{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T19:02:11Z","timestamp":1793041331179,"version":"4.5.0"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T00:00:00Z","timestamp":1611100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:p>Ischemic stroke has been becoming one of the leading causes resulting in mortality and adult long-term disability worldwide. Post-stroke pneumonia is a common complication in patients with ischemic stroke and always associated with 1-year mortality. Though ambroxol therapy often serves as a supplementary treatment for post-stroke pneumonia in ischemic stroke patients, its effect on functional recovery and potential mechanism after ischemic stroke remain elusive. In the present study, the results indicated that administration of 70 mg\/kg and 100 mg\/kg enhanced functional recovery by virtue of decreasing infarct volume. The potential mechanism, to some extent, was due to promoting NSCs differentiation into neurons and interfering NSCs differentiation into astrocytes through increasing GCase expression to activate Wnt\/\u03b2-catenin signaling pathway in penumbra after ischemic stroke, which advanced basic knowledge of ambroxol in regulating NSCs differentiation and provided a feasible therapy for ischemic stroke treatment, even in other brain disorders in clinic.<\/jats:p>","DOI":"10.3389\/fnmol.2020.596039","type":"journal-article","created":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T06:51:38Z","timestamp":1611125498000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Ambroxol Upregulates Glucocerebrosidase Expression to Promote Neural Stem Cells Differentiation Into Neurons Through Wnt\/\u03b2-Catenin Pathway After Ischemic Stroke"],"prefix":"10.3389","volume":"13","author":[{"given":"Hongfei","family":"Ge","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weixiang","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuanyu","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuheng","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongjie","family":"Zou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Feng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"860","DOI":"10.3389\/fcell.2020.00860","article-title":"Role of Wnt signaling in adult hippocampal neurogenesis in health and disease","volume":"8","author":"Arredondo","year":"2020","journal-title":"Front. Cell. Dev. Biol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1853","DOI":"10.1016\/j.stemcr.2017.10.029","article-title":"Altered differentiation potential of gaucher's disease iPSC neuronal progenitors due to Wnt\/\u03b2-catenin downregulation","volume":"9","author":"Awad","year":"2017","journal-title":"Stem Cell Rep."},{"key":"B3","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1016\/j.jinf.2019.06.012","article-title":"Pneumonia in acute ischemic stroke patients requiring invasive ventilation: impact on short and long-term outcomes","volume":"79","author":"de Montmollin","year":"2019","journal-title":"J. Infect."},{"key":"B4","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1007\/s12975-019-00717-8","article-title":"Adult Neurogenesis in the subventricular zone and its regulation after ischemic stroke: implications for therapeutic approaches","volume":"11","author":"Dillen","year":"2020","journal-title":"Transl. Stroke Res."},{"key":"B5","doi-asserted-by":"publisher","first-page":"517","DOI":"10.2174\/187152711795563912","article-title":"Molecular manipulation targeting regulation of dopaminergic differentiation and proliferation of neural stem cells or pluripotent stem cells","volume":"10","author":"Ding","year":"2011","journal-title":"CNS Neurol. Disord. Drug Targets"},{"key":"B6","doi-asserted-by":"publisher","first-page":"1009","DOI":"10.1038\/nn.2855","article-title":"Axin2 as regulatory and therapeutic target in newborn brain injury and remyelination","volume":"14","author":"Fancy","year":"2011","journal-title":"Nat. Neurosci."},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1177\/1073858420914509","article-title":"Wnt\/\u03b2-catenin signaling in neural stem cell homeostasis and neurological diseases","author":"Gao","year":"2020","journal-title":"Neuroscientist"},{"key":"B8","doi-asserted-by":"publisher","first-page":"15535","DOI":"10.1038\/srep15535","article-title":"Poly-L-ornithine promotes preferred differentiation of neural stem\/progenitor cells via ERK signalling pathway","volume":"5","author":"Ge","year":"2015","journal-title":"Sci. Rep."},{"key":"B9","doi-asserted-by":"publisher","first-page":"37681","DOI":"10.1038\/srep37681","article-title":"Poly-L-ornithine enhances migration of neural stem\/progenitor cells via promoting alpha-Actinin 4 binding to actin filaments","volume":"6","author":"Ge","year":"2016","journal-title":"Sci. Rep."},{"key":"B10","doi-asserted-by":"publisher","first-page":"297","DOI":"10.1016\/j.neuron.2015.05.041","article-title":"Novel stroke therapeutics: unraveling stroke pathophysiology and its impact on clinical treatments","volume":"87","author":"George","year":"2015","journal-title":"Neuron"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1469","DOI":"10.1002\/glia.22851","article-title":"Endogenous neural stem cell responses to stroke and spinal cord injury","volume":"63","author":"Gr\u00e9goire","year":"2015","journal-title":"Glia"},{"key":"B12","doi-asserted-by":"publisher","first-page":"468748","DOI":"10.1155\/2014\/468748","article-title":"Stem cell-based therapies for ischemic stroke","volume":"2014","author":"Hao","year":"2014","journal-title":"Biomed Res. Int."},{"key":"B13","doi-asserted-by":"publisher","first-page":"291","DOI":"10.3389\/fncel.2014.00291","article-title":"Neural precursor cells in the ischemic brain - integration, cellular crosstalk, and consequences for stroke recovery","volume":"8","author":"Hermann","year":"2014","journal-title":"Front. Cell. Neurosci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.pneurobio.2018.05.004","article-title":"Neural stem cell therapies and hypoxic-ischemic brain injury","volume":"173","author":"Huang","year":"2019","journal-title":"Prog. Neurobiol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1128\/MCB.22.4.1172-1183.2002","article-title":"Wnt\/beta-catenin\/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway","volume":"22","author":"Jho","year":"2002","journal-title":"Mol. Cell. Biol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"8131286","DOI":"10.1155\/2020\/7941716","article-title":"Ambroxol improves neuronal survival and reduces white matter damage through suppressing endoplasmic reticulum stress in microglia after intracerebral hemorrhage","volume":"2020","author":"Jiang","year":"2020","journal-title":"Biomed Res. Int."},{"key":"B17","doi-asserted-by":"publisher","first-page":"16970","DOI":"10.1073\/pnas.0808616105","article-title":"Wnt-mediated self-renewal of neural stem\/progenitor cells","volume":"105","author":"Kalani","year":"2008","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"B18","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s12975-016-0460-z","article-title":"Neurogenesis in stroke recovery","volume":"8","author":"Koh","year":"2017","journal-title":"Transl. Stroke Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3389\/fnagi.2018.00012","article-title":"Microglia polarization, gene-environment interactions and Wnt\/\u03b2-catenin signaling: emerging roles of glia-neuron and glia-stem\/neuroprogenitor crosstalk for dopaminergic neurorestoration in aged parkinsonian brain","volume":"10","author":"L'Episcopo","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"B20","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1007\/s12028-011-9642-4","article-title":"High-dose ambroxol reduces pulmonary complications in patients with acute cervical spinal cord injury after surgery","volume":"16","author":"Li","year":"2012","journal-title":"Neurocrit. Care"},{"key":"B21","doi-asserted-by":"publisher","first-page":"3743","DOI":"10.3390\/ijms19123743","article-title":"Wnt\/\u03b2-catenin signaling pathway governs a full program for dopaminergic neuron survival, neurorescue and regeneration in the MPTP mouse model of parkinson's disease","volume":"19","author":"Marchetti","year":"2018","journal-title":"Int. J. Mol. Sci"},{"key":"B22","doi-asserted-by":"publisher","first-page":"1550","DOI":"10.1111\/ejn.12166","article-title":"Uncovering novel actors in astrocyte-neuron crosstalk in Parkinson's disease: the Wnt\/\u03b2-catenin signaling cascade as the common final pathway for neuroprotection and self-repair","volume":"37","author":"Marchetti","year":"2013","journal-title":"Eur. J. Neurosci."},{"key":"B23","doi-asserted-by":"publisher","first-page":"144","DOI":"10.1016\/j.molmed.2012.12.001","article-title":"Wnt your brain be inflamed? Yes, it Wnt!","volume":"19","author":"Marchetti","year":"2013","journal-title":"Trends Mol. Med."},{"key":"B24","doi-asserted-by":"publisher","first-page":"e13101","DOI":"10.1111\/acel.13101","article-title":"Parkinson's disease, aging and adult neurogenesis: Wnt\/\u03b2-catenin signalling as the key to unlock the mystery of endogenous brain repair","volume":"19","author":"Marchetti","year":"2020","journal-title":"Aging Cell"},{"key":"B25","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1002\/ana.24790","article-title":"Ambroxol effects in glucocerebrosidase and alpha-synuclein transgenic mice","volume":"80","author":"Migdalska-Richards","year":"2016","journal-title":"Ann. Neurol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"e21967","DOI":"10.1002\/syn.21967","article-title":"Oral ambroxol increases brain glucocerebrosidase activity in a nonhuman primate","volume":"71","author":"Migdalska-Richards","year":"2017","journal-title":"Synapse"},{"key":"B27","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1001\/jamaneurol.2019.4611","article-title":"Ambroxol for the treatment of patients with parkinson disease with and without glucocerebrosidase gene mutations: a nonrandomized, noncontrolled trial","volume":"77","author":"Mullin","year":"2020","journal-title":"JAMA Neurol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.biomaterials.2015.12.009","article-title":"Tissue plasminogen activator followed by antioxidant-loaded nanoparticle delivery promotes activation\/mobilization of progenitor cells in infarcted rat brain","volume":"81","author":"Petro","year":"2016","journal-title":"Biomaterials"},{"key":"B29","doi-asserted-by":"publisher","first-page":"112","DOI":"10.3389\/fncel.2020.00112","article-title":"Neuroprotective effects of diabetes drugs for the treatment of neonatal hypoxia-ischemia encephalopathy","volume":"14","author":"Poupon-Bejuit","year":"2020","journal-title":"Front. Cell. Neurosci."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1451","DOI":"10.1001\/jama.2015.3058","article-title":"Acute stroke intervention: a systematic review","volume":"313","author":"Prabhakaran","year":"2015","journal-title":"JAMA"},{"key":"B31","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.brainres.2019.01.043","article-title":"Post-stroke gastrodin treatment ameliorates ischemic injury and increases neurogenesis and restores the Wnt\/\u03b2-catenin signaling in focal cerebral ischemia in mice","volume":"1712","author":"Qiu","year":"2019","journal-title":"Brain Res."},{"key":"B32","doi-asserted-by":"publisher","first-page":"2336","DOI":"10.1007\/s11064-017-2251-7","article-title":"Melatonin inhibits neural cell apoptosis and promotes locomotor recovery via activation of the Wnt\/\u03b2-catenin signaling pathway after spinal cord injury","volume":"42","author":"Shen","year":"2017","journal-title":"Neurochem. Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1186\/s12883-019-1252-3","article-title":"Ambroxol as a novel disease-modifying treatment for Parkinson's disease dementia: protocol for a single-centre, randomized, double-blind, placebo-controlled trial","volume":"19","author":"Silveira","year":"2019","journal-title":"BMC Neurol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.gene.2015.11.024","article-title":"The protective effect of different airway humidification liquids to lung after tracheotomy in traumatic brain injury: the role of pulmonary surfactant protein-A (SP-A)","volume":"577","author":"Su","year":"2016","journal-title":"Gene"},{"key":"B35","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/j.hrtlng.2018.09.010","article-title":"Mucoactive agents for adults with acute lung conditions: a systematic review","volume":"48","author":"Tarrant","year":"2019","journal-title":"Heart Lung."},{"key":"B36","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1007\/s10571-017-0550-9","article-title":"Interactions between the canonical WNT\/beta-catenin pathway and PPAR gamma on neuroinflammation, demyelination, and remyelination in multiple sclerosis","volume":"38","author":"Vall\u00e9e","year":"2018","journal-title":"Cell. Mol. Neurobiol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"3806","DOI":"10.1093\/brain\/awz319","article-title":"Decreased microglial Wnt\/\u03b2-catenin signalling drives microglial pro-inflammatory activation in the developing brain","volume":"142","author":"Van Steenwinckel","year":"2019","journal-title":"Brain"},{"key":"B38","doi-asserted-by":"publisher","first-page":"1050","DOI":"10.1038\/nm.4154","article-title":"3K3A-activated protein C stimulates postischemic neuronal repair by human neural stem cells in mice","volume":"22","author":"Wang","year":"2016","journal-title":"Nat. Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"133","DOI":"10.1159\/000065512","article-title":"Complications following acute ischemic stroke","volume":"48","author":"Weimar","year":"2002","journal-title":"Eur. Neurol."},{"key":"B40","doi-asserted-by":"publisher","first-page":"286","DOI":"10.1016\/j.amjmed.2018.10.019","article-title":"Management of acute ischemic stroke","volume":"132","author":"Xiong","year":"2019","journal-title":"Am. J. Med."},{"key":"B41","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1016\/j.cell.2004.08.026","article-title":"Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels","volume":"118","author":"Xiong","year":"2004","journal-title":"Cell"},{"key":"B42","doi-asserted-by":"publisher","first-page":"429","DOI":"10.3389\/fncel.2019.00429","article-title":"SVCT2 Promotes neural stem\/progenitor cells migration through activating CDC42 after ischemic stroke","volume":"13","author":"Yang","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"e007626","DOI":"10.1161\/JAHA.117.007626","article-title":"Epothilone B benefits nigrostriatal pathway recovery by promoting microtubule stabilization after intracerebral hemorrhage","volume":"7","author":"Yang","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"B44","doi-asserted-by":"publisher","first-page":"604","DOI":"10.1691\/ph.2017.7541","article-title":"Effects and mechanisms of ambroxol inhalation (Mucosolvan((R))) in the treatment of neonatal pneumonia","volume":"72","author":"Yang","year":"2017","journal-title":"Pharmazie"},{"key":"B45","doi-asserted-by":"publisher","first-page":"105760","DOI":"10.1016\/j.intimp.2019.105760","article-title":"Wnt-3a alleviates neuroinflammation after ischemic stroke by modulating the responses of microglia\/macrophages and astrocytes","volume":"75","author":"Zhang","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1772","DOI":"10.1523\/JNEUROSCI.2459-16.2017","article-title":"TREM2 Promotes microglial survival by activating Wnt\/\u03b2-catenin pathway","volume":"37","author":"Zheng","year":"2017","journal-title":"J. Neurosci."}],"container-title":["Frontiers in Molecular Neuroscience"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2020.596039\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T06:51:40Z","timestamp":1611125500000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fnmol.2020.596039\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,20]]},"references-count":46,"alternative-id":["10.3389\/fnmol.2020.596039"],"URL":"https:\/\/doi.org\/10.3389\/fnmol.2020.596039","relation":{},"ISSN":["1662-5099"],"issn-type":[{"value":"1662-5099","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,20]]},"article-number":"596039"}}