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L-F001, a Multifunction ROCK Inhibitor Prevents 6-OHDA Induced Cell Death Through Activating Akt/GSK-3beta and Nrf2/HO-1 Signaling Pathway in PC12 Cells and Attenuates MPTP-Induced Dopamine Neuron Toxicity in Mice

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Abstract

Amounting evidences demonstrated that Rho/Rho-associated kinase (ROCK) might be a novel target for the therapy of Parkinson’s disease (PD). Recently, we synthesized L-F001 and revealed it was a potent ROCK inhibitor with multifunctional effects. Here we investigated the effects of L-F001 in PD models. We found that L-F001 potently attenuated 6-OHDA-induced cytotoxicity in PC12 cells and significantly decreased intracellular reactive oxygen species (ROS), prevented the 6-OHDA-induced decline of mitochondrial membrane potential and intracellular GSH levels. In addition, L-F001 increased Akt and GSK-3beta phosphorylation and induced the nuclear Nrf2 and HO-1 expression in a time- and concentration-dependent manner. Moreover, L-F001 restored the levels of p-Akt and p-GSK-3beta (Ser9) as well as HO-1 expression reduced by 6-OHDA. Those effects were blocked by the specific PI3K inhibitor, LY294002, indicating the involvement of Akt/GSK-3beta pathway in the neuroprotective effect of L-F001. In addition, L-F001 significantly attenuated the tyrosinehydroxylase immunoreactive cell loss in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced mice PD model. Together, our findings suggest that L-F001 prevents 6-OHDA-induced cell death through activating Akt/GSK-3beta and Nrf2/HO-1 signaling pathway and attenuates MPTP-induced dopaminergic neuron toxicity in mice. L-F001 might be a promising drug candidate for PD.

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Acknowledgements

This study was supported by Guangdong Provincial International Cooperation Project of Science & Technology (No. 2012B050300015 and No. 2013B051000038) to R. Pi and the National Natural Science Foundation of China (No. 81560662) and Key projects of Natural Science Foundation of Jiangxi Province (No. 20151BDH80081 and No. 20161BAB205195) to R. Wang.

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    Authors and Affiliations

    1. National Pharmaceutical Engineering Center for Solid Preparation in Chinese Herbal Medicine, Jiangxi University of Traditional Chinese Medicine, Nanchang, 330006, China

      Liting Luo, Dan Su & Rikang Wang

    2. Department of Pharmacy, Zhuhai Maternal and Child Health Hospital, Zhuhai, 519000, China

      Liting Luo

    3. Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, 510080, China

      Liting Luo, Jingkao Chen, Meihui Chen & Rongbiao Pi

    4. International Joint Laboratory (SYSU-PolyU HK) of Novel Anti-Dementia Drugs of Guangdong, Guangzhou, 510006, China

      Liting Luo, Jingkao Chen, Meihui Chen & Rongbiao Pi

    5. National and Local United Engineering Lab of Druggability and New Drugs Evaluation, Sun Yat-Sen University, Guangzhou, 510080, China

      Liting Luo, Jingkao Chen, Meihui Chen & Rongbiao Pi

    6. State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Collaborative Innovation Center for Cancer Medicine, 651 Dongfeng East Road, Guangzhou, 510060, China

      Bingling Luo

    7. Department of Neurology, Puai Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430033, China

      Lan Wang & Wei Shen

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    Liting Luo and Jingkao Chen have contributed equally to this work.

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    Luo, L., Chen, J., Su, D. et al. L-F001, a Multifunction ROCK Inhibitor Prevents 6-OHDA Induced Cell Death Through Activating Akt/GSK-3beta and Nrf2/HO-1 Signaling Pathway in PC12 Cells and Attenuates MPTP-Induced Dopamine Neuron Toxicity in Mice. Neurochem Res 42, 615–624 (2017). https://doi.org/10.1007/s11064-016-2117-4

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