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

Authors

Nayef A Aldabaan, Basel A Abdel-Wahab, Ehab A M El-Shoura, Saad Misfer Alqahtani, Marwa B Bakir, Hebatallah M Saad, Zainab Mohammed Mahmoud Omar, Dalia Zaafar

Published in

Immunopharmacology and immunotoxicology. Pages 1-15. Aug 03, 2026. Epub Aug 03, 2026.

Abstract

Ivabradine (IVA), a broad-spectrum inhibitor of HCN cation channels, is recognized for enhancing cardiac function in the treatment of cardiovascular diseases and may serve as a potential therapeutic agent for mitigating drug-induced cardiotoxicity. This study aimed to investigate the protective effect of IVA against cardiac damage induced by cisplatin (Cis) and to elucidate the underlying mechanisms.
We investigated the impact of IVA (5 mg/kg, orally for 28 consecutive days) on Cisplatin-induced cardiac injury (7.5 mg/kg intraperitoneally on day 5) in rats. Biomarkers of oxidative stress and levels of inflammatory cytokines in cardiac tissue were assessed. H&E staining was employed to identify histopathological alterations in cardiac tissue. The molecular mechanisms of IVA in ameliorating cardiac injury were examined.
The results indicated that IVA enhanced cardiac tissue structure by suppressing the pathological alterations observed in H&E staining. IVA demonstrated antioxidant and anti-inflammatory properties through reducing malonaldehyde (MDA), NADPH oxidase, tumor necrosis factor-α (TNF-α), and interleukins (IL-1β and IL-6) levels, while elevating superoxide dismutase (SOD), IL-10, and eNOS levels. IVA diminished the expression of cAMP response element-binding protein (CREB), Extracellular signal-regulated kinase (ERK), Mitogen-activated protein kinase kinase (MEK), Protein Kinase C-epsilon (PKC epsilon), and microRNA-34a (miRNA-34a), while enhancing the expression of Protein Kinase G (PKG), Myosin Light Chain Phosphatase (MLCP), and Rapidly Accelerated Fibrosarcoma (Raf-1), as confirmed by western blotting and PCR results. Furthermore, its impact on cardiac tissue viability was supported by increased B-cell lymphoma 2 (Bcl2) levels and decreased caspase-3 staining in immunohistopathology.
IVA may significantly mitigate cardiac injury in Cis-induced cardiotoxicity through regulating multiple pathways and miRNA-34a levels.

PMID:
42544451
Bibliographic data and abstract were imported from PubMed on 03 Aug 2026.

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