HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

In vivo catecholaminergic metabolism in the medial prefrontal cortex of ENU2 mice: an investigation of the cortical dopamine deficit in phenylketonuria.

AbstractOBJECTIVE:
Phenylketonuria (PKU) is an inherited metabolic disease characterized by plasma hyperphenylalaninemia and several neurological symptoms that can be controlled by rigorous dietetic treatment. The cellular mechanisms underlying impaired brain functions are still unclear. It has been proposed, however, that phenylalanine interference in cognitive functions depends on impaired dopamine (DA) transmission in the prefrontal cortical area due to reduced availability of the precursor tyrosine. Here, using Pah(enu2) (ENU2) mice, the genetic murine model of PKU, we investigated all metabolic steps of catecholamine neurotransmission within the medial preFrontal Cortex (mpFC), availability of the precursor tyrosine, synthesis and release, to find an easy way to reinstate normal cortical DA neurotransmission.
METHODS AND RESULTS:
Analysis of blood and brain levels of tyrosine showed reduced plasma and cerebral levels of tyrosine in ENU2 mice. Western blot analysis demonstrated deficient tyrosine hydroxylase (TH) protein levels in mpFC of ENU2 mice. Cortical TH activity, determined in vivo by measuring the accumulation of l-3,4-dihydroxyphenylalanine (L-DOPA) in mpFC after inhibition of L-aromatic acid decarboxylase with NSD-1015, was reduced in ENU2 mice. Finally, a very low dose of L-DOPA, which bypasses the phenylalanine-inhibited metabolic steps, restored DA prefrontal transmission to levels found in healthy mice.
CONCLUSION:
The data suggests that a strategy of using tyrosine supplementation to treat PKU is unlikely to be effective, whereas small dose L-DOPA administration is likely to have a positive therapeutic effect.
AuthorsTiziana Pascucci, Giacomo Giacovazzo, Diego Andolina, David Conversi, Fabio Cruciani, Simona Cabib, Stefano Puglisi-Allegra
JournalJournal of inherited metabolic disease (J Inherit Metab Dis) Vol. 35 Issue 6 Pg. 1001-9 (Nov 2012) ISSN: 1573-2665 [Electronic] United States
PMID22447154 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Catecholamines
  • Tyrosine
  • Levodopa
  • Phenylalanine Hydroxylase
  • Tyrosine 3-Monooxygenase
  • Dopamine
Topics
  • Animals
  • Catecholamines (metabolism)
  • Disease Models, Animal
  • Dopamine (metabolism)
  • Levodopa (administration & dosage)
  • Male
  • Mice
  • Mice, Mutant Strains
  • Phenylalanine Hydroxylase (genetics)
  • Phenylketonurias (blood, drug therapy, genetics, metabolism)
  • Prefrontal Cortex (metabolism)
  • Synaptic Transmission (drug effects)
  • Tyrosine (administration & dosage, blood, metabolism)
  • Tyrosine 3-Monooxygenase (deficiency)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: