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 Ropiinduced 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.

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