Sevoflurane Induces Neurotoxicity and Cognitive Impairment by Up-Regulating Long Non-Coding RNA CEBPA-AS1.
Jinpeng Fu1, Ya-Wei Yuan2, Zhen Ma3
1Department of Anesthesiology, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, China.
Journal of Biochemical and Molecular Toxicology
|June 30, 2026
Summary
Sevoflurane triggers neurotoxicity and cognitive decline by increasing CEBPA-AS1, which sponges miR-455-3p and upregulates EPHA4. Inhibiting CEBPA-AS1 or EPHA4 ameliorates these effects, revealing a key regulatory axis.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Sevoflurane is a widely used anesthetic agent.
- Neurotoxicity and cognitive impairment are potential adverse effects of sevoflurane.
- The underlying molecular mechanisms of sevoflurane-induced neurotoxicity are not fully understood.
Purpose of the Study:
- To investigate the role of long non-coding RNA CEBPA-AS1 in sevoflurane-induced neurotoxicity and cognitive impairment.
- To elucidate the molecular mechanism involving CEBPA-AS1, microRNA-455-3p (miR-455-3p), and EPHA4 in sevoflurane neurotoxicity.
- To explore potential therapeutic targets for mitigating sevoflurane-induced neurological damage.
Main Methods:
- Establishment of sevoflurane exposure models using HT22 hippocampal neuronal cells and Sprague-Dawley rats.
- Quantitative real-time polymerase chain reaction (RT-qPCR) to assess gene expression.
- Cell counting kit-8 (CCK-8) assays, flow cytometry, ELISA, and oxidative stress kits for cellular analysis.
- Morris water maze test for evaluating cognitive function in rats.
- RNA immunoprecipitation (RIP) and dual luciferase assays to confirm molecular interactions.
Main Results:
- Sevoflurane exposure significantly increased CEBPA-AS1 expression while decreasing miR-455-3p and increasing EPHA4 expression in vitro and in vivo.
- Silencing CEBPA-AS1 attenuated sevoflurane-induced neurotoxicity, apoptosis, oxidative stress, inflammation, and improved cognitive impairment.
- Mechanistic studies revealed CEBPA-AS1 acts as a molecular sponge for miR-455-3p, regulating EPHA4 expression, forming the CEBPA-AS1/miR-455-3p/EPHA4 axis.
- Rescue experiments confirmed the regulatory role of this axis in sevoflurane neurotoxicity.
Conclusions:
- The CEBPA-AS1/miR-455-3p/EPHA4 axis plays a critical role in mediating sevoflurane-induced neurotoxicity and cognitive impairment.
- CEBPA-AS1 acts as a competing endogenous RNA (ceRNA) for miR-455-3p, thereby upregulating EPHA4.
- Targeting the CEBPA-AS1/miR-455-3p/EPHA4 pathway may offer a therapeutic strategy to prevent or treat sevoflurane-induced neurological deficits.
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