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 μmol/L) significantly enhanced neurite outgrowth in NGF-treated PC12 cells and N1E115 cells in a time-dependent manner. In cultured primary cortical neurons, ARDD (5, 10 μmol/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 μmol/L) significantly increased the phosphorylation of ERK1/2 and the downstream GSK-3β, subsequently induced β-catenin expression and up-regulated the gene expression of the Wnt ligands Fzd1 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 N1E115 cells, which was reversed by pretreatment with PD98059. In N1E115 cells subjected to oxygen and glucose deprivation (OGD), pretreatment with ARDD (1-10 μmol/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.

中文翻译：

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天然产物4,10-芳香族马ran丹二醇通过激活ERK途径在体外诱导神经元细胞中的神经形成。

最近的研究集中于促进神经突增生，以在脑损伤后重塑中枢神经网络。然而，目前，临床上很少有通过增强神经突生长来治疗脑部疾病的药物。在这项研究中，我们建立了NGF诱导的PC12分化模型，以筛选具有诱导神经元分化潜能的新型化合物，并进一步表征了从Baccharis gaudichaudiana植物的干燥树枝中分离出的4,10-芳基登糖二醇（ARDD）。在体外促进神经元细胞中神经突生长的能力。ARDD（1，10μmol/ L）以时间依赖性方式显着增强了NGF处理的PC12细胞和N1E115细胞的神经突生长。在培养的原代皮层神经元中，ARDD（5，10μmol/ L）不仅显着增加了神经突的向外生长，而且还增加了躯体上神经突的数量和分叉的数量。进一步的分析表明，ARDD（10μmol/ L）显着增加了神经元细胞中ERK1 / 2和下游GSK-3β的磷酸化，随后诱导了β-catenin表达并上调了Wnt配体Fzd1和Wnt3a的基因表达。通过用特异性ERK1 / 2抑制剂PD98059预处理消除了ARDD在神经元细胞中的神经突生长促进作用，但被Wnt /β-catenin途径抑制剂XAV939逆转了。ARDD还增加了N1E115细胞中BDNF，CREB和GAP-43的表达，通过用PD98059进行预处理可以逆转这种表达。在遭受氧气和葡萄糖剥夺（OGD）的N1E115细胞中，ARDD（1-10μmol/ L）预处理可显着增强ERK1 / 2的磷酸化并诱导神经突生长。这些结果表明，天然产物ARDD通过激活ERK信号通路在神经元中表现出神经突增生诱导活性，这可能对脑疾病的治疗有益。