Esketamine mitigates endotoxin-induced hippocampal injury by regulating calcium transient and synaptic plasticity via the NF-α1/CREB pathway.
Mu Xu, Jialiang Wang, Jia Shi, Xiuyun Wu, Qin Zhao, Hui Shen, Jingli Chen, Jianbo Yu
Neuropharmacology May 15, 2025 DOI: 10.1016/j.neuropharm.2025.110362 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | In vivo and in vitro experimental study Peer reviewed |
|---|---|
| Population | C57BL/6J mice administered lipopolysaccharide, plus primary neurons and HT22 cells |
| Intervention | Esketamine |
| Dose | 10 mg/kg |
| Topics | Esketamine Neuroplasticity |
| Keywords | Creb Calcium transients Nf-α1 Septic encephalopathy Psychopharmacology Brain-protection Sepsis-treatment Synaptic-function |
| Citations | 4 |
| Key findings | Esketamine protects against hippocampal neurotoxicity in sepsis by modulating calcium transients and synaptic plasticity via the NF-α1/CREB signaling pathway. |
Abstract
Esketamine (ES) has been shown to confer neuroprotection partly by exerting anti-inflammation, alleviating oxidative stress, enhancing neuronal vitality, and promoting synaptic remodeling. Nonetheless, its precise function in SAE and the associated mechanisms are not understood. In this study, we investigated the neuroprotective potential of ES at behavioral, structural, and functional levels in vivo and in vitro. C57BL/6J mice administered with lipopolysaccharide (LPS) served as the research model and were injected with 10 mg/kg ES intraperitoneally. Fiber photometry was performed to record Ca2+ transients during behavioral assays. The neuronal dendritic architecture and synaptic plasticity were examined using the Golgi staining and transmission electron microscopy. Stereotactic administration of siRNA was performed to suppress the NF-α1 expression and determine the role of the NF-α1/CREB pathway in vitro. The neuroprotective effects of ES were verified in primary neurons and HT22 cells using a conditioned culture. The ES treatment alleviated sepsis symptoms, cognitive impairment, and decreased mortality. It also upregulated the NF-α1 expression in the hippocampal CA1 region and reduced neuroinflammation, oxidative stress, and neuronal loss. Moreover, ES treatment normalized the Ca2+ transients and improved dendritic structure as well as synaptic plasticity. However, NF-α1 knockdown p-CREB downregulation abolished the protective effects of ES. This also reversed the phenotypic characteristics of Ca2+ transients, dendritic structure, and post-synaptic plasticity. ES can abolish the LPS-induced hippocampal neurotoxicity in vitro and in vivo models and modulate neuronal Ca2+ transients and post-synaptic plasticity via the NF-α1/CREB signaling pathway. These findings provide a theoretical basis that will guide the future application of ES to treat hippocampal injury in sepsis.
Comparable studies
Other preclinical and animal studies on esketamine, most cited first.
Citations in the library
Cited by 2
- Esketamine-induced dentate gyrus plasticity in treatment resistant depression: First-in-human evidence Research Square
- The Impact of Esketamine on Depression: Targeting Oxidative Stress and Neuronal Apoptosis Through BDNF/TrkB/PI3K/AKT Pathway Activation Neuropsychiatric Disease and Treatment August 1, 2025
Cites 9
- Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms Pharmacological Reviews June 26, 2018
- Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression JAMA Psychiatry December 27, 2017
- Pharmacological and behavioral divergence of ketamine enantiomers: implications for abuse liability Molecular Psychiatry April 15, 2021
- Microglial ERK-NRBP1-CREB-BDNF signaling in sustained antidepressant actions of (R)-ketamine Molecular Psychiatry November 24, 2021
- The Antidepressant Actions of Ketamine and its Enantiomers Pharmacology & Therapeutics May 1, 2023
and 4 more in the library