Neural Regeneration Research ›› 2025, Vol. 20 ›› Issue (5): 1455-1466.doi: 10.4103/NRR.NRR-D-23-00794

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Endoplasmic reticulum stress and autophagy in cerebral ischemia/reperfusion injury: PERK as a potential target for intervention

Ju Zheng1, 2, # , Yixin Li 3, # , Ting Zhang1 , Yanlin Fu1 , Peiyan Long1 , Xiao Gao1 , Zhengwei Wang1 , Zhizhong Guan1 , Xiaolan Qi 1, 4 , Wei Hong1, 4, * , Yan Xiao1, 4, *   

  1. 1 Key Laboratory of Endemic and Ethnic Diseases, Ministry of Educatton & Key Laboratory of Medical Molecular Biology of Guizhou Province, Guizhou Medical University, Guiyang, Guizhou Province, China;  2 Guizhou Center for Disease Control and Preventton, Guiyang, Guizhou Province, China;  3 Department of Histology and Embryology, Guizhou Medical University, Guiyang, Guizhou Province, China;  4 Collaborattve Innovatton Center for Preventton and Control of Endemic and Ethnic Regional Diseases Co-constructed by the Province and Ministry, Guiyang, Guizhou Province, China
  • Online:2025-05-15 Published:2024-10-31
  • Contact: Yan Xiao, PhD, xiaoyanhonan@hotmail.com; Wei Hong, PhD, hongwei@gmc.edu.cn.
  • Supported by:
    This work was supported by the Nattonal Natural Science Foundatton of China, Nos. 82260245 (to YX), 81660207 (to YX), 81960253 (to YL), 82160268 (to YL), U1812403 (to ZG); Science and Technology Projects of Guizhou Province, Nos. [2019]1440 (to YX), [2020]1Z067 (to WH); Culttvatton Foundatton of Guizhou Medical University, No. [20NSP069] (to YX); Excellent Young Talents Plan of Guizhou Medical University, No. (2022)101 (to WH).

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Abstract:

Several studies have shown that activation of unfolded protein response and endoplasmic reticulum (ER) stress plays a crucial role in severe cerebral ischemia/reperfusion injury. Autophagy occurs within hours after cerebral ischemia, but the relationship between ER stress and autophagy remains unclear. In this study, we established experimental models using oxygen-glucose deprivation/reoxygenation in PC12 cells and primary neurons to simulate cerebral ischemia/reperfusion injury. We found that prolongation of oxygen-glucose deprivation activated the ER stress pathway protein kinase-like endoplasmic reticulum kinase (PERK)/eukaryotic translation initiation factor 2 subunit alpha (eIF2α)-activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP), increased neuronal apoptosis, and induced autophagy. Furthermore, inhibition of ER stress using inhibitors or by siRNA knockdown of the PERK gene significantly attenuated excessive autophagy and neuronal apoptosis, indicating an interaction between autophagy and ER stress and suggesting PERK as an essential target for regulating autophagy. Blocking autophagy with chloroquine exacerbated ER stress-induced apoptosis, indicating that normal levels of autophagy play a protective role in neuronal injury following cerebral ischemia/reperfusion injury. Findings from this study indicate that cerebral ischemia/ reperfusion injury can trigger neuronal ER stress and promote autophagy, and suggest that PERK is a possible target for inhibiting excessive autophagy in cerebral ischemia/reperfusion injury. 

Key words:

apoptosis, ATF4, autophagy, C/EBP homologous protein, cerebral ischemia/reperfusion injury, eIF2α, endoplasmic reticulum stress,  PERK