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Chronic hyperphenylalaninemia produces cerebral hyperglycinemia in immature rats
Insights
Hyperphenylalaninemia in rats alters brain amino acid levels, increasing glycine and decreasing others. Methionine loading showed potential therapeutic benefits for managing these changes.
Area of Science:
- Biochemistry
- Neuroscience
- Metabolic Disorders
Background:
- Phenylalanine hydroxylase (PAH) deficiency causes hyperphenylalaninemia.
- Altered amino acid profiles in the brain can impact neurological function.
- Understanding these metabolic shifts is crucial for developing therapeutic strategies.
Purpose of the Study:
- To investigate the effects of induced hyperphenylalaninemia on amino acid concentrations in rat tissues.
- To examine the impact of chronic versus acute hyperphenylalaninemia on cerebral amino acid levels.
- To evaluate potential therapeutic interventions for managing altered brain amino acid profiles.
Main Methods:
- Inducing hyperphenylalaninemia in 10-day-old rats using phenylalanine and a PAH inhibitor.
- Measuring amino acid concentrations in cerebral hemispheres, spinal cord, and liver tissues.
- Assessing cerebral phosphoserine phosphatase activity and the impact of methionine loading.
Main Results:
- Hyperphenylalaninemia significantly decreased alanine, valine, methionine, isoleucine, and leucine in the cerebral hemispheres.
- Cerebral glycine levels were elevated, and this effect was observed with chronic but not acute hyperphenylalaninemia.
- Methionine loading partially reduced brain phenylalanine levels and increased methionine concentration.
Conclusions:
- Induced hyperphenylalaninemia profoundly alters brain amino acid homeostasis, particularly affecting glycine metabolism.
- Chronic hyperphenylalaninemia prevents the age-related decline in brain glycine.
- Methionine loading presents a potential therapeutic avenue for mitigating some biochemical consequences of hyperphenylalaninemia.
Abstract:
The amino acid content of three tissues was measured in 10-day-old rats made hyperphenylalaninemic from age 3 to 10 days by daily injection of phenylalanine plus alpha-methylphenylalanine to inhibit phenylalanine hydroxylase (PAH). At 12 h after the last injection, the concentrations of alanine, valine, methionine, isoleucine, and leucine in the cerebral hemispheres were depressed by 25-50%, whereas that of glycine was elevated 2.3-fold. In the spinal cord, the levels of phosphoserine, methionine, and leucine were decreased by 40-50%, and those of serine and threonine increased by 50%. Tyrosine and phenylalanine concentrations were high in all tissues, 2-3 and 15-30 times normal, respectively; of the amino acids investigated, they were the only ones changed in the liver. Cerebral hyperglycinemia was also produced by chronic treatment with phenylalanine plus p-chlorophenylalanine to inhibit PAH, but not by acute (12 h) hyperphenylalaninemia. An increase in cerebral phosphoserine phosphatase activity was greater in rats treated with phenylalanine plus PAH inhibitor than with inhibitor alone. The content of brain glycine normally declines with age from birth to 15 days; this decrease was prevented by chronic hyperphenylalaninemia. Attempts to reduce the cerebral glycine content of the hyperphenylalaninemic rats were unsuccessful. However, one of the therapeutic protocols, methionine loading, may be useful because it increased the methionine and decreased the phenylalanine contents in the brain.