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The ROCK/GGTase Pathway Are Essential to the Proliferation and Differentiation of Neural Stem Cells Mediated by Simvastatin

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Abstract

Simvastatin, a lipophilic and fermentation-derived natural statin, is reported to treat neurological disorders, such as traumatic brain injury, Parkinson’s disease (PD), Alzheimer disease (AD), etc. Recently, research also indicated that simvastatin could promote regeneration in the dentate gyrus of adult mice by Wnt/β-catenin signaling (Robin et al. in Stem Cell Reports 2:9–17, 2014). However, the effect and mechanisms by which simvastatin may affect the neural stem cells (NSCs; from the embryonic day 14.5 (E14.5) SD rat brain) are not fully understood. Here, we investigated the effects of different doses of simvastatin on the survival, proliferation, differentiation, migration, and cell cycle of NSCs as well as underlying intracellular signaling pathways. The results showed that simvastatin not only inhibits the proliferation of NSCs but also enhances the βIII-tubulin+ neuron differentiation rate. Additionally, we find that simvastatin could also promote NSC migration and induce cell cycle arrest at M2 phrase. All these effects of simvastatin on NSCs were mimicked with an inhibitor of Rho kinase (ROCK) and a specific inhibitor of geranylgeranyl transferase (GGTase). In conclusion, these data indicate that simvastatin could promote neurogenesis of neural stem cells, and these effects were mediated through the ROCK/GGTase pathway.

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Acknowledgments

The project was supported by the Zhejiang Provincial Natural Science Foundation of China (LY13H090007) and Zhejiang Provincial Natural Science Foundation of China (LQ13C090004) and National Natural Sciences Foundation of China (Grant No. 81201589).

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Authors and Affiliations

  1. School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China

    Chan Zhang

  2. Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China

    Jian-Min Wu

  3. Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Cha Shan, University Town, Wenzhou, Zhejiang, 325035, China

    Min Liao & Chao-Jin Xu

  4. Department of Clinical Laboratory, Fudan University Affiliated Huadong Hospital, Shanghai, 200040, China

    Jun-ling Wang

Authors
  1. Chan Zhang
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  2. Jian-Min Wu
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  3. Min Liao
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  4. Jun-ling Wang
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  5. Chao-Jin Xu
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Correspondence to Jun-ling Wang or Chao-Jin Xu.

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The authors declare that they have no conflict of interest.

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Chan-Zhang and Jian-Min Wu contributed equally to this work

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Zhang, C., Wu, JM., Liao, M. et al. The ROCK/GGTase Pathway Are Essential to the Proliferation and Differentiation of Neural Stem Cells Mediated by Simvastatin. J Mol Neurosci 60, 474–485 (2016). https://doi.org/10.1007/s12031-016-0811-y

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  • DOI: https://doi.org/10.1007/s12031-016-0811-y

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