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The Role of 3-O-Methyldopa in the Side Effects of l-dopa

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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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Acknowledgement

Support for this research project is provided by National Institutes of Health grants NIH/NS28432, RR03020, and GM08111.

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  1. Department of Neurobiology and Neurotoxicology, Meharry Medical College, Nashville, TN, 37208, USA

    Eun-Sook Y. Lee, Hongtao Chen, Jennifer King & Clivel Charlton

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  1. Eun-Sook Y. Lee
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  2. Hongtao Chen
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Correspondence to Eun-Sook Y. Lee.

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Lee, ES.Y., Chen, H., King, J. et al. The Role of 3-O-Methyldopa in the Side Effects of l-dopa. Neurochem Res 33, 401–411 (2008). https://doi.org/10.1007/s11064-007-9442-6

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  • DOI: https://doi.org/10.1007/s11064-007-9442-6

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