Ivabradine alleviates the cisplatin-induced cardiotoxicity in rats through regulating the crosstalk between MLCP/PKG, MEK/ERK pathways and miRNA-34a levels.

Bibliographic Details
Title:	Ivabradine alleviates the cisplatin-induced cardiotoxicity in rats through regulating the crosstalk between MLCP/PKG, MEK/ERK pathways and miRNA-34a levels.
Authors:	Aldabaan NA; Department of Pharmacology, College of Pharmacy, Najran University, Najran, Saudi Arabia., Abdel-Wahab BA; Department of Pharmacology, College of Pharmacy, Najran University, Najran, Saudi Arabia., El-Shoura EAM; Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Azhar University, Assiut, Egypt., Alqahtani SM; Department of Pathology, College of Medicine, The University Hospital, Najran University, Najran, Saudi Arabia., Bakir MB; Department of Medical Education, Faculty of Medicine, Najran University, Najran, Saudi Arabia., Saad HM; Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Marsa Matruh, Egypt., Mahmoud Omar ZM; Department of Basic Medical Sciences, College of Medicine, Prince Sattam Bin Abdulaziz University, Al-Kharj, Kingdom of Saudi Arabia.; Department of Pharmacology, Faculty of Medicine, Al- Azhar University, Assiut, Egypt., Zaafar D; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Giza, Egypt.
Source:	Immunopharmacology and immunotoxicology [Immunopharmacol Immunotoxicol] 2026 Oct; Vol. 48 (5), pp. 857-869. Date of Electronic Publication: 2026 Aug 12.
Publication Type:	Journal Article
Language:	English
Journal Info:	Publisher: Informa Healthcare Country of Publication: England NLM ID: 8800150 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-2513 (Electronic) Linking ISSN: 08923973 NLM ISO Abbreviation: Immunopharmacol Immunotoxicol Subsets: MEDLINE
Imprint Name(s):	Publication: London : Informa Healthcare Original Publication: New York, N.Y. : Marcel Dekker, c1987-
MeSH Terms:	Cisplatin/toxicity , MicroRNAs/metabolism , MicroRNAs/biosynthesis , Ivabradine/pharmacology , Ivabradine/therapeutic use , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/physiology , Cardiotoxicity/metabolism , Cardiotoxicity/prevention & control , Cyclic GMP-Dependent Protein Kinases/metabolism, Oxidative Stress/drug effects ; Animals ; Rats ; Male ; Rats, Sprague-Dawley
Abstract:	Background: Ivabradine (IVA), a broad-spectrum hyperpolarization-activated cyclic nucleotide-gated (HCN) channel inhibitor, improves cardiac function in cardiovascular diseases and may protect against drug-induced cardiotoxicity. This study investigated the cardioprotective effects of IVA against cisplatin (Cis)-induced cardiac injury and explored the underlying molecular mechanisms. Methods: Rats received IVA (5 mg/kg, orally) for 28 consecutive days and Cis (7.5 mg/kg, intraperitoneally) on day 5. Cardiac oxidative stress biomarkers, inflammatory cytokines, histopathological alterations, and molecular signaling pathways were evaluated using biochemical assays, H&E staining, western blotting, PCR, and immunohistopathology. Results: IVA markedly improved cardiac histoarchitecture and attenuated Cis-induced pathological alterations. It exerted antioxidant and anti-inflammatory effects by reducing malondialdehyde (MDA), NADPH oxidase, tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 levels, while increasing superoxide dismutase (SOD), IL-10, and endothelial nitric oxide synthase (eNOS). IVA downregulated cAMP response element-binding protein (CREB), extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase kinase (MEK), protein kinase C-epsilon (PKCε), and microRNA-34a (miRNA-34a), while upregulating protein kinase G (PKG), myosin light chain phosphatase (MLCP), and rapidly accelerated fibrosarcoma-1 (Raf-1). Furthermore, IVA enhanced cardiac cell survival, as evidenced by increased B-cell lymphoma 2 (Bcl-2) expression and reduced caspase-3 immunostaining. Conclusion: IVA significantly attenuates Cis-induced cardiotoxicity through antioxidant, anti-inflammatory, anti-apoptotic, and miRNA-34a-mediated mechanisms involving multiple cardioprotective signaling pathways.
Contributed Indexing:	Keywords: Cisplatin; Ivabradine; MEK/ERK; MLCP/PKG/PKC; cardiotoxicity; miRNA-34a
Substance Nomenclature:	Q20Q21Q62J (Cisplatin) 0 (MicroRNAs) 3H48L0LPZQ (Ivabradine) 0 (MIRN34 microRNA, rat) EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases)
Entry Date(s):	Date Created: 20260803 Date Completed: 20260915 Latest Revision: 20260915
Update Code:	20260915
DOI:	10.1080/08923973.2026.2713465
PMID:	42544451
Database:	MEDLINE

Description
ISSN:	1532-2513
DOI:	10.1080/08923973.2026.2713465