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  3. The role of Atp2a2-mediated calcium imbalance and endoplasmic reticulum stress in hydrocortisone-induced neurotoxicity

The role of Atp2a2-mediated calcium imbalance and endoplasmic reticulum stress in hydrocortisone-induced neurotoxicity

  • Cell Stress Chaperones. 2025 Sep 17;30(6):100112. doi: 10.1016/j.cstres.2025.100112.
Weihua Kong 1,  Pei Jiang 2,  Xinglu Miao 3,  Ben Sang 3,  Shunxin Hu 3,  Lei Feng 4
Affiliations

Affiliations

  • 1 Institute of Central Nervous Vascular Injury and Repair, Jining Academy of Medical Sciences, Jining, China; Jining Key Laboratory of Stroke and Neural Repair, Jining, China.
  • 2 Translational Pharmaceutical Laboratory, Jining First People's Hospital, Jining, Shandong, China.
  • 3 Department of Neurosurgery, Jining First People's Hospital, Jining, Shandong, China.
  • 4 Institute of Central Nervous Vascular Injury and Repair, Jining Academy of Medical Sciences, Jining, China; Department of Neurosurgery, Jining First People's Hospital, Jining, Shandong, China. Electronic address: flneuro@163.com.
PMID: 40972936 DOI: 10.1016/j.cstres.2025.100112
Abstract

Glucocorticoids (GCs), as commonly used anti-inflammatory and immunosuppressive drugs, may induce neurotoxicity with long-term use, although the specific mechanisms remain unclear. This study utilized zebrafish as a model to investigate the mechanisms and potential intervention targets of hydrocortisone (HC)-induced neurotoxicity. Transcriptome analysis revealed that HC exposure significantly downregulated the expression of Atp2a2 (encoding the endoplasmic reticulum calcium pump SERCA2). Functional experiments confirmed that HC disrupts cellular calcium homeostasis: endoplasmic reticulum Ca²⁺ levels decreased, mitochondrial Ca²⁺ accumulation occurred, accompanied by mitochondrial membrane potential depolarization, increased Reactive Oxygen Species (ROS) generation, and cell Apoptosis. Additionally, fluorescent signals in brain and spinal cord neurons were weakened, and significant decreases in movement distance, time, and average speed were observed. Intervention experiments with the GR antagonist RU486 and the SERCA2 activator demonstrated that both could partially restore calcium homeostasis, reduce ROS and Apoptosis, and improve motor behavior. The findings revealed that HC disrupted calcium homeostasis by downregulating Atp2a2, activating endoplasmic reticulum stress, and triggering mitochondrial dysfunction, ultimately leading to neuronal damage and behavioral abnormalities. SERCA2 may serve as a potential target for alleviating GC-associated neurotoxicity, and this study provides experimental evidence for elucidating its mechanisms.

Keywords

Calcium homeostasis; Endoplasmic reticulum stress; Glucocorticoids; Mitochondrial dysfunction; Neurotoxicity; Zebrafish.

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