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Blockade of Rapid Influx of Extracellular Zn2+ into Nigral Dopaminergic Neurons Overcomes Paraquat-Induced Parkinson’s Disease in Rats

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Abstract

The herbicide paraquat (PQ) has been reported to enhance the risk of developing Parkinson’s disease (PD) from epidemiological studies. PQ-induced reactive oxygen species (ROS) are linked with a selective loss of nigrostriatal dopaminergic neurons. Here, we first report a unique mechanism of nigrostriatal dopaminergic degeneration, in which rapid intracellular Zn2+ dysregulation via PQ-induced ROS production causes PD in rats. When the substantia nigra pars compacta (SNpc) of rats was perfused with PQ, extracellular concentrations of glutamate and Zn2+ were increased and decreased, respectively, in the SNpc. These changes were ameliorated by co-perfusion with Trolox, an antioxidative agent. In in vitro slice experiments, PQ rapidly increased extracellular Zn2+ influx via AMPA receptor activation. Both loss of nigrostriatal dopaminergic neurons and increase in turning behavior in response to apomorphine were markedly reduced by coinjection of PQ and intracellular Zn2+ chelator, i.e., ZnAF-2DA into the SNpc. Furthermore, loss of nigrostriatal dopaminergic neurons induced with a low dose of PQ, which did not induce any behavioral abnormality, was completely blocked by coinjection of ZnAF-2DA. The present study indicates that rapid influx of extracellular Zn2+ into dopaminergic neurons via AMPA receptor activation, which is initially induced by PQ-mediated ROS production in the SNpc, induces nigrostriatal dopaminergic degeneration, resulting in PQ-induced PD in rats. Intracellular Zn2+ dysregulation in dopaminergic neurons is the cause of PQ-induced pathogenesis in the SNpc, and the block of intracellular Zn2+ toxicity leads to defending PQ-induced pathogenesis.

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Authors and Affiliations

  1. Department of Neurophysiology, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka, 422-8526, Japan

    Haruna Tamano, Hiroki Morioka, Ryusuke Nishio, Azusa Takeuchi & Atsushi Takeda

Authors
  1. Haruna Tamano
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  2. Hiroki Morioka
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  3. Ryusuke Nishio
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  4. Azusa Takeuchi
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  5. Atsushi Takeda
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Correspondence to Atsushi Takeda.

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All experiments were performed in accordance with the Guidelines for the Care and Use of Laboratory Animals of the University of Shizuoka that refer to the American Association for Laboratory Animals Science and the guidelines laid down by the NIH (NIH Guide for the Care and Use of Laboratory Animals) in the USA. The ethics committee of the University of Shizuoka has approved all experimental protocols (approval number, 136043).

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The authors declare that they have no conflict of interest.

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Tamano, H., Morioka, H., Nishio, R. et al. Blockade of Rapid Influx of Extracellular Zn2+ into Nigral Dopaminergic Neurons Overcomes Paraquat-Induced Parkinson’s Disease in Rats. Mol Neurobiol 56, 4539–4548 (2019). https://doi.org/10.1007/s12035-018-1398-9

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