Lidocaine, a typical local anesthetic, has been shown to directly induce neurotoxicity in clinical settings. Dexmedetomidine (DEX) is an alpha-2-adrenoreceptor agonist that has been used as anxiolytic, sedative, and analgesic agent which has recently found to protect against lidocaine-induced neurotoxicity. Nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-1 (SIRT1)/forkhead box O3 (FOXO3a) signaling is critical for maintaining neuronal function and regulation of the apoptotic pathway. In the present study, we designed in vitro and in vivo models to investigate the potential effects of lidocaine and DEX on SIRT1 and FOXO3a and to verify whether SIRT1/FOXO3a-mediated regulation of apoptosis is involved in DEX-induced neuroprotective effects against lidocaine. We found that in both PC12 cells and brains of mice, lidocaine decreased SIRT1 level through promoting the degradation of SIRT1 protein. Lidocaine also increased FOXO3a protein level and increased the acetylation of SIRT1 through inhibiting SIRT1. Upregulation of SIRT1 or downregulation of FOXO3a significantly inhibited lidocaine-induced changes in both cell viability and apoptosis. DEX significantly inhibited the lidocaine-induced decrease of SIRT1 protein level and increase of FOXO3a protein level and acetylation of FOXO3a. Downregulation of SIRT1 or upregulation of FOXO3a suppressed DEX-induced neuroprotective effects against lidocaine. The data suggest that SIRT1/FOXO3a is a potential novel target for alleviating lidocaine-induced neurotoxicity and provide more theoretical support for the use of DEX as an effective adjunct to alleviate chronic neurotoxicity induced by lidocaine.

利多卡因是一种典型的局部麻醉药，已被证明可在临床环境中直接诱导神经毒性。右美托咪定（DEX）是一种α-2-肾上腺素受体激动剂，已被用作抗焦虑药，镇静药和镇痛药，最近发现它可以防止利多卡因引起的神经毒性。烟酰胺腺嘌呤二核苷酸依赖性脱乙酰基酶Sirtuin-1（SIRT1）/叉头盒O3（FOXO3a）信号对于维持神经元功能和调节细胞凋亡通路至关重要。在本研究中，我们设计了体外和体内模型，以研究利多卡因和DEX对SIRT1和FOXO3a的潜在影响，并验证SIRT1 / FOXO3a介导的凋亡调控是否与DEX诱导的针对利多卡因的神经保护作用有关。我们发现在PC12细胞和小鼠的大脑中，利多卡因通过促进SIRT1蛋白降解来降低SIRT1水平。利多卡因还可以通过抑制SIRT1而增加FOXO3a蛋白的水平，并提高SIRT1的乙酰化程度。SIRT1的上调或FOXO3a的下调显着抑制利多卡因诱导的细胞活力和凋亡的变化。DEX显着抑制利多卡因诱导的SIRT1蛋白水平的降低和FOXO3a蛋白水平的提高以及FOXO3a的乙酰化。SIRT1的下调或FOXO3a的上调抑制了DEX诱导的针对利多卡因的神经保护作用。数据表明，SIRT1 / FOXO3a是减轻利多卡因引起的神经毒性的潜在新靶标，并为使用DEX作为减轻利多卡因引起的慢性神经毒性的有效辅助手段提供了更多的理论支持。