Sinomenine promotes neuronal differentiation and neurite out-growth via Akt activation in vitro
Keywords:
Sinomenine; Neuronal differentiation; Neurite outgrowth; Neural stem/progenitor cells; Akt signalingAbstract
Sinomenine, a bioactive alkaloid from Sinomenium acutum, exhibits anti-inflammatory and neuroprotective effects, but its role in neuronal differentiation and morphological maturation remains unclear. This study used Neuro-2a cells and primary neural stem/progenitor cells (NSPCs) to examine the pro-differentiation effects of sinomenine. Sinomenine increased Neuro-2a cell viability at concentrations of 0.1–20 μM and showed no detectable cytotoxicity up to 100 μM. Under differentiation conditions, sinomenine enhanced neuronal differentia-tion and neurite outgrowth in Neuro-2a cells dose-dependently (5–50 μM), increased the proportion of β-tubulin III–positive neurons, promoted multi-neurite formation, and enhanced dendritic comple-xity in NSPCs. Mechanistically, sinomenine selectively induced Akt phosphorylation without activating ERK, p38, or JNK pathways, and pharmacological inhibition of Akt abolished sinomenine-induced neuritogenesis. These findings suggest sinomenine promotes neuronal differentiation and neurite outgrowth via the Akt pathway, supporting its potential in neuroregeneration.
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References
Abdipranoto A, Wu S, Stayte S, Vissel B. The role of neuro-genesis in neurodegenerative diseases and its implications for therapeutic development. CNS Neurol. Disord Drug Targets. 2008; 2: 187-210.
Guan QH, Pei DS, Zhang QG, Hao ZB, Xu TL, Zhang GY. The neuroprotective action of SP600125, a new inhibitor of JNK, on transient brain ischemia/reperfusion-induced neuronal death in rat hippocampal CA1 via nuclear and non-nuclear pathways. Brain Res. 2005; 1: 51-59.
Hong H, Lu X, Lu Q, Huang C, Cui Z. Potential therapeutic effects and pharmacological evidence of sinomenine in central nervous system disorders. Front Pharmacol. 2022; 13: 1015035.
Janesick A, Wu SC, Blumberg B. Retinoic acid signaling and neuronal differentiation. Cell Mol Life Sci. 2015; 8: 1559-76.
Jiang H, Lu Q, Xu J, Huo G, Cai Y, Geng S, Xu H, Zhang J, Li H, Yuan K. Sinomenine ameliorates adjuvant-induced arthritis by inhibiting the autophagy/NETosis/inflamma-tion axis. Sci Rep. 2023a; 1: 3933.
Jiang Q, Liu J, Huang S, Wang XY, Chen X, Liu GH, Ye K, Song W, Masters CL, Wang J. Antiaging strategy for neuro-degenerative diseases: From mechanisms to clinical advan-ces. Signal Transduct Tar. 2025; 1: 76.
Jiang W, Fan W, Gao T, Li T, Yin Z, Guo H, Wang L, Han Y, Jiang JD. Analgesic mechanism of sinomenine against chronic pain. Pain Res Manag. 2020; 1: 1876862.
Jiang X, Hu Z, Qiu X, Wu L, Zhou R, Yang Y, Xiang X. Poria cocos (Schw.) Wolf, a traditional Chinese edible medicinal herb, promotes neuronal differentiation, and the morpho-logical maturation of newborn neurons in neural stem/progenitor Cells. Molecules 2023b; 22: 7480.
Jiang X, Shu Z, Wu L, Wen J, Xiang X. Lithocarpus litseifolius Hance) Chun, widely known as sweet tea, promotes neuronal differentiation and maturation of neural stem/progenitor cells. J Ethnopharmacol. 2026; 355: 120753.
Kanzawa T, Iwado E, Aoki H, Iwamaru A, Hollingsworth E, Sawaya R, Kondo S, Kondo Y. Ionizing radiation induces apoptosis and inhibits neuronal differentiation in rat neural stem cells via the c-Jun NH2-terminal kinase (JNK) path-way. Oncogene 2006; 26: 3638-48.
Lai WD, Wang S, You WT, Chen S J, Wen JJ, Yuan CR, Zheng MJ, Jin Y, Yu J, Wen CP. Sinomenine regulates immune cell subsets: Potential neuro-immune intervene for precise treat-ment of chronic pain. Front Cell Dev Biol. 2022; 10: 1041006.
Liao KK, Wu M J, Chen PY, Huang SW, Chiu SJ, Ho CT, Yen JH. Curcuminoids promote neurite outgrowth in PC12 cells through MAPK/ERK-and PKC-dependent pathways. J Agric Food Chem. 2012; 1: 433-43.
Liu F, Xuan A, Chen Y, Zhang J, Xu L, Yan Q, Long D. Com-bined effect of nerve growth factor and brain‑derived neurotrophic factor on neuronal differentiation of neural stem cells and the potential molecular mechanisms. Mol Med Report. 2014; 4: 1739-45.
Llorente V, Velarde P, Desco M, Gómez-Gaviro MV. Current understanding of the neural stem cell niches. Cells 2022; 19: 3002.
Luo YR, Kudo TA, Tominami K, Izumi S, Tanaka T, Hayashi Y, Noguchi T, Matsuzawa A, Nakai J, Hong G. SP600125 enhances temperature-controlled repeated thermal stimula-tion-induced neurite outgrowth in PC12-P1F1 cells. Int J Mol Sci. 2022; 24: 15602.
Naveen C, Gaikwad S, Agrawal-Rajput R. Berberine induces neuronal differentiation through inhibition of cancer stem-ness and epithelial-mesenchymal transition in neuroblas-toma cells. Phytomedicine 2016; 7: 736-44.
Ozpak L, Bagca BG. Neuroprotective effects of resveratrol through modulation of PI3K/Akt/GSK‐3β pathway and metalloproteases. IUBMB Life 2024; 12: 1199-208.
Park SJ, Jin ML, An HK, Kim KS, Ko MJ, Kim CM, Choi YW, Lee YC. Emodin induces neurite outgrowth through PI3K/Akt/GSK-3β-mediated signaling pathways in Neuro2a cells. Neurosci Lett. 2015; 588: 101-07.
Ramazi S, Fahanik-Babaei J, Mohamadi-Zarch S M, Tashakori-Miyanroudi M, Nourabadi D, Nazari-Serenjeh M, Roghani M, Baluchnejadmojarad T. Neuroprotective and anticonvu-lsant effects of sinomenine in kainate rat model of temporal lobe epilepsy: Involvement of oxidative stress, inflammation and pyroptosis. J. Chem Neuroanat. 2020; 108: 101800.
Rostami A, Taleahmad F, Haddadzadeh-Niri N, Joneidi E, Afshin-Majd S, Baluchnejadmojarad T, Roghani M. Sinome-nine attenuates trimethyltin-induced cognitive decline via targeting hippocampal oxidative stress and neuroinflamma-tion. J Mol Neurosci. 2022; 8: 1609-21.
Sánchez-Alegria K, Flores-Leon M, Avila-Munoz E, Rodríguez-Corona N, Arias C. PI3K signaling in neurons: A central node for the control of multiple functions. Int J Mol Sci. 2018; 12: 3725.
Shinomiya M, Kawamura K, Tanida E, Nagoshi M, Motoda H, Kasanami Y, Hiragami F, Kano Y. Neurite outgrowth of PC12 mutant cells induced by orange oil and d-limonene via the p38 MAPK pathway. Acta Med Okayama. 2012; 2: 111-18.
St-Cyr G, Garneau D, Gévry N, Blouin R. Quantitative phos-phoproteomics reveals that nestin is a downstream target of dual leucine zipper kinase during retinoic acid-induced neu-ronal differentiation of Neuro-2a cells. BMC Mol Cell Biol. 2025; 1: 10.
Sultan S, Li L, Moss J, Petrelli F, Casse F, Gebara E, Lopatar J, Pfrieger F W, Bezzi P, Bischofberger J. Synaptic integration of adult-born hippocampal neurons is locally controlled by astrocytes. Neuron 2015; 5: 957-72.
Vittori DC, Chamorro ME, Hernández YV, Maltaneri RE, Nesse AB. Erythropoietin and derivatives: Potential benefi-cial effects on the brain. J Neurochem. 2021; 5: 1032-57.
Wang W, Wang Z, Ling A, Zhang C, Lv M, Huang L, Niu Y. Research progress in treatment of rheumatoid arthritis with sinomenine and related formulations based on different administration routes. Front Pharmacol. 2025; 16: 1613679.
Wei S, Dong J, Hu Q, Bai J, Gao X, Shan H, Sheng L, Dai J, Jiang F, Tao L. Advances in mesenchymal stem cells and their derivatives for promoting peripheral nerve regenera-tion. Burns Trauma. 2025; tkaf027.
Wilson DM, Cookson MR, Van Den Bosch L, Zetterberg H, Holtzman DM, Dewachter I. Hallmarks of neurodegenera-tive diseases. Cell 2023, 4: 693-714.
Xiang X, Jiang X, Lu X. Regulation of neural stem cell self-renewal, proliferation and differentiation by the RhoA guanine nucleotide exchange factor arhgef 1. Gene 2023; 863: 147306.
Xiang X, Zhuang X, Li S, Shi L. Arhgef1 is expressed in cortical neural progenitor cells and regulates neurite outgrowth of newly differentiated neurons. Neurosci Lett. 2017; 638: 27-34.
Zhang J, Guo R, Zhou Z, Fu Z, Akogo HY, Li Y, Zhang X, Wang N, Liu Y, Li H. Neural stem/progenitor cell therapy in patients and animals with amyotrophic lateral sclerosis: A systematic review and meta-analysis. Mol Neurobiol. 2025; 5: 6521-36.
Zhang L, Zhang W, Zheng B, Tian N. Sinomenine attenuates traumatic spinal cord injury by suppressing oxidative stress and inflammation via Nrf2 pathway. Neurochem Res. 2019; 4: 763-75.
Zhang MW, Wang XH, Shi J, Yu JG. Sinomenine in cardio-cerebrovascular diseases: Potential therapeutic effects and pharmacological evidences. Front Cardiovasc Med. 2021; 8: 749113.
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