Traxoprodil is a selective N-methyl-d-aspartate receptor subunit 2B (NR2B) receptor inhibitor with rapid and long-lasting antidepressant effects. However, the appropriate dosage, duration of administration, and underlying mechanism of traxoprodil’s 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 mg/kg, 20 mg/kg, and 40 mg/kg) groups, and CUMS + fluoxetine (5 mg/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 mg/kg or 40 mg/kg of traxoprodil after 7 or 14 days of administration and with 10 mg/kg of traxoprodil or 5 mg/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 mg/kg doses of traxoprodil producing rapid and strong antidepressant effects. However, at 21 days of administration, 10 and 20 mg/kg doses of traxoprodil exerted more pronounced antidepressant effects. The mechanism of traxoprodil’s antidepressant effects may be closely related to the BDNF/ERK/CREB and AKT/FOXO/Bim signaling pathway.

中文翻译：

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Traxoprodil 通过 BDNF/ERK/CREB ​​和 AKT/FOXO/Bim 信号通路在慢性不可预测的轻度应激小鼠中产生抗抑郁样行为

Traxoprodil 是一种选择性 N-甲基-d-天冬氨酸受体亚基 2B (NR2B) 受体抑制剂，具有快速和持久的抗抑郁作用。然而，曲索普地尔抗抑郁作用的合适剂量、给药持续时间和潜在机制仍不清楚。本研究旨在比较曲索地尔不同剂量、不同给药时间的抗抑郁作用，探讨曲索地尔是否通过脑源性神经营养因子/细胞外信号调节激酶/cAMP反应元件结合蛋白发挥抗抑郁作用（ BDNF/ERK/CREB) 和蛋白激酶 B/Forkhead box O/建筑信息模型 (AKT/FOXO/Bim) 信号通路。小鼠随机分为对照组、慢性不可预测轻度应激（CUMS）+载体组、CUMS + traxoprodil（10 mg/kg、20 mg/kg 和 40 mg/kg）组和 CUMS + 氟西汀（5 mg/kg）组，随后进行强迫游泳测试、悬尾测试和蔗糖偏好测试。蛋白质印迹和免疫组织化学用于测量 BDNF、p-ERK1/2、p-CREB、NR2B、AKT、FOXO1、FOXO3a 和 Bim 的蛋白表达。与对照组相比，CUMS治疗增加了不动时间；降低蔗糖偏好；BDNF、p-ERK1/2 和 p-CREB ​​表达减少；海马体中 AKT、FOXO 和 Bim 的表达增加。这些改变通过在给药 7 或 14 天后给予 20 mg/kg 或 40 mg/kg 曲索地尔以及在给药 21 天后给予 10 mg/kg 曲索地尔或 5 mg/kg 氟西汀得到改善。在第 7 天和第 14 天时间点，traxoprodil 显示出剂量依赖性抗抑郁作用，20 和 40 mg/kg 剂量的 traxoprodil 产生快速和强烈的抗抑郁作用。然而，在给药 21 天时，10 和 20 mg/kg 剂量的曲唑地尔发挥了更显着的抗抑郁作用。曲索地尔的抗抑郁作用机制可能与BDNF/ERK/CREB和AKT/FOXO/Bim信号通路密切相关。