The Role of 3-<Emphasis Type="Italic">O</Emphasis>-Methyldopa in the Side Effects of <Emphasis Type="SmallCaps">l</Emphasis>-dopa |
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Authors: | Eun-Sook Y Lee Hongtao Chen Jennifer King Clivel Charlton |
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Institution: | (1) Department of Neurobiology and Neurotoxicology, Meharry Medical College, Nashville, TN 37208, USA |
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Abstract: | Long-term treatment of l-dopa for Parkinson’s disease (PD) patients induces adverse effects, including dyskinesia, on–off and wearing-off symptoms.
However, the cause of these side effects has not been established to date. In the present study, therefore, 3-O-methyldopa (3-OMD), which is a major metabolite of l-dopa, was tested to determine whether it plays a role in the aforementioned adverse effects. The effects of 3-OMD on the
dopaminergic nervous system in the brain were investigated, by examining behavioral, biochemical, and cellular changes in
male Sprague–Dawley rats and catecholamine-producing PC12 neuronal cells. The results revealed that the intracerebroventricular
(icv) injection of 1 μmol of 3-OMD impaired locomotor activities by decreasing movement time (MT), total distance (TD), and
the number of movement (NM) by 70, 74 and 61%, respectively. The biochemical analysis results showed that a single administration
of 1 μmole of 3-OMD decreased the dopamine turnover rate (DOPAC/DA) by 40.0% in the rat striatum. 3-OMD inhibited dopamine
transporter and uptake in rat brain striatal membranes and PC12 cells. The subacute administration of 3-OMD (5 days, icv)
also significantly impaired the locomotor activities and catecholamine levels. 3-OMD induced cytotoxic effects via oxidative
stress and decreased mitochondrial membrane potential in PC12 cells, indicating that 3-OMD can damage neuronal cells. Furthermore,
3-OMD potentiated l-dopa toxicity and these toxic effects induced by both 3-OMD and l-dopa were blocked by vitamin E (α-tocopherol) in PC12 cells, indicating that 3-OMD may increase the toxic effects of l-dopa to some extent by oxidative stress. Therefore, the present study reveals that 3-OMD accumulation from long-term l-dopa treatment may be involved in the adverse effects of l-dopa therapy. Moreover, l-dopa treatment might accelerate the progression of PD, at least in part, by 3-OMD. |
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Keywords: | l-dopa" target="_blank">l-dopa 3-O-methyldopa Parkinson’ s disease Locomotor activity Oxidative stress |
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