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Cadmium-induced lung injury is associated with oxidative stress, apoptosis, and altered SIRT1 and Nrf2/HO-1 signaling; protective role of the melatonin agonist agomelatine

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Abstract

Cadmium (Cd) is a hazardous heavy metal extensively employed in manufacturing polyvinyl chloride, batteries, and other industries. Acute lung injury has been directly connected to Cd exposure. Agomelatine (AGM), a melatonin analog, is a drug licensed for treating severe depression. This study evaluated the effect of AGM against Cd-induced lung injury in rats. AGM was administered in a dose of 25 mg/kg/day orally, while cadmium chloride (CdCl2) was injected intraperitoneally in a dose of 1.2 mg/kg to induce lung injury. Pre-treatment with AGM remarkably ameliorated Cd-induced lung histopathological abrasions. AGM decreased reactive oxygen species (ROS) production, lipid peroxidation, suppressed NDAPH oxidase, and boosted the antioxidants. AGM increased Nrf2, GCLC, HO-1, and TNXRD1 mRNA, as well as HO-1 activity and downregulated Keap1. AGM downregulated Bax and caspase-3 and upregulated Bcl-2, SIRT1, and FOXO3 expression levels in the lung. In conclusion, AGM has a protective effect against Cd-induced lung injury via its antioxidant and anti-apoptotic effects mediated via regulating Nrf2/HO-1 and SIRT1/FOXO3 signaling.

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Acknowledgements

Princess Nourah bint Abdulrahman University Researchers Supporting Project Number (PNURSP2023R381), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

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Princess Nourah bint Abdulrahman University Researchers Supporting Project Number (PNURSP2023R381), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia.

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Authors and Affiliations

  1. Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, 11671, Saudi Arabia

    Reem S. Alruhaimi & May N. Bin-Jumah

  2. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, 71562, Egypt

    Emad H. M. Hassanein

  3. Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, M1 5GD, UK

    Ayman M. Mahmoud

  4. Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, 62514, Egypt

    Ayman M. Mahmoud

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  1. Reem S. Alruhaimi
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Contributions

Author contribution Conceptualization: A.M.M., and E.M.H.; Methodology: R.S.A., M.N.B-J., E.M.H., and A.M.M.; Data curation: R.S.A., E.M.H., and A.M.M.; Formal analysis: E.M.H., and A.M.M.; Investigation: R.S.A., E.M.H., and A.M.M.; Resources: R.S.A., M.N.B-J., E.M.H., and A.M.M.; Validation: A.M.M.; Writing—original draft preparation: R.S.A., E.M.H., and A.M.M.; writing—review and editing: A.M.M.; Funding acquisition: R.S.A. All authors have read and agreed to the final version of the manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Ayman M. Mahmoud.

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Alruhaimi, R.S., Hassanein, E.H.M., Bin-Jumah, M.N. et al. Cadmium-induced lung injury is associated with oxidative stress, apoptosis, and altered SIRT1 and Nrf2/HO-1 signaling; protective role of the melatonin agonist agomelatine. Naunyn-Schmiedeberg's Arch Pharmacol 397, 2335–2345 (2024). https://doi.org/10.1007/s00210-023-02754-5

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