Esketamine mitigates endotoxin-induced hippocampal injury by regulating calcium transient and synaptic plasticity via the NF-α1/CREB 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.