Cadmium cardiotoxicity is associated with oxidative stress and upregulated TLR-4/NF-kB pathway in rats; protective role of agomelatine

Reem S Alruhaimi; Emad H M Hassanein; May N Bin-Jumah; Ayman M Mahmoud

doi:10.1016/j.fct.2023.114055

Cadmium cardiotoxicity is associated with oxidative stress and upregulated TLR-4/NF-kB pathway in rats; protective role of agomelatine

Food Chem Toxicol. 2023 Oct:180:114055. doi: 10.1016/j.fct.2023.114055. Epub 2023 Sep 20.

Authors

Reem S Alruhaimi¹, Emad H M Hassanein², May N Bin-Jumah¹, Ayman M Mahmoud³

Affiliations

¹ Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, 11671, Saudi Arabia.
² Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, Assiut, 71562, Egypt.
³ Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester, M1 5GD, UK; Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, 62514, Egypt. Electronic address: a.mahmoud@mmu.ac.uk.

PMID: 37739054
DOI: 10.1016/j.fct.2023.114055

Abstract

Cardiotoxicity is one of the hazardous effects of the exposure to the heavy metal cadmium (Cd). Inflammation and oxidative injury are implicated in the cardiotoxic mechanism of Cd. The melatonin receptor agonist agomelatine (AGM) showed promising effects against oxidative and inflammatory responses. This study evaluated the effect of AGM on Cd-induced cardiotoxicity in rats, pointing to its modulatory effect on TLR-4/NF-kB pathway and HSP70. Rats received AGM for 14 days and a single dose of Cd on day 7 and blood and heart samples were collected for analyses. Cd increased serum CK-MB, AST and LDH and caused cardiac tissue injury. Cardiac malondialdehyde (MDA), nitric oxide (NO) and MPO were elevated and GSH, SOD and GST decreased in Cd-administered rats. AGM ameliorated serum CK-MB, AST and LDH and cardiac MDA, NO and MPO, prevented tissue injury and enhanced antioxidants. AGM downregulated serum CRP and cardiac TLR-4, NF-kB, iNOS, IL-6, TNF-α and COX-2 in Cd-administered rats. HSP70 was upregulated in the heart of Cd-challenged rats treated with AGM. In silico findings revealed the binding affinity of AGM with TLR-4 and NF-kB. In conclusion, AGM protected against Cd cardiotoxicity by preventing myocardial injury and oxidative stress and modulating HSP70 and TLR-4/NF-kB pathway.

Keywords: Cardiotoxicity; Heavy metals; Inflammation; Melatonergic receptor agonists; Oxidative stress.