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Etomidate Improves the Antidepressant Effect of Electroconvulsive Therapy by Suppressing Hippocampal Neuronal Ferroptosis via Upregulating BDNF/Nrf2

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Abstract

Electroconvulsive therapy (ECT) performed under general anesthesia is an effective treatment for severe depression. Etomidate is an intravenous anesthetic that shows beneficial effects on ECT. However, the potential mechanisms have rarely been reported. In this study, male rats were exposed to chronic unpredictable mild stress for 4 weeks, followed by ECT for 10 days, with or without intervention with ferrostatin-1 (2 mg/kg) or all-trans retinoic acid (ATRA, 5 mg/kg). Rats subjected to etomidate (20 mg/kg) or propofol (120 mg/kg) treatment were administered with designated anesthetic before ECT. Compared to depressive rats without ECT, those who received ECT showed increased numbers of hippocampal neurons, increased expression of negative regulators of ferroptosis including glutathione peroxidase 4, ferritin heavy chain 1, and ferroptosis suppressor protein 1, upregulation of brain-derived neurotrophic factor and nuclear factor erythroid 2-related factor, and downregulation of acyl-CoA synthetase long-chain family member 4, a positive regulator of ferroptosis in the hippocampus. Additionally, compared with propofol, etomidate used in ECT resulted in higher upregulation of BDNF/Nrf2 and inhibited neuronal ferroptosis in hippocampus. These results showed etomidate may enhance the antidepressant effect of ECT by protecting hippocampal neurons against ferroptosis.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors thank all of the patients who kindly participated in this study.

Funding

This study was supported partly by the National Natural Science Foundation of China (Grant No. 82102297), Natural Science Foundation of Guangdong Province (Grant No. 2018A0303130224, 2022A1515012603), and Young Talent Support Project of Guangzhou Association for Science and Technology (Grant No. QT20220101257).

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  1. Xiaoyue Li, Jingping Hu, and Xiangyang Zang contributed equally to the work.

Authors and Affiliations

  1. Department of Anesthesiology, The Third Affiliated Hospital of Sun Yat-Sen University, No. 600 Tianhe Road, Guangzhou, Guangdong Province, 510630, People’s Republic of China

    Xiaoyue Li, Jingping Hu, Xiangyang Zang, Jibin Xing, Xingying Mo, Ziqing Hei, Chulian Gong, Chaojin Chen & Shaoli Zhou

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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Xiaoyue Li, Jingping Hu, and Xiangyang Zang. The first draft of the manuscript was written by Xiaoyue Li, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Chulian Gong, Chaojin Chen or Shaoli Zhou.

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This study was approved by the Institutional Animal Care and Use Committee of Ruige Biotechnology (China).

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Li, X., Hu, J., Zang, X. et al. Etomidate Improves the Antidepressant Effect of Electroconvulsive Therapy by Suppressing Hippocampal Neuronal Ferroptosis via Upregulating BDNF/Nrf2. Mol Neurobiol 60, 6584–6597 (2023). https://doi.org/10.1007/s12035-023-03499-1

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