Effects of acute and sub-chronic l-dopa therapy on striatal l-dopa methylation and dopamine oxidation in an MPTP mouse model of Parkinsons disease

摘要

Aims: The molecular mechanisms for the loss of 3,4-dihydroxyphenylalanine (L-dopa) efficacy during the treatment of Parkinson's disease (PD) are unknown. Modifications related to catecholamine metabolism such as changes in L-dopa and dopamine (DA) metabolism, the modulation of catecholamine enzymes and the production of interfering metabolites are the primary concerns of this study.Main methods: Normal (saline) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) pre-treated mice were primed with 100 mg/kg of L-dopa twice a day for 14 days, and a matching group remained L-dopa na?ve. L-dopa naive and primed mice received a challenge dose of 100 mg/kg of L-dopa and were sacrificed 30 min later. Striatal catecholamine levels and the expression and activity of catechol-O-methyltransferase (COMT) were determined.Key findings: Normal and MPTP pre-treated animals metabolize L-dopa and DA similarly during L-dopa therapy. Administration of a challenge dose of L-dopa increased L-dopa and DA metabolism in L-dopa na?ve animals, and this effect was enhanced in L-dopa primed mice. The levels of 3-OMD in MPTP pre-treated animals were almost identical to those in normal mice, which we found are likely due to increased COMT activity in MPTP pre-treated mice.Significance: The results of this comparative study provide evidence that sub-chronic administration of L-dopa decreases the ability of the striatum to accumulate L-dopa and DA, due to increasedmetabolismvia methylation and oxidation. This data supports evidence for the metabolic adaptation of the catecholamine pathway during long-term treatment with L-dopa, which may explain the causes for the loss of L-dopa efficacy.