The Impact of Esketamine on Depression: Targeting Oxidative Stress and Neuronal Apoptosis Through BDNF/TrkB/PI3K/AKT Pathway Activation
- Neuropsychiatr Dis Treat. 2025 Aug 25:21:1783-1793. doi: 10.2147/NDT.S502090.
- 1. Tianjin Medical College Pharmacy and Biotechnology Department, Tianjin, People's Republic of China.
- 2. The Rehabilitation Center of Tianjin Hospital in Tianjin, Tianjin, People's Republic of China.
- 3. Department of Human Resources, Tianjin Medical University General Hospital Airport Hospital, Tianjin, People's Republic of China.
- 4. Department of Pharmacy, Tianjin First Central Hospital, Tianjin, People's Republic of China.
- # Contributed equally.
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.