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The role of ferroptosis in chronic intermittent hypoxia-induced cognitive impairment

  • Sleep Breathing Physiology and Disorders • Original Article
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Abstract

Purpose

Obstructive sleep apnea (OSA) is a sleep disorder that may lead to cognitive impairment. The primary pathophysiological feature of OSA is chronic intermittent hypoxia (CIH), but the underlying mechanisms of CIH are not known. There have been few studies on the role of ferroptosis, a novel form of programmed cell death, during CIH-induced cognitive impairment. Therefore, this paper examined ferroptosis’ effect on CIH-mediated cognitive impairment.

Methods

The study randomized twenty-four Sprague–Dawley (SD) male rats to control or CIH group. CIH rats were subjected to intermittent hypoxia for 4 weeks. Rat learning and memory were analyzed by the Morris water maze (MWM) test. Alterations of hippocampal neuronal ultrastructure were observed by transmission electron microscopy (TEM). Malondialdehyde (MDA) and ferrous iron (Fe2+) levels and superoxide dismutase (SOD) and reduced glutathione (GSH) contents were determined. Ferroptosis-associated protein levels were examined by Western blotting.

Results

The MWM test indicated that rats in the CIH group exhibited neurocognitive impairment. TEM showed that CIH induced mitochondrial damage. Significant increases in Fe2+ and MDA levels were observed in the CIH group, and GSH and SOD levels were decreased. Expression of Acyl-CoA synthetase long-chain family member 4 (ACSL4) increased, and glutathione peroxidase 4 (GPX4) protein levels were decreased, suggesting that ferroptosis was induced in CIH model rats. The NF-E2-related factor 2 (Nrf2) protein level in the CIH group was decreased.

Conclusion

Ferroptosis had an essential effect on CIH-mediated cognitive impairment, and it may occur via Nrf2 dysregulation. These findings lay a solid foundation for the subsequent study of OSA-associated cognitive impairment offering potential evidence for the development of therapeutic strategies.

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Data availability

Data utilized and/or analyzed in this work can be obtained from corresponding author upon request.

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Authors and Affiliations

  1. The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Zhi-li Liu, Yin-pei Huang, Xin Wang, Yu-xin He, Juan Li & Bing Li

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  1. Zhi-li Liu
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  2. Yin-pei Huang
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  3. Xin Wang
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Correspondence to Juan Li or Bing Li.

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Liu, Zl., Huang, Yp., Wang, X. et al. The role of ferroptosis in chronic intermittent hypoxia-induced cognitive impairment. Sleep Breath 27, 1725–1732 (2023). https://doi.org/10.1007/s11325-022-02760-6

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  • DOI: https://doi.org/10.1007/s11325-022-02760-6

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