Inhibition of the bioactivation of the neurotoxin MPTP by antioxidants, redox agents and monoamine oxidase inhibitors

Food Chem Toxicol. 2011 Aug;49(8):1773-81. doi: 10.1016/j.fct.2011.04.026. Epub 2011 Apr 29.


Monoamine oxidase (MAO) enzymes located in human mitochondria oxidize neurotransmitters and bioactivate the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) by oxidation to directly-acting neurotoxic pyridinium cations (MPDP⁺/MPP⁺) that produce Parkinsonism. Antioxidants and MAO inhibitors are useful as neuroprotectants. Naturally-occurring substances, antioxidants and redox agents were assessed as inhibitors of the oxidation (bioactivation) of MPTP by human mitochondria and MAO enzymes. Methylene blue, 5-nitroindazole, norharman (β-carboline), 9-methylnorharman (9-methyl-β-carboline) and menadione (vitamin-K analogue) highly inhibited the oxidation of MPTP to the neurotoxic species, MPDP⁺/MPP⁺, in human mitochondria (IC₅₀ of 0.18, 3.1, 9.9, 7.3, and 12.6 μM, respectively). Inhibition by methylene blue was similar to R-deprenyl (IC₅₀ of 0.15 μM), a known neuroprotectant. The naturally-occurring β-carbolines, harmine, harmaline and tetrahydro-β-carboline, and the antioxidants, melatonin, resveratrol, quercetin and catechin showed little or no inhibition. Oxidation of MPTP in mitochondria was performed by human MAO-B and the above active compounds were also inhibitors of this isozyme. Norharman and 5-nitroindazole were competitive inhibitors of MAO-B whereas methylene blue inhibited MPTP oxidation (IC₅₀ of 50 nM) under a mixed type and predominantly uncompetitive mechanism. Methylene blue, 5-nitroindazole, norharman, 9-methylnorharman and menadione inhibit MAO-B in mitochondria and afford protective effects, as suggested by a reduced conversion of MPTP to neurotoxic species.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / antagonists & inhibitors*
  • Antioxidants / pharmacology*
  • Carbolines / pharmacology
  • Chromatography, High Pressure Liquid
  • Harmine / analogs & derivatives
  • Harmine / pharmacology
  • Humans
  • Indazoles / pharmacology
  • Mass Spectrometry
  • Methylene Blue / pharmacology
  • Mitochondria / metabolism
  • Monoamine Oxidase / adverse effects
  • Monoamine Oxidase / metabolism
  • Monoamine Oxidase Inhibitors / pharmacology*
  • Neuroprotective Agents / pharmacology
  • Neurotoxins / antagonists & inhibitors*
  • Oxidation-Reduction
  • Selegiline / pharmacology


  • 9-methyl-beta-carboline
  • Antioxidants
  • Carbolines
  • Indazoles
  • Monoamine Oxidase Inhibitors
  • Neuroprotective Agents
  • Neurotoxins
  • 5-nitroindazole
  • Selegiline
  • Harmine
  • norharman
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
  • Monoamine Oxidase
  • Methylene Blue