The role of 3-O-methyldopa in the side effects of L-dopa

Neurochem Res. 2008 Mar;33(3):401-11. doi: 10.1007/s11064-007-9442-6. Epub 2007 Aug 24.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antiparkinson Agents / metabolism
  • Antiparkinson Agents / toxicity*
  • Benzazepines / pharmacology
  • Brain Chemistry / drug effects
  • Catecholamines / metabolism
  • Cell Survival / drug effects
  • Chromatography, High Pressure Liquid
  • Dopamine / metabolism
  • Dopamine / physiology
  • Dopamine Antagonists / pharmacology
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Levodopa / metabolism
  • Levodopa / toxicity*
  • Male
  • Membrane Potentials / drug effects
  • Mitochondrial Membranes / drug effects
  • Motor Activity / drug effects
  • PC12 Cells
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / metabolism
  • Receptors, Dopamine D1 / drug effects
  • Synaptic Transmission / physiology
  • Tyrosine / analogs & derivatives*
  • Tyrosine / metabolism
  • Tyrosine / toxicity


  • Antiparkinson Agents
  • Benzazepines
  • Catecholamines
  • Dopamine Antagonists
  • Dopamine Plasma Membrane Transport Proteins
  • Reactive Oxygen Species
  • Receptors, Dopamine D1
  • Tyrosine
  • Levodopa
  • 3-methoxytyrosine
  • Dopamine