School of Pharmacy, China Medical University, Shenyang 110122, China.
School of Medicine, Indiana University, Fort Wayne 46805, USA.
Oxid Med Cell Longev. 2023 Feb 10;2023:1131422. doi: 10.1155/2023/1131422. eCollection 2023.
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.
曲唑酮是一种选择性 N-甲基-D-天冬氨酸受体亚单位 2B（NR2B）受体抑制剂，具有快速而持久的抗抑郁作用。然而，曲唑酮的适当剂量、给药持续时间和抗抑郁作用的潜在机制尚不清楚。本研究旨在比较曲唑酮在不同剂量和不同给药时间的抗抑郁作用，并探讨曲唑酮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（BDNF/ERK/CREB）和蛋白激酶 B/Forkhead 盒 O/建筑信息建模（AKT/FOXO/Bim）信号通路发挥抗抑郁作用。小鼠随机分为对照组、慢性不可预知性轻度应激（CUMS）+载体组、CUMS+曲唑酮（10mg/kg、20mg/kg 和 40mg/kg）组和 CUMS+氟西汀（5mg/kg）组，随后进行强迫游泳试验、悬尾试验和蔗糖偏好试验。Western blot 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 处理增加了不动时间；减少了蔗糖偏好；降低了 BDNF、p-ERK1/2 和 p-CREB 的表达；增加了海马中的 AKT、FOXO 和 Bim 的表达。这些变化在连续 7 或 14 天给予 20mg/kg 或 40mg/kg 的曲唑酮后以及连续 21 天给予 10mg/kg 的曲唑酮或 5mg/kg 的氟西汀后得到改善。在第 7 天和第 14 天时间点，曲唑酮显示出剂量依赖性的抗抑郁作用，20 和 40mg/kg 的曲唑酮剂量产生快速而强烈的抗抑郁作用。然而，在给药 21 天后，10 和 20mg/kg 的曲唑酮表现出更明显的抗抑郁作用。曲唑酮抗抑郁作用的机制可能与 BDNF/ERK/CREB 和 AKT/FOXO/Bim 信号通路密切相关。
