Evaluation of the oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to toxic pyridinium cations by monoamine oxidase (MAO) enzymes and its use to search for new MAO inhibitors and protective agents

J Enzyme Inhib Med Chem. 2012 Dec;27(6):810-7. doi: 10.3109/14756366.2011.616946. Epub 2011 Oct 12.


Monoamine oxidase (MAO) enzymes catalyze the oxidative deamination of amines and neurotransmitters and inhibitors of MAO are useful as neuroprotectants. This work evaluates the human MAO-catalyzed oxidation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a dopaminergic neurotoxin, to the directly-acting neurotoxic metabolites, 1-methyl-4-phenyl-2,3-dihydropyridinium (MPDP(+)) and 1-methyl-4-phenylpyridinium (MPP(+)) measured by High-Performance Liquid Chromatography (HPLC), and this approach is subsequently used as a new method for screening of MAO inhibitors and protective agents. Oxidation of MPTP by human MAO-B was more efficient than by MAO-A. R-Deprenyl, a known neuroprotectant, norharman (β-carboline), 5-nitroindazole and menadione (vitamin K3) inhibited MAO-B and reduced the formation of toxic pyridinium cations. Clorgyline and the β-carbolines, harman and norharman, inhibited the oxidation of MPTP by MAO-A. Cigarette smoke, as well as the naturally occurring β-carbolines (norharman and harman) isolated from smoke and coffee inhibited the oxidation of MPTP by MAO-B and/or MAO-A, suggesting protective effects against MPTP. The results show the suitability of the approach used to search for new MAO inhibitors with eventual neuroprotective activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / antagonists & inhibitors
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / chemistry*
  • 1-Methyl-4-phenylpyridinium / chemistry*
  • Carbolines
  • Chromatography, High Pressure Liquid
  • Clorgyline / chemistry
  • Enzyme Assays
  • Harmine / analogs & derivatives
  • Harmine / chemistry
  • Humans
  • Indazoles / chemistry
  • Isoenzymes / antagonists & inhibitors
  • Monoamine Oxidase / chemistry*
  • Monoamine Oxidase Inhibitors / chemistry*
  • Neuroprotective Agents / chemistry*
  • Oxidation-Reduction
  • Pyridinium Compounds / chemistry*
  • Recombinant Proteins / antagonists & inhibitors
  • Selegiline / chemistry
  • Smoke
  • Tobacco / chemistry
  • Vitamin K 3 / chemistry


  • Carbolines
  • Indazoles
  • Isoenzymes
  • Monoamine Oxidase Inhibitors
  • Neuroprotective Agents
  • Pyridinium Compounds
  • Recombinant Proteins
  • Smoke
  • 5-nitroindazole
  • Selegiline
  • Harmine
  • Vitamin K 3
  • 1-methyl-4-phenyl-2,3-dihydropyridinium
  • norharman
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Monoamine Oxidase
  • Clorgyline
  • 1-Methyl-4-phenylpyridinium