Ellagic acid mediates cardioprotection against adrenaline-induced toxicity via PI3K/AKT and Keap1-NRF2 axes

Ellagic acid (Ea) is an example of a bioactive polyphenolic compound with numerous beneficial effects; therefore, it is used to counteract adrenaline toxicity in this study. Thirty-six male rats were categorized into 6 groups of 6 rats. Group (1) was given oral purified distilled water for thirty successive days and injected with a saline for the next two days. Groups (2) and (3) received 7.5 and 15 mg/kg body weight Ea orally, followed by saline injection for two days. Group (4) was given distilled water orally for 30 uninterrupted days, followed by adrenaline injections for the next two days. Groups (5) and (6) received 7.5 and 15 mg/kg Ea for 30 days, followed by adrenaline injections for the next two days. Electrocardiogram (ECG) changes, oxidative stress, inflammation, immunohistochemistry, and histopathological alterations were evaluated. Specific biomarkers associated with kidney, liver, and heart injuries were recorded. At the higher dose, the Ea counteracted adrenaline-induced heart rate decrease, prolongation of the QT interval, and elevation of the ST interval in rats. It also enhanced kidney, liver, and heart function, ameliorating abnormal ECG patterns and tissue architecture changes. Ea suppressed PI3K/AKT signaling pathway and promoted nuclear factor erythroid 2-related factor 2 (NRF2) expression in the heart, possibly due to its antioxidative and anti-inflammation potential. Additionally, the study suggested a mechanistic aspect regarding the Ea's antioxidant activity through modulating the Keap1-NRF2 axis based on a validated computational approach that warrants further investigation. This study highlights the potential benefits of Ea in reducing heart injury.