The Impact of Esketamine on Depression: Targeting Oxidative Stress and Neuronal Apoptosis Through BDNF/TrkB/PI3K/AKT Pathway Activation
Yue-Yue Zhang, Qianqian Cai, Lingshan Wang, Bei Zhang
Neuropsychiatric Disease and Treatment August 1, 2025 DOI: 10.2147/ndt.s502090 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Rats subjected to chronic unpredictable mild stress |
| Interventions | Esketamine PI3K-IN-6 |
| Dose | 5 mg/kg |
| Topics | Depression Esketamine |
| Key points | Esketamine alleviates depressive behaviors in a CUMS rat model by activating the BDNF/TrkB/PI3K/AKT signaling pathway, reducing oxidative stress and inhibiting neuronal apoptosis. |
Abstract
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.
Methods: 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.
Results: 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.
Conclusion: 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.
Comparable studies
Other preclinical and animal studies on esketamine for depression, most cited first.