PMID- 26363255 OWN - NLM STAT- MEDLINE DCOM- 20160808 LR - 20191210 IS - 1879-0712 (Electronic) IS - 0014-2999 (Linking) VI - 765 DP - 2015 Oct 15 TI - Tanshinone II A, a multiple target neuroprotectant, promotes caveolae-dependent neuronal differentiation. PG - 437-46 LID - S0014-2999(15)30238-7 [pii] LID - 10.1016/j.ejphar.2015.09.006 [doi] AB - 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. CI - Copyright (c) 2015 Elsevier B.V. All rights reserved. FAU - Zhao, Yuming AU - Zhao Y AD - 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. FAU - Xu, Pingxiang AU - Xu P AD - Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China. FAU - Hu, Shengquan AU - Hu S AD - Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, PR China. FAU - Du, Libo AU - Du L AD - 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. FAU - Xu, Zhiqing AU - Xu Z AD - Beijing Institute of Brain Disorders & Research Center for Brain Disorders, Capital Medical University, Beijing 100069, PR China. FAU - Zhang, Huan AU - Zhang H AD - Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, PR China. FAU - Cui, Wei AU - Cui W AD - Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, PR China. FAU - Mak, Shinghung AU - Mak S AD - Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, PR China. FAU - Xu, Daping AU - Xu D AD - Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, PR China. FAU - Shen, Jianggang AU - Shen J AD - School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong Special Administrative Region, PR China. FAU - Han, Yifan AU - Han Y AD - Department of Applied Biology and Chemical Technology, Institute of Modern Medicine, The Hong Kong Polytechnic University, Hong Kong Special Administrative Region, PR China. FAU - Liu, Yang AU - Liu Y AD - 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. FAU - Xue, Ming AU - Xue M AD - Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, PR China. Electronic address: xuem@ccmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20150910 PL - Netherlands TA - Eur J Pharmacol JT - European journal of pharmacology JID - 1254354 RN - 0 (Abietanes) RN - 0 (Neuroprotective Agents) RN - 03UUH3J385 (tanshinone) SB - IM MH - Abietanes/*administration & dosage MH - Animals MH - Caveolae/*drug effects/physiology MH - Cell Differentiation/*drug effects/physiology MH - Cells, Cultured MH - Dose-Response Relationship, Drug MH - Drug Delivery Systems/*methods MH - Neural Stem Cells/drug effects/physiology MH - Neurogenesis/drug effects/physiology MH - Neurons/*drug effects/physiology MH - Neuroprotective Agents/*administration & dosage MH - PC12 Cells MH - Rats MH - Rats, Sprague-Dawley OTO - NOTNLM OT - BDNF OT - Caveolin-1 OT - DAPI (PubChem CID: 2954) OT - K252a (PubChem CID:11612445) OT - NGF OT - NGF (PubChem CID: 60160600) OT - Neurodegeneration OT - Neuronal differentiation OT - PD98059 (PubChem CID: 4713) OT - Tanshinone II A OT - Tanshinone II A (PubChem CID: 164676) EDAT- 2015/09/13 06:00 MHDA- 2016/08/09 06:00 CRDT- 2015/09/13 06:00 PHST- 2015/06/28 00:00 [received] PHST- 2015/09/02 00:00 [revised] PHST- 2015/09/03 00:00 [accepted] PHST- 2015/09/13 06:00 [entrez] PHST- 2015/09/13 06:00 [pubmed] PHST- 2016/08/09 06:00 [medline] AID - S0014-2999(15)30238-7 [pii] AID - 10.1016/j.ejphar.2015.09.006 [doi] PST - ppublish SO - Eur J Pharmacol. 2015 Oct 15;765:437-46. doi: 10.1016/j.ejphar.2015.09.006. Epub 2015 Sep 10.