N-Acetylcysteine Prevents the Increase in Spontaneous Oxidation of Dopamine During Monoamine Oxidase Inhibition in PC12 Cells

Neurochem Res. 2017 Nov;42(11):3289-3295. doi: 10.1007/s11064-017-2371-0. Epub 2017 Aug 24.

Abstract

The catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease proposes that the deaminated dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) is toxic to nigrostriatal dopaminergic neurons. Inhibiting monoamine oxidase (MAO) should therefore slow the disease progression; however, MAO inhibition increases spontaneous oxidation of dopamine, as indicated by increased 5-S-cysteinyl-dopamine (Cys-DA) levels, and the oxidation products may also be toxic. This study examined whether N-acetylcysteine (NAC), a precursor of the anti-oxidant glutathione, attenuates the increase in Cys-DA production during MAO inhibition. Rat pheochromocytoma PC12 cells were incubated with NAC, the MAO-B inhibitor selegiline, or both. Selegiline decreased DOPAL and increased Cys-DA levels (p < 0.0001 each). Co-incubation of NAC at pharmacologically relevant concentrations (1-10 µM) with selegiline (1 µM) attenuated or prevented the Cys-DA response to selegiline, without interfering with the selegiline-induced decrease in DOPAL production or inhibiting tyrosine hydroxylation. NAC therefore mitigates the increase in spontaneous oxidation of dopamine during MAO inhibition.

Keywords: Cysteinyl-dopamine; DOPAL; Monoamine oxidase; N-Acetylcysteine; Parkinson’s disease.

MeSH terms

  • Acetylcysteine / pharmacology*
  • Animals
  • Dopamine / metabolism*
  • Dose-Response Relationship, Drug
  • Monoamine Oxidase / metabolism*
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Oxidation-Reduction / drug effects
  • PC12 Cells
  • Rats
  • Selegiline / pharmacology*

Substances

  • Monoamine Oxidase Inhibitors
  • Selegiline
  • Monoamine Oxidase
  • Dopamine
  • Acetylcysteine