Sevoflurane Induces Neurotoxicity and Cognitive Impairment by Up‐Regulating Long Non‐Coding RNA CEBPA‐AS1

ABSTRACT

Sevoflurane may induce neurotoxicity and cognitive impairment, though the associated mechanisms remain unclear. This study aimed to investigate how long non‐coding RNA CEBPA‐AS1 contributed to the neurotoxicity and cognitive impairment induced by sevoflurane. This study employed HT22 hippocampal neuronal cells and 18‐month‐old Sprague‐Dawley rats to establish a sevoflurane exposure model. Reverse transcription quantitative real‑time polymerase chain reaction (RT‑qPCR) was employed to detect relevant gene expression. Cell proliferation, apoptosis, inflammatory levels, and oxidative stress indicators were assessed using cell counting kit‑8 (CCK‑8) assays, flow cytometry, enzyme‑linked immunosorbent assay (ELISA), and oxidative stress kits. The Morris water maze was used to evaluate rats' learning and memory abilities. The RNA immunoprecipitation (RIP) assay and dual luciferase assay were utilised to validate the targeted binding relationship of the target molecules. Sevoflurane treatment significantly increased CEBPA‐AS1 expression in HT22 cells and rat hippocampal tissue while simultaneously downregulating microRNA‐455‐3p (miR‐455‐3p) and upregulating erythropoietin‐producing hepatocellular carcinoma A4 (EPHA4). Silencing CEBPA‐AS1 significantly alleviated sevoflurane‐induced cellular and brain tissue injury, apoptosis, oxidative stress, and inflammatory responses, whilst concurrently improving cognitive impairment at the in vivo level. Mechanistic studies showed CEBPA‐AS1 acted as a molecular sponge for miR‐455‐3p, which targeted and repressed EPHA4, thus forming the CEBPA‐AS1/miR‐455‐3p/EPHA4 regulatory axis. Rescue experiments showed that miR‐455‐3p inhibition partially reversed the attenuation of sevoflurane neurotoxicity by CEBPA‐AS1 silencing, restoring neurotoxicity, oxidative stress, inflammation, and cognitive impairment in vitro and in vivo. On this basis, EPHA4 inhibition blocked the competitive endogenous RNA (ceRNA) axis‐mediated toxic effects, relieving these neurotoxic phenotypes and cognitive dysfunction again. The CEBPA‐AS1/miR‐455‐3p/EPHA4 axis mediated sevoflurane‐induced neurotoxicity and subsequent cognitive impairment.