The role of 3-O-methyldopa in the side effects of L-dopa.
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 micromol 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 micromole 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 (alpha-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.
Lee
Eun-Sook Y
ES
Department of Neurobiology and Neurotoxicology, Meharry Medical College, Nashville, TN 37208, USA. elee@mmc.edu
Chen
Hongtao
H
King
Jennifer
J
Charlton
Clivel
C
D000818:Animals; D000978:Antiparkinson Agents / Q000378:metabolism / Q000633:toxicity*; D001552:Benzazepines / Q000494:pharmacology; D001923:Brain Chemistry / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism / Q000502:physiology; D018492:Dopamine Antagonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051336:Mitochondrial Membranes / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D009435:Synaptic Transmission / Q000502:physiology; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity
D000978:Antiparkinson Agents; D001552:Benzazepines; D002395:Catecholamines; D018492:Dopamine Antagonists; D050483:Dopamine Plasma Membrane Transport Proteins; D017382:Reactive Oxygen Species; D017447:Receptors, Dopamine D1; D014443:Tyrosine; D007980:Levodopa; C008404:3-methoxytyrosine; D004298:Dopamine
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