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2′,3′-Dideoxycytidine Protects Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease

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Abstract

DNA polymerase-β (DNA pol-β) plays a crucial role in the pathogenesis of Parkinson’s disease (PD). The aim of this study was to investigate the neuroprotective effects of a DNA polymerase-β inhibitor 2′,3′-dideoxycytidine (DDC) in PD models. In the in vitro studies, primary cultured neurons were challenged with 1-methyl-4-phenylpyridinium ion (MPP+). The expression of DNA pol-β was assessed using western blot. The neuroprotective effect of DNA pol-β knockdown and DNA pol-β inhibitor DDC was determined using cell viability assay and caspase-3 activity assay. We found that MPP+ induced neuronal death and the activation of caspase-3 in a dose-dependent manner. The expression of DNA pol-β increased after the neurons were exposed to MPP+. DNA pol-β siRNA or DNA pol-β inhibitor DDC attenuated neuronal death induced by MPP+. In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD, MPTP treatment triggered behavioral deficits and nigrostriatal lesions. Pretreatment with DDC attenuated MPTP-induced behavioral deficits, dopaminergic neuronal death and striatal dopamine depletion in the MPTP mouse model. These results indicate that DNA pol-β inhibitors may present a novel promising therapeutic option for the neuroprotective treatment of PD.

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Acknowledgements

This work was supported by grants from National Natural Science Foundation of China (Grant No. 81571249 to Zhentao Zhang, Grant No. 81501107 to Jing Xiong, and Grant No. 81671051 to Zhaohui Zhang).

Author Contributions

ZZ and ZZ conceived and designed study; JN and JX performed most of animal research and part of the in vitro experiments; DH, FZ, SN and TW performed some of the in vitro experiments. SM helped in writing the manuscript.

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    Authors and Affiliations

    1. Department of Neurology, Yidu Central Hospital, Weifang Medical University, Qingzhou, 262500, Shandong, China

      Jianyi Niu

    2. Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, 430060, Hubei, China

      Jing Xiong, Dan Hu, Fei Zeng, Shuke Nie, Shanping Mao, Zhentao Zhang & Zhaohui Zhang

    3. Department of Neurology, Union Hospital, Huazhong University of Science and Technology, Wuhan, 430022, Hubei, China

      Tao Wang

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    1. Jianyi Niu
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    Correspondence to Zhaohui Zhang.

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    Jianyi Niu and Jing Xiong have contributed equally to this work.

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    Niu, J., Xiong, J., Hu, D. et al. 2′,3′-Dideoxycytidine Protects Dopaminergic Neurons in a Mouse Model of Parkinson’s Disease. Neurochem Res 42, 2996–3004 (2017). https://doi.org/10.1007/s11064-017-2330-9

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