The Influence of High Phenylalanine and Tyrosine on the Concentrations of Essential Amino Acids in Brain

McKean, Charles M.; Boggs, Dallas E.; Peterson, N. A.

doi:10.1111/j.1471-4159.1968.tb06202.x

Cited by 159 publications

(49 citation statements)

References 7 publications

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“…Neither we nor Snyderman et al (24) found evidence for tyrosine deficiency in CSF of infants with PKU. Older untreated PKU patients in our study showed the depression in large neutral amino acids reported by other investigators (20). The depression in plasma and CSF amino acids may develop slowly over time in the presence of chronic high levels of circulating phenylalanine.…”

Section: Discussionsupporting

confidence: 76%

“…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).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 1982

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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...

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

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

et al. 1982

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“…It was shown that the influx of PHE through the blood-brain barrier continued during our whole observ ation period. In an animal study reported by McKean et al (24), brain PHE showed a much steeper incr ease after loading rats with L-PHE intraperitoneally. The plasmalbrain ratio incre ased from a baseline value of 1.1 to 4.35 at 30 min postload and then decreased again to 2.4 at 60 min postl oad .…”

Section: 5 -------------------mentioning

confidence: 84%

The Dynamics of Brain Concentrations of Phenylalanine and Its Clinical Significance in Patients with Phenylketonuria Determined by in Vivo H Magnetic Resonance Spectroscopy

et al. 1995

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Cerebral concentrations of phenylalanine (PHE) were measured by means of quantitative in vivo IH MR spectroscopy in 8 adult patients treated early for phenylketonuria type I. A 1.5-Tesla routine magnetic resonance scanner, localization sequence with short echo time (20 ms), and a fully automated data processing scheme were used. Baseline plasma PHE concentrations were 1.04 (0.70-1.39) mmol/L PHE with concurrent brain PHE concentrations of 0.27 (0.13-0.41) mmol/kg of wet weight resulting in a plasma/brain ratio of 4.12. Plasma and brain concentrations correlated significantly (Kendall T b = 0.91, P < 0.01). During an oral load with a single dose of 100 mg L-PHE per kg of body weight in four patients, plasma levels steeply increased. Concurrent brain PHE increase was less steep, was significantly delayed , and still continued up to 20 h postload. Despite the proven rise in plasma and brain concentr ations of PHE, neuropsychologic examinations revealed no impairment of attentional and fine motor abilities from preload up to 20 h postload. tPediatr Res 38: 657-663, 1995) Some 40 Y after its first description (1), the PHErestricted diet for pati ents with PKU is still an out standing example of the successful treatment of inborn errors of metabolism. Despite the overall favor able outcome compared with untreated patients, open questions rem ain and new problems arise. 1) The influence of the strictness of the diet on outcome has been demonstrated clearl y (2), but it is still uncl ear why some patients with norm al outcome see m to be "protected," in spite of adhering to no diet at all (3), where as other patients on diet show a decline in e.g . IQ. 2) A rever sible impairment of cognitive function and EEG Received February 27, 1995; accepted May 11, 1995 activit y has been dem onstrated during PHE challenges (4). The decre ase in performance was , however, onl y weakl y relat ed to the total increase of plasma PHE , dem onstrating an intcrindividuall y variable sensitivity to PHE. 3) Neurologic symptoms have been observed in adult pati ent s off diet (5), which were partly reversible after reinstitution of a PHE-restr icted diet. In thes e, but also in neur ologicall y unaffec ted PKU patients, white matter chan ges have been obs erved in MRI (6). Lowering plasma PHE levels improved changes in some case s.In all areas mentioned, PHE and its impact on brain morphology and function seems to be a key explanatory factor. Access to a comp artment "closer to the brain" is possible by lumbar puncture, although in otherwise healthy patients it is ethically questionable. Using an animal model of hyperphenylalanin emia, Avison et at. (7) were able to show that PHE was detectable by 1H MRS in the brains of rabbits in vivo. Post-

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“…The hypothalamus and cerebellum have a higher concentration of tyrosine than other regions of the brain, and these regional variations in the concentration of the amino acids may be an important factor involved in the regulation of various different functions of the sepa rate brain regions (17). On the other hand, McKean et al (20) reported that the admi nistration of tyrosine caused cerebral depletions in essential amino acids in rats. All these factors concerning L-tyrosine feeding should be taken into account before making a correlation between blood pressure and tyrosine content in the brain of SHR.…”

Section: T_-tyrosine Feeding In Shrmentioning

confidence: 99%

Levels of Tyrosine and Tryptophan in the Plasma and Brain of Spontaneously Hypertensive Rats

Osumi

Tanaka

Takaori

1974

Japanese Journal of Pharmacology

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Abstract-Tyrosine and tryptophan contents in the plasma and brain, and noradre naline and serotonin contents in the brain were measured in spontaneously hyper tensive rats (SHR) and two normotensive strains, Wistar/Kyoto rats (WKR) and Wistar/Carworth rats (WCR) to investigate the quantitative relationship between monoamines and their precursor amino acids in the brain of SHR. WKR is the parent strain of SHR. Tyrosine level in the plasma and brain of SHR was significantly lower than that in WCR, whereas tryptophan level in the plasma and brain of SHR was higher than that of WCR. The levels of these amino acids were the same in SHR and WKR. Noradrenaline and serotonin contents in the brain stem of SHR and WKR were lower than the respective contents of WCR, while no difference was found in noradrenaline and serotonin contents in the telencephalon of these 3 strains. In SHR, 1.0% L-tyrosine ingestion for 5 days produced a slight but significant fall of the blood pressure accompanied by an increase of tyrosine in the plasma and brain. However, noradrenaline in the brain stem did not change following the L-tyrosinc feeding. These results suggest that differences in contents of the monoamines and their precursor amino acids in SHR and WKR could be due to genetic factors in a specific closed colony. (7) demonstrated that the catecholamine level, turnover rate and in vivo synthesis rate were lower in SHR than in the normotensive Wistar/NIH strain rats but similar to those in the normotensive Wistar/Kyoto rats (WKR), from which the SHR were isolated. Brain serotonin level in SHR over 6 months of age was found to be higher than that of normo tensive WKR (8).Although there are several views concerning the relationship between central mono amine metabolism and blood pressure, there is still a paucity in information concerning precursor amino acids of these monoamines in SHR.In the present experiment, tyrosine and tryptophan levels in the plasma and brain of SHR were compared with those of two normotensive strains, WKR and Wistar/Carworth strain rats (WCR). In addition, ef fects of L-tyrosine feeding on the blood pressure and contents of tyrosine and noradrena line were studied in SHR.

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The Influence of High Phenylalanine and Tyrosine on the Concentrations of Essential Amino Acids in Brain

Cited by 159 publications

References 7 publications

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

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

The Dynamics of Brain Concentrations of Phenylalanine and Its Clinical Significance in Patients with Phenylketonuria Determined by in Vivo H Magnetic Resonance Spectroscopy

Levels of Tyrosine and Tryptophan in the Plasma and Brain of Spontaneously Hypertensive Rats

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