miR-497-5p augments sevoflurane-induced neurotoxicity by facilitating ubiquitination-dependent degradation of NOTCH1 via targeting SMURF2

This study aimed to explore how miR-497-5p affects sevoflurane-induced neurotoxicity and cognitive impairment in neonatal rats, examining its role in promoting neuronal survival by regulating the protein SMURF2 and its effect on NOTCH1 signaling. Neonatal rats were exposed to sevoflurane, and their learning and memory were assessed using the Morris water maze and fear conditioning tests. RNA sequencing identified a significant decrease in miR-497-5p levels. To further investigate miR-497-5p's protective role, we treated neuronal cells with miR-497-5p mimics and sevoflurane, conducting cell viability assays, LDH release assays, apoptosis analysis and Western blotting for apoptosis markers. Bioinformatics tools predicted target genes of miR-497-5p, confirming that SMURF2 was a direct target through co-immunoprecipitation and dual-luciferase reporter assays. Increasing miR-497-5p levels improved cell viability and reduced apoptosis in neuronal cultures exposed to sevoflurane. MiR-497-5p directly targeted SMURF2, reducing its levels and increasing NOTCH1 protein levels. Silencing SMURF2 preserved NOTCH1 signaling and improved cell viability, while knocking down NOTCH1 eliminated these protective effects, highlighting its importance for neuronal survival. In vivo, miR-497-5p mimic treatment significantly alleviated sevoflurane-induced cognitive deficits and neuronal damage in rats by reducing hippocampal apoptosis, promoting neuronal proliferation, and restoring SMURF2/NOTCH1 signaling.These findings demonstrate that miR-497-5p protects against sevoflurane-induced neurotoxicity by affecting SMURF2 and NOTCH1 pathways. By improving cognitive function and supporting neuronal health, miR-497-5p could be a potential therapeutic target for reducing anesthetic-related neurotoxicity, emphasizing its role in preserving cognitive and neuronal integrity during anesthetic exposure and suggesting future research directions for neuroprotective therapies.