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Esketamine alleviates LPS-induced depression-like behavior by activating Nrf2-mediated anti-inflammatory response in
Xinxu Ma1, Shanshan Xue2, Hongzhe Ma2
1Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Psychiatry, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
Esketamine rapidly reduces depressive behaviors in adolescents by decreasing neuroinflammation. This effect is mediated by activating the Nrf2 pathway, which combats inflammatory responses.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- The precise mechanisms behind esketamine's antidepressant effects are not fully understood.
- Adolescent depression is a significant public health concern with limited treatment options.
Purpose of the Study:
- To investigate the impact of esketamine on lipopolysaccharide (LPS)-induced depressive behaviors in adolescent mice.
- To explore the role of the Nrf2 (Nuclear factor erythroid 2-related factor 2) pathway in esketamine's rapid antidepressant efficacy.
Main Methods:
- Adolescent mice were administered LPS and/or esketamine (15 mg/kg).
- Behavioral tests (OFT, NFST, TST) assessed depressive-like behaviors.
- Western blot and ELISA measured Nrf2, inflammatory cytokines (TNF-α, IL-1β, iNOS), and plasma cytokines.
- The Nrf2 inhibitor ML385 was used to probe the Nrf2 pathway's involvement.
Main Results:
- Esketamine treatment significantly alleviated LPS-induced depressive-like behaviors.
- Esketamine increased Nrf2 expression and decreased inflammatory markers in the hippocampus and mPFC.
- Inhibition of Nrf2 with ML385 reversed esketamine's behavioral and anti-inflammatory effects.
- Esketamine reduced peripheral pro-inflammatory cytokines and increased anti-inflammatory cytokines, an effect also reversed by Nrf2 inhibition.
Conclusions:
- Esketamine demonstrates rapid antidepressant effects in an adolescent depression model.
- The findings suggest esketamine attenuates neuroinflammation via Nrf2 pathway activation.
- Nrf2-mediated anti-inflammatory signaling is a potential mechanism underlying esketamine's therapeutic action.
