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

Area of Science:

• Neuroscience
• Anesthesiology
• Endocrinology

Background:

• Sevoflurane neurotoxicity is age-dependent, with sex differences and estrogen's role being unclear.
• Existing research highlights testosterone's protective effects, but estrogen's impact on anesthetic-induced neurotoxicity requires investigation.

Purpose of the Study:

• To investigate the sex-specific effects of sevoflurane on neurotoxicity across different age groups in mice.
• To elucidate the role of estrogen and its receptor alpha (ERα) in mitigating sevoflurane-induced neurotoxicity.

Main Methods:

• Assessment of neurotoxicity markers including Tau phosphorylation, cognitive function, and neuronal structural integrity in the dorsal hippocampal CA1 region.
• Utilized estrogen receptor antagonists, inhibitors, viral vectors for overexpression, ERα knockout models, GRAMM docking, ITC, and competitive ELISA to explore mechanisms.

Main Results:

• Sevoflurane induced neurotoxicity in middle-aged female mice, but not males. Estrogen administration ameliorated Tau phosphorylation, cognitive deficits, and neuronal signaling/structural changes in these females.
• The protective effects of estrogen were dependent on ERα, as demonstrated by the abolition of benefits in ERα knockout mice.
• In aged females, estrogen's protective effect was contingent upon ERα upregulation, and estrogen and Tau were found to competitively bind to ERα, an interaction enhanced by sevoflurane.

Conclusions:

• Estrogen exerts a protective effect against sevoflurane-induced neurotoxicity in a sex- and age-dependent manner.
• The findings indicate that estrogen mitigates sevoflurane neurotoxicity primarily through the modulation of the ERα-Tau interaction, offering a potential therapeutic target.