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One-Electron Reduction of 6-Hydroxydopamine Quinone is Essential in 6-Hydroxydopamine Neurotoxicity

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Abstract

6-Hydroxydamine has widely been used as neurotoxin in preclinical studies related on the neurodegenerative process of dopaminergic neurons in Parkinson’s disease based on its ability to be neurotoxic as a consequence of free radical formation during its auto-oxidation to topaminequinone. We report that 50-µM 6-hydroxydopamine is not neurotoxic in RCSN-3 cells derived from substantia nigra incubated during 24 h contrasting with a significant sixfold increase in cell death (16 ± 2 %; P < 0.001) was observed in RCSN-3NQ7 cells expressing a siRNA against DT-diaphorase that silence the enzyme expression. To observe a significant cell death in RCSN-3 cells induced by 6-hydroxydopamine (24 ± 1 %; P < 0.01), we have to increase the concentration to 250 μm while a 45 ± 2 % cell death (P < 0.001) was observed at this concentration in RCSN-3NQ7 cells. The cell death induced by 6-hydroxydopamine in RCSN-3NQ7 cells was accompanied with a (i) significant increase in oxygen consumption (P < 0.01), (ii) depletion of reduced glutathione and (iii) a significant decrease in ATP level (P < 0.05) in comparison with RCSN-3 cells. In conclusion, our results suggest that one-electron reduction of 6-hydroxydopamine quinone seems to be the main reaction responsible for 6-hydroxydopamine neurotoxic effects in dopaminergic neurons and DT-diaphorase seems to play an important neuroprotective role by preventing one-electron reduction of topaminequinone.

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Acknowledgments

This work was supported by FONDECYT 1100165; Zeneca fellowship; 04553/GERM/06 & CICYT; MICINN BFU2011-28716.

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Authors and Affiliations

  1. Program of Molecular and Clinical Pharmacology, ICBM, Faculty of Medicine, University of Chile, Independencia 1027, Santiago, Chile

    Monica Villa, Patricia Muñoz, Ulises Ahumada-Castro, Irmgard Paris & Juan Segura-Aguilar

  2. Department Basic Sciences, Universidad Santo Tomás, Viña del Mar, Chile

    Irmgard Paris

  3. Department of Stress Biology and Plant Pathology, CEBAS-CSIC, Murcia, Spain

    Ulises Ahumada-Castro, Ana Jiménez, Isabel Martínez & Francisca Sevilla

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  1. Monica Villa
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  2. Patricia Muñoz
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Correspondence to Juan Segura-Aguilar.

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Monica Villa and Patricia Muñoz should be considered as first author.

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Villa, M., Muñoz, P., Ahumada-Castro, U. et al. One-Electron Reduction of 6-Hydroxydopamine Quinone is Essential in 6-Hydroxydopamine Neurotoxicity. Neurotox Res 24, 94–101 (2013). https://doi.org/10.1007/s12640-013-9382-7

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