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

Esketamine treatment alleviated sepsis symptoms, cognitive impairment, and decreased mortality in a mouse model of sepsis-associated encephalopathy. It reduced neuroinflammation, oxidative stress, and neuronal loss, and normalized calcium transients while improving dendritic structure and synaptic plasticity in the hippocampal CA1 region. These effects depended on the NF-α1/CREB signaling pathway, as suppressing NF-α1 abolished the protective effects and reversed improvements in calcium transients, dendrites, and post-synaptic plasticity. The findings suggest esketamine protects against hippocampal injury in sepsis through this pathway.

Study at a glance

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.