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The present study aimed to investigate the antidepressant\u2010like effects of IRN in chronic unpredictable mild stress (CUMS)\u2010induced depressive\u2010like behaviors in mice and to illustrate its possible mechanisms of action. The mice were subjected to CUMS for 6 wk and administered with IRN (20 or 40 mg\/kg) daily by oral gavage for 3 wk. The PI3K\/protein kinase B (Akt) inhibitor and glycogen synthase kinase\u20103\u03b2 (GSK\u20103\u03b2) inhibitors were used to determine the involvement of the PI3K\/Akt\/GSK\u20103\u03b2 pathway in the antidepressant\u2010like effects of IRN in the mice. The results showed that CUMS caused depression\u2010like behaviors in the mice, such as behavioral despair by the forced swim test (FST) and anhedonia by the sucrose preference test. In addition, CUMS could significantly reduce the levels of nerve growth factor and brain\u2010derived neurotrophic factor but markedly increase the release of TNF\u2010\u03b1 and IL\u20106 in the hippocampus and cerebral cortex of the mice. Western blotting analysis showed that CUMS markedly suppressed the levels of phosphorylated GSK\u20103\u03b2 (Ser9) and phosphorylated Akt (Ser473) but significantly enhanced the translocation of NF\u2010\u03baB p65 from cytosol to nuclei in the hippocampus and cerebral cortex of the mice. CUMS could also significantly increase the NF\u2010\u03baB binding activity in the hippocampus and cerebral cortex of the mice, whereas IRN treatment could significantly reverse the behavioral and biochemical changes induced by CUMS in the mice. Moreover, the antidepressant\u2010like effect of IRN was completely abolished by the PI3K\/Akt inhibitor. Combination treatment with IRN and GSK\u20103\u03b2 inhibitors in the mice exerted a synergistic anti\u2010immobility action in the FST. The results of mechanistic investigations indicated that the antidepressant\u2010like action of IRN was mediated, at least in part, by enhancing neurotrophins and attenuating neuroinflammation\n                    <jats:italic>via<\/jats:italic>\n                    modulating the PI3K\/Akt\/GSK\u20103\u03b2 pathway.\u2014Xian, Y.\u2010F., Ip, S.\u2010P., Li, H.\u2010Q., Qu, C., Su, Z.\u2010R., Chen, J.\u2010N., Lin, Z.\u2010X. Isorhynchophylline exerts antidepressant\u2010like effects in mice\n                    <jats:italic>via<\/jats:italic>\n                    modulating neuroinflammation and neurotrophins: involvement of the PI3K\/Akt\/GSK\u20103\u03b2 signaling pathway. FASEB J. 33, 10393\u201310408 (2019).\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/www.fasebj.org\">www.fasebj.org<\/jats:ext-link>\n                  <\/jats:p>","DOI":"10.1096\/fj.201802743rr","type":"journal-article","created":{"date-parts":[[2019,6,24]],"date-time":"2019-06-24T15:29:56Z","timestamp":1561390196000},"page":"10393-10408","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":61,"title":["Isorhynchophylline exerts antidepressant\u2010like effects in mice\n                    <i>via<\/i>\n                    modulating neuroinflammation and neurotrophins: involvement of the PI3K\/Akt\/GSK\u20103\u03b2 signaling pathway"],"prefix":"10.1096","volume":"33","author":[{"given":"Yan\u2010Fang","family":"Xian","sequence":"first","affiliation":[{"name":"School of Chinese Medicine Faculty of Medicine The Chinese University of Hong Kong  Hong Kong China"},{"name":"Brain Research Center School of Chinese Medicine Faculty of Medicine The Chinese University of Hong Kong  Hong Kong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siu\u2010Po","family":"Ip","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine Faculty of Medicine The Chinese University of Hong Kong  Hong Kong China"},{"name":"Brain Research Center School of Chinese Medicine Faculty of Medicine The Chinese University of Hong Kong  Hong Kong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui\u2010Qin","family":"Li","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine Faculty of Medicine The Chinese University of Hong Kong  Hong Kong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang","family":"Qu","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine Faculty of Medicine The Chinese University of Hong Kong  Hong Kong China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zi\u2010Ren","family":"Su","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine Mathematical Engineering Academy of Chinese Medicine Guangzhou University of Chinese Medicine  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian\u2010Nan","family":"Chen","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of New Drug Development and Research of Chinese Medicine Mathematical Engineering Academy of Chinese Medicine Guangzhou University of Chinese Medicine  Guangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhi\u2010Xiu","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Chinese Medicine Faculty of Medicine The Chinese University of Hong Kong  Hong Kong China"},{"name":"Brain Research Center School of Chinese Medicine Faculty of Medicine The Chinese University of Hong Kong  Hong Kong China"},{"name":"Hong Kong Institute of Integrative Medicine The Chinese University of Hong Kong  Hong Kong China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,6,24]]},"reference":[{"key":"e_1_2_9_2_1","unstructured":"World Health Organization. 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