PUBLICATION
The Role of Atp2a2-Mediated Calcium Imbalance and Endoplasmic Reticulum Stress in Hydrocortisone-Induced Neurotoxicity
- Authors
- Kong, W., Jiang, P., Miao, X., Sang, B., Hu, S., Feng, L.
- ID
- ZDB-PUB-250920-13
- Date
- 2025
- Source
- Cell stress & chaperones : 100112 (Journal)
- Registered Authors
- Keywords
- Zebrafish Glucocorticoids Neurotoxicity Endoplasmic reticulum stress Mitochondrial dysfunction Calcium homeostasis
- MeSH Terms
-
- Animals
- Apoptosis/drug effects
- Calcium*/metabolism
- Endoplasmic Reticulum Stress*/drug effects
- Homeostasis/drug effects
- Hydrocortisone*/toxicity
- Membrane Potential, Mitochondrial/drug effects
- Mitochondria/drug effects
- Mitochondria/metabolism
- Neurons/drug effects
- Neurons/metabolism
- Neurotoxicity Syndromes*/metabolism
- Reactive Oxygen Species/metabolism
- Sarcoplasmic Reticulum Calcium-Transporting ATPases*/genetics
- Sarcoplasmic Reticulum Calcium-Transporting ATPases*/metabolism
- Zebrafish/metabolism
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- PubMed
- 40972936 Full text @ Cell Stress Chaperones
Citation
Kong, W., Jiang, P., Miao, X., Sang, B., Hu, S., Feng, L. (2025) The Role of Atp2a2-Mediated Calcium Imbalance and Endoplasmic Reticulum Stress in Hydrocortisone-Induced Neurotoxicity. Cell stress & chaperones. :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 Hydrocortisone disrupted calcium homeostasis by downregulating Atp2a2, activates endoplasmic reticulum stress, and triggers 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping