The protective role of dexmedetomidine against anaesthetics-induced neurotoxicity through downregulating miR-34a.

Abstract

This study aimed to unravel the underlying mechanism of dexmedetomidine (Dex) in mitigating anesthesia-induced neurotoxicity secondary to sevoflurane (Sev) exposure. Human Neuroblastoma Cells (SK-N-SH) were assessed for cytotoxicity by quantifying cell viability via CCK-8 assay, lactate dehydrogenase (LDH) release using an LDH kit, inflammatory cytokines factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) levels via ELISA kits, reactive oxygen species (ROS) production with an ROS assay kit, and apoptosis by flow cytometry, respectively. Cellular expression of miR-34a and SIRT1 was measured using RT-qPCR. Dual-luciferase assays mechanistically validated the functional binding of miR-34a to the SIRT1 3’UTR. Sev concentration-dependently reduced cell viability and promoted LDH release, ROS production, cytokines generation, and apoptosis, whereas Dex attenuated Sev-induced neurotoxicity. Sev significantly elevates cellular expression levels of miR-34a, which subsequently binds to and functionally suppresses SIRT1 through post-transcriptional regulatory mechanisms. Dex reduced Sev-induced miR-34a upregulation and increased SIRT1 expression, thereby enhancing SK-N-SH cell viability while decreasing LDH release, ROS production, cytokine generation, and apoptosis. These findings indicated that Dex attenuated Sev-induced neurotoxicity by downregulating miR-34a expression to subsequently upregulate SIRT1 levels.