Esketamine alleviates LPS-induced depression-like behavior by activating Nrf2-mediated anti-inflammatory response in adolescent mice.
Xinxu Ma, Shanshan Xue, Hongzhe Ma, Saboor Saeed, Yunyun Zhang, Yumeng Meng, Haixia Chen, Huan Yu, Huaizhi Wang, Shaohua Hu, Min Cai
Neuroscience February 16, 2025 DOI: 10.1016/j.neuroscience.2024.12.062 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical experimental study Peer reviewed |
|---|---|
| Population | Adolescent male C57BL/6J mice |
| Intervention | Esketamine |
| Dose | 15 mg/kg |
| Topics | Depression Esketamine |
| Keywords | Depression treatment Antidepressants Mental health Inflammation |
| Citations | 12 |
| Key findings | Esketamine treatment alleviates LPS-induced depressive-like behaviors and reduces neuroinflammation in adolescent male mice, an effect that depends on activation of the Nrf2 signaling pathway. |
Abstract
The mechanisms underlying esketamine's therapeutic effects remain elusive. The study aimed to explore the impact of single esketamine treatment on LPS-induced adolescent depressive-like behaviors and the role of Nrf2 regulated neuroinflammatory response in esketamine-produced rapid antidepressant efficacy. Adolescent male C57BL/6J mice were randomly assigned to three groups: control, LPS, and LPS + esketamine (15 mg/kg, i.p.). Depressive-like behaviors were evaluated via the OFT, NFST, and TST. Protein expression of Nrf2 and inflammatory cytokines, including TNF-α, IL-1β, and iNOS in the hippocampus and mPFC, were measured by western blot. Moreover, the Nrf2 inhibitor, ML385, was also applied in the current study. The depressive-like behaviors and the protein expression of Nrf2, TNF-α, IL-1β, and iNOS in mPFC and hippocampus were also measured. Additionally, the plasma's pro-inflammatory cytokines and anti-inflammatory cytokines were assessed using ELISA methods with or without ML385. A single administration of esketamine treatment alleviated the LPS-induced depressive-like behaviors. Esketamine increased the expression of Nrf2 and reduced the expression of the inflammatory cytokines, including TNF-α, IL-1β, and iNOS, in the mPFC and hippocampus. Notably, pharmacological inhibition of Nrf2 via ML385 administration abrogated the antidepressive-like behaviors and anti-inflammatory effects induced by esketamine. In the periphery, esketamine mitigated the LPS-induced elevation of pro-inflammatory cytokines, and the reduction of anti-inflammatory cytokines, and this effect was reversed by Nrf2 inhibition. Esketamine treatment exerts rapid antidepressant effects and attenuates neuroinflammation in LPS-induced adolescent depressive-like behaviors, potentially through the activation of Nrf2-mediated anti-inflammatory signaling.
Comparable studies
Other preclinical and animal studies on esketamine for depression, most cited first.
Citations in the library
Cited by 8
- Oxidative Stress in Treatment-Resistant and Refractory Depression: A Hidden Therapeutic Target? Molecular Neurobiology February 5, 2026
- Esketamine/Ketamine: Dual‐Action Mechanisms and Clinical Prospects beyond Anesthesia in Psychiatry, Immunology, and Oncology Advanced Science December 14, 2025
- Effectiveness of ketamine/esketamine in alleviating postoperative fatigue: a systematic review International Journal of Clinical Pharmacy November 12, 2025
- Esketamine for postoperative sleep disturbance: clinical evidence, mechanisms, and future directions. Frontiers in Psychiatry 2025
- Esketamine relieves depressive-like behaviors in MPTP-induced Parkinson disease mice via GPR109A-dependent reduction of neuroinflammation Brain Research Bulletin October 27, 2025
and 3 more in the library
Cites 14
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Mechanisms of Ketamine Action as an Antidepressant Molecular Psychiatry March 13, 2018
- Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study American Journal of Psychiatry May 21, 2019
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Efficacy and Safety of Fixed-Dose Esketamine Nasal Spray Combined With a New Oral Antidepressant in Treatment-Resistant Depression: Results of a Randomized, Double-Blind, Active-Controlled Study (TRANSFORM-1) The International Journal of Neuropsychopharmacology July 9, 2019
and 9 more in the library