-acetyl-L-aspartate (NAA), a predominant substance in the CNS, has not yet been determined. To investigate the possible function of NAA as a lipid precursor [¹⁴C]-N-acetyl-L-aspartate (NAA) or [¹⁴C]-acetate (AcA) was injected intracerebrally into 8, 15- and 22-day-old rats. These time points were selected because NAA concentration and the activity of the NAA synthetizing enzyme L-aspartate-N-acetyltransferase (ANAT) were low in 8-day-old rats, intermediate in 15-day-old rats and high in 22-day-old rats. During an incubation period of 4 h the radioactive acetyl group of NAA is incorporated into the lipid fraction in amounts of 42.9 to 65.7% of recovered total radioactivity, increasing with the age of the rats. In contrast, radioactivity incorporated from AcA is constant for all three ages. With NAA as precursor only 7.2–9.4% of the recovered total radioactivity is incorporated into the protein fraction. With AcA as precursor 27.0–18.1% of recovered radioactivity is incorporated into the protein fraction, the amounts decreasing with age. Taking into account that in vivo NAA concentration in the brain is much higher than the AcA concentration, NAA is clearly the more efficient precursor for lipid synthesis than AcA. Further, we compared NAA and AcA as lipid precursors by analyzing the radioactivity in single lipid fractions, expressed as normalized specific incorporation or normalized incorporation. The measured differences between NAA and AcA in normalized specific and normalized incorporation of acetyl groups imply that NAA is not simply degraded to AcA before incorporated into lipids. We conclude that NAA is a major source of acetyl groups for lipid synthesis during rat brain development.

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Section: Discussionmentioning

confidence: 99%

N-Acetyl-<i>L</i>-Aspartate is a Major Source of Acetyl Groups for Lipid Synthesis during Rat Brain Development

1991

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“…To better understand the biochemical, developmental, physiological, and behavioral changes associated with hyperphenylalanemia, a number of animal models have been developed by treatments with their onset at various postnatal ages for different durations using specific metabolites of Phe given alone (e.g., phenylacetate [9, 10]), or different doses of Phe either alone [11] or in combination with an inhibitor of Phe hydroxylase (p-chlorophenylalanine (pCPhe) or α-methylphenylalanine (αMePhe) [12]). A PKU mouse model (BTBR background-Pah enu2 ) was subsequently developed by producing germline mutagenesis with ethylnitrosourea (enu) and identification of Phe hydroxylase deficiency by Phe clearance screening [13].…”

Section: Introductionmentioning

confidence: 99%

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

Dienel

Cruz

2015

Neurochem Res

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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.

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The effect of caffeine on some mouse brain free amino acid levels

1989

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Changes in free amino acids were examined in the central nervous system of mice treated with caffeine for three weeks. Caffeine was administered in the drinking water, and at the end of three weeks the level of caffeine in the cerebral cortex was 113 +/- 19 micrograms/g. When amino acid levels in cerebral hemispheres, midbrain, pons and medulla, and cerebellum were measured a significant increase in glutamine levels was found in all four regions. Glycine, alanine, serine, threonine, and GABA were significantly reduced in some regions. Caffeine appears to alter some of the metabolic or transport processes regulating amino acid pools in the brain. The decrease of GABA found in pons and medulla may contribute to the observed increase in reflex excitability after caffeine.

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A Biochemical Explanation of Phenyl Acetate Neurotoxicity in Experimental Phenylketonuria

Cited by 8 publications

References 37 publications

N-Acetyl-<i>L</i>-Aspartate is a Major Source of Acetyl Groups for Lipid Synthesis during Rat Brain Development

N-Acetyl-<i>L</i>-Aspartate is a Major Source of Acetyl Groups for Lipid Synthesis during Rat Brain Development

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

The effect of caffeine on some mouse brain free amino acid levels

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