Pharmacologic inhibition of L-tyrosine degradation ameliorates cerebral dopamine deficiency in murine phenylketonuria (PKU).

[phenylketonuria]

Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU ). Two proposed explanations for neurotransmitter deficiency in PKU include first , that chronically elevated blood L-phenylalanine (Phe ) inhibits the transport of L-tyrosine (Tyr ) and L-tryptophan (Trp ), the substrates for dopamine and serotonin synthesis respectively , into brain . In the second hypothesis , elevated Phe competitively inhibits brain tyrosine hydroxylase (TH ) and tryptophan hydroxylase (TPH ) activities , the rate limiting steps in dopamine and serotonin synthesis . Dietary supplementation with large neutral amino acids (LNAA ) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain . As a potential alternative treatment approach , we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC ) yielded sustained increases in blood and brain Tyr , decreased blood and brain Phe , and consequently increased dopamine synthesis in a murine model of PKU . Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU . Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU .

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phenylketonuria

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