Abstract
Oxidative stress and inflammation have been linked to doxorubicin (DOX)-induced cardiotoxicity, while the exact molecular processes are currently under investigation. The goal of this study is to investigate Metformin's preventive role in cardiotoxicity induced by DOX.
Male albino mice were divided randomly into 4 groups. Metformin (Met) 200 mg/kg orally (p.o.) was given either alone or when combined with a single DOX (15 mg/kg; i.p.). A control group of 5 mice was also provided. Met was initiated 7 days before DOX, lasting for 14 days. Besides, docking studies of Met towards HMGB1, NF-kB, and caspase 3 were performed.
Heart weight, cardiac troponin T (cTnT), creatine kinase Myocardial Band (CK-MB) levels, malondialdehyde (MDA), and nitric oxide (NO) contents all increased significantly when comparing the DOX group to the control normal group. Conversely, there was a substantial decline in superoxide dismutase (SOD) and glutathione peroxidase (GSH). DOX group depicts a high expression of TLR4, HMGB1, and caspase 3. Immunohistochemical staining revealed an increase in NLRP3 inflammasome and NF-κB expressions alongside histopathological modifications. Additionally, Met dramatically decreased cardiac weight, CK-MB, and cTnT while maintaining the tissues' histological integrity. Inflammatory biomarkers, including HMGB1, TLR4, NF-κB, inflammasome, and caspase 3 were reduced after Met therapy. Furthermore, molecular docking studies suggested the antagonistic activity of Met towards HMGB1, NF-κB, and caspase 3 target receptors.
According to recent evidence, Met is a desirable strategy for improving cardiac toxicity produced by DOX by inhibiting the HMGB1/NF-κB inflammatory pathway, thus preserving heart function.
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•To emphasize the localized expression of NF-κB and NLRP3 in cardiac tissue in doxorubicin-induced cardiotoxicity in mice.•Assessment of HMGB1 and TLR4 pathways in cardiac tissue as possible inflammatory mechanisms of doxorubicin.•Assess the potential prophylactic role of Metformin against experimentally induced cardiotoxicity in mice.•Docking studies were done for HMGB1, NF-кB, and Caspase 3.