Effect of Excess Phenylalanine and of Other Amino Acids on Brain Developmen in the Infant Rat

Abstract

The effects of excess phenylalanine and of a number of other amino acids on brain weight, total brain lipid, and formation of the myelin lipid cerebroside sulfate (sulfatide) have been studied in the newborn rat. Brain weight, amount of brain lipids, and the formation in vivo of sulfatide were reduced as a result of injections of phenylalanine or of certain other amino acids. Total brain cholesterol, cerebroside, and sulfatide were all significantly reduced in phenylalanine-injected animals, although sulfatide was the only lipid that was reduced per gram wet weight of brain. The in vitro activity of the brain enzyme, galactolipid sulfotransferase, which catalyzes the formation of sulfatide from cerebroside and adenosine 3'-phosphate 5'-phosphosulfate (PAPS), was significantly reduced only when exogenous PAPS was not added to the assay medium. This finding suggests that in the brains of animals injected with phenylalanine there was impairment in the formation of PAPS from ATP and sulfate. In both cerebrums and cerebellums of animals injected with phenylalanine for the first 18 days of life, the amount of brain DNA and protein was reduced. Speculation

Lipid Metabolism in Liver and Brain in Acute Hyperphenylalaninemia in Rats of Different Ages

“…The present studies thus indi cate that phosphatidylinositol and phosphatidic acid metabolism, as measured by acetate incorporation into their acyl moieties, is not affected by these phenylalanine-loading conditions. Sulfation reactions responsible for sulfatide synthesis are inhibited in suckling rats chronically injected with amino acids [11], No specific effects on sulfatide labeling with acetate were observed in the present acute experi ments. Inhibition of sulfatide labeling also occurs in hypothyroid suckling rats [47], undernourished suckling rats [10] and vitamin A-deficient suckling rats [13,24], The vitamin A deficiency effects were attributed to a secondary undernutrition [24].…”

“…This suggests that ammonia toxicity per se is not the factor causing the reduced acetate uptake into brain in the present experiments. Injections of ammonium carbonate in suckling rats [11] reduced brain growth and radioactive sulfate incorporation into brain sulfatide, indicating that at appropriate dosages ammonium ion can affect brain metabolism. Decreases in acetate incorpora tion did not correlate with brain phenylalanine levels, for 7-day-old brain had levels about two times higher than 2I-day-old brain, while acetate in corporation was depressed somewhat more in 21-day-old brain.…”

“…Previous studies have suggested that chronic administration of phenylalanine to immature animals results in retardation of brain growth and brain lipid accumulation [11,12,29,31,36], while dietary administration to more mature animals has little effect [17,23], Isolated myelin, while reduced in amount, was found to have a normal lipid class composition in rats which had received phenylalanine during their early development [31,36], Metabolic experiments have suggested an inhibition of brain protein synthesis [1,4,19,42] or lipid synthesis [5,6,11,19,35,37] in immature animals, while in mature animals no effects on protein synthesis have been detected [4,34], A proper evaluation of some of these studies is handicapped, however, by lack of data on brain precursor amino acidspecific radioactivity. Similarly, in the lipid incorporation experiments, brain precursor pool size and specific radioactivity have not been determined and in only a few experiments have specific lipids been assayed.…”

“…The effects have been studied in three distinct brain regions at several developmental stages. Because of greater reductions in accumulation of myelin than nonmyelin lipids in chronic hyperphenylalaninemia [11,12,29,31,36], myelin and nonmyelin-related lipids have been compared in brain regionsat differingstagesof myelination. Because mass accumulation cannot be measured in short-term experiments, precursor uptake was measured in the intact animal.…”

Development of Adenosine 5'-Triphosphate Sulfurylase and Adenosine Phosphosulfate Kinase in Rat Cerebrum and Liver

“…Earlier investigations have shown that the brain PAPS-forming system can be inhibited by phenylalanine, but not that system from liver [4,5], while kinetic dif ferences have been demonstrated between ATP-sulfurylase and APS-kinase of brain and liver, respectively [6]. Inhibition of PAPS synthesis by phenylalanine in the growing rat brain has been shown by Chase and O'Brien [7]. This inhibition has been localized at ATP-sulfurylase [6].…”