The melatonin receptor agonist agomelatine protects against acute pancreatitis induced by cadmium by attenuating inflammation and oxidative stress and modulating Nrf2/HO-1 pathway

Reem S Alruhaimi; Emad H M Hassanein; Mostafa K Abd El-Aziz; Maisa Siddiq Abduh; Albandari Bin-Ammar; Emadeldin M Kamel; Ayman M Mahmoud

doi:10.1016/j.intimp.2023.110833

The melatonin receptor agonist agomelatine protects against acute pancreatitis induced by cadmium by attenuating inflammation and oxidative stress and modulating Nrf2/HO-1 pathway

Int Immunopharmacol. 2023 Nov;124(Pt A):110833. doi: 10.1016/j.intimp.2023.110833. Epub 2023 Aug 25.

Authors

Reem S Alruhaimi¹, Emad H M Hassanein², Mostafa K Abd El-Aziz³, Maisa Siddiq Abduh⁴, Albandari Bin-Ammar⁵, Emadeldin M Kamel⁶, Ayman M Mahmoud⁷

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 Faculty of Pharmacy, Al-Azhar University, Assiut 71562, Egypt.
⁴ Immune Responses in Different Diseases Research Group, Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 22252, Saudi Arabia.
⁵ Department of Clinical Nutrition, College of Applied Medical Sciences, University of Hail, Saudi Arabia.
⁶ Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt.
⁷ 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: 37634447
DOI: 10.1016/j.intimp.2023.110833

Abstract

Pancreatitis is a serious effect of the heavy metal cadmium (Cd) and inflammation and oxidative stress (OS) are implicated in Cd-induced pancreatic injury. This study evaluated the effect of the melatonin receptor agonist agomelatine (AGM) on Cd-induced acute pancreatitis (AP), pointing to its modulatory effect on inflammation, OS, and Nrf2/HO-1 pathway. Rats were supplemented with AGM orally for 14 days and a single injection of cadmium chloride (CdCl₂) on day 7. Cd increased serum amylase and lipase and caused pancreatic endocrine and exocrine tissue injury. Malondialdehyde (MDA), nitric oxide (NO) and myeloperoxidase (MPO) were elevated, nuclear factor (NF)-kB p65, inducible NO synthase (iNOS), interleukin (IL)-6, tumor necrosis factor (TNF)-α and CD40 were upregulated, and antioxidants were decreased in the pancreas of Cd-administered rats. AGM ameliorated serum amylase and lipase and pancreatic OS, NF-kB p65, CD40, pro-inflammatory mediators and caspase-3, prevented tissue injury and enhanced antioxidants. AGM downregulated Keap1 and enhanced Nrf2 and HO-1 in the pancreas of Cd-administered rats. In silico findings revealed the binding affinity of AGM with Keap1, HO-1, CD40L and caspase-3. In conclusion, AGM protected against AP induced by Cd by preventing inflammation, OS and apoptosis and modulating Nrf2/HO-1 pathway.

Keywords: Heavy metals; Inflammation; Oxidative stress; Pancreatitis.