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

doi:10.1016/j.neuroscience.2024.12.062

Esketamine alleviates LPS-induced depression-like behavior by activating Nrf2-mediated anti-inflammatory response in adolescent mice

Neuroscience. 2025 Jan 2:S0306-4522(24)00775-9. doi: 10.1016/j.neuroscience.2024.12.062. Online ahead of print.

Authors

Xinxu Ma¹, Shanshan Xue², Hongzhe Ma², Saboor Saeed³, Yunyun Zhang⁴, Yumeng Meng², Haixia Chen², Huan Yu², Huaizhi Wang³, Shaohua Hu⁵, Min Cai⁶

Affiliations

¹ Department 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.
² Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
³ Department of Psychiatry, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
⁴ Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China.
⁵ Department of Psychiatry, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China; Nanhu Brain-computer Interface Institute, Hangzhou 311100, China; The Zhejiang Key Laboratory of Precision Psychiatry, Hangzhou 310003, China; MOE Frontier Science Center for Brain Science and Brain-Machine Integration, Zhejiang University School of Medicine, Hangzhou 310003, China; Brain Research Institute of Zhejiang University, Hangzhou, 310003, China; The State Key Lab of Brain-Machine Intelligence, Zhejiang University, Hangzhou, China; Zhejiang Engineering Center for Mathematical Mental Health, Hangzhou 310003, China. Electronic address: [email protected].
⁶ Department of Psychiatry, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi, China. Electronic address: [email protected].

PMID: 39755229
DOI: 10.1016/j.neuroscience.2024.12.062

Abstract

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.