title: Tanshinone II A, a multiple target neuroprotectant, promotes caveolae-dependent neuronal differentiation.
abstract: Neuron loss is one fundamental features of neurodegenerative diseases. Stimulating endogenous neurogenesis, especially neuronal differentiation, might potentially provide therapeutic effects to these diseases. In this study, tanshinone II A (TIIA), a multiple target neuroprotectant, was demonstrated to promote dose-dependent neuronal differentiation in three cell models of immortalized C17.2 neuronal stem cells, rat embryonic cortical neural stem cells (NSCs) and rat PC12 pheochromocytoma cells. In particular, TIIA exerted promising effects on NSCs even at the dose of 3 nM. In PC12 cells, TIIA activated mitogen-activated protein kinase 42/44 (MAPK42/44) and its downstream transcription factor, cAMP response element-binding protein (CREB). In addition, TIIA up-regulated the expressions of brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF). The MEK inhibitor and the antagonist to the receptors of NGF and BDNF could partially attenuate the differentiation effects, indicating that MAPK42/44 mediated BDNF and NGF signals were involved in TIIA's differentiation effects. Caveolin-1 (CAV-1), the major functional protein of membrane caveolae, plays critical roles in the endocytosis of exogenous materials. CAV1, which was activated by TIIA, might help TIIA transport across cell membrane to initiate its differentiation effects. It was proven by the evidences that suppressing the function of caveolin inhibited the differentiation effects of TIIA. Therefore, we concluded that TIIA promoted neuronal differentiation partially through MAPK42/44 mediated BDNF and NGF signals in a caveolae-dependent manner.
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China; Beijing Institute of Brain Disorders & Research Center for Brain Disorders, Capital Medical University, Beijing 100069, PR China.
authors.forename: Yuming
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China.
authors.forename: Pingxiang
authors.initials: P
authors.lastname: Xu
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, PR China.
authors.forename: Shengquan
authors.initials: S
authors.lastname: Hu
authors.affiliation: State Key Lab for Structural Chemistry of Unstable and Stable Species, Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China.
authors.forename: Libo
authors.initials: L
authors.lastname: Du
authors.affiliation: Beijing Institute of Brain Disorders & Research Center for Brain Disorders, Capital Medical University, Beijing 100069, PR China.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, PR China.
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cui
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, PR China.
authors.forename: Shinghung
authors.initials: S
authors.lastname: Mak
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, PR China.
authors.forename: Daping
authors.initials: D
authors.lastname: Xu
authors.affiliation: School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, PR China.
authors.forename: Jianggang
authors.initials: J
authors.lastname: Shen
authors.affiliation: Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, PR China.
authors.forename: Yifan
authors.initials: Y
authors.lastname: Han
authors.affiliation: State Key Lab for Structural Chemistry of Unstable and Stable Species, Beijing National Laboratory for Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, PR China. Electronic address: yliu@iccas.ac.cn.
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China. Electronic address: xuem@ccmu.edu.cn.
authors.forename: Ming
authors.initials: M
authors.lastname: Xue
mesh_terms: D045784:Abietanes / Q000008:administration & dosage*; D000818:Animals; D021941:Caveolae / Q000187:drug effects* / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D016503:Drug Delivery Systems / Q000379:methods*; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D016716:PC12 Cells; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D045784:Abietanes; D018696:Neuroprotective Agents; C021751:tanshinone
keywords: BDNF; Caveolin-1; DAPI (PubChem CID: 2954); K252a (PubChem CID:11612445); NGF; NGF (PubChem CID: 60160600); Neurodegeneration; Neuronal differentiation; PD98059 (PubChem CID: 4713); Tanshinone II A; Tanshinone II A (PubChem CID: 164676)