Dexmedetomidine protects against Ropivacaine-induced neuronal pyroptosis via the Nrf2/HO-1 pathway.

Abstract

Dexmedetomidine (DEX) has been demonstrated to protect against ropivacaine (Ropi)-induced neuronal damages. This study was conducted to explore the protective role of DEX in Ropi-induced neuronal pyroptosis and provide a strategy to eliminate Ropi-induced neurotoxicity. The impacts of different concentrations of Ropi and DEX on neurotoxicity in SK-N-SH cells were evaluated by cell counting kit-8 assay and lactic dehydrogenase assay kits. Levels of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), NLR family pyrin domain containing 3 (NLRP3), cleaved Caspase-1, cleaved N-terminal gasdermin D, interleukin (IL)-1β, and IL-18 were measured by real-time quantitative PCR, Western blotting, and enzyme linked immunosorbent assay. The Nrf2 level after nuclear/cytoplasmic separation was quantified. SK-N-SH cells were treated with si-Nrf2, Nigericin (NLRP3 activator), and Zinc Protoporphyrin (HO-1 inhibitor) to validate the mechanism. Ropi reduced SK-N-SH cell viability in a concentration- and time-dependent manner. DEX treatment alleviated Ropi-induced toxicity and inhibited pyroptosis. Ropi increased the expression levels of Nrf2 and HO-1, and DEX further enhanced the increases and promoted Nrf2 nuclear translocation. Nrf2/HO-1 inhibition or NLRP3 activation both neutralized the inhibitory role of DEX in Ropi-induced pyroptosis of SK-N-SH cells. Overall, DEX promoted the Nrf2/HO-1 pathway to inhibit NLRP3 expression, thus alleviating Ropi-induced neuronal pyroptosis.