Metformin's cardioprotective role in isoprenaline-induced myocardial infarction: Unveiling insights into the AMPK, NF-κB, JAK2/STAT3 pathways, and cholinergic regulation

Aim: Despite advancements in treatment modalities, myocardial infarction (MI) remains a significant global cause of mortality and morbidity. Metformin (MET), a commonly used antidiabetic medication, has demonstrated potential in various cardioprotective mechanisms. This study investigated whether MET could alleviate the histopathological, electrocardiographic, and molecular consequences of MI in rats. Materials and methods: The study hypothesis was tested using an isoprenaline (ISOP)-induced MI model, where male Wistar rats were injected with ISOP (85 mg/kg/day, s.c., for 2 days) and treated with MET at the doses of 500 and 1000 mg/kg/day for 18 days or left untreated. Key findings: ISOP-treated rats exhibited several indicators of MI, including significant ST-segment depression and prolonged QT-intervals on ECGs, worsened left ventricular histopathology with increased inflammatory cell infiltration, reduced expression of cardiac CHRM2, a cardioprotective cholinergic receptor, adaptive increases in AMPK and alpha 7nAchR levels, and elevated levels of iNOS, NO, STAT3, JAK2, IL-6, TNF-alpha, and NF-kappa B. kappa B. These effects were attenuated in rats treated with either low or high doses of MET. MET administration restored normal ECG recordings, diminished oxidative stress and inflammatory mediators, and downregulated NF-kappa B kappa B expression. Moreover, MET improved CHRM2 expression and normalized alpha 7nAchR levels. Additionally, MET influenced the expression of key signaling molecules such as Akt, STAT3, and JAK2. Significance: These findings might suggest that MET exerts cardioprotective effects in ISOP-induced MI in rats by mitigating critical inflammatory signaling pathways and regulating protective cholinergic mechanisms in the heart.