title: L-Dihydroxyphenylalanine modulates the steady-state expression of mouse striatal tyrosine hydroxylase, aromatic L-amino acid decarboxylase, dopamine and its metabolites in an MPTP mouse model of Parkinson's disease.
abstract: OBJECTIVE
  l-3,4-Dihydroxyphenylalanine (L-DOPA) is the most effective symptomatic treatment for Parkinson's disease (PD), but PD patients usually experience a successful response to L-DOPA therapy followed by a progressive loss of response. L-DOPA efficacy relies on its decarboxylation by aromatic l-amino acid decarboxylase (AAAD) to form dopamine (DA). So exogenous L-DOPA drives the reaction and AAAD becomes the rate limiting enzyme in the supply of DA. In turn, exogenous L-DOPA regulates the expression and activity of AAAD as well as the synthesis of DA and its metabolites, changes that may be linked to the efficacy and side-effects of L-DOPA.
  
  
  METHODS
  One-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse PD model was utilized to study the effects of L-DOPA on the steady-state level and activity of AAAD, tyrosine hydroxylase (TH), DA and the metabolites of DA. The MPTP and control mice were treated twice daily with PBS or with 100mg/kg of L-DOPA for 14days and the expression and activity of AAAD, the expression of TH and the levels of DA and its metabolites were determined 24h after L-DOPA or PBS treatment, when exogenous L-DOPA is eliminated.
  
  
  RESULTS
  In the MPTP model, L-DOPA reduced the steady-state expression and the activity of striatal AAAD by 52% and 50%, respectively, DA and metabolites were also significantly decreased.
  
  
  CONCLUSIONS
  The outcome shows that while L-DOPA replenishes striatal DA it also down-regulates AAAD and the steady-state synthesis and metabolic capability of the dopaminergic system. These findings are important in the precipitation of L-DOPA induced side effects and the management of L-DOPA therapy.
authors.affiliation: Department of Neuroscience and Pharmacology, 1005 Dr. D.B. Todd Jr. Blvd. Meharry Medical College, Nashville, TN 37208, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: King
authors.forename: Gladson
authors.initials: G
authors.lastname: Muthian
authors.forename: Veronica
authors.initials: V
authors.lastname: Mackey
authors.forename: Marquitta
authors.initials: M
authors.lastname: Smith
authors.forename: Clivel
authors.initials: C
authors.lastname: Charlton
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000031:analogs & derivatives; D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000494:pharmacology*; D001142:Aromatic-L-Amino-Acid Decarboxylases / Q000235:genetics / Q000378:metabolism*; D003342:Corpus Striatum / Q000201:enzymology / Q000378:metabolism*; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007980:Levodopa / Q000009:adverse effects / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010300:Parkinson Disease / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D010302:Parkinson Disease, Secondary / Q000139:chemically induced; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism*
chemical_list: D000978:Antiparkinson Agents; C040846:4-phenyl-1,2,3,6-tetrahydropyridine; D007980:Levodopa; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D001142:Aromatic-L-Amino-Acid Decarboxylases; D004298:Dopamine