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.

摘要

AIMS: 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. MAIN 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. KEY FINDINGS: 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. SIGNIFICANCE: 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.