Zhang Yueyi, Cai Qianqian, Wang Lingshan, Zhang Bei
Tianjin Medical College Pharmacy and Biotechnology Department, Tianjin, People's Republic of China.
The Rehabilitation Center of Tianjin Hospital in Tianjin, Tianjin, People's Republic of China.
Neuropsychiatr Dis Treat. 2025 Aug 25;21:1783-1793. doi: 10.2147/NDT.S502090. eCollection 2025.
BACKGROUND & AIMS: Esketamine, a promising treatment for treatment-resistant depression, has shown potential advantages over traditional antidepressants. However, its mechanisms remain unclear. This study explores how esketamine alleviates depressive behaviors through activation of the BDNF/TrkB/PI3K/AKT signaling pathway.
Using a Chronic Unpredictable Mild Stress (CUMS) rat model, behavioral assays (Sucrose Preference Test, Morris Water Maze Test) and histological analyses (HE and Nissl's staining) were performed. Esketamine (5 mg/kg) treatment was administered to evaluate its antidepressant effects, and the PI3K inhibitor, PI3K-IN-6, was used to investigate the role of the PI3K/AKT pathway in the underlying mechanism.
Esketamine treatment improved depressive behaviors, enhanced neuronal structure, and reduced apoptosis and oxidative stress. These effects were linked to the activation of the BDNF/TrkB/PI3K/AKT pathway. PI3K-IN-6 reversed the effects, confirming the pathway's involvement.
Esketamine alleviates depressive behaviors by activating the BDNF/TrkB/PI3K/AKT signaling pathway, reducing oxidative stress and inhibiting neuronal apoptosis. These findings highlight the therapeutic potential of esketamine in treating depression, particularly in cases where traditional treatments fail.
艾司氯胺酮是一种有前景的难治性抑郁症治疗药物，已显示出优于传统抗抑郁药的潜在优势。然而，其作用机制仍不清楚。本研究探讨艾司氯胺酮如何通过激活脑源性神经营养因子（BDNF）/酪氨酸激酶受体B（TrkB）/磷脂酰肌醇-3-激酶（PI3K）/蛋白激酶B（AKT）信号通路来减轻抑郁行为。
采用慢性不可预测轻度应激（CUMS）大鼠模型，进行行为学检测（蔗糖偏好试验、莫里斯水迷宫试验）和组织学分析（苏木精-伊红染色和尼氏染色）。给予艾司氯胺酮（5mg/kg）治疗以评估其抗抑郁作用，并使用PI3K抑制剂PI3K-IN-6来研究PI3K/AKT通路在潜在机制中的作用。
艾司氯胺酮治疗改善了抑郁行为，增强了神经元结构，并减少了细胞凋亡和氧化应激。这些作用与BDNF/TrkB/PI3K/AKT通路的激活有关。PI3K-IN-6逆转了这些作用，证实了该通路的参与。
艾司氯胺酮通过激活BDNF/TrkB/PI3K/AKT信号通路、减轻氧化应激和抑制神经元凋亡来减轻抑郁行为。这些发现突出了艾司氯胺酮在治疗抑郁症方面的治疗潜力，特别是在传统治疗失败的情况下。
