Research Paper Volume 12, Issue 13 pp 13463—13476

Mechanistic study of mtROS-JNK-SOD2 signaling in bupivacaine-induced neuron oxidative stress

Zhongjie Liu1, , Shiyuan Xu1, , Zhonghua Ji2, , Huali Xu1, , Wei Zhao1, , Zhengyuan Xia3, , Rui Xu1, ,

  • 1 Department of Anesthesiology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
  • 2 Department of Anesthesiology, Affiliated Zhuhai Hospital of Jinan University, Zhuhai, Guangdong Province, China
  • 3 Department of Anesthesiology, University of Hong Kong, Pokfulam, Hong Kong, China

Received: March 3, 2020       Accepted: May 23, 2020       Published: July 13, 2020
How to Cite

Copyright © 2020 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Manganese superoxide dismutase (SOD2) is a key enzyme to scavenge free radical superoxide in the mitochondrion. SOD2 deficiency leads to oxidative injury in cells. Bupivacaine, a local anesthetic commonly used in clinic, could induce neurotoxic injury via oxidative stress. The role and the mechanism of SOD2 regulation in bupivacaine-induced oxidative stress remains unclear. Here, bupivacaine was used to treat Sprague-Dawley rats with intrathecal injection and culture human neuroblastoma cells for developing vivo injury model and vitro injury model. The results showed that bupivacaine caused the over-production of mitochondrial reactive oxygen species (mtROS), the activation of C-Jun N-terminal kinase (JNK), and the elevation of SOD2 transcription. Decrease of mtROS with N-acetyl-L-cysteine attenuated the activation of JNK and the increase of SOD2 transcription. Inhibition of JNK signaling with a small interfering RNA (siRNA) or with sp600125 down-regulated the increase of SOD2 transcription. SOD2 gene knock-down exacerbated bupivacaine-induced mtROS generation and neurotoxic injury but had no effect on JNK phosphorylation. Mito-TEMPO (a mitochondria-targeted antioxidant) could protect neuron against bupivacaine-induced toxic injury. Collectively, our results confirm that mtROS stimulates the transcription of SOD2 via activating JNK signaling in bupivacaine-induced oxidative stress. Enhancing antioxidant ability of SOD2 might be crucial in combating bupivacaine-induced neurotoxic injury.


SOD2: manganese superoxide dismutase; mtROS: mitochondrial reactive oxygen species; JNK: c-Jun nterminal kinase; siRNA: Small interfering RNA; BPV: bupivacaine; NAC: N-acetyl-L-cysteine; LDH: lactate dehydrogenase; MDA: malondialdehyde; 8-OHdG: 8-hydroxydeoxyguanosine; PBS: phosphate buffer saline; PWT: paw withdrawal threshold; TWL: thermal withdrawal latency.