Bupivacaine Induces ROS-Dependent Autophagic Damage in DRG Neurons via TUG1/mTOR in a High-Glucose Environment
Bupivacaine Induces ROS-Dependent Autophagic Damage in DRG Neurons via TUG1/mTOR in a High-Glucose Environment
复制标题
布比卡因在高葡萄糖环境中通过 TUG1/mTOR 诱导 DRG 神经元中 ROS 依赖性自噬损伤
DOI：
10.1007/s12640-021-00461-8
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发表时间：
2022-01-18
影响因子：
3.7
通讯作者：
Xu, Shiyuan
中科院分区：
文献类型：
--
作者：
Lai, Luying;Wang, Yongwei;Xu, Shiyuan
布比卡因（BP）是临床上常用的局部麻醉剂（LA）。目前的研究表明糖尿病患者应用LA后神经系统并发症增加，但其分子机制尚不清楚。 LA 诱导的自噬和神经元损伤已有报道。我们假设高血糖环境会加剧 BP 诱导的自噬损伤。在高糖环境下用BP处理小鼠背根神经节（DRG）神经元，结果显示活性氧（ROS）水平升高，自噬被激活，自噬通量受阻，细胞活力下降。 ROS 清除剂 N-乙酰半胱氨酸 (NAC) 预处理减弱了 ROS 介导的自噬调节。此外，在高糖环境下经BP处理的DRG中，长非编码RNA（lncRNA）牛磺酸上调基因1（TUG1）的表达增加，NAC和TUG1 siRNA抑制TUG1/哺乳动物雷帕霉素靶点（mTOR）的表达。有趣的是，与之前关于对神经元产生积极影响的报道相反，我们发现雷帕霉素（一种自噬激活剂）和氯喹（一种自噬和溶酶体抑制剂）都会加剧自噬损伤。这些数据表明，高糖环境通过TUG1/mTOR信号通路加剧BP诱导DRG神经元ROS依赖性自噬损伤，这为临床防治糖尿病BP神经毒性提供了理论依据和靶点。
Bupivacaine (BP) is a commonly clinically used local anesthetic (LA). Current studies suggest that neurological complications are increased in diabetic patients after LA application, but the molecular mechanism is poorly understood. LA-induced autophagy and neuronal injury have been reported. We hypothesized that a high-glucose environment aggravates BP-induced autophagic damage. Mouse dorsal root ganglion (DRG) neurons were treated with BP in a high-glucose environment, and the results showed that reactive oxygen species (ROS) levels increased, autophagy was activated, autophagy flux was blocked, and cell viability decreased. Pretreatment with the ROS scavenger N-acetyl-cysteine (NAC) attenuated ROS-mediated autophagy regulation. Moreover, the expression of the long noncoding RNA (lncRNA) taurine upregulated gene 1 (TUG1) increased, and NAC and TUG1 siRNA inhibited the expression of TUG1/mammalian target of rapamycin (mTOR) in DRGs treated with BP in a high-glucose environment. Intriguingly, contrary to previous reports on a positive effect on neurons, we found that rapamycin, an autophagy activator, and chloroquine, an autophagy and lysosome inhibitor, both exacerbated autophagic damage. These data suggest that a high-glucose environment exacerbated BP induced ROS-dependent autophagic damage in DRG neurons through the TUG1/mTOR signaling pathway, which provides a theoretical basis and target for the clinical prevention and treatment of BP neurotoxicity in diabeties.