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The Mitochondrial ATP-Sensitive Potassium Channel Blocker 5-Hydroxydecanoate Inhibits Toxicity of 6-Hydroxydopamine on Dopaminergic Neurons

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Abstract

The neurotoxin 6-hydroxydopamine is commonly used in models of Parkinson’s disease, and a potential factor in the pathogenesis of the disease. However, the mechanisms responsible for 6-hydroxydopamine-induced dopaminergic degeneration have not been totally clarified. Reactive oxygen species (ROS) derived from 6-OHDA uptake and intraneuronal autooxidation, extracellular 6-OHDA autooxidation, and microglial activation have been involved. The mitochondrial implication is controversial. Mitochondrial ATP-sensitive K (mitoK(ATP)) channels may provide a convergent target that could integrate these different mechanisms. We observed that in primary mesencephalic cultures and neuron-enriched cultures, treatment with the mitoK(ATP) channel blocker 5-hydroxydecanoate, inhibits the dopaminergic degeneration induced by low doses of 6-OHDA. Furthermore, 5-hydroxydecanoate blocks the 6-OHDA-induced decrease in mitochondrial inner membrane potential and inhibits 6-OHDA-induced generation of superoxide-derived ROS in dopaminergic neurons. The results suggest that low doses of 6-OHDA may generate low levels of ROS through several mechanisms, which may be insufficient to induce neuron death. However, they could act as a trigger to activate mitoK(ATP) channels, thereby enhancing ROS production and the subsequent dopaminergic degeneration. Furthermore, the present study provides additional data for considering mitoK(ATP) channels as a potential target for neuroprotection.

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Acknowledgments

This study was funded by Spanish Ministry of Education (MEC, BFU2006-07414/BFI), Spanish Ministry of Health (RD06/0010/0013 and Ciberned), and Galician Government (XUGA). The authors thank Pilar Aldrey for her excellent technical assistance.

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  1. Laboratory of Neuroanatomy and Experimental Neurology, Department of Morphological Sciences, Faculty of Medicine, University of Santiago de Compostela, Santiago, 15782, Spain

    J. Rodriguez-Pallares, J. A. Parga, B. Joglar, M. J. Guerra & J. L. Labandeira-Garcia

  2. Networking Research Center on Neurodegenerative Diseases (CIBERNED), Sevilla, Spain

    J. Rodriguez-Pallares, J. A. Parga, B. Joglar, M. J. Guerra & J. L. Labandeira-Garcia

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  1. J. Rodriguez-Pallares
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  2. J. A. Parga
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Correspondence to J. L. Labandeira-Garcia.

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Rodriguez-Pallares, J., Parga, J.A., Joglar, B. et al. The Mitochondrial ATP-Sensitive Potassium Channel Blocker 5-Hydroxydecanoate Inhibits Toxicity of 6-Hydroxydopamine on Dopaminergic Neurons. Neurotox Res 15, 82–95 (2009). https://doi.org/10.1007/s12640-009-9010-8

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