title: The ROCK/GGTase Pathway Are Essential to the Proliferation and Differentiation of Neural Stem Cells Mediated by Simvastatin.
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.
authors.affiliation: School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Chan
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Institute of Genomic Medicine, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
authors.forename: Jian-Min
authors.initials: JM
authors.lastname: Wu
authors.affiliation: Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Cha Shan, University Town, Wenzhou, Zhejiang, 325035, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liao
authors.affiliation: Department of Clinical Laboratory, Fudan University Affiliated Huadong Hospital, Shanghai, 200040, China. Wangliujunling@163.com.
authors.forename: Jun-Ling
authors.initials: JL
authors.lastname: Wang
authors.affiliation: Department of Histology and Embryology, Institute of Neuroscience, Wenzhou Medical University, Cha Shan, University Town, Wenzhou, Zhejiang, 325035, China. xuzhaojin@gmail.com.
authors.forename: Chao-Jin
authors.initials: CJ
authors.lastname: Xu
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002453:Cell Cycle; D049109:Cell Proliferation; D002478:Cells, Cultured; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D055495:Neurogenesis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000924:Anticholesteremic Agents; D047428:Protein Kinase Inhibitors; D019821:Simvastatin; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; D054460:rho-Associated Kinases
keywords: GGTase; Neural stem cells; ROCK; Simvastatin