Abstract
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.
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References
Fath T, Fischer RS, Dehmelt L, Halpain S, Fowler VM . Tropomodulins are negative regulators of neurite outgrowth. Eur J Cell Biol 2011; 90: 291–300.
Bovolenta P, Fernaud-Espinosa I . Nervous system proteoglycans as modulators of neurite outgrowth. Prog Neurobiol 2000; 61: 113–32.
Prabhuanand S, Jane H, Alexander C, Nir S, Rina RA, Peng L . Neurotrophic factor-α1 modulates NGF-induced neurite outgrowth through interaction with Wnt-3a and Wnt-5a in PC12 cells and cortical neurons. Mol Cell Neurosci 2015; 68: 222–33.
Farida H, Andres H, Jörg R, Kevin F, Martina U, Lukas K, et al. Microtubule stabilization reduces scarring and causes axon regeneration after spinal cord injury. Science 2011; 331: 928–31.
Jonnala RR, Buccafusco JJ . Inhibition of nerve growth factor signaling by peroxynitrite. J Neurosci Res 2001; 63: 27–34.
Numakawaa T, Adachia N, Richardsa M, Chiba S, Kunugi H . Brain-derived neurotrophic factor and glucocorticoids: Reciprocal influence on the central nervous system. Neuroscience 2013; 239: 157–72.
Han BH, Holtzman DM . BDNF protects the neonatal brain from hypoxic-ischemic injury in vivo via the ERK pathway. J Neurosci 2000; 20: 5775–81.
Ying SW, Futter M, Rosenblum K, Webber MJ, Hunt SP, Bliss TV, et al. Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci 2002; 22: 1532–40.
Hussaini SM, Choi CI, Cho CH, Kim HJ, Jun H, Jang MH . Wnt signaling in neuropsychiatric disorders: ties with adult hippocampal neurogenesis and behavior. Neurosci Biobehav Rev 2014; 47: 369–83.
Ariga T . The pathogenic role of ganglioside metabolism in Alzheimer's disease-cholinergic neuron-specific gangliosides and neurogenesis. Mol Neurobiol 2016. doi: 10.1007/s12035-015-9641-0.
Mitran SI, Catalin B, Sfredel V, Balseanu TA . Neuroregeneration and dementia: new treatment options. J Mol Psychiatry 2013; 1: 12.
Hayashi K, Kanamori T, Yamazoe A, Yamada M, Nozaki H . Gaudichanolides A and B, clerodane diterpenes from Baccharis gaudichaudiana. J Nat Prod 2005; 68: 1121–4.
Huang JY, Yuan YH, Yan JQ, Wang YN, Chu SF, Zhu CG, et al. 20C, a bibenzyl compound isolated from Gastrodia elata, protects PC12 cells against rotenone-induced apoptosis via activation of the Nrf2/ARE/HO-1 signaling pathway. Acta Pharmacol Sin 2016; 37: 731–40.
Ishima T, Nishimura TM, lyo M, Hashimoto K . Potentiation of nerve growth factor-induced neurite outgrowth in PC12 cells by donepezil: role of sigma-1 receptors and IP3 receptors. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32: 1656–9.
Satoh SI, Kawasaki K, Hitomi A, Ikegaki I, Asano T . Fasudil protects cultured N1E-115 cells against lysophosphatidic acid-induced neurite retraction through inhibition of Rho-kinase. Brain Res Bull 2011; 84: 174–7.
Gao Y, Xu X, Chang S, Wang Y, Xu Y, Ran S, et al. Totarol prevents neuronal injury in vitro and ameliorates brain ischemic stroke: Potential roles of Akt activation and HO-1 induction. Toxicol Appl Pharmacol 2015; 289: 142–54.
Pang T, Sun LX, Wang T, Jiang ZZ, Liao H, Zhang LY . Telmisartan protects central neurons against nutrient deprivation-induced apoptosis in vitro through activation of PPARγ and the Akt/GSK-3β pathway. Acta Pharmacol Sin 2014; 35: 727–37.
Wang Y, Qiu B, Liu J, Zhu WG, Zhu S . Cocaine- and amphetamine-regulated transcript facilitates the neurite outgrowth in cortical neurons after oxygen and glucose deprivation through PTN-dependent pathway. Neuroscience 2014; 277: 103–10.
Pang T, Wang YJ, Gao YX, Xu Y, Li Q, Zhou YB, et al. A novel GSK-3β inhibitor YQ138 prevents neuronal injury induced by glutamate and brain ischemia through activation of the Nrf2 signaling pathway. Acta Pharmacol Sin 2016; 37: 741–52.
Su X, Wang C, Wang X, Han F, Lv C, Zhang X . Sweet dream liquid Chinese medicine ameliorates learning and memory deficit in a rat model of paradoxical sleep deprivation through the ERK/CREB signaling pathway. J Med Food 2016; 19: 472–80.
Wei HF, Zeng BF, Chen YF, Chen L, Gu YD . BDNF and GAP43 contribute to dynamic transhemispheric functional reorganization in rat brain after contralateral C7 root transfer following brachial plexus avulsion injuries. Neurosci Lett 2011; 500: 187–91.
Winner B, Winkler J . Adult neurogenesis in neurodegenerative diseases. Cold Spring Harb Perspect Biol 2015; 7: 445–60.
Kang YS, Bae MK, Kim JY, Jeong JW, Yun I, Jang HO, et al. Visfatin induces neurite outgrowth in PC12 cells via ERK1/2 signaling pathway. Neurosci Lett 2011; 504: 121–6.
Greene LA, Tischler AS . Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc Natl Acad Sci U S A 1976; 73: 2424–8.
Yamashita H, Muroi Y, Ishii T . Saccharin enhances neurite extension by regulating organization of the microtubules. Life Sci 2013; 93: 732–41.
Hao Y, Creson T, Zhang L, Li P, Du F, Yuan P, et al. Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci 2004; 24: 6590–9.
Dunican DJ, Doherty P . The generation of localized calcium rises mediated by cell adhesion molecules and their role in neuronal growth cone motility. Mol Cell Biol Res Commun 2000; 3: 255–63.
Liu Z, Cai H, Zhang P, Li H, Liu H, Li Z . Activation of ERK1/2 and PI3K/Akt by IGF-1 on GAP-43 expression in DRG neurons with excitotoxicity induced by glutamate in vitro. Cell Mol Neurobiol 2012; 32: 191–200.
Chen MM, Yin ZQ, Zhang LY, Liao H . Quercetin promotes neurite growth through enhancing intracellular cAMP level and GAP-43 expression. Chin J Nat Med 2015; 13: 667–72.
Li M, Li S, Li Y . Liraglutide promotes cortical neurite outgrowth via the MEK–ERK pathway. Cell Mol Neurobiol 2015; 35: 987–93.
Liu Y, Li C, Wang J, Fang Y, Sun H, Tao X . Nafamostat mesilate improves neurological outcome and axonal regeneration after stroke in rats. Mol Neurobiol 2016. doi: 10.1007/s12035-016-9999-7.
Acknowledgements
This study was supported by the National Natural Science Foundation of China (21402241), the Natural Science Foundation of Jiangsu Province (BK20160032), the Program for Jiangsu Province “Shuang Chuang” Team, the Open Project Program of State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University (SKLACLS1511), and the Scientific Research Foundation for Returned Overseas Chinese Scholars, State Education Ministry, China (to Tao PANG).
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Chang, S., Ruan, Wc., Xu, Yz. et al. The natural product 4,10-aromadendranediol induces neuritogenesis in neuronal cells in vitro through activation of the ERK pathway. Acta Pharmacol Sin 38, 29–40 (2017). https://doi.org/10.1038/aps.2016.115
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DOI: https://doi.org/10.1038/aps.2016.115
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