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 |
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Authors: | Marquitta L. Smith Jennifer King Lemuel Dent Veronica Mackey Gladson Muthian Brenya Griffin Clivel G. Charlton |
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Affiliation: | 1. Department of Neuroscience and Pharmacology, Meharry Medical College, Nashville, TN 37208, USA;2. University of Pennsylvania, 3451 Walnut Street, Philadelphia, PA 19104, USA |
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Abstract: | AimsThe 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 methodsNormal (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 naïve. 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 findingsNormal 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.SignificanceThe 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. |
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Keywords: | Parkinson's disease (PD) 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) 3,4-Dihydroxyphenyalanine (l-dopa) 3-O-methyldopa (3-OMD) l-dopa-induced dyskinesia (LID) Dopamine (DA) Monoamine oxidase (MAO) Catechol-O-methyltransferase (COMT) 3,4-Dihydroxyphenyl acetic acid (DOPAC) Homovanillic acid (HVA) 3-Methoxytyramine (3-MT) |
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