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Tetramethylpyrazine Analogue CXC195 Protects Against Dopaminergic Neuronal Apoptosis via Activation of PI3K/Akt/GSK3β Signaling Pathway in 6-OHDA-Induced Parkinson’s Disease Mice

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Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder and characterized by motor system disorders resulting in loss of dopaminergic (DA) neurons. CXC195, a novel tetramethylpyrazine derivative, has been shown strongest neuroprotective effects due to its anti-apoptotic activity. However, whether CXC195 protects against DA neuronal damage in PD and the mechanisms underlying its beneficial effects are unknown. The purpose of our study was to investigate the potential neuroprotective role of CXC195 and to elucidate its mechanism of action against 6-hydroxydopamine (6-OHDA)-induced mouse model of PD. CXC195 administration improved DA neurodegeneration in PD mice induced by 6-OHDA. Our further findings confirmed treatment of CXC195 at the dose of 10 mg/kg significantly inhibited the apoptosis by decreasing the level of cleaved caspase-3 and Bax, and increasing the level of Bcl-2 in 6-OHDA-lesioned mice. Meanwhile, 6-OHDA also decreased the amount of phosphorylated Akt while increased GSK-3β activity (the amount of phosphorylated GSK-3β at Ser9 was decreased) which was prevented by CXC195. Wortmannin, a specific PI3K inhibitor, dramatically abolished the changes induced by CXC195. Our study firstly demonstrated that CXC195 protected against DA neurodegeneration in 6-OHDA-induced PD model by its anti-apoptotic properties and PI3K/Akt/GSK3β signaling pathway was involved in it.

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Acknowledgements

This work was financially supported by National Natural Science Foundation of China (No. 81571171) and Shandong Province Science and Technology Plan (No. 2014GSF118003).

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Authors and Affiliations

  1. Department of Pharmacology, Shandong University School of Medicine, 44#, Wenhua Xi Road, Jinan, 250012, Shandong, People’s Republic of China

    Lin Chen, Li Cheng, Xinbing Wei, Zheng Yuan, Yanmei Wu, Zhiping Ren & Huiqing Liu

  2. Institute of Medicinal Chemistry, Shandong University School of Pharmaceutical Sciences, 44#, Wenhua Xi Road, Jinan, 250012, Shandong, People’s Republic of China

    Shuaishuai Wang & Xinyong Liu

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  1. Lin Chen
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  2. Li Cheng
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  3. Xinbing Wei
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Chen, L., Cheng, L., Wei, X. et al. Tetramethylpyrazine Analogue CXC195 Protects Against Dopaminergic Neuronal Apoptosis via Activation of PI3K/Akt/GSK3β Signaling Pathway in 6-OHDA-Induced Parkinson’s Disease Mice. Neurochem Res 42, 1141–1150 (2017). https://doi.org/10.1007/s11064-016-2148-x

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