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Life Sci. 2014 Aug 6;110(1):1-7. doi: 10.1016/j.lfs.2014.05.014. Epub 2014 May 29.

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.

Author information

1
Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA.
2
University of Pennsylvania, 3451 Walnut Street, Philadelphia, PA 19104, USA.
3
Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA. Electronic address: ccharlton@mmc.edu.

Abstract

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 100mg/kg of l-dopa twice a day for 14 days, and a matching group remained l-dopa naïve. l-dopa naive and primed mice received a challenge dose of 100mg/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 naïve 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 increased metabolism via 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.

KEYWORDS:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP); 3,4-Dihydroxyphenyalanine (l-dopa); 3,4-Dihydroxyphenyl acetic acid (DOPAC); 3-Methoxytyramine (3-MT); 3-O-methyldopa (3-OMD); Catechol-O-methyltransferase (COMT); Dopamine (DA); Homovanillic acid (HVA); Monoamine oxidase (MAO); Parkinson's disease (PD); l-dopa-induced dyskinesia (LID)

PMID:
24880075
DOI:
10.1016/j.lfs.2014.05.014
[Indexed for MEDLINE]
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