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

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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.

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Acknowledgements

The authors are thankful to Ali Jahanshahi (Postdoctoral Fellow at Maastricht University), João Oliveira (PhD student at Maastricht University) and Denise Hermes, and Hellen Steinbusch for all the technical support and guidance.

This work was supported by FONDECYT no. 1100165 (JSA), University of Chile ENL014/14 (JSA).

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Authors and Affiliations

  1. Molecular & Clinical Pharmacology, Faculty of Medicine, University of Chile, Independencia 1027, Casilla, 70000, Santiago 7, Chile

    Andrea Herrera-Soto, Gabriela Díaz-Veliz, Sergio Mora, Patricia Muñoz & Juan Segura-Aguilar

  2. Department of Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands

    Andrea Herrera-Soto & Harry W. M. Steinbusch

  3. Laboratorio de Neuroanatomía, Departamento de Anatomía Normal, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

    Pablo Henny

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  1. Andrea Herrera-Soto
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  2. Gabriela Díaz-Veliz
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  3. Sergio Mora
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  4. Patricia Muñoz
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  5. Pablo Henny
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  6. Harry W. M. Steinbusch
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  7. Juan Segura-Aguilar
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Correspondence to Juan Segura-Aguilar.

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Herrera-Soto, A., Díaz-Veliz, G., Mora, S. et al. On the Role of DT-Diaphorase Inhibition in Aminochrome-Induced Neurotoxicity In Vivo. Neurotox Res 32, 134–140 (2017). https://doi.org/10.1007/s12640-017-9719-8

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  • DOI: https://doi.org/10.1007/s12640-017-9719-8

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