Bupivacaine Induces ROS-Dependent Autophagic Damage in DRG Neurons via TUG1/mTOR in a High-Glucose Environment

Neurotox Res. 2022 Feb;40(1):111-126. doi: 10.1007/s12640-021-00461-8. Epub 2022 Jan 18.

Abstract

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.

Keywords: Autophagy; Bupivacaine; High glucose; ROS; TUG1; mTOR.

MeSH terms

  • Animals
  • Apoptosis
  • Autophagy
  • Bupivacaine* / toxicity
  • Ganglia, Spinal* / metabolism
  • Glucose / metabolism
  • Humans
  • Mammals / metabolism
  • Mice
  • Neurons / metabolism
  • Reactive Oxygen Species / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • Taurine / metabolism

Substances

  • Reactive Oxygen Species
  • Taurine
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Glucose
  • Bupivacaine