Estrogen Alleviates Sevoflurane‐Induced Neurotoxicity by Inhibiting ERα‐Tau Binding

Abstract Sevoflurane‐induced neurotoxicity is age‐dependent, but the role of sex differences is unclear. While testosterone has protective effects, the impact of estrogen remains unknown. This study investigates the effects of sevoflurane on neurotoxicity in adult, middle‐aged, and aged male and female mice. Neurotoxic effects are assessed through Tau phosphorylation, cognitive function, transient Ca 2 ⁺ signal amplitude, firing frequency, dendritic spine density, and dendritic axon count in the dorsal hippocampal CA1 (dCA1) region. Estrogen receptor antagonists, inhibitors, and overexpression viral vectors are used to explore estrogen receptor‐mediated actions. Protein–protein interactions are analyzed using GRAMM docking and ITC, and competitive ELISA is employed to investigate estrogen's mechanisms. Results show that sevoflurane induces neurotoxicity in middle‐aged female mice but not in males. Estrogen alleviates Tau phosphorylation, cognitive impairments, and reduces Ca 2 ⁺ signal amplitude, firing frequency, dendritic spine density, and dendritic shaft numbers in middle‐aged females. This protective effect is abolished with ERα knockout. In aged females, estrogen alone does not reverse neurotoxicity unless ERα expression is upregulated. Moreover, estrogen and Tau competitively bind to ERα, and sevoflurane exposure enhances this interaction. These findings suggest that estrogen mitigates sevoflurane‐induced neurotoxicity through modulation of the ERα‐Tau interaction.