The natural product 4,10-aromadendranediol induces neuritogenesis in neuronal cells in vitro through activation of the ERK pathway  

作　　者：Sai CHANG Wen-chen RUAN Ya-zhou XU Yun-jie WANG Jie PANG Lu-yong ZHANG Hong LIAO Tao PANG 

机构地区：[1]jiangsu Key Laboratory of Drug Screening, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing210009, China [2]jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases, China Pharmaceutical University, Nanjing 210009,China [3]State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, NanjingUniversity, Nanjing 210023, China [4]Key Laboratory of Drug Quality Control and Pharmacovigilance (China Pharmaceutical University),Ministry of Education, Nanjing 210009, China

出　　处：《Acta Pharmacologica Sinica》2017年第1期29-40,共12页中国药理学报（英文版）

摘　　要：Recent studies focus on promoting neurite outgrowth to remodel the central nervous network after brain injury. Currently, however, there are few drugs treating brain diseases in the clinic by enhancing neurite outgrowth. In this study, we established an NGF- induced PC12 differentiation model to screen novel compounds that have the potential to induce neuronal differentiation, and further characterized 4,10-Aromadendranediol （ARDD） isolated from the dried twigs of the Baccharis gaudichaudiana plant, which exhibited the capability of promoting neurite outgrowth in neuronal cells in vitro. ARDD （1, 10 pmol/L） significantly enhanced neurite outgrowth in NGF-treated PC12 cells and NIE115 cells in a time-dependent manner. In cultured primary cortical neurons, ARDD （5, 10 pmol/L） not only significantly increased neurite outgrowth but also increased the number of neurites on the soma and the number of bifurcations. Further analyses showed that ARDD （10 pmol/L） significantly increased the phosphorylation of ERK1/2 and the downstream GSK-313, subsequently induced 13-catenin expression and up-regulated the gene expression of the Wnt ligands Fzdl and Wnt3a in neuronal cells. The neurite outgrowth-promoting effect of ARDD in neuronal cells was abolished by pretreatment with the specific ERK1/2 inhibitor PD98059, but was partially reversed by XAV939, an inhibitor of the Wnt/β-catenin pathway. ARDD also increased the expression of BDNF, CREB and GAP-43 in NIE115 cells, which was reversed by pretreatment with PD98059. In NIE115 cells subjected to oxygen and glucose deprivation （OGD）, pretreatment with ARDD （1-10 pmol/L） significantly enhanced the phosphorylation of ERK1/2 and induced neurite outgrowth. These results demonstrated that the natural product ARDD exhibits neurite outgrowth-inducing activity in neurons via activation of the ERK signaling pathway, which may be beneficial to the treatment of brain diseases.Recent studies focus on promoting neurite outgrowth to remodel the central nervous network after brain injury. Currently, however, there are few drugs treating brain diseases in the clinic by enhancing neurite outgrowth. In this study, we established an NGF- induced PC12 differentiation model to screen novel compounds that have the potential to induce neuronal differentiation, and further characterized 4,10-Aromadendranediol （ARDD） isolated from the dried twigs of the Baccharis gaudichaudiana plant, which exhibited the capability of promoting neurite outgrowth in neuronal cells in vitro. ARDD （1, 10 pmol/L） significantly enhanced neurite outgrowth in NGF-treated PC12 cells and NIE115 cells in a time-dependent manner. In cultured primary cortical neurons, ARDD （5, 10 pmol/L） not only significantly increased neurite outgrowth but also increased the number of neurites on the soma and the number of bifurcations. Further analyses showed that ARDD （10 pmol/L） significantly increased the phosphorylation of ERK1/2 and the downstream GSK-313, subsequently induced 13-catenin expression and up-regulated the gene expression of the Wnt ligands Fzdl and Wnt3a in neuronal cells. The neurite outgrowth-promoting effect of ARDD in neuronal cells was abolished by pretreatment with the specific ERK1/2 inhibitor PD98059, but was partially reversed by XAV939, an inhibitor of the Wnt/β-catenin pathway. ARDD also increased the expression of BDNF, CREB and GAP-43 in NIE115 cells, which was reversed by pretreatment with PD98059. In NIE115 cells subjected to oxygen and glucose deprivation （OGD）, pretreatment with ARDD （1-10 pmol/L） significantly enhanced the phosphorylation of ERK1/2 and induced neurite outgrowth. These results demonstrated that the natural product ARDD exhibits neurite outgrowth-inducing activity in neurons via activation of the ERK signaling pathway, which may be beneficial to the treatment of brain diseases.

关 键 词：4 10-aromadendranediol neurite growth PC12 cells NIE115 cells cortical neurons ERK1/2 OGD brain diseases NGF PD98059 XAV939 

分 类 号：Q421[生物学—神经生物学] Q426[生物学—生理学]