Neurotoxicity Research

, Volume 32, Issue 1, pp 134–140 | Cite as

On the Role of DT-Diaphorase Inhibition in Aminochrome-Induced Neurotoxicity In Vivo

  • Andrea Herrera-Soto
  • Gabriela Díaz-Veliz
  • Sergio Mora
  • Patricia Muñoz
  • Pablo Henny
  • Harry W. M. Steinbusch
  • Juan Segura-Aguilar
ORIGINAL ARTICLE

Abstract

Dopamine oxidation in the pathway leading to neuromelanin formation generates the ortho-quinone aminochrome, which is potentially neurotoxic but normally rapidly converted by DT-diaphorase to nontoxic leukoaminochrome. However, when administered exogenously into rat striatum, aminochrome is able to produce damage to dopaminergic neurons. Because of a recent report that substantia nigra pars compacta (SNpc) tyrosine hydroxylase (T-OH) levels were unaltered by aminochrome when there was cell shrinkage of dopaminergic neurons along with a reduction in striatal dopamine release, the following study was conducted to more accurately determine the role of DT-diaphorase in aminochrome neurotoxicity. In this study, a low dose of aminochrome (0.8 nmol) with or without the DT-diaphorase inhibitor dicoumarol (0.2 nmol) was injected into the left striatum of rats. Intrastriatal 6-hydroxydopamine (6-OHDA, 32 nmol) was used as a positive neurotoxin control in other rats. Two weeks later, there was significant loss in numbers of T-OH immunoreactive fibers in SNpc, also a loss in cell density in SNpc, and prominent apomorphine (0.5 mg/kg sc)-induced contralateral rotations in rats that had been treated with aminochrome, with aminochrome/dicoumarol, or with 6-OHDA. Findings demonstrate that neurotoxic aminochrome is able to exert neurotoxicity only when DT-diaphorase is suppressed—implying that DT-diaphorase is vital in normally suppressing toxicity of in vivo aminochrome, generated in the pathway towards neuromelanin formation.

Keywords

Aminochrome DT-diaphorase Neurotoxicity Substantia nigra Dopamine Neurodegeneration Neuroprotection 

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Andrea Herrera-Soto
    • 1
    • 2
  • Gabriela Díaz-Veliz
    • 1
  • Sergio Mora
    • 1
  • Patricia Muñoz
    • 1
  • Pablo Henny
    • 3
  • Harry W. M. Steinbusch
    • 2
  • Juan Segura-Aguilar
    • 1
  1. 1.Molecular & Clinical Pharmacology, Faculty of MedicineUniversity of ChileSantiago 7Chile
  2. 2.Department of Neuroscience, Faculty of Health, Medicine and Life SciencesMaastricht UniversityMaastrichtThe Netherlands
  3. 3.Laboratorio de Neuroanatomía, Departamento de Anatomía Normal, Escuela de MedicinaPontificia Universidad Católica de ChileSantiagoChile

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