Neuroprotection by urate on 6-OHDA-lesioned rat model of Parkinson's disease: linking to Akt/GSK3β signaling pathway

Authors

  • Li Gong,

    1. Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, China
    2. Institute of Neuroscience, Soochow University, Suzhou, China
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    • These two authors contribute equally to this work.
  • Qi-Lin Zhang,

    1. Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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    • These two authors contribute equally to this work.
  • Ning Zhang,

    1. Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, China
    2. Institute of Neuroscience, Soochow University, Suzhou, China
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  • Wen-Yan Hua,

    1. Department of Pharmacy, The Second Affiliated Hospital of Soochow University, Suzhou, China
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  • Yi-Xian Huang,

    1. Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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  • Ping-Wei Di,

    1. Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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  • Tingting Huang,

    1. Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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  • Xing-Shun Xu,

    1. Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, China
    2. Institute of Neuroscience, Soochow University, Suzhou, China
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  • Chun-Feng Liu,

    1. Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, China
    2. Institute of Neuroscience, Soochow University, Suzhou, China
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  • Li-Fang Hu,

    Corresponding author
    1. Institute of Neuroscience, Soochow University, Suzhou, China
    • Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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  • Wei-Feng Luo

    Corresponding author
    1. Institute of Neuroscience, Soochow University, Suzhou, China
    • Department of Neurology, The Second Affiliated Hospital of Soochow University, Suzhou, China
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Address correspondence and reprint requests to Li-Fang Hu, Ph.D., Institute of Neuroscience, Soochow University, 199 Ren-Ai Road, Suzhou Industrial Park, Suzhou 215123, P.R. China. E-mail: hulifang@suda.edu.cn Wei-Feng Luo, MD, Ph.D., Department of Neurology, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou, 215004, China. E-mail: lwfwxx@126.com

Abstract

Higher plasma urate level is reported to be associated with a reduced risk and slower progression of Parkinson's disease (PD). In this study, we explored the effects of urate on dopaminergic neurons in nigrostriatal pathway in the 6-hydroxydopamine (6-OHDA) unilaterally lesioned rats. Uric acid (UA), when given twice daily at 200 mg/kg intraperitoneally for 10 consecutive days, elevated urate (the anionic form of UA) in plasma and striatum by 55% and 36.8%, respectively, as compared with vehicle group. This regimen of UA was found to ameliorate the behavioral deficits, dopaminergic neuron loss as well as dopamine depletion in the nigrostriatal system. Moreover, UA administration was capable of increasing glutathione level and superoxide dismutase activity while decreasing malondialdehyde accumulation in striatum. In addition, the phosphorylation of both protein kinase B (Akt) and glycogen synthase kinase 3 beta (GSK3β) in the lesioned striata of 6-OHDA-lesioned rats was dramatically reduced as compared with sham-operated rats. This reduction was attenuated in the Parkinsonian rats receiving UA treatment. Similarly, in vitro findings showed that UA alleviated the decrease in Akt activation and the increase in GSK3β activity caused by 6-OHDA. Furthermore, neuroprotection by urate and its regulation on GSK3β phosphorylation at Ser9 was found to be abolished in the presence of PI3K inhibitor. Therefore, our findings demonstrated that urate was able to protect dopaminergic neurons in rat nigrostriatal pathway against the neurotoxicity of 6-OHDA, and showed that its beneficial effects may be related to its regulation on Akt/GSK3β signaling.

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