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

Andrea Herrera-Soto, Gabriela Diaz-Veliz, Sergio Mora, Patricia Munoz, Pablo Henny, Harry W. M. Steinbusch, Juan Segura-Aguilar*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

13 Citations (Web of Science)

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.

Original languageEnglish
Pages (from-to)134-140
Number of pages7
JournalNeurotoxicity Research
Volume32
Issue number1
DOIs
Publication statusPublished - Jul 2017

Keywords

  • Aminochrome
  • DT-diaphorase
  • Neurotoxicity
  • Substantia nigra
  • Dopamine
  • Neurodegeneration
  • Neuroprotection
  • PARKINSONS-DISEASE
  • PRECLINICAL MODEL
  • CELL-DEATH
  • DOPAMINE
  • TOXICITY
  • PROTECTS
  • NEURONS
  • EXPRESSION
  • MECHANISM
  • AUTOPHAGY

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