Oxidation of dopamine to aminochrome as a mechanism for neurodegeneration of dopaminergic systems in Parkinson's disease. Possible neuroprotective role of DT-diaphorase

Pol J Pharmacol. 2002 Nov-Dec;54(6):573-9.


Although it is generally accepted that free radicals are involved in the neurodegenerative process occurring in the dopaminergic neurons of the nigro-striatal system in Parkinson's disease, the exact mechanism of neurodegeneration in vivo is still unknown. We propose that the degeneration of dopaminergic nigrostriatal system in this condition may depend on: (a) existence of free dopamine which oxidizes to aminochrome as a consequence of: (i) overproduction of dopamine; (ii) inhibition and/or low expression of synaptic vesicle catecholamine transporter; (iii) inhibition or low expression of monoamine oxidases; (b) one-electron reduction of aminochrome to leukoaminochrome o-semiquinone radical, which induces neurotoxicity, due to inhibition of DT-diaphorase or the existence of a polymorphism with a point mutation (C --> T) in the cDNA 609 expressing an inactive DT-diaphorase. We suggest that DT-diaphorase plays a neuroprotective role in dopaminergic neurons, which is supported by the following observations: (i) Cu-toxicity is dependent on DT-diaphorase inhibition with dicoumarol in RCSN-3 cells derived from the rat substantia nigra; (ii) the cytotoxic effect of monoamine oxidase-A inhibitor amiflamine in RCSN-3 cells is increased by 2.4-fold (p < 0.001) in the presence of the inhibitor of DT-diaphorase, dicoumarol; (iii) concomitant intracerebral administration of manganese (Mn3+) together with the DT-diaphorase inhibitor dicoumarol into the left medial forebrain bundle produced a behavioral pattern characterized by contralateral rotational behavior when the rats were stimulated with apomorphine, in a manner similar to that observed in animals injected unilaterally with 6-hydroxydopamine; (iv) incubation of RCSN-3 cells with salsolinol in the presence of DT-diaphorase inhibitor significantly decreased cell survival by 2.5-fold (p < 0.001).

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Dopamine / metabolism*
  • Dopamine / physiology
  • Humans
  • Indolequinones*
  • Indoles / metabolism*
  • Indoles / pharmacology
  • NAD(P)H Dehydrogenase (Quinone) / metabolism
  • NAD(P)H Dehydrogenase (Quinone) / physiology*
  • Neurodegenerative Diseases / drug therapy
  • Neurodegenerative Diseases / metabolism
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • Oxidation-Reduction / drug effects
  • Parkinson Disease / drug therapy
  • Parkinson Disease / enzymology
  • Parkinson Disease / metabolism*


  • Indolequinones
  • Indoles
  • Neuroprotective Agents
  • aminochrome 1
  • NAD(P)H Dehydrogenase (Quinone)
  • Dopamine