L-dopa-induced dopamine synthesis and oxidative stress in serotonergic cells

Neuropharmacology. 2013 Apr;67:243-51. doi: 10.1016/j.neuropharm.2012.11.010. Epub 2012 Nov 27.

Abstract

L-dopa is a precursor for dopamine synthesis and a mainstay treatment for Parkinson's disease. However, l-dopa therapy is not without side effects that may be attributed to non-dopaminergic mechanisms. Synthesized dopamine can be neurotoxic through its enzymatic degradation by monoamine oxidase (MAO) to form the reactive byproduct, hydrogen peroxide and hydroxyl radicals or through auto-oxidation to form highly reactive quinones that can bind proteins and render them non-functional. Since l-dopa could be decarboxylated by aromatic amino acid decarboxylase (AADC) present within both dopamine and serotonin neurons, it was hypothesized that serotonin neurons convert l-dopa into dopamine to generate excessive reactive oxygen species and quinoproteins that ultimately lead to serotonin neuron death. To examine the effects of l-dopa on serotonin neurons, the RN46A-B14 cell line was used. These immortalized serotonergic cell cultures were terminally differentiated and then incubated with varying concentrations of l-dopa. Results show that RN46A-B14 cells contain AADC and can synthesize dopamine after incubation with l-dopa. Furthermore, l-dopa dose-dependently increased intracellular reactive oxygen species (ROS) and cell death. Dopamine, ROS production and cell death were attenuated by co-incubation with the AADC inhibitor, NSD-1015. The MAO inhibitor, pargyline, also attenuated cell death and ROS after l-dopa treatment. Lastly, quinoprotein formation was enhanced significantly by incubation with l-dopa. Taken together, these data illustrate that serotonergic cells can produce dopamine and that the accumulation of dopamine after l-dopa and its subsequent degradation can lead to ROS production and death of RN46A-B14 serotonergic cells.

Publication types

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

MeSH terms

  • Cell Line, Transformed
  • Dopamine / biosynthesis*
  • Humans
  • Levodopa / pharmacology*
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology*
  • Reactive Oxygen Species / metabolism
  • Serotonergic Neurons / drug effects*
  • Serotonergic Neurons / metabolism*

Substances

  • Reactive Oxygen Species
  • Levodopa
  • Dopamine