TUDCA protects against tunicamycin-induced apoptosis of dorsal root ganglion neurons by suppressing activation of ER stress

Fangyi Chen; Zhe Ge; Nan Li; Zuochong Yu; Rongbo Wu; Yan Zhao; Xianwei He; Guoping Cai

doi:10.3892/etm.2022.11436

TUDCA protects against tunicamycin-induced apoptosis of dorsal root ganglion neurons by suppressing activation of ER stress

Exp Ther Med. 2022 Jun 10;24(2):509. doi: 10.3892/etm.2022.11436. eCollection 2022 Aug.

Authors

Fangyi Chen¹, Zhe Ge¹, Nan Li², Zuochong Yu¹, Rongbo Wu¹, Yan Zhao³, Xianwei He¹, Guoping Cai¹

Affiliations

¹ Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai 201508, P.R. China.
² Department of Stomatology, Jinshan Hospital, Fudan University, Shanghai 201508, P.R. China.
³ Department of Clinical Laboratory, Jinshan Hospital, Fudan University, Shanghai 201508, P.R. China.

Abstract

The existence of endoplasmic reticulum (ER) stress in neurodegenerative diseases has been well established. Tauroursodeoxycholic acid (TUDCA) is a bile acid taurine conjugate derived from ursodeoxycholic acid, which has been reported to exert cytoprotective effects on several types of cells by inhibiting ER stress. The present study explored the effects of TUDCA on primary cultured rat dorsal root ganglion (DRG) neurons. Cell viability and apoptosis of DRG neurons treated with TUDCA and tunicamycin were detected by CellTiter-Blue assay and TUNEL staining, respectively. The protein levels and phosphorylation of apoptosis and ERS-related signaling pathway molecules were detected by western blot, and the mRNA levels of related genes were assessed by reverse transcription-quantitative PCR. Notably, TUDCA had no significant cytotoxic effect on DRG neurons at concentrations ≤250 µM. In addition, the apoptosis induced by tunicamycin exposure was markedly suppressed by TUDCA, as indicated by the percentage of TUNEL-positive cells, the activities of caspases and the changes in expression levels of critical apoptosis factors. Furthermore, the cytotoxicity of tunicamycin in DRG neurons was accompanied by an increase in malondialdehyde (MDA) content, reactive oxygen species (ROS) and lactate dehydrogenase (LDH) production, and a decrease in glutathione (GSH) levels. The changes in oxidative stress-related factors (ROS, LDH, MDA and GSH) were reversed by TUDCA. Furthermore, as determined by western blotting, the increase in C/EBP homologous protein, glucose-regulated protein 78 and cleaved caspase-12 expression following tunicamycin treatment suggested the activation of ER stress. Downregulation of ER stress components and unfolded protein response sensors by TUDCA confirmed the implication of ER stress in the effects of TUDCA on DRG neurons. In conclusion, the present study indicated that TUDCA may protect against tunicamycin-induced DRG apoptosis by suppressing the activation of ER stress. The protective effect and the therapeutic value of TUDCA in nervous system injury require further study in animal models.

Keywords: apoptosis; dorsal root ganglia; endoplasmic reticulum stress; tauroursodeoxycholic acid; tunicamycin.

Grants and funding

Funding: This study was supported by the Youth Project of Shanghai Municipal Health and Family Planning Commission (grant no. 2018Y0141).