Reversal of Hypotonia in Infants With Down's Syndrome by Administration of 5-Hydroxytryptophan

Bazelon, Mary; Paine, RichmondS.; Cowie, ValerieA.; Hunt, Patricia; Houck, JohnC.; Mahanand, Dersh

doi:10.1016/s0140-6736(67)91708-4

Cited by 91 publications

(23 citation statements)

References 15 publications

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“…Since platelet 5HT is thought to derive predominantly from the uptake of circulating 5HT rather than from synthesis in the platelet, the altered transport of 5HT observed provides a mechanism for explaining the change in endogenous 5HT levels. The low endogenous content is in agreement with that reported in several other studies [1][2][3][4], and a defect in the total accumulation of 5HT by mongol platelets was previously reported by Jerome and Kamoun using high concentrations of nonradiolabeled 5HT [13].…”

Section: Discussionsupporting

confidence: 92%

“…The possibility that low levels of 5HT in platelets relate to the central nervous system defect in Down's syndrome is suggested by recent evidence that the human platelet has certain structural and functional similarities to amine-containing neurons [1,[19][20][21]. On the assumption that the whole blood abnormality of 5HT in Down's syndrome may reflect defective metabolism of this putative neurotransmitter amine in the central nervous system, L-5-hydroxytryptophan, the immediate precursor of 5HT, has been administered to neonatal mongols and has been shown to produce some alteration in neuromuscular function [2].…”

Section: Introductionmentioning

confidence: 99%

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Down's Syndrome: Transport, Storage, and Metabolism of Serotonin in Blood Platelets

1972

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ExtractSerotonin (5HT) transport and metabolism were studied in platelets from 14 trisomy-21 patients who were matched with 12 sibling and 9 non-sibling control subjects with regard to age, sex, home environment, diet and weight. Endogenous 5HT content, in nanograms per milligram platelet protein, was reduced from 446 ± 66 in the sibling controls and from 492 ± 74 in the non-sibling controls to 158 ± 16 in the Down's syndrome group, a difference of 61% and 68% respectively (P < 0.001). Initial uptake of 14 G-5HT measured after a 3-min incubation period was reduced 35% (P < 0.05) in the platelets from Down's syndrome patients, while the efflux of radiolabeled amine from platelets was not significantly altered in these patients. Since platelets do not synthesize 5HT, the decreased transport found may explain the lower 5HT levels in these patients. Mongols did not differ from control subjects in the activity of platelet monoamine oxidase. SpeculationSimilarities in the uptake, storage, and release of 5HT between the human blood platelet and the serotonergic neuron suggest that the 5HT abnormality observed in mongol platelets may reflect disordered metabolism of the monoamine within the central nervous system.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Down's Syndrome: Transport, Storage, and Metabolism of Serotonin in Blood Platelets

1972

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“…VITAMIN B6 / 5-HYDROXYTRYPTAMINE (5-HTP) SUPPLEMENTATION Individuals with DS have been treated with vitamin B6 or 5-HTP in order to increase their serotonin level 74 , which is frequently reported to be reduced [75][76][77] . Despite two uncontrolled studies 76,78 which reported improvements in the muscle tone of 23 babies and children with DS treated with 5-HTP, two randomised controlled trials 74,79 failed to find any significant clinical improvements in a total of 108 babies with DS treated with vitamin B6 or 5-HTP for 3 years.…”

Section: Vitamin a Supplementationmentioning

confidence: 99%

Nutritional supplementation in Down syndrome: theoretical considerations and current status

Ani

Grantham‐McGregor

Muller

2000

Develop Med Child Neuro

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“…The tissue slices (1.4 g, wet weight) were placed in a 25-ml flask containing 5 ml of the same pH 7.2 buffer and shaken at 60 strokes per min for 20 20 min and the supernatant was combined with the incubation medium. The recovery of total radioactivity with these procedures was 92-95% of the initial radioactivity added to the incubation medium in each sample.…”

mentioning

confidence: 99%

“…The formation of 5-HKA by the 5-HK pathway is of great interest because this compound has been reported to antagonize 5-HT-induced vasoconstriction of dog basilar artery (11) and aggregation of human platelets (19). Furthermore, because 5-HTP has recently been used as a precursor of 5-HT in the therapy of mongolism (20), Parkinson disease (21), and depression (22,23), it should be emphasized that, as well as the 5-HT pathway, the 5-HK pathway or resulting metabolites such as 5-HK and 5-HKA may also contribute to the clinical features noted after administration of 5-HTP.…”

mentioning

confidence: 99%

Formation of 5-hydroxykynurenine and 5-hydroxykynurenamine from 5-hydroxytryptophan in rabbit small intestine

Fujiwara

Shibata

Nomiyama

et al. 1979

Proc. Natl. Acad. Sci. U.S.A.

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In order to clarify the role of indoleamine 2,3-dioxygenase [indole:oxygen 2,3-oxidoreductase (decyclizing), EC 1.13.11.17j in the metabolism of serotonin, DL-5-hydroxy-[methylene-4Citryptophan, a precursor of serotonin, was incubated with slices of rabbit ileum. Resulting metabolites were separated by DEAE-cellulose column and polyamide column chromatography and identified by various chromatographic techniques and enzymatic analysis. Metabolites obtained in significant amounts were serotonin, 5-hydroxyindoleacetic acid, 5-hydroxytryptophol, 5-hydroxykynurenine, 5-hydroxykynurenamine, and 4,6-dihydroxyquinoline, representing 13.2, 15.8, 7.0,21.9, 1.3, and 2.6% of the total metabolites, respectively. The first three compounds were previously reported to be major metabolites produced from 5-hydroxytryptophan by the action of aromatic L-amino acid decarboxylase and monoamine oxidase, whereas the last three are formed by the cleavage of the indole ring by the action of indoleamine 2,3-dioxygenase. In the presence of pargyline, a monoamine oxidase inhibitor, the major metabolites obtained were serotonin, 5-hydroxykynurenine, and 5-hydroxykynurenamine, representing 29.6, 26.6, and 5.4% of the total metabolites, respectively. In the presence of R04-4602, an aromatic amino acid decarboxylase inhibitor, 5-hydroxykynurenine was the sole major product. These results strongly suggest that the newly discovered metabolic pathway involving the cleavage of the indole ring of 5-hydroxytryptophan operates in vivo to a significant extent and that indoleamine 2,3-dioxygenase plays an important role in the regulation of serotonin levels in the small intestine of the rabbit.Studies on serotonin (5-HT) metabolism in mammalian tissues have established a pathway that includes successive hydroxylation and decarboxylation of tryptophan and further degradation to 5-hydroxyindoleacetic acid (5-HIAA) or 5-hydroxytryptophol (5-HTOH). However, reports on the natural occurrence of 5-hydroxykynurenine (5-HK) in the urine of hens (1), 5-hydroxykynurenamine (5-HKA) in the brain and urine of mice (2, 3), and 4,6-dihydroxyquinoline (4, in the urine of hens (4) have strongly suggested the existence of another pathway involving oxidative cleavage of the indole ring of various indoleamine derivatives. From 5-hydroxytryptophan (5-HTP), 5-HK was formed in crude extracts of rat intestine (5) or rat brain (6). In our own experiments, it was demonstrated that indoleamine 2,3-dioxygenase [indole:oxygen 2,3-oxidoreductase (decyclizing), EC 1.13.11.17] highly purified from rabbit ileum cleaved the indole ring of 5-HTP and 5-HT oxidatively (7). However, because the enzyme has an absolute requirement for an artificial oxidation-reduction dye (e.g., methylene blue) when acting in vitro (8, 9), the question has been raised as to whether or not this enzyme functions in vivo.In the present work using slices of rabbit ileum, we investi- Tissue Preparation. Adult male rabbits (2.5-3 kg) were anesthetized with pentobarbital sodium (50 mg/kg, intravenously), and...

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Reversal of Hypotonia in Infants With Down's Syndrome by Administration of 5-Hydroxytryptophan

Cited by 91 publications

References 15 publications

Down's Syndrome: Transport, Storage, and Metabolism of Serotonin in Blood Platelets

Down's Syndrome: Transport, Storage, and Metabolism of Serotonin in Blood Platelets

Nutritional supplementation in Down syndrome: theoretical considerations and current status

Formation of 5-hydroxykynurenine and 5-hydroxykynurenamine from 5-hydroxytryptophan in rabbit small intestine

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