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However, the appropriate dosage, duration of administration, and underlying mechanism of traxoprodil\u2019s antidepressant effects remain unclear. The purpose of this study is to compare the antidepressant effects of traxoprodil in different doses and different durations of administration and to explore whether traxoprodil exerts antidepressant effects via the brain-derived neurotrophic factor\/extracellular signal-regulated kinase\/cAMP-response element binding protein (BDNF\/ERK\/CREB) and protein kinase B\/Forkhead box O\/building information modelling (AKT\/FOXO\/Bim) signaling pathway. Mice were randomly divided into control group, chronic unpredictable mild stress (CUMS) + vehicle group, CUMS + traxoprodil (10\u2009mg\/kg, 20\u2009mg\/kg, and 40\u2009mg\/kg) groups, and CUMS + fluoxetine (5\u2009mg\/kg) group, followed by a forced swimming test, tail suspension test, and sucrose preference test. Western blotting and immunohistochemistry were used to measure the protein expression of BDNF, p-ERK1\/2, p-CREB, NR2B, AKT, FOXO1, FOXO3a, and Bim. Compared with the control group, CUMS treatment increased immobility time; decreased sucrose preference; reduced expression of BDNF, p-ERK1\/2, and p-CREB; and increased expression of AKT, FOXO, and Bim in the hippocampus. These alterations were ameliorated by administration of 20\u2009mg\/kg or 40\u2009mg\/kg of traxoprodil after 7 or 14 days of administration and with 10\u2009mg\/kg of traxoprodil or 5\u2009mg\/kg of fluoxetine after 21 days of administration. At the 7-day and 14-day timepoints, traxoprodil displayed dose-dependent antidepressant effects, with 20 and 40\u2009mg\/kg doses of traxoprodil producing rapid and strong antidepressant effects. However, at 21 days of administration, 10 and 20\u2009mg\/kg doses of traxoprodil exerted more pronounced antidepressant effects. The mechanism of traxoprodil\u2019s antidepressant effects may be closely related to the BDNF\/ERK\/CREB and AKT\/FOXO\/Bim signaling pathway.<\/jats:p>","DOI":"10.1155\/2023\/1131422","type":"journal-article","created":{"date-parts":[[2023,2,11]],"date-time":"2023-02-11T01:20:09Z","timestamp":1676078409000},"page":"1-19","source":"Crossref","is-referenced-by-count":13,"title":["Traxoprodil Produces Antidepressant-Like Behaviors in Chronic Unpredictable Mild Stress Mice through BDNF\/ERK\/CREB and AKT\/FOXO\/Bim Signaling Pathway"],"prefix":"10.1155","volume":"2023","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6403-7222","authenticated-orcid":true,"given":"Yahui","family":"Wang","sequence":"first","affiliation":[{"name":"School of Pharmacy, China Medical University, Shenyang 110122, 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